tiotropium-bromide and Pulmonary-Disease--Chronic-Obstructive

The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Bronchodilator Agents; Cholinergic Antagonists; Glycopyrrolate; Humans; Inflammation; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Four long-acting muscarinic antagonists (LAMAs), tiotropium, glycopyrronium, aclidinium, and umeclidinium, are currently available for the treatment of stable chronic obstructive pulmonary disease (COPD). However, no integrated analysis has sought to determine the effectiveness of these LAMAs. Thus, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LAMA versus placebo in patients with stable COPD.. A literature search of relevant randomized control trials that administered LAMA to stable COPD patients was conducted, and the exacerbations, quality of life (QoL), dyspnea score, lung function, and adverse event of patients were evaluated.. LAMA is superior to placebo due to lower frequency of exacerbations and adverse events, as well as higher trough FEV

Topics: Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Tiotropium Bromide; Treatment Outcome

Long-acting muscarinic antagonists (LAMAs) have been used in the treatment of obstructive pulmonary diseases for years. Long-acting muscarinic antagonists were previously mainly used as bronchodilators in chronic obstructive pulmonary disease, but the use of LAMAs in the treatment of asthma has gained great interest. There is now ample evidence of the efficacy and safety of LAMAs as add-on therapy to inhaled corticosteroid (ICS) plus long-acting β. PubMed review using the following words: long-acting muscarinic antagonists, asthma, muscarinic receptors, tiotropium, glycopyrronium, umeclidinium.. This review focused on the key trials that led to the inclusion of LAMAs in asthma guidelines. In addition, we highlighted a number of studies with other study designs and populations.. We identified 6 major studies that led to inclusion in asthma guidelines and 3 studies with other study designs and populations.. Long-acting muscarinic antagonists add-on therapy to ICS-LABA improves lung function, reduces exacerbations, and modestly improves asthma control in patients with moderate to severe asthma who are uncontrolled despite the use of ICS-LABA. Long-acting muscarinic antagonists are effective in all asthma phenotypes and endotypes.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in the US.. To conduct a targeted systematic review to update the evidence on the effectiveness of screening for COPD and the treatment of COPD to inform the US Preventive Services Task Force (USPSTF) update of the 2016 recommendation statement on COPD screening.. MEDLINE, the Cochrane Central Register of Controlled Trials, and CINAHL for relevant studies published between January 1, 2015, to January 22, 2021; surveillance through March 25, 2022.. English-language studies of screening in individuals who do not recognize or report respiratory symptoms; studies of treatment in persons with mild or moderate, or minimally symptomatic, COPD.. Two reviewers independently appraised the articles and extracted relevant data from fair- or good-quality studies; no quantitative synthesis was conducted.. COPD-related morbidity or mortality, measures of health-related quality of life, and adverse events.. The review included no trials on the effectiveness of screening, 3 trials or analyses (n = 20 058) of pharmacologic treatment published since 2015, 13 trials (n = 3657) on nonpharmacologic interventions, and 2 large observational studies (n = 243 517) addressing the harms of pharmacologic treatment published since 2015. The results from the clinical trials of pharmacologic therapy are consistent with the previous review supporting the USPSTF that bronchodilators with or without inhaled corticosteroids can reduce COPD exacerbations and tiotropium can improve health-related quality of life in adults with moderate COPD. Overall, there was no consistent benefit observed for any type of nonpharmacologic intervention across a range of patient outcomes. None of the included treatment trials that reported adverse effects found significant harms. Two large observational studies in a screen-relevant population demonstrated an association of the initiation of a long-acting muscarinic antagonist or long-acting beta agonist with the risk of a serious cardiovascular event in treatment-naïve patients and an association of inhaled corticosteroids use with the risk of developing diabetes.. The findings of this targeted evidence update are generally consistent with the findings of the previous systematic review supporting the 2016 USPSTF recommendation. Evidence of pharmacologic treatment was still largely limited to persons with moderate airflow obstruction, and there was no consistent benefit observed for a range of nonpharmacologic interventions in mild to moderate COPD or in minimally symptomatic persons with COPD.

Topics: Adrenergic beta-Agonists; Adult; Advisory Committees; Bronchodilator Agents; Glucocorticoids; Humans; Mass Screening; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide; United States

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Dyspnea; Forced Expiratory Volume; Glycopyrrolate; Humans; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome

The aim of this study was to review clinical evidence supporting the use of fixed-dose combination of tiotropium and olodaterol, a long-acting muscarinic antagonist (LAMA) and a long-acting β. For this narrative review, the available literature was searched to identify studies including patients with COPD receiving tiotropium and olodaterol as either monotherapy or combination therapy and studies including patients with COPD receiving inhaled corticosteroids (ICS) in addition to long-acting bronchodilators. Relevant studies were included in the review.. Patients with COPD are often prescribed ICS therapy, which, when used over a long term, can be associated with local and systemic adverse effects. The GOLD 2020 report recommends dual bronchodilator therapy as both an initial and follow-up treatment option. A LABA + LAMA combination is mechanistically synergistic, and cumulative evidence surrounding the efficacy and safety of fixed-dose combination of tiotropium and olodaterol supports therapeutic advantages over monotherapy in most patients with COPD.. The early stages of COPD may represent a "window of therapeutic opportunity" during which initiation of tiotropium and olodaterol dual bronchodilator therapy may improve lung function and quality of life and reduce exacerbations in patients with COPD.

Topics: Benzoxazines; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Dyspnea; Exercise; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide; Treatment Outcome

The role of long-acting muscarinic antagonists (LAMAs) is well established in uncontrolled asthma, but not in milder stages.. This review examines the main randomized controlled trials (RCTs) that have investigated LAMAs administered as monotherapy or in combination to asthmatic patients, according to the different phenotypes. It offers an overview of the role of LAMAs or their fixed dose combinations (FDCs) in the treatment across all the different stages of asthma.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Bronchodilator Agents; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Topics: Arrhythmias, Cardiac; Benzoxazines; Bronchodilator Agents; Cardiovascular Diseases; Drug Combinations; Heart Failure; Humans; Myocardial Infarction; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Stroke; Tiotropium Bromide

Tiotropium have been recommended as first-line maintenance therapy for chronic obstructive pulmonary disease (COPD) to reduce the frequency, duration, and severity of exacerbations and improve quality of life. Recently, it was reported that tiotropium use might link to cardiovascular risk in COPD patients. But it is controversial. We aimed to clarify the associations between tiotropium use and cardiovascular risk in patients with COPD.. We searched PubMed, EMBASE, Cochrane Library, and Clinical Trials.gov to identify potentially relevant articles. We included randomized controlled trials of any inhaled tiotropium versus non-anticholinergic treatment for COPD, with reporting of cardiovascular events as an adverse event. We conducted meta-analyses by the Peto and Mantel-Haenszel approaches with corresponding 95% CIs.. Our work included 20 RCTs with more than 27,699 subjects. Pooled results indicated that tiotropium treatment did not increase the risk of cardiovascular events (Peto OR, 0.97, 95% CI, 0.84-1.12; I. Inhaled tiotropium does not increase the risk of cardiovascular events and cardiovascular mortality in patients with COPD.

Topics: Cardiovascular Diseases; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide

Combinations of long-acting bronchodilators with different mechanisms of action are recommended to improve prognosis and reduce risk of adverse events of chronic obstructive pulmonary disease (COPD). It is unclear whether the new combination therapy with long-acting muscarinic antagonist (LAMA) tiotropium (TIO) and long acting beta-agonists (LABA) olodaterol (OLO) was superior to tiotropium alone.. We measured the efficacy of the TIO/OLO combination vsTIO alone for COPD patients based on electronic databases up to February 2019. After rigorous quality review, data was extracted from eligible trials. All the main outcomes were pooled analysis using RevMan software.. A total of 6 randomized controlled trials (RCTs) were identified. The pooled results of our meta-analysis demonstrated that FEV1 [MD = 0.03, 95% CI (-0.01,0.07), P = .18], FVC [MD = -0.03, 95%CI (-0.06,0.00), P = .09] and FEV1%pred [MD = 0.35, 95%CI (-0.30, 0.99), P = .29] all showed no significant difference between the 2 groups. The overall incidence of adverse effects (AEs) [OR = 1.01,95%CI (0.93,1.09), P = .87] and serious AEs [OR = 1.04,95% CI (0.82, 1.32), P = .72] in the combination group was similar to that of the TIO alone group, without statistical significance.. These studies reported that the TIO/OLO combination did not show superior effects than tiotropium alone for COPD. Additionally, both therapies were well tolerated.

Topics: Benzoxazines; Bronchodilator Agents; Drug Combinations; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Vital Capacity

Relevant publications related to medicinal and toxic aerosols are discussed in this review. Treatment of COPD includes a combination of long-acting bronchodilators and long-acting muscarinic antagonists. A combination of aclidinium bromide and formoterol fumarate was approved in the United States. The combination was superior to its components alone, as well as tiotropium and a salmeterol-fluticasone combination. Increased risk of an asthma exacerbation was reported in children exposed to electronic nicotine delivery systems. A smart inhaler capable of recording inspiratory flow was approved in the United States. The use of as-needed budesonide-formoterol was reported to be superior to scheduled budesonide and as-needed terbutaline for the treatment of adults with mild-to-moderate asthma. A survey among teens with asthma and their caregivers revealed a disagreement in the number of inhaled controller medications the teen was taking. Treatment with inhaled hypertonic saline resulted in a decreased lung clearance index in infants and preschool children with cystic fibrosis. Surgical masks were well tolerated and significantly decreased the burden of aerosolized bacteria generated by coughing in adults with cystic fibrosis. Inhaled liposomal amikacin in addition to guideline-based therapy was reported to be superior to guideline-based therapy alone in achieving negative sputum cultures in adult subjects with

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Budesonide; Child; Electronic Nicotine Delivery Systems; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Tropanes

Bronchodilators are the mainstay of pharmacological treatment in chronic obstructive pulmonary disease (COPD), and long-acting muscarinic antagonist (LAMA) monotherapy is recommended as initial treatment for Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups B, C, and D.. Tiotropium bromide was the first LAMA available for COPD in clinical practice and, because of its long duration of action, is administered once daily. Tiotropium was initially available as an inhalation powder delivered via a dry-powder inhaler (DPI). Later, tiotropium also became available as an inhalation spray delivered via a soft mist inhaler (SMI). The SMI was designed to overcome or minimize some of the issues associated with other inhaler types (eg, the need for strong inspiratory airflow with DPIs). Results of short- and long-term randomized, controlled clinical trials of tiotropium in patients with COPD indicated tiotropium was safe and significantly improved lung function, health-related quality of life, and exercise endurance, and reduced dyspnea, lung hyperinflation, exacerbations, and use of rescue medication compared with placebo or active comparators. These positive efficacy findings triggered the evaluation of tiotropium in fixed-dose combination with olodaterol (a long-acting β. Tiotropium is safe and efficacious as a long-term, once-daily LAMA for the maintenance treatment of COPD and for reducing COPD exacerbations. The SMI generates a low-velocity, long-duration aerosol spray with a high fine-particle fraction, which results in marked lung drug deposition. In addition, high inspiratory flow rates are not required.

Topics: Administration, Inhalation; Bronchodilator Agents; Drug Development; Forced Expiratory Volume; Humans; Lung; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide

To systematically review the efficacy and safety of Buzhong Yiqi Decoction in the treatment of stable chronic obstructive pulmonary disease(COPD) at the stable stage. Three English databases and four Chinese databases were systematically searched from the database establishment to August 1, 2020. Randomized controlled trials(RCTs) were screened according to the pre-determined inclusion and exclusion criteria, and then the data were extracted. Methodological quality of the included studies was assessed based on Cochrane bias risk tool, and RevMan 5.3 was used for data analysis. A total of 389 articles were retrieved and finally 18 RCTs were included in this study, involving 1 566 patients, and the overall quality of the included studies was not high. Meta-analysis showed that, in terms of improving 6-minute walk distance(6 MWD), and delaying the decline of forced expiratory volume in one second(FEV_1) or its % in the expected value as well as the decline in ratio of FEV_1 to forced vital capacity(FVC), Buzhong Yiqi Decoction alone or in combination with conventional Western medicine was superior to conventional therapy Western medicine alone. Subgroup analysis showed that, in terms of reducing traditional Chinese medicine symptom scores, Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment. In terms of reducing the grade of modified medical research council(mMRC), Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment. In terms of improving 6 MWD, Buzhong Yiqi Decoction combined with conventional treatment or Tiotropium Bromide Powder for Inhalation was superior to conventional treatment alone or Tiotropium Bromide Powder for Inhalation alone. In terms of delaying the decline of FEV_1 or its % in the expected value, Buzhong Yiqi Decoction combined with conventional treatment or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation or Tiotropium Bromide Powder for Inhalation was superior to conventional treatment or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation or Tiotropium Bromide Powder for Inhalation alone, and Buzhong Yiqi Decoction alone was superior to Theophylline alone. In terms of delaying the decline in FEV_1/FVC, Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment, and Buzhong Yiqi Decoction alone was superior to Theophylline alone. Meta-analysis of other outcome measures

Topics: Forced Expiratory Volume; Humans; Medicine, Chinese Traditional; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Vital Capacity

The natural course of chronic obstructive pulmonary disease usually includes exacerbations. chronic obstructive pulmonary disease patients suffer from 1-4 exacerbations per year on average. These are associated with worsening quality of life and increased mortality. Reducing and controlling the number of exacerbations is one of the main goals of chronic obstructive pulmonary disease treatment. Among current treatments, tiotropium is the active substance with the strongest evidence in the reduction of moderate/severe exacerbations, together with a good safety and tolerability profile. The addition of olodaterol to tiotropium offers well-tolerated and effective double bronchodilation for improving lung function, quality of life, and decreased dyspnoea compared to its single components. This also reduces the annual rate of moderate/severe exacerbations vs. tiotropium by 7%, although not reaching the pre-specified statistical significance level of P<.01.

Topics: Benzoxazines; Bronchodilator Agents; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide

Maintenance bronchodilator therapy with long-acting β-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is the cornerstone treatment for patients with stable chronic obstructive pulmonary disease (COPD). Fixed-dose combinations (FDCs) of LABA/LAMA are recommended for the majority of symptomatic COPD patients by global guidelines; regional guidelines such as the Japanese and Korean guidelines also provide similar recommendations for the use of LABA/LAMA FDCs. This review comprehensively describes the latest clinical evidence from key studies on the efficacy and safety of four approved LABA/LAMA fixed-dose combinations: indacaterol/glycopyrronium, vilanterol/umeclidinium, formoterol/aclidinium, and olodaterol/tiotropium. Additionally, in this review we describe the rationale behind the use of LABA/LAMA FDC therapy, key findings from the preclinical and clinical trial evaluation of respective LABA and LAMA monocomponents, and the efficacy and safety of LABA/LAMA FDCs. Special emphasis is placed on the clinical evidence for the monocomponents and LABA/LAMA FDCs from the Asian population. This detailed overview of the efficacy and safety of LABA/LAMA FDCs in global and Asian COPD patients is envisaged to provide a better understanding of the benefits of these therapies and to inform healthcare providers and patients on their appropriate use.Funding: Novartis Pharma K.K.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Asian People; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Tiotropium Bromide; Treatment Outcome; Tropanes

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Drug Combinations; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide; Treatment Outcome

Recent updates to the GOLD guidelines emphasize the use of combination LABA and LAMA bronchodilators for patients with chronic obstructive pulmonary disease with persistent dyspnea despite monotherapy or frequent exacerbations despite LAMA monotherapy. There are several commercially available LABA/LAMA fixed dose combination inhalers, which are likely to become the principle therapy for many patients with COPD.. In the last 4 years, there have been a number of large clinical trials evaluating the efficacy and safety of combined LAMA and LABA bronchodilators. LAMA/LABA fixed dose combination therapies have consistently demonstrated clinically significant improvements to airway obstruction, dyspnea, and quality of life whenever compared with placebo, and more modest improvements compared with bronchodilator monotherapies and combined bronchodilator/inhaled corticosteroid therapy.. New guidelines emphasize combination bronchodilators as a mainstay of therapy for many patients with symptomatic COPD and there are several new combination bronchodilator therapies available to patients. It is important for physicians and patients to understand the range and degree of expected clinical effects and the safety profiles of these new medications.

Topics: Administration, Inhalation; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delayed-Action Preparations; Drug Combinations; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Tiotropium Bromide; Tropanes

Population-based studies have shown a significant heterogeneity in patients with chronic obstructive pulmonary disease (COPD), regarding both the attainment of maximal lung function and the subsequent decline over time. This review will highlight recent advances in the understanding of lung function trajectory in COPD, focusing on factors that influence peak adult lung function, markers of accelerated lung function decline and pharmacologic interventions in early phases of the disease.. Recent data have shown that individuals with lower lung function early in life will go on to develop lower forced expiratory volume in 1 s (FEV1) in adulthood. Smoking can amplify the effect of specific childhood exposures on maximal adult lung function. Clinical symptoms such as chronic mucous hypersecretion and the biomarker club cell secretory protein have been associated with lung function decline over time. New computed tomography imaging markers also show promise as a way to detect early small airway disease, but need to be examined more longitudinally. In addition to these advances, a slower decline in FEV1 has been demonstrated in two randomized clinical trials studying tiotropium and inhaled fluticasone.. A better understanding of lung function development and eventual decline in those at risk for progression to COPD will aide in a precision medicine approach, in which markers for those at risk of low maximal lung function and accelerated decline are identified. Targeted therapy can then be used early to modify disease activity and outcomes.

Topics: Biomarkers; Bronchitis, Chronic; Bronchodilator Agents; Disease Progression; Fluticasone; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Smoking; Tiotropium Bromide; Tomography, X-Ray Computed; Uteroglobin

In this review, we focused on original manuscripts published in the 2017 that provided additional information on the clinical and therapeutic features of the chronic obstructive pulmonary disease (COPD). We have chosen eight of these studies, collected in four topics concerning the pharmacological treatment (tiotropium) of mild-moderate patients, the pharmacological (fluticasone furoate/vilanterol/umeclidinium) and non-pharmacological treatment (non-invasive mechanical ventilation) of severe patients, the etiology of acute exacerbation of COPD involving seasonal airway pathogens and the role of eosinophils with particular interest to the monoclonal antibody directed against interleukin-5 (mepolizumab). For each topic, we report a brief description of studies, take-home messages, and brief comments.

Topics: Androstadienes; Antibodies, Monoclonal, Humanized; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Common Cold; Disease Progression; Drug Combinations; Eosinophils; Glucocorticoids; Haemophilus Infections; Humans; Interleukin-5; Moraxellaceae Infections; Muscarinic Antagonists; Noninvasive Ventilation; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Seasons; Severity of Illness Index; Tiotropium Bromide

Topics: Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Topics: Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Oral inhalation is the recommended delivery method of medications for the treatment of patients with chronic obstructive pulmonary disease (COPD). However, patients may struggle when using the various available inhaler platforms, and, as a result, may fail to achieve the benefit of the prescribed medication. Propellant-based, pressurized metered-dose inhaler and powder-based, dry powder inhaler devices are currently the most commonly prescribed delivery systems. Each of these devices has its own advantages and challenges. The Respimat® Soft Mist™ inhaler (SMI) (Boehringer Ingelheim) is a delivery system that incorporates features intended to improve orally inhaled drug delivery to these patients. These features include simple device actuation, patient inspiratory effort-independent aerosol generation, and a slower spray emission with a longer spray duration, helping to mitigate issues with precise aerosol release and breath coordination. We review the clinical trials assessing lung deposition, efficacy, and safety, and patient satisfaction for the Respimat® SMI. These data indicate that the Respimat® SMI is a device capable of delivering a consistent, clinically effective dose of medication that patients can use and prefer, which may provide significant clinical benefits for patients with COPD.

Topics: Administration, Inhalation; Benzoxazines; Bronchodilator Agents; Drug Combinations; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Respiratory Therapy; Tiotropium Bromide

Inhaled bronchodilators are the key-stone of chronic obstructive pulmonary disease (COPD) management. Olodaterol 5 µg, a long-acting β2-adrenoceptor agonist (LABA) is one such bronchodilator indicated as a once-daily maintenance therapy. Areas covered: This article reviews the several trials that have assessed olodaterol as a COPD therapy. It covers safety and tolerability data and provides the reader with an expert opinion on its use as a treatment for COPD. Expert opinion: Olodaterol improves lung function for 24 h and reduces rescue medication use. It may also improve dyspnea, exercise tolerance, and health-related quality of life. It is well tolerated with an acceptable cardiovascular and respiratory adverse event profile. There is some evidence that olodaterol, as well as other LABAs, can reduce exacerbation frequency, but not FEV1 decline and death. LABAs alone are indicated in group A/B COPD subjects. Olodaterol and indacaterol are administered once-daily and may offer an adherence advantage over other LABAs with more frequent dosing schedules. Co-administration of an olodaterol/tiotropium fixed dose combination in a single inhaler device is recommended as step-up in group A/B COPD subjects not sufficiently treated by olodaterol alone or as initial therapy in those with severe exertional dyspnea.

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Exercise Tolerance; Forced Expiratory Volume; Half-Life; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

This meta-analysis was performed to compare the risks and benefits of combined treatment with tiotropium plus formoterol versus tiotropium alone for stable moderate-to-severe COPD.. A comprehensive search of MEDLINE, EMBASE, CINAHL, and the Cochrane Library was performed to identify randomized controlled trials (RCTs) that compared formoterol plus tiotropium to tiotropium alone in COPD patients with a duration of at least 4 weeks. The cut-off date for the search was July 1, 2015. The odds ratio (OR) or mean difference (MD) was used to pool the results with 95% confidence intervals (CI).. Eight randomized controlled trials were eligible for this meta-analysis. A significant improvement was observed among patients treated with tiotropium plus formoterol compared with tiotropium alone in the following spirometric indices: mean change in trough FEV1 (P = .02), trough FVC (P = .007), peak FEV1 (P < .00001), and peak FVC (P < .00001). A similar result was noted for the transitional dyspnea index (TDI) (MD 1.46; 95% CI 1.07-1.85) and a clinically significant change in TDI between the tiotropium plus formoterol and tiotropium alone groups (P < .00001). Moreover, a trend toward fewer adverse events was seen in the combination treatment group compared with the tiotropium group (OR .88; 95% CI .70-1.11), although this difference was not statistically significant.. Compared with tiotropium alone, tiotropium in combination with formoterol improved lung function and the symptoms of dyspnea in stable moderate-to-severe COPD patients. Moreover, the combined treatment group tended to have fewer adverse events compared with the tiotropium treatment alone group.

Topics: Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) and asthma are leading causes of morbidity and mortality. This narrative review provides an appraisal of the pharmacological and clinical characteristics of tiotropium in COPD and asthma, and examines how these compare with other long-acting bronchodilators. The evidence base is placed into context by relating it to factors affecting clinicians' choice of therapy.. Desirable attributes of a long-acting muscarinic antagonist (LAMA) maintenance therapy include effective pharmacological bronchodilation, improved lung function, exacerbation efficacy, and positive effects on symptom control, exercise capacity and quality of life across a broad patient population. Tolerability and convenience of use are also important for patient well-being and treatment adherence. Tiotropium shows higher affinity for muscarinic receptors than ipratropium, and prolonged binding to the M. With over 10 years' prescribing history and 50 million patient-years of use, tiotropium has the benefit of a more extensive clinical evidence base than other long-acting bronchodilators, with demonstrated efficacy and safety in COPD and symptomatic asthma.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Asthma; Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Exercise Tolerance; Forced Expiratory Volume; Humans; Ipratropium; Muscarinic Antagonists; Nebulizers and Vaporizers; Patient Outcome Assessment; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Tiotropium Bromide

Long-acting bronchodilators are the cornerstone of pharmacologic treatment of COPD. The new combination of long-acting muscarinic antagonist (LAMA) tiotropium (TIO) and long acting beta-agonists (LABA) olodaterol (OLO) has been introduced as fist line therapy for COPD. This article analyses the evidence of efficacy and safety of the TIO/OLO combination.. A systematic review and metaanalysis of randomized controlled trials (RCT) with a period of treatment of at least 6 weeks, in patients with COPD confirmed by spirometry, comparing combined treatment with TIO/OLO (approved doses only), with any of the mono-components or any other active comparator administered as an inhalator.. Treatment with TIO/OLO provided significant improvements in lung function versus mono-components and LABA/ICS with more patients achieving significant improvements in dyspnea and health status. No differences in adverse events were observed compared with other active treatments.. PROSPERO register of systematic reviews ( CRD42016040162 ).

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Spirometry; Tiotropium Bromide; Treatment Outcome

Chronic Obstructive Pulmonary Disease (COPD) is a chronic airway disease that can be prevented and treated. The recommendations for therapy include bronchodilators from two classes (LAMA (Long Acting Muscarinic Antagonists) and LABA (Long Acting Beta2 Agonists)). Spiolto Respimat® is a LAMA/LABA combination therapy and comprises tiotropium (Spiriva®) and olodaterol (a LABA). Clinical studies show that Spiolto Respimat® is able to improve lung function tests (Increased FEV1, decreased hyperinflation and residual volume) and quality of life as compared to tiotropium or olodaterol. Studies also suggest that COPD exacerbations are decreased in patients treated by Spiolto Respimat® as compared to those treated with olodaterol (results of studies with exacerbations as primary outcome are not available yet). Safety of Spiolto Respimat® appears similar to tiotropium or olodaterol. Spiolto Respimat® indications is maintenance therapy for COPD. Reimbursement in Belgium requires that patients still display symptoms although already treated and that he/she has been previously treated by a LAMA.. La bronchopneumopathie chronique obstructive (BPCO) est une maladie chronique des voies aériennes qui est évitable et soignable. Le schéma de prise en charge comprend, entre autres, la prescription de bronchodilatateurs de la classe des LAMA (Long Acting Muscarinic Antagonists) et des LABA (Long Acting Beta2 Agonists). Le Spiolto Respimat® combine le tiotropium (un LAMA commercialisé sous le nom de Spiriva®) et l’olodatérol qui est un LABA. Les études cliniques montrent que le Spiolto Respimat® permet d’améliorer les indices de fonction respiratoire (augmentation du VEMS, diminution de l’hyperinflation et du volume résiduel) et d’améliorer la qualité de vie par rapport au tiotropium ou à l’olodatérol utilisés seuls. Le nombre d’exacerbations de la BPCO est également moindre chez les patients traités par Spiolto Respimat® par rapport à un traitement par olodatérol en monothérapie, mais des études dédiées à l’observation des exacerbations sont actuellement toujours en cours. La sécurité d’utilisation du Spiolto Respimat® est similaire à celle des deux mono-composants. Le Spiolto Respimat® est indiqué pour le traitement d’entretien de patients atteints de BPCO. Il est remboursé en Belgique chez les patients qui restent symptomatiques dans le cadre de la BPCO et qui sont déjà traités par un LAMA.

Topics: Administration, Inhalation; Belgium; Benzoxazines; Bronchodilator Agents; Drug Combinations; Humans; Insurance, Health, Reimbursement; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is a respiratory disorder characterised by largely irreversible changes in air flow due to irritants such as tobacco smoke. Patients with COPD experience acute exacerbations. Severe disease may progress to chronic respiratory failure. We reviewed the literature on basic medications available for COPD, using the standard Prescrire methodology. There are few clinical data on treatment of mild COPD. Regular medication is not necessary for patients who do not have recurrent symptoms. Eliminating exposure to cigarette smoke and other irritants such as workplace irritants, is the only measure known to improve the outcome of COPD. Evaluation of inhaled short-acting beta-2 agonists is based mainly on short-term trials. These drugs have been shown to improve dyspnoea. Salmeterol and formoterol, two long-acting beta-2 agonists, have been extensively evaluated in symptomatic patients. Compared with no treatment, these drugs reduce breathlessness and acute exacerbations, preventing about two hospital admissions per 100 patients with moderate to severe COPD treated for 7 months. Indacaterol and olodateroldo not have a better harm-benefit balance. Inhaled beta-2 agonists occasionally provoke cardiovascular disorders. No excess mortality has been reported among the thousands of COPD patients included in clinical trials. There Is little evidence that ipratropium, an inhaled short-acting anti-muscarinic bronchodilator, improves COPD symptoms. A risk of Increased mortality among COPD patients treated with ipratroplum cannot be ruled out. Tiotroplum, an inhaled long-acting antimuscarinic bronchodilator, has been extensively evaluated In COPD. Tiotroplum has symptomatic efficacy in COPD, reducing dyspnoea and acute exacerbations. Tiotroplum had no tangible advantages over long-acting beta-2 agonists in seven randomised trials including more than 12 000 patients. Glycopyrronium and aclidinium, two other Inhaled long-acting antimuscarinics, do not appear to be more effective. Tiotroplum, like other inhaled anti-muscarinics, has antimuscarinic adverse effects including cardiac, visual and buccal disorders. Glycopyronium may carry a higher risk of serious cardiovascular effects. Combination of an antimuscarinic with an inhaled beta-2 agonist improves symptoms in 7% to 10% of patients. In patients with one or two COPD exacerbations per year, adding an Inhaled corticosterold (beclometa- sone, budesonide or fluticasone) to a long-acting

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aminopyridines; Benzamides; Bronchodilator Agents; Budesonide; Cyclopropanes; Fluticasone; Formoterol Fumarate; Humans; Ipratropium; Muscarinic Antagonists; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Recurrence; Salmeterol Xinafoate; Theophylline; Tiotropium Bromide

Tiotropium/olodaterol (Stiolto™ Respimat®, Spiolto™ Respimat®) is a fixed-dose combination of the long-acting antimuscarinic agent tiotropium bromide (hereafter referred to as tiotropium) and the long-acting β2-adrenoreceptor agonist olodaterol delivered via the Respimat® Soft Mist™ inhaler. It is indicated for the maintenance treatment of airflow obstruction in adults with COPD. Several randomized, phase III studies of 6-52 weeks' duration evaluated the efficacy of once-daily tiotropium/olodaterol in patients with GOLD stage 2-3 or 2-4 COPD. Tiotropium/olodaterol maintenance therapy improved lung function to a greater extent than the individual components or placebo and provided clinically meaningful improvements in health-related quality of life and dyspnoea in 12- and 52-week studies. Tiotropium/olodaterol consistently improved 24-h lung function in 6-week studies, providing greater benefits than the monotherapies, placebo or twice-daily fixed-dose fluticasone propionate/salmeterol. Inspiratory capacity and exercise endurance were also improved with tiotropium/olodaterol following 6 or 12 weeks' treatment. The tolerability profile of tiotropium/olodaterol in the phase III studies was generally similar to that of the component monotherapies. The most common adverse events and serious adverse events during 52 weeks' therapy were respiratory in nature, with COPD exacerbation, unsurprisingly, reported most frequently with tiotropium/olodaterol and component monotherapies. Although additional data assessing the effect of tiotropium/olodaterol on exacerbations and comparative studies with other recommended therapies are needed to definitively position tiotropium/olodaterol, current evidence indicates that tiotropium/olodaterol is a useful treatment option for patients with COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Drug Combinations; Humans; Lung; Muscarinic Antagonists; Physical Endurance; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide

The objective of this study was to estimate the relative efficacy and safety of fixed-dose combination aclidinium/formoterol 400/12 μg twice daily compared to tiotropium 18 μg once daily in adult patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).. A systematic literature review performed in March 2014, using a predefined search strategy in MEDLINE, EMBASE and Cochrane Library, identified 17 randomized placebo-controlled trials, (tiotropium n = 15; aclidinium/formoterol n = 2). Outcomes of interest were: bronchodilation (peak and trough forced expiratory volume in 1 s (FEV1)), COPD symptoms [Transition Dyspnea Index (TDI) focal score and % of responders (>1 unit improvement)] and Health Related Quality of Life (HRQoL) [St. George's Respiratory Questionnaire (SGRQ) total score and % responders (>4 unit improvement)], % of patients with ≥1 exacerbations, adverse events (AE), serious adverse events (SAE), hospitalization and mortality, all at 24 weeks. In the absence of head-to-head trials between aclidinium/formoterol and tiotropium, a Bayesian indirect treatment comparison (ITC) was used with placebo as common control.. Regarding bronchodilation, aclidinium/formoterol was found to be more efficacious than tiotropium at peak FEV1, with mean difference in change from baseline (DCFB) 143 mL [95% credible interval (CrI): 112, 174] and at trough FEV1 [DCFB 26 mL (95% CrI -2, 55)]. Aclidinium/formoterol is expected to be more efficacious than tiotropium in improving dyspnea symptoms measured by TDI [DCFB 0.54 points (95% CrI 0.09, 0.99); odds ratio (OR) of responders 1.51 (95% CrI 1.11, 2.06)]. SGRQ results are comparable for aclidinium/formoterol versus tiotropium [DCFB -0.52 (95% CrI -2.21, 1.17); OR of responders 1.16 (95% CrI 0.47, 2.87)]. The ITC results suggest similar safety profiles regarding AEs, SAEs and hospitalization.. Based on the ITC, aclidinium/formoterol is expected to be more efficacious than tiotropium in terms of lung function and symptom control while providing comparable HRQoL results and safety profile.. AstraZeneca.

Topics: Bayes Theorem; Bronchodilator Agents; Drug Combinations; Dyspnea; Forced Expiratory Volume; Formoterol Fumarate; Hospitalization; Humans; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Tiotropium Bromide; Tropanes

Topics: Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States.. To systematically review literature on the accuracy of screening questionnaires and office-based screening pulmonary function testing and the efficacy and harms of treatment of screen-detected COPD.. MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant English-language studies published through January 2015.. Two reviewers independently screened abstracts and studies. The search yielded 13,141 unique citations; 465 full-text articles were reviewed, and 33 studies met the inclusion criteria.. Two reviewers rated the quality of each study using USPSTF criteria.. Diagnostic accuracy (sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]; treatment efficacy (COPD exacerbations, all-cause mortality, quality of life, and dyspnea); and treatment harms.. All screening questionnaires were based on symptoms as well as risk factors such as age and smoking history. The COPD Diagnostic Questionnaire was the most extensively studied (5 studies, n = 3048), with moderate overall performance for COPD detection: area under the receiver operating characteristic curve (AUC), 0.65 to 0.72; sensitivity, 80% to 93%; and specificity, 24% to 49%, at a threshold of greater than 16.5. Positive predictive value and NPV ranged from 17% to 45% and 76% to 98%, respectively. For pulmonary function-based screening tools, FEV1/FEV6 was the best studied (3 studies, n = 1587), with AUC ranging from 0.84 to 0.85. Sensitivity ranged from 51% to 80%. Specificity (range, 90%-95%) and PPV (range, 63%-75%) appeared better than questionnaires. There was not strong evidence to support that screening and supplying smokers with spirometry results improves smoking cessation rates. Treatment trials were unavailable for screen-detected patients. Trials that reported outcomes in patients with mild to moderate COPD included 2 trials of long-acting β-agonists (LABAs) (n = 3174), 1 RCT of LABAs and inhaled corticosteroids (ICS) (n = 1097), 5 RCTs of the long-acting muscarinic antagonist tiotropium (n = 4592), and 6 RCTs of ICS (n = 3983). They suggested no benefit in all-cause mortality, but a decrease in annual rates of exacerbations with pharmacologic treatments. Few trials reported harms for any individual drug class. Adverse effects were generally mild (eg, dry mouth and cough).. There was no direct evidence available to determine the benefits and harms of screening asymptomatic adults for COPD using questionnaires or office-based screening pulmonary function testing or to determine the benefits of treatment in screen-detected populations. Indirect evidence suggests that the COPD Diagnostic Questionnaire has moderate overall performance for COPD detection. Among patients with mild to moderate COPD, the benefit of pharmacotherapy for reducing exacerbations was modest.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Advisory Committees; Age Factors; Area Under Curve; Asymptomatic Diseases; Evidence-Based Medicine; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Recurrence; Respiratory Function Tests; ROC Curve; Secondary Prevention; Sensitivity and Specificity; Smoking; Smoking Cessation; Spirometry; Surveys and Questionnaires; Tiotropium Bromide; United States

Exacerbation frequency is related to disease progression, quality of life, and prognosis in COPD. Earlier diagnosis, along with interventions aimed at preventing exacerbations and delaying progression, may help reduce the global burden of disease. Long-acting inhaled bronchodilators are effective at maintaining symptom relief and are recommended as first-choice therapy for more symptomatic patients and those at risk of exacerbation.. As prevention of exacerbations is a priority goal in COPD management and a number of different long-acting bronchodilators are available, we conducted a systematic review of exacerbation data from randomized controlled trials (published January 2000 to May 2014) comparing the effect of tiotropium versus placebo and/or other maintenance therapies.. Exacerbations were a primary endpoint in 12 publications (five studies: four comparing tiotropium with placebo; one with active comparator) and a secondary endpoint in 17 publications (seven studies: six comparing tiotropium with placebo; one with active comparator). Overall, tiotropium was associated with a longer time to first exacerbation event and fewer exacerbations (including severe exacerbations/hospitalizations) compared with placebo and long-acting β2-agonists. Tiotropium also showed similar efficacy to glycopyrronium and a fixed long-acting muscarinic antagonist/long-acting β2-agonist combination (glycopyrronium/indacaterol), although not all studies were powered to demonstrate differences in exacerbation outcomes. Exacerbation outcomes were comparable with both formulations of tiotropium (HandiHaler(®) 18 μg/Respimat(®) 5 μg).. The results of this comprehensive systematic review demonstrate tiotropium is beneficial in reducing exacerbation risk versus placebo or other maintenance treatments.

Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is a respiratory problem with the highest prevalence and strongest socio-economic impact in the world and whose morbimortality keeps increasing. Treating this disease is a challenge in the field of pneumology since the market now offers a wide range of bronchodilators. Tiotropium bromide, a long-acting anticholinergic bronchodilator, is a drug used to deal with this pathology.. The UPLIFT study was a 4-year (2004-2008) clinical multi-center trial in which tiotropium bromide was compared with a placebo. We present a bibliographic resume covering the multiple sub-analyses published since the end of the clinical trial, between 2009-2015. These sub-analyses analyzed the results obtained in UPLIFT in parallel, provided additional data about safety profiles, exacerbations, hospitalization and mortality rates, and lung function, among others. Expert Commentary: Tiotropium bromide is a significant advance for the maintenance treatment of patients with COPD. The favorable results obtained leave the door open to the possibility of improving the natural history of COPD and confirmed tiotropium bromide as the gold standard drug as monotherapy for treatment of COPD.

Topics: Bronchodilator Agents; Hospitalization; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Several new fixed-dose combination bronchodilators have been launched in the world, and 3 different types are now available in Japan. Assessing their efficacy relative to each other has not been performed yet. In the present manuscript, characteristics of glycopyrronium/indacaterol, umeclidinium/vilanterol and tiotropium/olodaterol were reviewed. In particular, changes in trough and peak forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) total scores, and transitional dyspnea index (TDI) focal scores were reviewed in these bronchodilators.

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delayed-Action Preparations; Drug Combinations; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Respiratory Function Tests; Tiotropium Bromide; Treatment Outcome

In the treatment of chronic obstructive pulmonary disease (COPD), bronchodilators such as long acting muscarinic antagonist (LAMA) and long acting β agonist(LABA) play key roles for improving respiratory function and symptoms, and reducing risk of exacerbation. However, inhaled corticosteroid (ICS), a key medicine for bronchial asthma, is limitedly used in COPD treatment. Japanese Respiratory Society recommends to use ICS for severe COPD patients who have been frequently exacerbated, because previous clinical studies indicated that ICS reduces exacerbation in moderate to severe COPD patients. Asthma sometimes overlaps with COPD, and symptoms of those patients are not well controlled by the bronchodilation therapy alone. Therefore, ICS/LABA or ICS/LAMA should be prescribed to those overlapped patients. Concentration of exhaled nitrogen oxide and percentage of peripheral eosinophil may be good biomarkers for discriminating the COPD patients who have good response to ICS treatment.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Asthma; Biomarkers; Breath Tests; Bronchodilator Agents; Budesonide, Formoterol Fumarate Drug Combination; Delayed-Action Preparations; Disease Progression; Drug Combinations; Drug Therapy, Combination; Eosinophils; Fluticasone; Glucocorticoids; Humans; Leukocyte Count; Muscarinic Antagonists; Nitrogen Oxides; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Severity of Illness Index; Tiotropium Bromide

The long-acting bronchodilator tiotropium and single-inhaler combination therapy of inhaled corticosteroids and long-acting beta2-agonists (ICS/LABA) are commonly used for maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Combining these treatments, which have different mechanisms of action, may be more effective than administering the individual components.. To assess relative effects of the following treatments on markers of exacerbations, symptoms, quality of life and lung function in patients with COPD.• Tiotropium plus LABA/ICS versus tiotropium.• Tiotropium plus LABA/ICS versus LABA/ICS.. We searched the Cochrane Airways Group Specialised Register of Trials (April 2015), ClinicalTrials.gov (www.ClinicalTrials.gov), the World Health Organization (WHO) trials portal and reference lists of relevant articles.. We included parallel, randomised controlled trials (RCTs) lasting three months or longer conducted to compare ICS and LABA combination therapy in addition to inhaled tiotropium versus tiotropium alone or combination therapy alone.. We independently assessed trials for inclusion, then extracted data on trial quality and outcome results. We contacted study authors to ask for additional information. We collected trial information on adverse effects.. Tiotropium plus LABA/ICS versus tiotropiumWe included six studies (1902 participants) with low risk of bias that compared tiotropium in addition to inhaled corticosteroid and long-acting beta2-agonist combination therapy versus tiotropium alone. Investigators found no statistically significant differences in mortality between treatments (odds ratio (OR) 1.80, 95% confidence interval (CI) 0.55 to 5.91; two studies; 961 participants), a reduction in all-cause hospitalisations with the use of combined therapy (tiotropium + LABA/ICS) (OR 0.61, 95% CI 0.40 to 0.92; two studies; 961 participants; number needed to treat for an additional beneficial outcome (NNTB) 19.7, 95% CI 10.75 to 123.41). The effect on exacerbations was heterogeneous among trials and was not meta-analysed. Health-related quality of life measured by St. George's Respiratory Questionnaire (SGRQ) showed a statistically significant improvement in total scores with use of tiotropium + LABA/ICS compared with tiotropium alone (mean difference (MD) -3.46, 95% CI -5.05 to -1.87; four studies; 1446 participants). Lung function was significantly different in the combined therapy (tiotropium + LABA/ICS) group, although average benefit with this therapy was small. None of the included studies included exercise tolerance as an outcome.A pooled estimate of these studies did not show a statistically significant difference in adverse events (OR 1.16, 95% CI 0.92 to 1.47; four studies; 1363 participants), serious adverse events (OR 0.86, 95% CI 0.57 to 1.30; four studies; 1758 participants) and pneumonia (Peto OR 1.62, 95% CI 0.54 to 4.82; four studies; 1758 participants). Tiotropium plus LABA/ICS versus LABA/ICSOne of the six studies (60 participants) also compared combined therapy (tiotropium + LABA/ICS) versus LABA/ICS therapy alone. This study was affected by lack of power; therefore results did not allow us to draw conclusions for this comparison.. In this update, we found new moderate-quality evidence that combined tiotropium + LABA/ICS therapy compared with tiotropium plus placebo decreases hospital admission. Low-quality evidence suggests an improvement in disease-specific quality of life with combined therapy. However, evidence is insufficient to support the benefit of tiotropium + LABA/ICS for mortality and exacerbations (moderate- and low-quality evidence, respectively). Of note, not all participants enrolled in the included studies would be candidates for triple therapy according to current international guidance.Compared with the use of tiotropium plus placebo, tiotropium + LABA/ICS-based therapy does not increase undesirable effects such as adverse events or serious non-fatal adverse events.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Therapy, Combination; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide

Topics: Asthma; Bronchodilator Agents; Humans; Lung; Models, Neurological; Muscarinic Antagonists; Muscle, Smooth; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Vagus Nerve

In many countries worldwide, the long-acting anticholinergic drug tiotropium is available as a dry powder formulation delivered by means of the HandiHaler® inhalation device and as an aqueous solution delivered via the Respimat® Soft Mist™ Inhaler. Tiotropium HandiHaler® is a single-dose, dry powder, breath-actuated inhaler that provides delivered doses and lung deposition of tiotropium that are, over a wide range, not influenced by the severity of chronic obstructive pulmonary disease (COPD). Tiotropium Respimat® is a propellant-free, multi-dose inhaler that delivers a metered dose of medication as a fine, slow-moving, long-lasting soft mist, independently of patient inspiratory effort. The high fine-particle fraction of droplets produced by the Respimat® inhaler optimizes the efficiency of drug delivery to the lungs.. To help inform the choice of tiotropium inhaler for prescribers and patients, this systematic review summarizes the available pharmacokinetic, efficacy and safety data from comparative studies of tiotropium Respimat® and tiotropium HandiHaler® in COPD, focusing on the licensed once-daily doses of 5 and 18 μg, respectively. Data sources reviewed include publications and abstracts identified from database searches.. Published evidence from comparative studies suggests that tiotropium Respimat® 5 μg and tiotropium HandiHaler® 18 μg provide similar clinical outcomes in patients with COPD.. The findings indicate that physicians can base their decision about an inhaler for tiotropium on factors other than efficacy or safety. These could be patient preference for a particular inhaler, ease of use and the efficiency of drug delivery, with the aim of optimizing adherence and clinical outcomes with long-term tiotropium maintenance therapy.

Topics: Administration, Inhalation; Bronchodilator Agents; Forced Expiratory Volume; Humans; Lung; Metered Dose Inhalers; Patient Preference; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide

Tiotropium is prescribed for the treatment of chronic obstructive pulmonary disease (COPD) and delivered via HandiHaler(®) (18 μg once daily) or Respimat(®) Soft Mist™ inhaler (5 μg once daily). The recent TIOtropium Safety and Performance In Respimat(®) (TIOSPIR™) study demonstrated that both exhibit similar safety profiles. This analysis provides an updated comprehensive safety evaluation of tiotropium(®) using data from placebo-controlled HandiHaler(®) and Respimat(®) trials.. Pooled analysis of adverse event (AE) data from tiotropium HandiHaler(®) 18 μg and Respimat(®) 5 μg randomized, double-blind, parallel-group, placebo-controlled, clinical trials in patients with COPD (treatment duration ≥4 weeks). Incidence rates, rate ratios (RRs), and 95% confidence intervals (CIs) were determined for HandiHaler(®) and Respimat(®) trials, both together and separately.. In the 28 HandiHaler(®) and 7 Respimat(®) trials included in this analysis, 11,626 patients were treated with placebo and 12,929 with tiotropium, totaling 14,909 (12,469 with HandiHaler(®); 2,440 with Respimat(®)) patient-years of tiotropium exposure. Mean age was 65 years, and mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.16 L (41% predicted). The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and of serious AEs (SAEs) (0.94 [0.89, 0.99]) was significantly lower in the tiotropium than in the placebo group (HandiHaler(®) and Respimat(®) pooled results), and there was a numerically lower risk of fatal AEs (FAEs) (0.90 [0.79, 1.01]). The risk of cardiac AEs (0.93 [0.85, 1.02]) was numerically lower in the tiotropium group. Incidences of typical anticholinergic AEs, but not SAEs, were higher with tiotropium. Analyzed separately by inhaler, the risks of AE and SAE in the tiotropium groups remained lower than in placebo and similarly for FAEs.. This analysis indicates that tiotropium is associated with lower rates of AEs, SAEs, and similar rates of FAEs than placebo when delivered via HandiHaler(®) or Respimat(®) (overall and separately) in patients with COPD.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Equipment Design; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Odds Ratio; Patient Safety; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Factors; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

COPD guidelines recommend the combined use of inhaled long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) if symptoms are not improved by a single agent. This systematic review tested the hypothesis that the bronchodilator effect of the LABA/LAMA combination, umeclidinium (UMEC)/vilanterol (VIL), would translate into better outcomes without incurring increased adverse events (AEs).. This was a systematic review of randomized, placebo-controlled or crossover trials (> 4 weeks) involving UMEC/VIL compared with its monocomponents, tiotropium, or fluticasone/salmeterol. Primary outcomes were trough FEV1, serious adverse events (SAEs), and serious cardiovascular events (SCVEs).. Eleven trials from 10 studies (9,609 patients) showed that UMEV/VIL provided superior improvements in lung function compared with UMEC, VIL, tiotropium, and fluticasone propionate/salmeterol (mean trough FEV1, 60, 110, 90, and 90 mL, respectively; P < .0001). Also, UMEC/VIL had a greater likelihood of demonstrating a minimal clinically important difference on the Transition Dyspnea Index compared with UMEC and VIL (number needed to treat for benefit [NNTB] = 14 and 10, respectively). UMEC/VIL therapy significantly reduced the risk of COPD exacerbations compared with UMEC and VIL (NNTB = 42 and 41, respectively). On the contrary, we noted no significant differences between UMEC/VIL and tiotropium with respect to dyspnea, health status, or risk of COPD exacerbation. Regarding safety issues, the incidence of AEs, SAEs, SCVEs, and mortality on treatment was similar across treatments, suggesting reduced safety concerns with the use of the UMEC/VIL combination.. Once-daily inhaled UMEC/VIL showed superior efficacy compared with its monocomponents, tiotropium, and fluticasone/combination in patients with moderate to severe COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Benzyl Alcohols; Chlorobenzenes; Drug Combinations; Fluticasone-Salmeterol Drug Combination; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Two once-daily inhaled bronchodilators, indacaterol and tiotropium, are widely used as first-line therapy in stable COPD patients. This study was performed to compare the clinical efficacy and safety between indacaterol and tiotropium in patients with moderate-to-severe COPD. MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched to identify all published randomized controlled trials (RCTs). The primary outcome was trough forced expiratory volume in 1 second (FEV1) at week 12. Four RCTs were eligible for inclusion (three RCTs with moderate-to-severe COPD patients and one RCT with only severe COPD patients). Trough FEV₁ at weeks 12 and 26 were not significantly different between indacaterol and tiotropium by the standardized mean difference with 0.014 (95% CI, -0.036, 0.063, I²= 23.5%) and with 0.037 (95% CI, -0.059 to 0.133, I²= 0%) along with differences in means of 0.003L and 0.014L, respectively. Indacaterol and tiotropium also showed similar St. George's Respiratory Questionnaire (SGRQ) total scores and percentages of patients with SGRQ improvement (≥ 4 units) at week 26. The incidences of nasopharyngitis, serious cardiovascular events, and serious adverse events were not different between indacaterol and tiotropium, while those of cough (OR = 1.68, P < 0.001, and RR = 1.63) and COPD worsening (OR = 1.18, P = 0.003, and RR = 1.12) were higher for indacaterol than tiotropium. However, when one study with only severe COPD patients was removed from the meta-analysis, the difference in the incidence of COPD worsening between indacaterol and tiotropium became non-significant (OR = 1.13, P = 0.204, and RR = 1.09). The clinical efficacy and serious adverse events between indacaterol and tiotropium were equivocal in patients with moderate-to-severe COPD. Cough is a common complaint associated with indacaterol, and COPD worsening needs to be carefully monitored in severe COPD patients when treated with indacaterol.

Topics: Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Forced Expiratory Volume; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Tiotropium Bromide; Treatment Outcome

Exacerbations of chronic obstructive pulmonary disease (COPD) have important consequences for lung function, health status and mortality. Furthermore, they are associated with high economic costs, predominantly related to hospitalization. They are managed acutely with short-acting bronchodilators, systemic corticosteroids or antibiotics; however, a large proportion of COPD exacerbations are unreported and therefore untreated or self-managed. There is evidence to suggest that these unreported exacerbations also have important consequences for health status; therefore, reducing exacerbation risk is an important goal in the management of COPD. Current guidelines recommend long-acting muscarinic antagonists (LAMAs) as first-line bronchodilator therapy in patients with stable COPD who have a high risk of exacerbation or increased symptoms. To date, three LAMAs, tiotropium bromide, aclidinium bromide and glycopyrronium bromide, have been approved as maintenance bronchodilator treatments for stable COPD. These all provide clinically significant improvements in lung function, reduce symptoms and improve health status compared with placebo in patients with COPD. This paper reviews evidence from randomized, controlled clinical trials demonstrating that tiotropium, aclidinium and glycopyrronium reduce exacerbation risk in patients with COPD. Reductions were seen irrespective of the exacerbation measure used, whether time to first event or annualized exacerbation rate. Furthermore, studies with aclidinium suggest LAMAs can reduce exacerbation risk irrespective of whether exacerbation events are assessed, using an event-based approach or a symptom-based method which includes unreported events. Together these results demonstrate that LAMAs have the potential to provide clinical benefit in the management of exacerbations in patients with stable COPD.

Topics: Clinical Trials as Topic; Delayed-Action Preparations; Glycopyrrolate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Tropanes

There is an ongoing debate on whether patients with chronic obstructive pulmonary disease (COPD) seen in real-life clinical settings are represented in randomized controlled trials (RCTs) of COPD. It is thought that the stringent inclusion and exclusion criteria of RCTs may prevent the participation of patients with specific characteristics or risk factors.. We surveyed a database of patients recruited into 35 placebo-controlled tiotropium RCTs and also conducted a systematic literature review of large-scale observational studies conducted in patients with a documented diagnosis of COPD between 1990 and 2013. Patient demographics and comorbidities with a high prevalence in patients with COPD were compared between the two patient populations at baseline. Using the Medical Dictionary for Regulatory Activities (MedDRA; v 14.0), patient comorbidities in the pooled tiotropium RCTs were classified according to system organ class, pharmacovigilance (PV) endpoints, and Standardised MedDRA Queries to enable comparison with the observational studies.. We identified 24,555 patients in the pooled tiotropium RCTs and 61,361 patients among the 13 observational studies that met our search criteria. The Global initiative for chronic Obstructive Lung Disease (GOLD) staging of patients in the RCTs differed from that in observational studies: the proportion of patients with GOLD stages I+II disease ranged from 40.0% to 51.5% in the RCTs but 24.5% to 44.1% in the observational studies; for GOLD stage III or IV disease these ranges were 7.2%-45.8% (RCTs) and 13.7-42.1% (observational studies). The comorbidities with the highest prevalence reported in the RCTs and observational studies were: hypertension (39.4%-40.0% vs 40.1%-60.6%), other ischemic heart disease (12.3%-14.2% vs 12.5%-41.0%), diabetes (10.3%-10.9% vs 4.0%-38.9%), depression (8.5%-9.5% vs 17.0%-20.6%), and cardiac arrhythmia (7.8%-11.4% vs 11.3%-15.8%).. The clinical profile of COPD patients treated in the tiotropium trial program appears to be largely in the range of clinical characteristics, including cardiovascular comorbidities, reported for "real-life patients." The tiotropium RCTs tended to include patients with more severe disease than the observational studies.

Topics: Aged; Bronchodilator Agents; Cardiovascular Diseases; Cholinergic Antagonists; Comorbidity; Female; Humans; Lung; Male; Middle Aged; Observational Studies as Topic; Prevalence; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

Exacerbations of chronic obstructive pulmonary disease (COPD) have a negative effect on the clinical course and outcome of the disease thus causing considerable social and economic burden. As the natural course of the disease may vary, the treatment should take into account an individual approach to a patient. The appropriate treatment makes it possible to control the symptoms, improves effort tolerance and decreases the risk of exacerbations and death. Tiotropium is a muscarinic receptor antagonist, which is taken once daily, in maintenance therapy, in every stage of the disease progress. The efficacy of tiotropium in regards to exacerbations of chronic obstructive pulmonary disease has been evaluated in many clinical trials against placebo and several different active comparators. This review presents the results of those studies with the main goal to evaluate the efficacy of treatment with tiotropium in terms of prevention and course of exacerbations.

Topics: Administration, Inhalation; Bronchodilator Agents; Clinical Trials as Topic; Disease Progression; Drug Administration Schedule; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disorder that results in frequent exacerbations and impacts quality of life. It represents a growing burden of health care cost, both from societal and economic perspectives. Short- and long-acting bronchodilators remain the mainstay of therapy in COPD patients. New fixed-dose combination inhalers with novel pharmacological combinations of long-acting β2-agonists and muscarinic antagonists and delivered once-daily through a variety of devices are currently being developed and licensed for the treatment of COPD. There is mounting research suggesting that combining a fixed dose of a β2-agonist and a muscarinic antagonist achieves better bronchodilation and clinical outcomes compared with either agent alone. These once-daily dosing inhalers are anticipated to impact favorably on patient preference and compliance. This review examines the fixed-dose combination of tiotropium bromide and olodaterol delivered by a Respimat(®) Soft Mist™ inhaler at doses of 2.5/5 μg and 5/5 μg in moderate-to-very-severe COPD, and its potential role in COPD compared with other long-acting β2-agonist with long-acting muscarinic antagonist combinations and delivery devices.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Cholinergic Antagonists; Drug Combinations; Dry Powder Inhalers; Exercise Tolerance; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recovery of Function; Tiotropium Bromide; Treatment Outcome

The purpose of this review is to discuss the cardiovascular risk associated with inhaled anticholinergics in chronic obstructive pulmonary disease. Several meta-analyses of data for tiotropium raised the possibility of an increased risk for arrhythmia, angina, myocardial infarction, etc. This review includes the data of retrospective studies of databases using databases, randomized controlled trials, and meta-analyses of clinical trials. The conclusions of studies were inconsistent. In most clinical trials the incidence of cardiovascular adverse events was similar in active treatment and placebo groups, especially in patients with previous cardiovascular diseases. Considering meta-analyses, there is little, if any, evidence for the association between anticholinergics and the development of cardiovascular symptoms. The author discusses the presence and function of cholinergic receptor subtypes in human heart, and cardiac functions controlled by the autonomic nervous system via these receptors, their possible role, and pharmacokinetic properties of inhaled anticholinergics. The author concludes that it is not possible to find evidence of increased cardiovascular harm of inhaled anticholinergics.

Topics: Administration, Inhalation; Bronchodilator Agents; Cardiovascular Diseases; Cardiovascular System; Cholinergic Antagonists; Clinical Trials as Topic; Glycopyrrolate; Humans; Incidence; Ipratropium; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide

A solid scientific rationale and an increasing body of clinical evidence for combining a β2-agonist with an antimuscarinic agent in COPD fully support the opinion that patients not controlled by a single bronchodilator should be given two bronchodilators with different mechanisms of action. Tiotropium is an established choice for the management of patients with stable COPD, and olodaterol is a new effective and safe once-daily long-acting β2-agonist. The parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The large ongoing TOviTO Phase III trial program is documenting the efficacy and safety of olodaterol/tiotropium fixed dose combination delivered via the Respimat Soft Mist Inhaler as maintenance therapy in patients with moderate to very severe COPD. However, we must still know whether this fixed-dose combination will affect exacerbations and hospitalizations, and ultimately death, and also the precise estimates of its relative cardiovascular safety.

Topics: Administration, Inhalation; Animals; Benzoxazines; Bronchodilator Agents; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide

Tiotropium and ipratropium bromide are both recognised treatments in the management of people with stable chronic obstructive pulmonary disease (COPD). There are new studies which have compared tiotropium with ipratropium bromide, making an update necessary.. To compare the relative effects of tiotropium to ipratropium bromide on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in patients with COPD using available randomised controlled trial (RCT) data.. We identified RCTs from the Cochrane Airways Group Specialised Register of trials (CAGR) and ClinicalTrials.gov up to August 2015.. We included parallel group RCTs of 12 weeks duration or longer comparing treatment with tiotropium with ipratropium bromide for patients with stable COPD.. Two review authors independently assessed studies for inclusion and then extracted data on study quality and outcome results. We contacted trial sponsors for additional information. We analysed the data using Cochrane Review Manager.. This review included two studies of good methodological quality that enrolled 1073 participants with COPD. The studies used a similar design and inclusion criteria and were of at least 12 weeks duration; the participants had a mean forced expiratory volume in one second (FEV1) of 40% predicted value at baseline. One study used tiotropium via the HandiHaler (18 µg) for 12 months and the other via the Respimat device (5 µg and 10 µg) for 12 weeks. In general, the treatment groups were well matched at baseline but not all outcomes were reported for both studies. Overall the risk of bias across the included RCTs was low.For primary outcomes this review found that at the three months trough (the lowest level measured before treatment) FEV1 significantly increased with tiotropium compared to ipratropium bromide (mean difference (MD) 109 mL; 95% confidence interval (CI) 81 to 137, moderate quality evidence, I(2) = 62%). There were fewer people experiencing one or more non-fatal serious adverse events on tiotropium compared to ipratropium (odds ratio (OR) 0.5; 95% CI 0.34 to 0.73, high quality evidence). This represents an absolute reduction in risk from 176 to 97 per 1000 people over three to 12 months. Concerning disease specific adverse events, the tiotropium group were also less likely to experience a COPD-related serious adverse event when compared to ipratropium bromide (OR 0.59; 95% CI 0.41 to 0.85, moderate quality evidence).For secondary outcomes, both studies reported fewer hospital admissions in the tiotropium group (OR 0.34; 95% CI 0.15 to 0.70, moderate quality evidence); as well as fewer patients experiencing one or more exacerbations leading to hospitalisation in the people on tiotropium in both studies (OR 0.56; 95% CI 0.31 to 0.99, moderate quality evidence). There was no significant difference in mortality between the treatments (OR 1.39; 95% CI 0.44 to 4.39, moderate quality evidence). One study measured quality of life using the St George's Respiratory Questionnaire (SGRQ); the mean SGRQ score at 52 weeks was lower in the tiotropium group than the ipratropium group (lower on the scale is favourable) (MD -3.30; 95% CI -5.63 to -0.97, moderate quality evidence). There were fewer participants suffering one of more exacerbations in the tiotropium arm (OR 0.71; 95% CI 0.52 to 0.95, high quality evidence) and there was also a reported difference in the mean number of exacerbations per person per year which reached statistical significance (MD -0.23;. This review shows that tiotropium treatment, when compared with ipratropium bromide, was associated with improved lung function, fewer hospital admissions (including those for exacerbations of COPD), fewer exacerbations of COPD and improved quality of life. There were both fewer serious adverse events and disease specific events in the tiotropium group, but no significant difference in deaths with ipratropium bromide when compared to tiotropium. Thus, tiotropium appears to be a reasonable choice (instead of ipratropium bromide) for patients with stable COPD, as proposed in guidelines. A recent large double-blind trial of the two delivery devices found no substantial difference in mortality using 2.5 µg or 5 µg of tiotropium via Respimat in comparison to 18 µg via Handihaler.

Topics: Bronchodilator Agents; Forced Expiratory Volume; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Several new fixed-dose combination bronchodilators have been recently launched, and assessing their efficacy relative to each other, and with open dual combinations is desirable. This network meta-analysis (NMA) assessed the efficacy of umeclidinium and vilanterol (UMEC/VI) with that of available dual bronchodilators in single/separate inhalers.. A systematic literature review identified randomized controlled trials of ≥10 weeks among chronic obstructive pulmonary disease patients (≥40 years), assessing the efficacy of combination bronchodilators in single or separate inhalers. Comparative assessment was conducted on change from baseline in trough forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) total scores, transitional dyspnea index (TDI) focal scores, and rescue medication use at 12 weeks and 24 weeks using an NMA within a Bayesian framework.. A systematic literature review identified 77 articles of 26 trials comparing UMEC/VI, indacaterol/glycopyrronium (QVA149), formoterol plus tiotropium (TIO) 18 μg, salmeterol plus TIO, or indacaterol plus TIO, with TIO and placebo as common comparators at 12 weeks and approximately 24 weeks. The NMA showed that at 24 weeks, efficacy of UMEC/VI was not significantly different compared with QVA149 on trough FEV1 (14.1 mL [95% credible interval: -14.2, 42.3]), SGRQ total score (0.18 [-1.28, 1.63]), TDI focal score (-0.30 [-0.73, 0.13]), and rescue medication use (0.02 [-0.27, 0.32]); compared with salmeterol plus TIO on trough FEV1 (67.4 mL [-25.3, 159.4]), SGRQ total score (-0.11 [-1.84, 1.61]), and TDI focal score (0.58 [-0.33, 1.50]); and compared with formoterol plus TIO 18 μg on SGRQ total score (-0.68 [-1.77, 0.39]). Results at week 12 were consistent with week 24 outcomes. Due to lack of availability of evidence, no comparison was made with formoterol plus TIO on FEV1 or TDI at 24 weeks.. UMEC/VI has comparable efficacy to other dual-bronchodilator combinations on available efficacy endpoints.

Topics: Bronchodilator Agents; Drug Combinations; Drug Therapy, Combination; Dyspnea; Forced Expiratory Volume; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome

Long-acting bronchodilators, comprising long-acting beta2-agonists (LABA) and long-acting anti-muscarinic agents (LAMA, principally tiotropium), are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease (COPD). Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and LABAs for the treatment of COPD are unclear.. To compare the relative effects on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in people with COPD randomised to LABA plus tiotropium versus tiotropium alone; or LABA plus tiotropium versus LABA alone.. We searched the Cochrane Airways Group Specialised Register of trials and ClinicalTrials.gov up to July 2015.. We included parallel-group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to LABA against tiotropium or LABA alone for people with COPD.. Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.. This review included 10 trials on 10,894 participants, mostly recruiting participants with moderate or severe COPD. All of the trials compared tiotropium in addition to LABA to tiotropium alone, and four trials additionally compared LAMA plus LABA with LABA alone. Four studies used the LABA olodaterol, three used indacaterol, two used formoterol, and one used salmeterol.Compared to tiotropium alone, treatment with tiotropium plus LABA resulted in a slightly larger improvement in mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) (mean difference (MD) -1.34, 95% confidence interval (CI) -1.87 to -0.80; 6709 participants; 5 studies). The MD was smaller than the four units that is considered clinically important, but a responder analysis indicated that 7% more participants receiving tiotropium plus LABA had a noticeable benefit (greater than four units) from treatment in comparison to tiotropium alone. In the control arm in one study, which was tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with tiotropium plus LABA the improvement was a fall of a further 1.3 units (on average). Most of the data came from studies using olodaterol. High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator forced expiratory volume in one second (FEV1) showed a small mean increase with the addition of LABA over the control arm (MD 0.06, 95% CI 0.05 to 0.07; 9573 participants; 10 studies), which showed a change from baseline ranging from 0.03 L to 0.13 L with tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There was moderate heterogeneity for both exacerbations and withdrawals.This review included data on four LABAs: two administered twice daily (salmeterol, formoterol) and two once daily (indacaterol, olodaterol). The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.Comparing LABA plus tiotropium treatment with LABA alone, there was a small but significant improvement in SGRQ (MD -1.25, 95% CI -2.14 to -0.37; 3378 participants; 4 st. The results from this review indicated a small mean improvement in health-related quality of life and FEV1 for participants on a combination of tiotropium and LABA compared to either agent alone, and this translated into a small increase in the number of responders on combination treatment. In addition, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not. Hospital admission and mortality were not altered by adding LABA to tiotropium, although there may not be enough data. While it is possible that this is affected by higher attrition in the tiotropium group, one would expect that participants withdrawn from the study would have had less favourable outcomes; this means that the expected direction of attrition bias would be to reduce the estimated benefit of the combination treatment. The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Bronchodilator Agents; Ethanolamines; Formoterol Fumarate; Humans; Indans; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Anticholinergic bronchodilators such as tiotropium, a potent long-acting drug, are central to the symptomatic treatment of chronic obstructive pulmonary disease. Its role in asthma treatment has been recently investigated. This review critically evaluates documented evidence of clinical trials and assesses the therapeutic implications of anticholinergic drugs in asthma management. So far, the results of 10 Phases II and III randomized controlled trials evaluating the effect of adding tiotropium to the treatment of mild-to-moderate or severe asthma have been published. These trials had a duration of 4 to 52 weeks and involved 3368 subjects with mild-to-moderate asthma and 1019 subjects with severe asthma [corrected]. Also, 1 systematic review and 6 meta-analyses have appraised the results of published and unpublished trials investigating the role of tiotropium in asthma. The results of the trials in mild to moderate asthma showed that adding tiotropium to inhaled corticosteroids (ICSs) was not inferior to adding long-acting β2-agonists (LABAs). In addition, the safety and efficacy of tiotropium were similar to those of salmeterol. The results of studies on severe asthma showed that adding tiotropium to a treatment with high doses of an ICS plus LABA results in further improvement in lung function, increases the time to the first severe exacerbation of asthma and to worsening of asthma, and improves asthma control. Except for dry mouth, the safety profile of tiotropium was similar to placebo both in moderate and in severe asthma. Adding tiotropium to an ICS or ICS plus LABA improves lung function, symptoms, and asthma control, and in severe asthma, it increases the time to exacerbations, with good safety profile. The effect seems independent of baseline characteristics such as age, level of bronchial obstruction, smoking status, allergic status, and bronchial reversibility.

Topics: Administration, Inhalation; Asthma; Bronchodilator Agents; Drug Administration Schedule; Glucocorticoids; Humans; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide; Treatment Outcome

Increasing evidence suggests pharmacological treatments may impact on overall survival in Chronic Obstructive Pulmonary Disease (COPD) patients. Individual clinical trials are rarely powered to detect mortality differences between treatments and may not include all treatment options relevant to healthcare decision makers.. A systematic review was conducted to identify RCTs of COPD treatments reporting mortality; evidence was synthesised using network meta-analysis (NMA). The analysis included 40 RCTs; a quantitative indirect comparison between 14 treatments using data from 55,220 patients was conducted.. The analysis reported two treatments reducing all-cause mortality; salmeterol/fluticasone propionate combination (SFC) was associated with a reduction in mortality versus placebo in the fixed effects (HR 0.79; 95 % Crl 0.67, 0.94) but not the random effects model (0.79; 0.56, 1.09). Indacaterol was associated with a reduction in mortality versus placebo in fixed (0.28; 0.08 to 0.85) and random effects (0.29; 0.08, 0.89) models. Mean estimates and credible intervals for hazard ratios for indacaterol versus placebo are based on a small number of events; estimates may change when the results of future studies are included. These results were maintained across a variety of assumptions and provide evidence that SFC and indacaterol may lead to improved survival in COPD patients.. Results of an NMA of COPD treatments suggest that SFC and indacaterol may reduce mortality. Further research is warranted to strengthen this conclusion.

Topics: Albuterol; Aminopyridines; Beclomethasone; Benzamides; Benzyl Alcohols; Bronchodilator Agents; Budesonide; Chlorobenzenes; Cyclopropanes; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Glucocorticoids; Humans; Indans; Ipratropium; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Quinolones; Survival Rate; Theophylline; Tiotropium Bromide; Triamcinolone

Topics: Administration, Inhalation; Animals; Benzoxazines; Bronchodilator Agents; Drug Combinations; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD), a respiratory disease characterized by a progressive decline in lung function, is considered to be a leading cause of morbidity and mortality. Long-acting inhaled bronchodilators, such as long-acting β2 agonists (LABAs) or long-acting muscarinic antagonists (LAMAs), are the cornerstone of maintenance therapy for patients with moderate-to-very-severe COPD. For patients not sufficiently controlled on a single long-acting bronchodilator, a combination of different bronchodilators has shown a significant increase in lung function. Tiotropium, a once-daily dosing LAMA, demonstrated sustained improvements in lung function as well as improved health-related quality of life, reduced exacerbations, and increased survival without altering the rate of decline in the mean forced expiratory volume in 1 second (FEV1) with fairly tolerable side effects. Olodaterol is a once-daily dosing LABA that has proven to be effective in improving lung function, reducing rescue medication use, and improving dyspnea and health-related quality of life, as well as improving exercise endurance with an acceptable safety profile. The combination of olodaterol and tiotropium provided additional improvements in lung function greater than monotherapy with each drug alone. Several well-designed randomized trials confirmed that the synergistic effect of both drugs in combination was able to improve lung function and health-related quality of life without a significant increase in adverse effects. The objective of this paper is to review available evidence on the clinical efficacy and safety of tiotropium, olodaterol, and their combination in patients with COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Cholinergic Antagonists; Cost-Benefit Analysis; Drug Administration Schedule; Drug Combinations; Drug Costs; Drug Synergism; Forced Expiratory Volume; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recovery of Function; Tiotropium Bromide; Treatment Outcome

Although tiotropium (TIO) and inhaled corticosteroid (ICS)/long-acting β-agonists are frequently prescribed together, the efficacy of "triple therapy" has not been scientifically demonstrated. We conducted a systematic review and meta-analysis using Bayesian methods to compare triple therapy and TIO monotherapy.. We searched the MEDLINE, EMBASE, and Cochrane Library databases for randomized controlled trials comparing the efficacy and safety of triple therapy and TIO monotherapy in patients with chronic obstructive pulmonary disease (COPD). We conducted a meta-analysis to compare the effectiveness and safety of triple therapy and TIO monotherapy using Bayesian random effects models.. Seven trials were included, and the risk of bias in the majority of the studies was acceptable. There were no statistically significant differences in the incidence of death and acute exacerbation of disease in the triple therapy and TIO monotherapy groups. Triple therapy improved the prebronchodilator forced expiratory volume in 1 second (mean difference [MD], 63.68 mL; 95% credible interval [CrI], 45.29-82.73), and patients receiving triple therapy showed more improvement in St George Respiratory Questionnaire scores (MD, -3.11 points; 95% CrI, -6.00 to -0.80) than patients receiving TIO monotherapy. However, both of these differences were lower than the minimal clinically important difference (MCID). No excessive adverse effects were reported in triple therapy group.. Triple therapy with TIO and ICSs/long-acting β-agonists was only slightly more efficacious than TIO monotherapy in treating patients with COPD. Further investigations into the efficacy of new inhaled drugs are needed.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bayes Theorem; Bronchodilator Agents; Cholinergic Antagonists; Drug Combinations; Forced Expiratory Volume; Humans; Lung; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

Randomized, controlled trials comparing long-acting muscarinic antagonist (LAMA) efficacy in COPD are limited. This network meta-analysis (NMA) assessed the relative efficacy of tiotropium 18 µg once-daily (OD) and newer agents (aclidinium 400 µg twice-daily, glycopyrronium 50 µg OD, and umeclidinium 62.5 µg OD).. A systematic literature review identified randomized, controlled trials of adult COPD patients receiving LAMAs. A NMA within a Bayesian framework examined change from baseline in trough forced expiratory volume in 1 second (FEV1), transitional dyspnea index focal score, St George's Respiratory Questionnaire score, and rescue medication use.. Twenty-four studies (n=21,311) compared LAMAs with placebo/each other. Aclidinium, glycopyrronium, tiotropium, and umeclidinium, respectively, demonstrated favorable results versus placebo, for change from baseline (95% credible interval) in 12-week trough FEV1 (primary endpoint: 101.40 mL [77.06-125.60]; 117.20 mL [104.50-129.90]; 114.10 mL [103.10-125.20]; 136.70 mL [104.20-169.20]); 24-week trough FEV1 (128.10 mL [84.10-172.00]; 135.80 mL [123.10-148.30]; 106.40 mL [95.45-117.30]; 115.00 mL [74.51-155.30]); 24-week St George's Respiratory Questionnaire score (-4.60 [-6.76 to -2.54]; -3.14 [-3.83 to -2.45]; -2.43 [-2.92 to -1.93]; -4.69 [-7.05 to -2.31]); 24-week transitional dyspnea index score (1.00 [0.41-1.59]; 1.01 [0.79-1.22]; 0.82 [0.62-1.02]; 1.00 [0.49-1.51]); and 24-week rescue medication use (data not available; -0.41 puffs/day [-0.62 to -0.20]; -0.52 puffs/day [-0.74 to -0.30]; -0.30 puffs/day [-0.81 to 0.21]). For 12-week trough FEV1, differences in change from baseline (95% credible interval) were -12.8 mL (-39.39 to 13.93), aclidinium versus tiotropium; 3.08 mL (-7.58 to 13.69), glycopyrronium versus tiotropium; 22.58 mL (-11.58 to 56.97), umeclidinium versus tiotropium; 15.90 mL (-11.60 to 43.15), glycopyrronium versus aclidinium; 35.40 mL (-5.06 to 76.07), umeclidinium versus aclidinium; and 19.50 mL (-15.30 to 54.38), umeclidinium versus glycopyrronium. Limitations included inhaler-related factors and safety; longer-term outcomes were not considered.. The new LAMAs studied had at least comparable efficacy to tiotropium, the established class standard. Choice should depend on physician's and patient's preference.

Topics: Aged; Bayes Theorem; Bronchodilator Agents; Drug Administration Schedule; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic; Recovery of Function; Spirometry; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes

Tiotropium HandiHaler (TioH) has been shown to improve lung function, exacerbations, and quality of life when added to the pharmacotherapy of patients with stable chronic obstructive pulmonary disease (COPD). The purpose of this meta-analysis was to synthesize current evidence regarding the impact of TioH on the survival rate of these patients, which is still controversial.. A systematic search in the electronic databases of the Cochrane Library, Medline, Scopus, EMBASE, PschINFO, CINAHL, and Web of Science was conducted by two independent authors (December 2012). Randomized clinical trials (RCTs) comparing inhaled TioH versus control (placebo or open control) were included. Data on total mortality were extracted, and missing data were obtained from authors. Relative risk (RR) for total mortality was calculated for each study and pooled. Heterogeneity, the risk of bias, and the publication bias were assessed in accordance with Cochrane's guidance.. Twenty-eight RCTs, evaluating 33,538 patients, met the inclusion criteria. Data were nonheterogeneous, so fixed-effects model analysis was used. The effect of TioH versus placebo was assessed in 19 RCTs, with a total population of 19,826 patients (31,914 patient years), of whom 1,018 died during the study period. A statistically significant decrease in all-cause mortality was associated with the administration of TioH [RR 0.86, 95% confidence interval (CI) 0.76-0.98]. The number needed to treat to prevent one fatality was estimated to be 64 (95% CI 56-110). Comparisons of tiotropium against six more comparators were identified, but the insufficient sample size did not allow robust comparisons with respect to mortality.. Our meta-analysis of RCTs showed that TioH prolongs the survival of COPD patients compared with placebo. Further RCTs are needed to confirm the potential superiority of prescriptions with versus without TioH in mortality reduction.

Topics: Administration, Inhalation; Bronchodilator Agents; Chi-Square Distribution; Humans; Lung; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Risk Factors; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

The inhaled route is considered to be the best route to administer drugs for treating respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD), for both safety and efficacy. Inhalation devices are classified into four types - pressuriszed metered dose inhalers (pMDIs), dry powder inhalers, breath actuated inhalers and nebulizers. pMDIs are portable, convenient, multi-dose devices and these advantages have made them very popular with patients. They were introduced in the 1950s as the first portable, multi-dose delivery system for bronchodilators. Even though pMDIs are the most widely used devices for inhalation therapy in asthma and COPD, studies establishing their use and providing clinical data with bronchodilators and combination therapies in patients with COPD are limited. A summary of the use of pMDI with spacers in patients with COPD in terms of lung deposition and impact on lung function are presented in this review article. A review of use of the pMDI device in patients with COPD with different available and prescribed medications (bronchodilators-β2-agonists and anticholinergics, and their combination with inhaled corticosteroids) is discussed.

Topics: Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Equipment Design; Ethanolamines; Formoterol Fumarate; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Combinations of two long-acting bronchodilators and long-acting bronchodilators with inhaled corticosteroids (ICS) are recommended therapies in the management of chronic obstructive pulmonary disease (COPD). Three fixed-dose combination products have recently been approved for the treatment of COPD (the long-acting β2-agonist plus long-acting muscarinic antagonist [LABA/LAMA] combinations glycopyrronium/indacaterol [QVA149] and umeclidinium/vilanterol, and the LABA/ICS fluticasone furoate/vilanterol), with others currently in late-stage development. LABA/LAMA and LABA/ICS combination therapies demonstrate positive effects on both lung function and patient-reported outcomes, with significant improvements observed with LABA/LAMA combinations compared with placebo, each component alone and other comparators in current use. No new safety concerns have been observed with combinations of long-acting bronchodilators. Combinations of two long-acting bronchodilators represent a new and convenient treatment option in COPD. This review summarizes published efficacy and safety data from clinical trials of both LABA/LAMA and novel LABA/ICS combinations in patients with COPD.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Disease Management; Disease Progression; Drug Combinations; Ethanolamines; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

This meta-analysis was performed to evaluate the efficacy and safety of adding fluticasone propionate/salmeterol (FSC) to tiotropium (Tio) in COPD patients.. A systematic search was made of MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases, and a hand search of leading respiratory journals. Randomized clinical trials on treatment of stable COPD with the addition of FSC, compared with tiotropium alone, were reviewed. Studies were pooled to odds ratio (OR) and weighted mean differences (WMD), with 95% confidence interval (CI).. Six trials met the inclusion criteria. Compared with tiotropium, addition of FSC presented significant effects on trough forced expiratory volume in 1s (FEV1) (WMD 54.64 mL; 95% CI 51.76 to 57.52 mL; P<0.001), COPD exacerbations (OR 0.73; 95% CI 0.55 to 0.96; p=0.03), and health-related quality of life (WMD 4.63; 95% CI 4.26 to 5.01; P<0.001). No significant increase was noticed in adverse events in the Tio+FSC group (OR 1.24; 95% CI 0.98 to 1.57; p=0.07).. The addition of FSC to subjects with COPD treated with tiotropium significantly improves lung function, quality of life and COPD exacerbations without increasing the risk of adverse events.

Topics: Albuterol; Androstadienes; Disease Progression; Drug Combinations; Drug Therapy, Combination; Fluticasone-Salmeterol Drug Combination; Humans; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Tiotropium bromide, once daily, long-acting anticholinergic bronchodilator is either administered by handihaler metered dose inhaler or by respimat soft mist inhaler. It has been proved to improve lung function, daily symptoms and quality of life and to decrease the exacerbation and hospitalisation rate of patients with Chronic Obstructive Pulmonary Disease (COPD). Although the efficacy of both formulations is undeniable, concerns have been raised on their effect on cardiovascular and general mortality.. Two independent authors systematically reviewed Medline, Scopus, Cochrane Library and ClinicalTrials.gov to collect clinical trials, observational studies and meta-analyses studying the safety of tiotropium. The reference list of all the included studies were also reviewed.. Limited, early studies suggested a potential increase in cardiovascular and general mortality associated with tiotropium handihaler, but these data were outweighed by following larger trials, real-life studies and meta-analyses which proved the opposite. On the other hand, data on tiotropium respimat (5 μg) have been contradictory, with different studies suggesting increased cardiovascular and general mortality compared to handihaler (18 μg) or placebo, especially in patients with comorbid diseases. TIOSPIR trial suggests comparable safety of the two formulations. However the exclusion of patients with pre-existing unstable cardiovascular disease, moderate or severe kidney disease or any other significantly disease may limit the generizability of these results.. Although the two tiotropium formulations have similar efficacy, current data cannot prove safety equivalence, since respimat may be associated with increased cardiovascular and general mortality, especially in patients with comorbid diseases.

Topics: Administration, Inhalation; Bronchodilator Agents; Cardiovascular Diseases; Humans; Metered Dose Inhalers; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Empirical results indicate an increased risk for cardiovascular (CV) adverse drug events (ADE) in chronic obstructive pulmonary disease (COPD) patients treated with beta-2-agonists (B2A) and muscarinic antagonists (MA). A systematic review (including a meta-analysis for drug classes with sufficient sample size) was conducted assessing the association between B2A or MA and acute myocardial infarctions (MI) in COPD patients.. Comprehensive literature search in electronic databases (MEDLINE, Cochrane database) was performed (January 1, 1946-April 1, 2013). Results were presented by narrative synthesis including a comprehensive quality assessment. In the meta-analysis, a random effects model was used for estimating relative risk estimates for acute MI.. Eight studies (two systematic reviews, two randomized controlled trials, and four observational studies) were comprised. Most studies comparing tiotropium vs. placebo showed a decreased MI risk for tiotropium, whereas for studies with active control arms no clear tendency was revealed. For short-acting B2A, an increased MI risk was shown after first treatment initiation. For all studies, a good quality was found despite some shortcomings in ADE-specific criteria. A meta-analysis could be conducted for tiotropium vs. placebo only, showing a relative risk reduction of MI (0.74 [0.61-0.90]) with no evidence of statistical heterogeneity among the included trials (I(2) = 0%; p = 0.8090).. An MI-protective effect of tiotropium compared to placebo was found, which might be attributable to an effective COPD treatment leading to a decrease in COPD-related cardiovascular events. Further studies with effective control arms and minimal CV risk are required determining precisely tiotropium's cardiovascular risk.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Cholinergic Antagonists; Epidemiologic Methods; Humans; Muscarinic Antagonists; Myocardial Infarction; Pulmonary Disease, Chronic Obstructive; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium is an anticholinergic agent which has gained widespread acceptance as a once daily maintenance therapy for symptoms and exacerbations of stable chronic obstructive pulmonary disease (COPD). In the past few years there have been several systematic reviews of the efficacy of tiotropium, however, several new trials have compared tiotropium treatment with placebo, including those of a soft mist inhaler, making an update necessary.. To evaluate data from randomised controlled trials (RCTs) comparing the efficacy of tiotropium and placebo in patients with COPD, upon clinically important endpoints.. We searched the Cochrane Airways Group's Specialised Register of Trials (CAGR) and ClinicalTrials.gov up to February 2012.. We included parallel group RCTs of three months or longer comparing treatment with tiotropium against placebo for patients with COPD.. Two review authors independently assessed studies for inclusion and then extracted data on study quality and the outcome results. We contacted study authors and trial sponsors for additional information, and collected information on adverse effects from all trials. We analysed the data using Cochrane Review Manager 5, RevMan 5.2.. This review included 22 studies of good methodological quality that had enrolled 23,309 participants with COPD. The studies used similar designs, however, the duration varied from three months to four years. In 19 of the studies, 18 mcg tiotropium once daily via the Handihaler dry powder inhaler was evaluated, and in three studies, 5 or 10 mcg tiotropium once daily via the Respimat soft mist inhaler was evaluated. Compared to placebo, tiotropium treatment significantly improved the mean quality of life (mean difference (MD) -2.89; 95% confidence interval (CI) -3.35 to -2.44), increased the number of participants with a clinically significant improvement (odds ratio (OR) 1.52; 95% CI 1.38 to 1.68), and reduced the number of participants with a clinically significant deterioration (OR 0.65; 95% CI 0.59 to 0.72) in quality of life (measured by the St George's Respiratory Questionnaire (SGRQ)). Tiotropium treatment significantly reduced the number of participants suffering from exacerbations (OR 0.78; 95% CI 0.70 to 0.87). This corresponds to a need to treat 16 patients (95% CI 10 to 36) with tiotropium for a year in order to avoid one additional patient suffering exacerbations, based on the average placebo event rate of 44% from one-year studies. Tiotropium treatment led to fewer hospitalisations due to exacerbations (OR 0.85; 95% CI 0.72 to 1.00), but there was no statistically significant difference in all-cause hospitalisations (OR 1.00; 95% CI 0.88 to 1.13) or non-fatal serious adverse events (OR 1.03; 95% CI 0.97 to 1.10). Additionally, there was no statistically significant difference in all-cause mortality between the tiotropium and placebo groups (Peto OR 0.98; 95% CI 0.86 to 1.11). However, subgroup analysis found a significant difference between the studies using a dry powder inhaler and those with a soft mist inhaler (test for subgroup differences: P = 0.01). With the dry powder inhaler there were fewer deaths in the tiotropium group (Peto OR 0.92; 95% CI 0.80 to 1.05) than in the placebo group (yearly rate 2.8%), but with the soft mist inhaler there were significantly more deaths in the tiotropium group (Peto OR 1.47; 95% CI 1.04 to 2.08) than in the placebo group (yearly rate 1.8%). It is noted that the rates of patients discontinuing study treatment were uneven, with significantly fewer participants withdrawing from tiotropium treatment than from placebo treatment (OR 0.66; 95% CI 0.59 to 0.73). Participants on tiotropium had improved lung func. This review shows that tiotropium treatment was associated with a significant improvement in patients' quality of life and it reduced the risk of exacerbations, with a number needed to treat to benefit (NNTB) of 16 to prevent one exacerbation. Tiotropium also reduced exacerbations leading to hospitalisation but no significant difference was found for hospitalisation of any cause or mortality. Thus, tiotropium appears to be a reasonable choice for the management of patients with stable COPD, as proposed in guidelines. The trials included in this review showed a difference in the risk of mortality when compared with placebo depending on the type of tiotropium delivery device used. However, these results have not been confirmed in a recent trial when 2.5 mcg or 5 mcg of tiotropium via Respimat was used in a direct comparison to the 18 mcg Handihaler.

Topics: Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Dry Powder Inhalers; Humans; Nebulizers and Vaporizers; Placebo Effect; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Bronchodilators are the mainstay for symptom relief in the management of stable chronic obstructive pulmonary disease (COPD). Aclidinium bromide is a new long-acting muscarinic antagonist (LAMA) that differs from tiotropium by its higher selectivity for M3 muscarinic receptors with a faster onset of action. However, the duration of action of aclidinium is shorter than for tiotropium. It has been approved as maintenance therapy for stable, moderate to severe COPD, but its efficacy and safety in the management of COPD is uncertain compared to other bronchodilators.. To assess the efficacy and safety of aclidinium bromide in stable COPD.. We identified randomised controlled trials (RCT) from the Cochrane Airways Group Specialised Register of trials (CAGR), as well as www.clinicaltrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), US Food and Drug Administration (FDA) website and Almirall Clinical Trials Registry and Results. We contacted Forest Laboratories for any unpublished trials and checked the reference lists of identified articles for additional information. The last search was performed on 7 April 2014 for CAGR and 11 April 2014 for other sources.. Parallel-group RCTs of aclidinium bromide compared with placebo, long-acting beta2-agonists (LABA) or LAMA in adults with stable COPD.. Two review authors independently selected studies, assessed the risk of bias, and extracted data. We sought missing data from the trial authors as well as manufacturers of aclidinium. We used odds ratios (OR) for dichotomous data and mean difference (MD) for continuous data, and reported both with their 95% confidence intervals (CI). We used standard methodological procedures expected by The Cochrane Collaboration. We applied the GRADE approach to summarise results and to assess the overall quality of evidence.. This review included 12 multicentre RCTs randomly assigning 9547 participants with stable COPD. All the studies were industry-sponsored and had similar inclusion criteria with relatively good methodological quality. All but one study included in the meta-analysis were double-blind and scored low risk of bias. The study duration ranged from four weeks to 52 weeks. Participants were more often males, mainly Caucasians, mean age ranging from 61.7 to 65.6 years, and with a smoking history of 10 or more pack years. They had moderate to severe symptoms at randomisation; the mean post-bronchodilator forced expiratory volume in one second (FEV1) was between 46% and 57.6% of the predicted normal value, and the mean St George's Respiratory Questionnaire score (SGRQ) ranged from 45.1 to 50.4 when reported.There was no difference between aclidinium and placebo in all-cause mortality (low quality) and number of patients with exacerbations requiring a short course of oral steroids or antibiotics, or both (moderate quality). Aclidinium improved quality of life by lowering the SGRQ total score with a mean difference of -2.34 (95% CI -3.18 to -1.51; I(2) = 48%, 7 trials, 4442 participants) when compared to placebo. More patients on aclidinium achieved a clinically meaningful improvement of at least four units decrease in SGRQ total score (OR 1.49; 95% CI 1.31 to 1.70; I(2) = 34%; number needed to treat (NNT) = 10, 95% CI 8 to 15, high quality evidence) over 12 to 52 weeks than on placebo. Aclidinium also resulted in a significantly greater improvement in pre-dose FEV1 than placebo with a mean difference of 0.09 L (95% CI 0.08 to 0.10; I(2) = 39%, 9 trials, 4963 participants). No trials assessed functional capacity. Aclidinium reduced the number of patients with exacerbations requiring hospitalisation by 4 to 20 fewer per 1000 over 4 to 52 weeks (OR 0.64; 95% CI 0.46 to 0.88; I(2) = 0%, 10 trials, 5624 people; NNT = 77, 95% CI 51 to 233, high quality evidence) compared to placebo. There was no difference in non-fatal serious adverse events (moderate quality evidence) between aclidinium and placebo.Compared to tiotropium, aclidinium did not demonstrate significant differences for exacerbations requiring oral steroids or antibiotics, or both, exacerbation-related hospitalisations and non-fatal serious adverse events (very low quality evidence). Inadequate data prevented the comparison of aclidinium to formoterol or other LABAs.. Aclidinium is associated with improved quality of life and reduced hospitalisations due to severe exacerbations in patients with moderate to severe stable COPD compared to placebo. Overall, aclidinium did not significantly reduce mortality, serious adverse events or exacerbations requiring oral steroids or antibiotics, or both.Currently, the available data are insufficient and of very low quality in comparisons of the efficacy of aclidinium versus tiotropium. The efficacy of aclidinium versus LABAs cannot be assessed due to inaccurate data. Thus additional trials are recommended to assess the efficacy and safety of aclidinium compared to other LAMAs or LABAs.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Disease Progression; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide; Tropanes

The long-acting anticholinergic agent tiotropium bromide (Spiriva(®)) is available as a solution for inhalation via Respimat(®) Soft Mist™ Inhaler in the EU and various other countries for the treatment of chronic obstructive pulmonary disease (COPD). With the Respimat(®) Soft Mist™ Inhaler there is improved lung deposition of drug (allowing a reduced dosage compared with tiotropium HandiHaler(®)), the delivered drug dose is independent of inspiratory effort and the prolonged duration of the aerosol cloud should make the co-ordination of actuation and inhalation easier. In patients with COPD, tiotropium Respimat(®) improved lung function, COPD exacerbations, health-related quality of life and dyspnoea and was at least as effective as tiotropium HandiHaler(®). Tiotropium Respimat(®) was generally well tolerated in patients with COPD, with anticholinergic adverse events among the most commonly reported adverse events. In the TIOSPIR trial, tiotropium Respimat(®) was noninferior to tiotropium HandiHaler(®) in terms of all-cause mortality, and the risk of cardiovascular mortality or major adverse cardiovascular events did not significantly differ between the two treatment groups. In conclusion, tiotropium Respimat(®) Soft Mist™ Inhaler is a useful option for the treatment of patients with COPD.

Topics: Administration, Inhalation; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium bromide is an anticholinergic agent that has gained worldwide acceptance as a first-line, once daily maintenance therapy for patients with moderate-to-severe chronic obstructive pulmonary disease. The purpose of this review is to synthesize the evidence base in the past 10 years on the development of tiotropium and its efficacy compared to other able interventions such as long-acting beta agonists (LABAs), as well as to assess its safety profile and its effects on health-related outcomes in patients with COPD. Treatment with tiotropium bromide has generally improved patients' health-related quality of life, reduced the number of patients suffering from acute exacerbations, decreased the number of hospitalizations, improved dyspnea, and reduced adverse events compared to placebo. In the past decade, several studies have examined the safety and efficacy of tiotropium in comparison to placebo and to LABAs (salmeterol, formoterol, and indacaterol) over periods ranging from 3 months to 48 months of follow-up. Head-to-head comparisons of tiotropium 18μg (once daily) with salmeterol 50μg (twice daily) in well-controlled trials demonstrated that tiotropium was superior in reducing acute exacerbation events and in improving quality of life. In a few short-term studies, indacaterol was comparable to tiotropium in its efficacy in improving health-related outcomes. Although the safety record of tiotropium has been exemplary in comparison to placebo, anticholinergic events such as dry mouth can be encountered in some patients. While the long-term safety of tiotropium when delivered in the HandiHaler® has been well documented, its delivery using the Respimat® Soft Mist Inhaler™ was associated with an elevated risk of cardiovascular complications, including increased mortality when compared to placebo. The exact mechanism for this is not known but is being investigated in a large multinational study that will evaluate the long-term safety of different doses of tiotropium delivered by the Respimat® soft mist inhaler versus the HandiHaler®. Further studies are required to investigate the efficacy and safety of tiotropium in comparison with novel LABAs such as indacaterol and vilanterol, and with other emerging novel anticholinergic agents such as aclidinium bromide and NVA237 (glycopyrronium bromide).

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Bronchodilator Agents; Dyspnea; Ethanolamines; Formoterol Fumarate; Humans; Indans; Medication Adherence; Mucociliary Clearance; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Although there are some challenges with current therapies, the growing evidence that tiotropium bromide is important in the maintenance treatment of chronic obstructive pulmonary disease (COPD) has led to enthusiastic investigation in search of novel muscarinic antagonists which share some of the beneficial characteristics of tiotropium and perhaps improve upon less desirable ones.. Aclidinium bromide is a new muscarinic antagonist that has been developed to relieve symptoms in patients with COPD. Preclinical data showed that it has an intriguing pharmacodynamic and pharmacokinetic profile. Aclidinium bromide was initially assessed as a once-daily bronchodilator. Subsequently, it has been evaluated as a twice-daily agent to increase the size of the clinical effect. Pivotal Phase III trials have documented that aclidinium bromide 400 μg twice-daily shows clinically meaningful effects in lung function and other important supportive outcomes, such as health-related quality of life, dyspnea and night-time/early morning symptoms, and is safe.. Aclidinium bromide can to be used as an alternative to tiotropium or a long-acting β₂-agonist. It is likely that the device used to deliver aclidinium, Genuair inhaler, a novel, multidose and a breath-actuated dry powder inhaler (DPI), will be important for the possible success of this drug. However, additional Phase III trials to assess advantages over tiotropium bromide and long-acting β₂-agonists are required to allow the place of aclidinium bromide to be fully elucidated.

Topics: Administration, Inhalation; Animals; Bronchodilator Agents; Clinical Trials, Phase III as Topic; Dry Powder Inhalers; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Tropanes

Combination therapy (inhaled corticosteroids and long-acting beta2-agonists) and tiotropium are both used in the treatment of chronic obstructive pulmonary disease (COPD). There is uncertainty about the relative benefits and harms of these treatments.. To compare the relative effects of inhaled combination therapy and tiotropium on markers of exacerbations, symptoms, quality of life, lung function, pneumonia and serious adverse events in patients with chronic obstructive pulmonary disease.. We searched the Cochrane Airways Group Specialised Register of trials (November 2012) and reference lists of articles. We also contacted authors of the studies.. We included only parallel, randomised controlled trials comparing inhaled combination corticosteroid and long-acting beta2-agonist against inhaled tiotropium bromide.. Two authors independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. We resolved discrepancies through discussion.. One large, two-year trial (INSPIRE) and two smaller, shorter trials on a total of 1528 participants were found. The results from these trials were not pooled. The number of withdrawals from each arm of the INSPIRE trial was large and imbalanced and outcome data were not collected for patients who withdrew, raising concerns about the reliability of data from this study.In INSPIRE, there were more deaths on tiotropium than on fluticasone/salmeterol (Peto odds ratio (OR) 0.55; 95% confidence interval (CI) 0.33 to 0.93). This was a statistically significant difference, however the number of withdrawals from each of the arms was 11 times larger than the observed number of deaths for participants on fluticasone/salmeterol and seven times larger for participants on tiotropium. There were more all-cause hospital admissions in patients on fluticasone/salmeterol than those on tiotropium in INSPIRE (Peto OR 1.32; 95% CI 1.04 to 1.67). There was no statistically significant difference in hospital admissions due to exacerbations, the primary outcome of INSPIRE. There was no significant difference in exacerbations in patients on fluticasone/salmeterol compared to tiotropium when compared as either an odds ratio or a rate ratio (mean number of exacerbations per patient per year). Exacerbations requiring treatment with oral corticosteroids were less frequent in patients on fluticasone/salmeterol (rate ratio 0.81; 95% CI 0.67 to 0.99). Conversely exacerbations requiring treatment with antibiotics were more frequent in patients treated with fluticasone/salmeterol (rate ratio 1.19; 95% CI 1.02 to 1.38). There were more cases of pneumonia in patients on fluticasone/salmeterol than in those on tiotropium (Peto OR 2.13; 95% CI 1.33 to 3.40). Confidence intervals for these outcomes do not reflect the additional uncertainty arising from unknown outcome data for patients who withdrew.. Since the proportion of missing outcome data compared to the observed outcome data is enough to induce a clinically relevant bias in the intervention effect, the relative efficacy and safety of combined inhalers and tiotropium remains uncertain. Further large, long-term randomised controlled trials comparing combination therapy to tiotropium are required, including adequate follow-up of all participants randomised (similar to the procedures undertaken in TORCH and UPLIFT). Additional studies comparing alternative inhaled long-acting beta2-agonist/steroid combination therapies with tiotropium are also required.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Humans; Patient Dropouts; Pneumonia; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

The use of anticholinergic medications is well established as maintenance therapy for chronic obstructive pulmonary disease (COPD). There is a growing interest in the use of anticholinergic medications in the treatment of moderate to severe asthma. The purpose of this review is to summarize the scientific evidence for the use of anticholinergic therapy in the management of asthma.. Early case reports and small studies evaluated the use of the anticholinergic agent, tiotropium bromide, as maintenance therapy in asthma. Included in this review are several recent clinical trials which provide additional evidence for the use of tiotropium as add-on therapy for asthma. The use of tiotropium was demonstrated to be superior to doubling the dose of an inhaled corticosteroid (ICS) and more effective than placebo based on change in morning peak expiratory flow (PEF). Two large multinational trials provide evidence for the use of tiotropium in a subset of asthmatic patients who have not achieved control using combination therapy with an ICS and a long-acting β2 agonist (LABA).. The use of the long-acting anticholinergic agent, tiotropium, as maintenance of therapy in asthma, has been shown to be effective in some patients with moderate to severe asthma who are uncontrolled on combination therapy with ICS and LABA. Further studies are needed to better define which phenotypic subset of patients would benefit from the use of tiotropium.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Cholinergic Antagonists; Drug Therapy, Combination; Humans; Multicenter Studies as Topic; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Inhaled bronchodilators are the first-line therapy for COPD. Indacaterol is a novel addition to existing long-acting bronchodilators.. Systematic review of randomized controlled trials (RCT) ON efficacy and safety of indacaterol as compared: 1) with placebo at different dosages, 2) with existing bronchodilators; (3) as add-on treatment to tiotropium.. We searched 13 electronic databases, including MEDLINE, EMBASE and CENTRAL, and contacted the manufacturer for unpublished data. Primary outcome was mean FEV1 change at 12(th) week, secondary outcomes included changes in SGRQ, TDI and BODE index at 6 months, exacerbation at 1 year, and worsening of symptoms.. Twelve eligible RCTs of moderate risk of bias included data from 10,977 patients. Compared to placebo, indacaterol improved FEV1 by a weighted mean difference (WMD) of 0.16 L (95%CI: 0.15, 0.18 L, p<0.001), homogeneously above the minimally important difference of 0.10 L. It offered clinically relevant improvement in all secondary outcomes except exacerbation. Magnitude of benefit did not differ significantly by dosage, but one treatment related death was reported at 300 ug. Efficacy of Indacaterol was similar to formoterol and salmeterol (FEV1 WMD = 0.04 L, 95%CI: 0.01 L, 0.07 L, p = 0.02); and tiotropium (FEV1 WMD = 0.01 L, 95%CI: -0.01, 0.03 L, p = 0.61). The use of indacaterol on top of tiotropium yielded additional improvement on FEV1 (WMD = 0.07 L, 95%CI: 0.05 L, 0.10 L, p<0.001).. Indacaterol is safe and beneficial for patients with COPD at dosage ≤150 ug. It may serve as a good alternative to existing bronchodilators, or as an add-on to tiotropium for unresponsive patients. Use of higher dosage requires further justification.

Topics: Bronchodilator Agents; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Exacerbations are a defining outcome of chronic obstructive pulmonary disease (COPD). We evaluated the effect of tiotropium on COPD exacerbations and related hospitalizations among patients from the USA enrolled in clinical trials.. Data were pooled from six randomized, double-blind, placebo-controlled trials (6 to ≥ 12 months' duration) of tiotropium in patients with COPD. Exacerbations were defined retrospectively as an increase in or new onset of >1 respiratory symptom lasting for ≥ 3 days and requiring treatment with systemic corticosteroids and/or antibiotics. Time to first exacerbation or hospitalization and exacerbation rates were analyzed at 6 months, and at 1 year for studies ≥ 1 year.. In total, 4355 patients (tiotropium, 2268, placebo, 2087; mean age 66.5 years; forced expiratory volume in 1 s [FEV1] 1.03 L [35.5% predicted]) were analyzed at 6 months and 2455 at 1 year (tiotropium 1317, placebo 1138; mean age 65.5 years; FEV1 1.03 L [37.0% predicted]). Tiotropium delayed time to first exacerbation or first hospitalized exacerbation at 6 months (hazard ratios [HRs], 0.80, 0.65, respectively; p < 0.001 vs placebo) and 1 year (HRs, 0.73 and 0.55; p < 0.001 vs placebo) and reduced exacerbation rates and hospitalization rates (6 months: HRs, 0.79, 0.64; 1 year: HRs, 0.78, 0.56, respectively; all p < 0.01 vs placebo). Tiotropium significantly reduced exacerbations, irrespective of inhaled corticosteroid use at baseline. Tiotropium was not associated with an increased risk of cardiac-related events.. Tiotropium significantly reduced the risk and rates of exacerbations and hospitalizations among US patients with COPD.

Topics: Acute Disease; Adult; Aged; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Heart Diseases; Hospitalization; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

Tiotropium and ipratropium bromide are both recognised treatments in the management of people with stable chronic obstructive pulmonary disease (COPD). There are new studies which have compared tiotropium with ipratropium bromide, making an update necessary.. To compare the relative effects of tiotropium to ipratropium bromide on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in patients with COPD using available randomised controlled trial (RCT) data.. We identified RCTs from the Cochrane Airways Group Specialised Register of trials (CAGR) and ClinicalTrials.gov up to November 2012.. We included parallel group RCTs of 12 weeks duration or longer comparing treatment with tiotropium with ipratropium bromide for patients with stable COPD.. Two review authors independently assessed studies for inclusion and then extracted data on study quality and outcome results. We contacted trial sponsors for additional information. We analysed the data using Cochrane Review Manager (RevMan 5.2).. This review included two studies of good methodological quality that enrolled 1073 participants with COPD. The studies used a similar design and inclusion criteria and were of at least 12 weeks duration; the participants had a mean forced expiratory volume in one second (FEV1) of 40% predicted value at baseline. One study used tiotropium via the HandiHaler (18 µg) for 12 months and the other via the Respimat device (5 µg and 10 µg) for 12 weeks. In general, the treatment groups were well matched at baseline but not all outcomes were reported for both studies. Overall the risk of bias across the included RCTs was low.For primary outcomes this review found that at the three months trough (the lowest level measured before treatment) FEV1 significantly increased with tiotropium compared to ipratropium bromide (mean difference (MD) 109 mL; 95% confidence interval (CI) 81 to 137, moderate quality evidence, I(2) = 62%). There were fewer people experiencing one or more non-fatal serious adverse events on tiotropium compared to ipratropium (odds ratio (OR) 0.5; 95% CI 0.34 to 0.73, high quality evidence). This represents an absolute reduction in risk from 176 to 97 per 1000 people over three to 12 months. Concerning disease specific adverse events, the tiotropium group were also less likely to experience a COPD-related serious adverse event when compared to ipratropium bromide (OR 0.59; 95% CI 0.41 to 0.85, moderate quality evidence).For secondary outcomes, both studies reported fewer hospital admissions in the tiotropium group (OR 0.34; 95% CI 0.15 to 0.70, moderate quality evidence); as well as fewer patients experiencing one or more exacerbations leading to hospitalisation in the people on tiotropium in both studies (OR 0.56; 95% CI 0.31 to 0.99, moderate quality evidence). There was no significant difference in mortality between the treatments (OR 1.39; 95% CI 0.44 to 4.39, moderate quality evidence). One study measured quality of life using the St George's Respiratory Questionnaire (SGRQ); the mean SGRQ score at 52 weeks was lower in the tiotropium group than the ipratropium group (lower on the scale is favourable) (MD -3.30; 95% CI -5.63 to -0.97, moderate quality evidence). There were fewer participants suffering one of more exacerbations in the tiotropium arm (OR 0.71; 95% CI 0.52 to 0.95, high quality evidence) and there was also a reported difference in the mean number of exacerbations per person per year which reached statistical significance (MD -0.23;. This review shows that tiotropium treatment, when compared with ipratropium bromide, was associated with improved lung function, fewer hospital admissions (including those for exacerbations of COPD), fewer exacerbations of COPD and improved quality of life. There were both fewer serious adverse events and disease specific events in the tiotropium group, but no significant difference in deaths with ipratropium bromide when compared to tiotropium. Thus, tiotropium appears to be a reasonable choice (instead of ipratropium bromide) for patients with stable COPD, as proposed in guidelines. We would advise some caution with tiotropium via the Respimat inhaler and suggest waiting for further information from an ongoing head-to-head trial comparing mortality in relation to tiotropium delivery devices and doses.

Topics: Bronchodilator Agents; Forced Expiratory Volume; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Aclidinium bromide is a new long-acting muscarinic antagonist (LAMA) indicated for maintenance bronchodilator treatment of chronic obstructive pulmonary disease (COPD). The efficacy of aclidinium was compared with tiotropium and glycopyrronium, using a network meta-analysis (NMA) of randomized controlled trials (RCTs) in moderate-to-severe COPD patients.. A systematic review was performed to identify RCTs evaluating aclidinium 400 μg twice daily (BID), glycopyrronium 50 μg once daily (OD), tiotropium 18 μg OD, or tiotropium 5 μg OD in adults with moderate-to-severe COPD. The outcomes of interest were: trough forced expiratory volume in 1 second (FEV1); St George's Respiratory Questionnaire (SGRQ) total score and proportion of patients achieving ≥4 unit change; Transition Dyspnea Index (TDI) focal score and proportion of patients achieving ≥1 point change. The results were synthesized by means of a Bayesian NMA.. Twenty-one studies (22,542 patients) were included: aclidinium 400 μg BID (three studies); tiotropium 5 μg OD (three studies); tiotropium 18 μg OD (13 studies); and glycopyrronium 50 μg OD (two studies). Regarding trough FEV1 at 24 weeks, aclidinium demonstrated comparable efficacy to tiotropium 5 μg (difference in change from baseline [CFB]), (0.02 L [95% credible interval CrI -0.05, 0.09]); tiotropium 18 μg (0.02 L [95% CrI -0.05, 0.08]); and glycopyrronium (0.00 L [95% CrI -0.07, 0.07]). Aclidinium resulted in higher improvement in SGRQ score at 24 weeks, compared to tiotropium 5 μg (difference in CFB, -2.44 [95% CrI -4.82, -0.05]); and comparable results to tiotropium 18 μg (-1.80 [95% CrI -4.52, 0.14]) and glycopyrronium (-1.52 [95% CrI -4.08, 1.03]). Improvements in TDI score were comparable for all treatments.. Maintenance treatment with aclidinium 400 μg BID is expected to produce similar improvements in lung function, health-related quality of life, and dyspnea compared to tiotropium 5 μg OD; tiotropium 18 μg OD; and glycopyrronium 50 μg OD.

Topics: Bayes Theorem; Bronchodilator Agents; Forced Expiratory Volume; Glycopyrrolate; Humans; Lung; Muscarinic Antagonists; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Tropanes

Clinicians are faced with an increasingly difficult choice regarding the optimal bronchodilator for patients with chronic obstructive pulmonary disease (COPD) given the number of new treatments. The objective of this study is to evaluate the comparative efficacy of indacaterol 75/150/300 μg once daily (OD), glycopyrronium bromide 50 μg OD, tiotropium bromide 18 μg/5 μg OD, salmeterol 50 μg twice daily (BID), formoterol 12 μg BID, and placebo for moderate to severe COPD.. Forty randomized controlled trials were combined in a Bayesian network meta-analysis. Outcomes of interest were trough and post-dose forced expiratory volume in 1 second (FEV1), St. George's Respiratory Questionnaire (SGRQ) score and responders (≥4 points), and Transition Dyspnea Index (TDI) score and responders (≥1 point) at 6 months.. Indacaterol was associated with a higher trough FEV1 than other active treatments (difference for indacaterol 150 μg and 300 μg versus placebo: 152 mL (95% credible interval (CrI): 126, 179); 160 mL (95% CrI: 133, 187)) and the greatest improvement in SGRQ score (difference for indacaterol 150 μg and 300 μg versus placebo: -3.9 (95% CrI -5.2, -2.6); -3.6 (95% CrI -4.8, -2.3)). Glycopyrronium and tiotropium 18 μg resulted in the next best estimates for both outcomes with minor differences (difference for glycopyrronium versus tiotropium for trough FEV1 and SGRQ: 18 mL (95% CrI: -16, 51); -0.55 (95% CrI: -2.04, 0.92).. In terms of trough FEV1 and SGRQ score indacaterol, glycopyrronium, and tiotropium are expected to be the most effective bronchodilators.

Topics: Albuterol; Bayes Theorem; Bronchodilator Agents; Delayed-Action Preparations; Dose-Response Relationship, Drug; Ethanolamines; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

Olodaterol (Striverdi(®) Respimat(®)) is a novel, long-acting, β2-adrenergic receptor agonist developed by Boehringer Ingelheim for the treatment of chronic obstructive pulmonary disease (COPD). The drug is delivered via the Respimat(®) Soft Mist™ inhaler. Olodaterol received its first global approval for the once-daily maintenance treatment of COPD in Canada and Russia, and submissions for regulatory approval have also been made in the USA, the EU and elsewhere. Phase II trials have been conducted in patients with asthma. The company is also developing a fixed-dose combination of olodaterol with tiotropium bromide, a long-acting anti-muscarinic agent, for the treatment of COPD. This article summarizes the milestones in the development of olodaterol leading to this first approval for COPD.

Topics: Administration, Inhalation; Asthma; Benzoxazines; Bronchodilator Agents; Clinical Trials, Phase II as Topic; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease is a significant syndrome of internal medicine with serious health, social and economic impacts. Globally, tiotropium is the longest used and through the randomised studies the most examined representative of inhalation long-acting antimuscarinics. In routine practice, this treatment group is identified with a globally known abbreviation LAMA (or U-LAMA, U means ultralong-acting with dosing every 24 hours). Pharmacological agents of the LAMA (U-LAMA) group are included in a significant number of all important treatment guidelines. The Czech guidelines place these medicines into the first line of general medication - for all symptomatic patients, regardless of the stage, age and comorbidities. The article describes the role of LAMA (namely tiotropium) in the treatment of chronic obstructive pulmonary disease and also relevant evidence of the efficacy and safety of both tiotropium dosage forms (HandHaler and Respimat) in detail.

Topics: Administration, Inhalation; Bronchodilator Agents; Delayed-Action Preparations; Drug Therapy, Combination; Female; Humans; Muscarinic Antagonists; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

The majority of deaths in COPD are from cardiovascular causes. Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events, including cardiovascular mortality. Tiotropium Respimat is associated with a statistically significant increased risk of mortality (RR 1.52; 95% CI 1.06 to 2.16) and cardiovascular death (RR 2.05; 95% CI 1.06 to 3.99) compared with placebo in a meta-analysis of clinical trials. In the largest study, the subgroup of patients with COPD in the Respimat group with known rhythm and cardiac disorders at baseline had an especially high risk for cardiac death (RR 8.6; 95% CI 1.1 to 67.2). Although there was no significantly increased risk of mortality (HR 0.89; 95% CI 0.79 to 1.02) or myocardial infarction (MI) (RR 0.73; 95% CI 0.53 to 1.00) with tiotropium handihaler in the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, the reported excess of angina (RR 1.44; 95% CI 0.91 to 2.26), imbalance in strokes related to ischaemia and rates of supraventricular tachyarrhythmias are consistent with the pro-ischemic and pro-arrhythmic effects. The subjects at greatest risk of cardiovascular death, such as those with a recent history of MI, unstable or life-threatening cardiac arrhythmias or hospitalisation with heart failure, were excluded from the UPLIFT trial. The Prevention of Exacerbations with Tiotropium in COPD trial showed an excess of serious coronary ischaemic events of angina, myocardial ischaemia and MI with the tiotropium Handihaler compared with salmeterol. The authors urge caution in prescribing inhaled anticholinergics for patients with pre-existing arrhythmias or cardiac disorders.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Arrhythmias, Cardiac; Cause of Death; Cholinergic Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Ipratropium; Male; Middle Aged; Myocardial Ischemia; Prognosis; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Safety Management; Scopolamine Derivatives; Survival Analysis; Tiotropium Bromide; Treatment Outcome

The active-treatment comparative safety information for all inhaled medications in patients with chronic obstructive pulmonary disease (COPD) is limited. We aimed to compare the risk of overall and cardiovascular death for inhaled medications in patients with COPD.. Through systematic database searching, we identified randomised controlled trials of tiotropium Soft Mist Inhaler, tiotropium HandiHaler, long-acting β2 agonists (LABAs), inhaled corticosteroids (ICS), and LABA-ICS combination with at least a 6-month treatment duration. Direct comparison and mixed treatment comparison (MTC) meta-analyses were conducted to estimate the pooled ORs of death for each comparison.. 42 trials with 52 516 subjects were included. The MTC meta-analysis with the fixed effect model indicated tiotropium Soft Mist Inhaler was associated with an universally increased risk of overall death compared with placebo (OR 1.51; 95% CI 1.06 to 2.19), tiotropium HandiHaler (OR 1.65; 95% CI 1.13 to 2.43), LABA (OR 1.63; 95% CI 1.10 to 2.44) and LABA-ICS (OR 1.90; 95% CI 1.28 to 2.86). The risk was more evident for cardiovascular death, in patients with severe COPD, and at a higher daily dose. LABA-ICS was associated with the lowest risk of death among all treatments. No excess risk was noted for tiotropium HandiHaler or LABA. The results were similar for MTC and direct comparison meta-analyses, with less precision in the random effects model.. Our study provided a comparative safety spectrum for each category of inhaled medications. Tiotropium Soft Mist Inhaler had a higher risk of mortality and should be used with caution.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Albuterol; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Humans; Male; Prognosis; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Risk Assessment; Scopolamine Derivatives; Severity of Illness Index; Survival Rate; Tiotropium Bromide; Treatment Outcome

Indacaterol is a once-daily, long-acting β(2)-agonist bronchodilator that improves dyspnoea and health status in patients with moderate-to-severe COPD. While its bronchodilator effects have been shown to be maintained in different patient subgroups, effects on clinical outcomes in certain subgroups are not yet defined.. Post-hoc analysis of pooled clinical study data to investigate efficacy and safety of indacaterol compared with placebo and other long-acting bronchodilators (formoterol, salmeterol, open-label tiotropium) in patient subgroups defined by COPD severity (GOLD stage II or III; n = 4082) and ICS use at baseline (no/yes; n = 4088). Efficacy outcomes were trough (24-h post-dose) FEV(1), dyspnoea (transition dyspnoea index; TDI) and health status (St George's Respiratory Questionnaire; SGRQ) after 26 weeks.. All active treatments significantly improved trough FEV(1) and dyspnoea compared with placebo, and all apart from open-label tiotropium improved health status compared with placebo. Among active treatments, indacaterol 150 μg had the best overall efficacy profile in the GOLD II and no-ICS subgroups. In the GOLD III and ICS subgroups, indacaterol 300 μg had the best overall efficacy, including a marked effect on dyspnoea (1.4-point improvement in TDI total score vs. placebo; p < 0.001). Within subgroups, the incidence of adverse events was similar between treatments.. Indacaterol maintained its efficacy regardless of disease severity or use of concurrent ICS. Indacaterol 150 μg had the best overall efficacy profile in the GOLD stage II patients while, in patients with more severe disease, indacaterol 300 μg provided useful improvements in dyspnoea.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Albuterol; Bronchodilator Agents; Drug Administration Schedule; Drug Therapy, Combination; Dyspnea; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Guidelines recommend the use of inhaled long-acting bronchodilators, inhaled corticosteroids (ICS) and their combinations for maintenance treatment of moderate to severe COPD. However, there are limited data supporting combination therapy.. This systematic review assessed the efficacy of three therapeutic approaches: tiotropium plus long-acting beta2-agonist (LABA) ("dual" therapy), LABA/ICS ("combined" therapy), and tiotropium plus LABA/ICS ("triple" therapy), all compared with tiotropium monotherapy. Randomized controlled trials were identified after a search of different databases of published and unpublished trials.. Twenty trials (6803 participants) were included. "Dual" therapy showed significant improvements in forced volume in the first second (FEV(1)), health-related quality of life (HRQoL), and dyspnea. However, it failed to reduce the risk of COPD exacerbations. Compared with tiotropium, "combined" therapy presented modest but significant effects on FEV(1), HRQoL, and dyspnea. Again, there was no significant difference in exacerbations, but it was associated with a significant increase of serious adverse effects (SAE) (number need to treat for harm [NNTH] = 20; 95% CI: 11-119). Finally, "triple therapy" increased FEV(1), improved HRQoL (both benefits exceeded minimal important differences) and decrease COPD exacerbations in anon-significant way. (Odds ratio [OR] = 0.57; 95% CI: 0.24 to 1.37, p = 0.21).. "Dual" and "triple" therapy seem like the most promising for patients with moderate to very severe COPD. However, data are still scarce and studies too short to generate a strong recommendation. Future studies should examine long-term efficacy and safety.

Topics: Aged; Bronchodilator Agents; Data Collection; Data Interpretation, Statistical; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Research Design; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The anticholinergic agent tiotropium bromide (Spiriva®) is a long-acting bronchodilator that is indicated for the treatment of chronic obstructive pulmonary disease (COPD). This article reviews the clinical efficacy and tolerability of tiotropium bromide inhalation powder, administered using the HandiHaler® device, in patients with COPD, as well as reviewing its pharmacological properties and the results of pharmacoeconomic analyses. Shorter-term placebo-controlled trials in patients with COPD demonstrated significantly higher trough forced expiratory volume in 1 second (FEV(1)) responses with tiotropium bromide than with placebo, confirming it has a duration of action of ≥24 hours and is suitable for once-daily administration. Lung function improved to a greater extent with tiotropium bromide than with ipratropium bromide or, in most instances, salmeterol. Indacaterol was shown to be noninferior to tiotropium bromide in terms of the trough FEV(1) response. The large, 4-year UPLIFT® trial did not show a significant reduction in the annual rate of decline in FEV(1) with tiotropium bromide versus placebo in patients with COPD, although subgroup analyses demonstrated a significantly lower rate of decline with tiotropium bromide than with placebo in some patient groups (e.g. patients with moderate COPD, patients aged ≥50 years, patients not receiving maintenance therapy at baseline). Tiotropium bromide prevented exacerbations in patients with COPD, with a significantly lower exacerbation rate and a significantly longer time to first exacerbation seen with tiotropium bromide than with placebo or salmeterol. Exacerbation rates did not significantly differ between patients receiving tiotropium bromide and those receiving salmeterol/fluticasone propionate. Tiotropium bromide also had beneficial effects on health-related quality of life (HR-QOL) and other endpoints, such as dyspnoea and rescue medication use. Combination therapy with tiotropium bromide plus formoterol with or without budesonide improved lung function to a significantly greater extent than tiotropium bromide alone in patients with COPD. In addition, exacerbation rates were lower and HR-QOL was improved with tiotropium bromide plus budesonide/formoterol versus tiotropium bromide alone. Although the addition of salmeterol/fluticasone propionate to tiotropium bromide did not reduce the COPD exacerbation rate, it did improve lung function and HR-QOL. Tiotropium bromide inhalation powder is generally we

Topics: Administration, Inhalation; Bronchodilator Agents; Cost-Benefit Analysis; Humans; Powders; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

Bronchodilators are central to the symptomatic management of patients with COPD.Previous data have shown that inhaled indacaterol improved numerous clinical outcomes over placebo.. This systematic review explored the efficacy and safety of indacaterol in comparison with tiotropium or bid long-acting β 2 -agonists (TD-LABAs) for treatment of moderate to severe COPD. Randomized controlled trials were identified after a search of different databases of published and unpublished trials.. Five trials (5,920 participants) were included. Compared with tiotropium, indacaterol showed statistically and clinically significant reductions in the use of rescue medication and dyspnea(43% greater likelihood of achieving a minimal clinically important difference [MCID] in the transitional dyspnea index [TDI]; number needed to treat for benefit [NNTB] 5 10). Additionally,the MCID in health status was more likely to be achieved with indacaterol than with tiotropium (OR = 1.43; 95% CI, 1.22–1.68; P = .00001; [NNTB ]= 10). Trough FEV 1 was significantly higher at the end of treatment with indacaterol than with TD-LABAs (80 mL, P = .00001). Similarly, indacaterol signifi cantly improved dyspnea (61% greater likelihood of achieving an MCID in TDI, P = .008) and health status (21% greater likelihood of achieving an MCID in St. George’s Respiratory Questionnaire, P 5 .04) than TD-LABA. Indacaterol showed similar levels of safety and tolerability to both comparators.. Available evidence suggests that indacaterol may prove useful as an alternative to tiotropium or TD-LABA due to its effects on health status, dyspnea, and pulmonary function.

Topics: Adrenergic beta-Agonists; Bronchodilator Agents; Evidence-Based Medicine; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

Long-acting bronchodilators comprising long-acting beta(2)-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta(2)-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear.. To assess the relative effects of treatment with tiotropium in addition to long-acting beta(2)-agonist compared to tiotropium or long-acting beta(2)-agonist alone in patients with chronic obstructive pulmonary disease.. We searched the Cochrane Airways Group Specialised Register of trials and clinicaltrials.gov up to January 2012.. We included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta(2)-agonist against tiotropium or long-acting beta(2)-agonist alone for patients with chronic obstructive pulmonary disease.. Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.. Five trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta(2)-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta(2)-agonist (formoterol) alone. Two studies used the long-acting beta(2)-agonist indacaterol, two used formoterol and one used salmeterol.Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long-acting beta(2)-agonist resulted in a slightly larger improvement in the mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) MD -1.61; 95% CI -2.93 to -0.29). In the control arm, tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with both treatments the improvement was a fall of 6.1 units from baseline (on average). High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator FEV(1) showed a small mean increase with the addition of long-acting beta(2)-agonist (MD 0.07 L; 95% CI 0.05 to 0.09) over the control arm, which showed a change from baseline ranging from 0.03 L to 0.13 L on tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There were wide confidence intervals around these outcomes and moderate heterogeneity for both exacerbations and withdrawals.The results from the one trial comparing the combination of tiotropium and long-acting beta(2)-agonist to long-acting beta(2)-agonist alone (417 participants) were insufficient to draw firm conclusions for this comparison.. The results from this review indicate a small mean improvement in health-related quality of life for patients on a combination of tiotropium and long-acting beta(2)-agonist compared to tiotropium alone, but it is not clear how clinically important this mean difference may be. Hospital admission and mortality have not been shown to be altered by adding long-acting beta(2)-agonists to tiotropium. There were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta(2)-agonist compared to long-acting beta(2)-agonist alone. There were insufficient data to make comparisons between the different long-acting beta(2)-agonists when used in addition to tiotropium.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Bronchodilator Agents; Ethanolamines; Formoterol Fumarate; Humans; Indans; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Bronchodilators - long-acting b2-adrenergic agonists (formoterol and salmeterol) and a long-acting antimuscarinic drug (tiotropium), are the main drugs applied in symptomatic treatment of COPD. In patients with COPD, dyspnea is frequently associated with simple everyday activities. Two questionnaires have been published recently as a means of assessing the patients' ability to perform morning activities and symptoms. Dynamic hyperinflation is the pathophysiological disorder responsible for dyspnea and decreased exercise tolerance in COPD. Formoterol is faster than salmeterol in diminishing air-trapping. It has been shown that treatment with formoterol and tiotropium in COPD patients improves FEV(1), FVC, IC, symptoms score and quality of life in comparison with tiotropium applied alone. Among LABA and inhaled glucocorticosteroids combinations, those containing formoterol have a more beneficial effect on the ability to perform simple morning activities (budesonide/formoterol was better than fluticasone/salmeterol). Beclomethasone/formoterol - 400/24 mcg/die, in comparison with fluticasone/salmeterol - 500/100 mcg/die significantly reduced air-trapping and dyspnea in COPD patients. The comparison of budesonide/formoterol - 400/12 mcg 2 x die with beclomethasone/ /formoterol - 200/12 mcg 2 x die has shown similar influence of both combinations on FEV(1), dyspnea, 6-minute walk test, symptoms score and quality of life. The addition of budesonide and formoterol combination to tiotropium gives further benefits: reduces number of exacerbations, improves FEV1, symptoms score and performance of simple morning routines. Doctors should pay more attention to symptoms and limitations in simple activities in the morning and adequately adjust the treatment.

Topics: Activities of Daily Living; Administration, Inhalation; Bronchodilator Agents; Drug Combinations; Ethanolamines; Exercise Tolerance; Formoterol Fumarate; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Randomised, double-blind, controlled trials are considered the gold standard for evaluating a pharmacological agent, as they minimise any potential bias. However, it is not always possible to perform double-blind trials, particularly for medications delivered via specific devices, e.g. inhalers. In such cases, open-label studies can be employed instead. Methods used to minimise any potential bias introduced by open-label study design include randomisation, crossover study design, and objective measurements of primary efficacy and safety variables. Concise reviews analysing the effect of blinding procedures of comparator drugs on outcomes in respiratory trials are limited. Here, we compare data from different chronic obstructive pulmonary disease trials with once-daily indacaterol versus a blinded or non-blinded comparator. The clinical trial programme for indacaterol, a once-daily, long-acting β2-agonist, used tiotropium as a comparator either in an open-label or blinded fashion. Data from these studies showed that the effects of tiotropium were consistent for forced expiratory volume in 1 second, an objective measure, across blinded and non-blinded studies. The data were consistent with previous studies of double-blind tiotropium, suggesting that the open-label use of tiotropium did not introduce treatment bias. The effect of tiotropium on subjective measures (St George's Respiratory Questionnaire; transition dyspnoea index) varied slightly across blinded and non-blinded studies, indicating that minimal bias was introduced by using open-label tiotropium. Importantly, the studies used randomised, open-label tiotropium patients to treatment allocation, a method shown to minimise bias to a greater degree than blinding. In conclusion, it is important when reporting a clinical trial to be transparent about who was blinded and how the blinding was performed; if the design is open-label, additional efforts must be made to minimise risk of bias. If these recommendations are followed, and the data are considered in the full knowledge of any potential sources of bias, results with tiotropium suggest that data from open-label studies can provide valuable and credible evidence of the effects of therapy.

Topics: Bias; Bronchodilator Agents; Evidence-Based Medicine; Humans; Outcome Assessment, Health Care; Prevalence; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Research Design; Scopolamine Derivatives; Single-Blind Method; Tiotropium Bromide; Treatment Outcome

The objective of this study was to evaluate the comparative efficacy of indacaterol 75 μg once daily (OD), tiotropium 18 μg OD, salmeterol 50 μg twice daily (BID), formoterol 12 μg BID, and placebo for the treatment of chronic obstructive pulmonary disease (COPD) based on individual patient data (IPD) from randomized controlled trials (RCTs) from the indacaterol trial program and aggregate data (AD) identified from a systematic review of RCTs.. 22 RCTs were included in the AD analysis that evaluated: indacaterol 75 μg (n = 2 studies), indacaterol 150 μg n = 5 (i.e. salmeterol 50 μg) (n = 5), indacaterol 300 μg (n = 2), tiotropium 18 μg (n = 10), salmeterol 50 μg (n = 7), and formoterol 12 μg (n = 4). All of the studies except for one head-to-head comparison (tiotropium vs. salmeterol) were placebo controlled. Outcomes of interest were trough forced expiratory volume in 1 second (FEV1) and St. George's Respiratory Questionnaire (SGRQ) total score at week 12. The AD from all trials was analysed simultaneously using a Bayesian network meta-analysis (NMA) and relative treatment effects between all regimens were obtained. In a separate analysis, the IPD available from the 6 indacaterol RCTs was analysed in a NMA. Treatment-by-covariate interactions were included in both analyses to improve similarity of the trials.. All interventions compared were more efficacious than placebo regarding FEV1 at 12 weeks. Indacaterol 75 μg is expected to result in a comparable FEV1 at 12 weeks to tiotropium and salmeterol based on both IPD and AD analyses. In comparison to formoterol, the IPD and AD results indicate indacaterol 75 μg is more efficacious (IPD = 0.07 L difference; 95%Credible Interval (CrI) 0.02 to 0.11; AD = 0.05 L difference; 95%CrI 0.01; 0.09). In terms of SGRQ total score at 12 weeks, indacaterol 75 μg and formoterol were more efficacious than placebo, whereas for tiotropium and salmeterol the credible intervals included zero for the AD results only (tiotropium: -2.99 points improvement versus placebo; 95%CrI -6.48 to 0.43; salmeterol:-2.52; 95%CrI: -5.34; 0.44). Both IPD and AD results suggest that indacaterol 75 μg is expected to be comparable to all active treatments.. Based on a synthesis of currently available AD RCT evidence as well as an IPD network meta-analysis of six RCTs, indacaterol 75 μg is expected to be at least as efficacious as formoterol and comparable to tiotropium and salmeterol regarding FEV1. Furthermore, indacaterol 75 μg shows comparable level of improvement in health-related quality of life to tiotropium, salmeterol, and formoterol, as measured by the SGRQ.

Topics: Adrenergic beta-2 Receptor Antagonists; Adult; Aged; Aged, 80 and over; Albuterol; Bronchodilator Agents; Dose-Response Relationship, Drug; Ethanolamines; Female; Formoterol Fumarate; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Tiotropium is an anticholinergic agent which has gained widespread acceptance as a once daily maintenance therapy for symptoms and exacerbations of stable chronic obstructive pulmonary disease (COPD). In the past few years there have been several systematic reviews of the efficacy of tiotropium, however, several new trials have compared tiotropium treatment with placebo, including those of a soft mist inhaler, making an update necessary.. To evaluate data from randomised controlled trials (RCTs) comparing the efficacy of tiotropium and placebo in patients with COPD, upon clinically important endpoints.. We searched the Cochrane Airways Group's Specialised Register of Trials (CAGR) and ClinicalTrials.gov up to February 2012.. We included parallel group RCTs of three months or longer comparing treatment with tiotropium against placebo for patients with COPD.. Two review authors independently assessed studies for inclusion and then extracted data on study quality and the outcome results. We contacted study authors and trial sponsors for additional information, and collected information on adverse effects from all trials. We analysed the data using Cochrane Review Manager 5, RevMan 5.1.. This review included 22 studies of good methodological quality that had enrolled 23,309 participants with COPD. The studies used similar designs, however, the duration varied from three months to four years. In 19 of the studies, 18 μg tiotropium once daily via the Handihaler dry powder inhaler was evaluated, and in three studies, 5 or 10 μg tiotropium once daily via the Respimat soft mist inhaler was evaluated. Compared to placebo, tiotropium treatment significantly improved the mean quality of life (mean difference (MD) -2.89; 95% confidence interval (CI) -3.35 to -2.44), increased the number of participants with a clinically significant improvement (odds ratio (OR) 1.52; 95% CI 1.38 to 1.68), and reduced the number of participants with a clinically significant deterioration (OR 0.65; 95% CI 0.59 to 0.72) in quality of life (measured by the St George's Respiratory Questionnaire (SGRQ)). Tiotropium treatment significantly reduced the number of participants suffering from exacerbations (OR 0.78; 95% CI 0.70 to 0.87). This corresponds to a need to treat 16 patients (95% CI 10 to 36) with tiotropium for a year in order to avoid one additional patient suffering exacerbations, based on the average placebo event rate of 44% from one-year studies. Tiotropium treatment led to fewer hospitalisations due to exacerbations (OR 0.85; 95% CI 0.72 to 1.00), but there was no statistically significant difference in all-cause hospitalisations (OR 1.00; 95% CI 0.88 to 1.13) or non-fatal serious adverse events (OR 1.03; 95% CI 0.97 to 1.10). Additionally, there was no statistically significant difference in all-cause mortality between the tiotropium and placebo groups (Peto OR 0.98; 95% CI 0.86 to 1.11). However, subgroup analysis found a significant difference between the studies using a dry powder inhaler and those with a soft mist inhaler (test for subgroup differences: P = 0.01). With the dry powder inhaler there were fewer deaths in the tiotropium group (Peto OR 0.92; 95% CI 0.80 to 1.05) than in the placebo group (yearly rate 2.8%), but with the soft mist inhaler there were significantly more deaths in the tiotropium group (Peto OR 1.47; 95% CI 1.04 to 2.08) than in the placebo group (yearly rate 1.8%). It is noted that the rates of patients discontinuing study treatment were uneven, with significantly fewer participants withdrawing from tiotropium treatment than from placebo treatment (OR 0.66; 95% CI 0.59 to 0.73). Participants on tiotropium had improved lung functi. This review shows that tiotropium treatment was associated with a significant improvement in patients' quality of life and it reduced the risk of exacerbations, with a number needed to treat to benefit (NNTB) of 16 to prevent one exacerbation. Tiotropium also reduced exacerbations leading to hospitalisation but no significant difference was found for hospitalisation of any cause or mortality. Thus, tiotropium appears to be a reasonable choice for the management of patients with stable COPD, as proposed in guidelines. The review however, shows that tiotropium delivered via the Respimat soft mist inhaler was associated with a significantly increased risk of mortality compared with placebo, which calls for caution with this device whilst awaiting the results of an ongoing head-to-head trial comparing tiotropium delivery devices and doses.

Topics: Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Dry Powder Inhalers; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium and long-acting beta(2)-agonists (LABAs) are both accepted in the routine management for people with stable chronic obstructive pulmonary disease (COPD). There are new studies which have compared tiotropium with LABAs, including some that have evaluated recently introduced LABAs.. To compare the relative clinical effects of tiotropium bromide alone versus LABA alone, upon measures of quality of life, exacerbations, lung function and serious adverse events, in people with stable COPD.To critically appraise and summarise current evidence on the costs and cost-effectiveness associated with tiotropium compared to LABA in people with COPD.. We identified randomised controlled trials (RCTs) from the Cochrane Airways Group Specialised Register of trials and economic evaluations from searching NHS EED and HEED (date of last search February 2012). We found additional trials from web-based clinical trial registers.. We included RCTs and full economic evaluations if they compared effects of tiotropium alone with LABAs alone in people with COPD. We allowed co-administration of standard COPD therapy.. Two review authors independently assessed studies for inclusion, then extracted data on study quality and outcomes. We contacted study authors and trial sponsors for additional information. We analysed data using the Cochrane Review Manager(RevMan 5.1) software.. Seven clinical studies totalling 12,223 participants with COPD were included in the review. The studies used similar designs and were generally of good methodological quality. Inclusion criteria for RCTs were similar across the included studies, although studies varied in terms of smoking history and COPD severity of participants. They compared tiotropium (which was delivered by HandiHaler in all studies) with salmeterol (four studies, 8936 participants), formoterol (one study, 431 participants) and indacaterol (two studies, 2856 participants). All participants were instructed to discontinue anticholinergic or long-acting beta(2)-agonist bronchodilators during treatment, but could receive inhaled corticosteroids (ICS) at a stable dose. Study duration ranged from 3 to 12 months. We extracted data for 11,223 participants. In general, the treatment groups were well matched at baseline. Overall, the risk of bias across the included RCTs was low.In the analysis of the primary outcomes in this review, a high level of heterogeneity amongst studies meant that we did not pool data for St George's Respiratory Questionnaire quality of life score. Subgroup analyses based on the type of LABA found statistically significant differences among effects on quality of life depending on whether tiotropium was compared with salmeterol, formoterol or indacaterol. Tiotropium reduced the number of participants experiencing one or more exacerbations compared with LABA (odds ratio (OR) 0.86; 95% confidence interval (CI) 0.79 to 0.93). For this outcome, there was no difference seen among the different types of LABA. There was no statistical difference in mortality observed between the treatment groups.For secondary outcomes, tiotropium was associated with a reduction in the number of COPD exacerbations leading to hospitalisation compared with LABA treatment (OR 0.87; 95% 0.77 to 0.99), but not in the overall rate of all-cause hospitalisations. There was no statistically significant difference in forced expiratory volume in one second (FEV(1)) or symptom score between tiotropium and LABA-treated participants. There was a lower rate of non-fatal serious adverse events recorded with tiotropium compared with LABA (OR 0.88; 95% CI 0.78 to 0.99). The tiotropium group was also associated with a lower rate of study withdrawals (OR 0.89; 95% CI 0.81 to 0.99).We identified six full economic evaluations assessing the cost and cost-effectiveness of tiotropium and salmeterol. The studies were b. In people with COPD, the evidence is equivocal as to whether or not tiotropium offers greater benefit than LABAs in improving quality of life; however, this is complicated by differences in effect among the LABA types. Tiotropium was more effective than LABAs as a group in preventing COPD exacerbations and disease-related hospitalisations, although there were no statistical differences between groups in overall hospitalisation rates or mortality during the study periods. There were fewer serious adverse events and study withdrawals recorded with tiotropium compared with LABAs. Symptom improvement and changes in lung function were similar between the treatment groups. Given the small number of studies to date, with high levels of heterogeneity among them, one approach may be to give a COPD patient a substantial trial of tiotropium, followed by a LABA (or vice versa), then to continue prescribing the long-acting bronchodilator that the patient prefers. Further studies are needed to compare tiotropium with different LABAs, which are currently ongoing. The available economic evidence indicates that tiotropium may be cost-effective compared with salmeterol in several specific settings, but there is considerable uncertainty around this finding.

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Bronchodilator Agents; Cost-Benefit Analysis; Disease Progression; Ethanolamines; Formoterol Fumarate; Hospitalization; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

The aim of this study was to estimate the cost-effectiveness of tiotropium versus salmeterol to inform decision making within the Dutch healthcare setting.. A previously published, validated COPD progression model was updated with new exacerbation data and adapted to the Dutch setting by including Dutch estimates of healthcare use for COPD maintenance treatment and Dutch unit costs. Exacerbation data from the POET-COPD trial were combined with evidence from earlier tiotropium studies using Bayesian meta-analysis. The model-based analysis was performed using a one- and five-year time horizon. Main health outcomes were the number of exacerbations and quality-adjusted life years (QALYs).. One-year costs per patient from the healthcare perspective were v1370 for tiotropium and v1359 for salmeterol; a difference of v11 (95% uncertainty interval (UI): -198-212). The annual number of exacerbations was 0.068 (-0.005-0.140) lower in the tiotropium group. The number of QALYs in the tiotropium group was 0.011 (-0.019-0.049) higher, resulting in an incremental cost-effectiveness ratio (ICER) of v1015 per QALY. After five years, the difference in exacerbations, QALYs and costs between the tiotropium and salmeterol group were -0.435 (-0.915-0.107), 0.079 (-0.272-0.520) and v-277 (-1586-1074), respectively, indicating that tiotropium was more effective and less costly. Using a societal perspective, tiotropium dominated salmeterol both after one and five years.. Tiotropium reduced exacerbations and exacerbation-related costs. After one year the cost per QALY of tiotropium compared with salmeterol was very low, while after five years tiotropium was found to dominate salmeterol.

Topics: Albuterol; Bronchodilator Agents; Cost-Benefit Analysis; Disease Progression; Humans; Markov Chains; Netherlands; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

Long-acting muscarinic antagonists (LAMAs) play a central role in the management of chronic obstructive pulmonary disease (COPD). Previously, only one LAMA (tiotropium) was available for the treatment of COPD, necessitating the development of other therapeutic options due to the heterogeneity of COPD and patient responses to treatment. This article reviews the COPD management potential of aclidinium bromide, a LAMA administered twice daily (BID) by a multidose dry powder inhaler that is indicated for maintenance treatment of COPD. Aclidinium possesses kinetic selectivity for the M(3) versus M(2) receptor and is rapidly hydrolyzed in plasma to two major inactive metabolites, resulting in a low and transient systemic exposure and minimizing the potential for systemic side effects. A pharmacokinetic study with multiple doses of twice-daily aclidinium demonstrated the short half-life of aclidinium in plasma, suggesting that a steady state may be reached as early as the second day postdose. In a phase II study, twice-daily aclidinium 400 µg provided 24-hour bronchodilation, with significant improvements versus tiotropium during the second half of the day. In two phase III studies (ACCORD I and ATTAIN), both aclidinium 200 µg and 400 µg BID provided statistically significant improvements in trough forced expiratory volume in 1 second (FEV(1)) and other related lung function measurements. Improvements in peak FEV(1) on day 1 were comparable to those at study end, demonstrating that aclidinium provides maximal bronchodilation after the first dose that is maintained over time. Health status was significantly improved and dyspnea, nighttime and morning symptoms of COPD were likewise significantly reduced with aclidinium. Numerically greater improvements in efficacy were observed with the 400 µg dose compared with the lower dose, with similar safety profiles between the two doses and a low incidence of anticholinergic side effects. The approved therapeutic dose of aclidinium 400 µg BID is thus an effective new treatment option for patients with COPD.

Topics: Animals; Bronchodilator Agents; Delayed-Action Preparations; Dry Powder Inhalers; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Scopolamine Derivatives; Tiotropium Bromide; Tropanes

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality across the globe and within the United States. Although several medication classes are used for COPD treatment, none of these medications have been shown to significantly improve long-term lung function or mitigate overall disease progression. This review describes the pharmacologic treatment options for COPD and highlights recent studies evaluating the impact of bronchodilators and combination therapy on lung function, mortality, quality of life, and exacerbations. Additionally, indacaterol and roflumilast, 2 new COPD treatment agents approved by the Food and Drug Administration in 2011, are discussed. Pharmacists play an important role in managing and educating patients with COPD and should utilize new evidence to make recommendations.

Topics: Aminopyridines; Benzamides; Bronchodilator Agents; Cyclopropanes; Humans; Indans; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

To describe the current data evaluating the efficacy and safety of ipratropium used in combination with tiotropium in patients with chronic obstructive pulmonary disease.. A literature search using MEDLINE (1966-August 2012) and EMBASE (1973-August 2012) was conducted using the search terms ipratropium, tiotropium, combination drug therapy, and chronic obstructive pulmonary disease. References of identified articles were reviewed for additional relevant citations.. All English-language articles regarding the concomitant use of ipratropium and tiotropium were reviewed.. Two prospective randomized controlled trials have demonstrated increases in bronchodilation with ipratropium when added to maintenance tiotropium therapy, suggesting potential benefits during short-term, combined use. One study reported significantly higher peak forced expiratory volume in 1 second (FEV(1)) responses with both ipratropium (230 mL) and fenoterol (315 mL) compared to placebo (178 mL) when added to maintenance tiotropium. The peak response with fenoterol was significantly higher than with ipratropium (FEV(1) difference = 84 mL). Another study reported a mean difference in FEV(1) of 81 mL (95% CI 27 to 136) with albuterol versus placebo and a mean difference in FEV(1) of 68 mL (95% CI 3 to 132) with ipratropium versus placebo. The difference between albuterol and ipratropium when added to maintenance tiotropium was not significant. One large observational study reported a significantly higher risk of acute urinary retention in individuals receiving combination therapy with a short- and long-acting anticholinergic agent compared to those receiving monotherapy (OR 1.84; 95% CI 1.25 to 2.71). Individuals at highest risk were men and those with evidence of benign prostatic hypertrophy.. While ipratropium may provide spirometric improvements in lung function for patients receiving tiotropium maintenance therapy, the clinical significance of these improvements has not been documented and the risk of anticholinergic adverse effects is increased with combination therapy. Further studies evaluating the safety and efficacy of concomitant ipratropium and tiotropium are warranted before combination use can be recommended for select patients.

Topics: Bronchodilator Agents; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Ipratropium; Male; Pulmonary Disease, Chronic Obstructive; Risk Factors; Scopolamine Derivatives; Sex Factors; Spirometry; Time Factors; Tiotropium Bromide

Chronic obstructive pulmonary disease is characterized by poorly reversible airflow obstruction. Long-acting bronchodilators improve lung function and relieve dyspnea. Aclidinium bromide is a novel long-acting antimuscarinic bronchodilator; Phase III clinical trials have demonstrated that administration of this drug twice per day improves lung function, dyspnea and health-related quality of life. Aclidinium bromide is delivered using the Genuair(®) device, which is an easy to use multidose dry powder inhaler. Aclidinium bromide is rapidly metabolized in the plasma, so there is low systemic exposure that minimizes the anticholinergic side effects. This new long-acting bronchodilator provides effective bronchodilation with minimal side effects.

Topics: Acetylcholine; Bronchodilator Agents; Clinical Trials as Topic; Dry Powder Inhalers; Exercise Tolerance; Humans; Ipratropium; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Signal Transduction; Tiotropium Bromide; Tropanes

It is not clear whether combination therapy with tiotropium plus formoterol has greater efficacy, without increasing the burden of adverse events, compared with tiotropium alone. This meta-analysis was performed to evaluate the differences in efficacy and adverse events associated with combination therapy compared with tiotropium alone, in patients with stable COPD.. MEDLINE, EMBASE, CINAHL and the Cochrane trials database were searched for this analysis. Randomized controlled trials of 2 or more weeks of treatment with tiotropium plus formoterol or arformoterol, compared with tiotropium alone, were reviewed. Studies were pooled to yield odds ratio (OR) or weighted mean differences (WMD), with 95% confidence interval (CI).. Eight trials, involving 1868 randomized patients, met the inclusion criteria. Treatment with tiotropium plus formoterol significantly improved the average FEV(1) (WMD 105 mL, 95% CI: 69-142), average FVC (WMD 135 mL, 95% CI: 96-174) and trough FEV(1) (WMD 53 mL, 95% CI: 30-76), compared with tiotropium alone, although the difference was not statistically significant for trough FVC. The mean change in transitional dyspnoea index (TDI) was markedly greater with tiotropium plus formoterol (WMD 1.50, 95% CI: 1.01-1.99) than with tiotropium alone, and there was a similar difference in the proportion of patients with a clinically significant change in TDI (OR 2.34, 95% CI: 1.58-3.46). There tended to be fewer adverse events and COPD exacerbations with tiotropium plus formoterol, compared with tiotropium alone, but the differences were not statistically significant.. Tiotropium plus formoterol significantly improved lung function and symptom scores compared with tiotropium alone. There was a trend towards a reduction in adverse events, although the difference was not statistically significant. Long-term trials are necessary to evaluate the effects of tiotropium plus formoterol and to clarify the role of combination therapy, compared with tiotropium alone.

Topics: Adult; Aged; Bronchodilator Agents; Drug Therapy, Combination; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

To systematically review recent evidence on the effectiveness of tiotropium versus placebo, ipratropium, and long-acting β(2) agonists on outcomes relevant to patients with stable COPD, including health-related quality of life, dyspnea, exacerbations and hospitalizations.. Our inclusion criteria for trials were: ≥ 12 weeks; compared tiotropium to placebo, ipratropium, or long-acting β agonists; patients ≥ 40 y old and with stable COPD. Sixteen trials (16,301 patients) met the inclusion criteria.. Tiotropium improved health-related quality of life (measured with St George's Respiratory Questionnaire) compared to placebo (odds ratio [OR] 1.61, 95% CI 1.38-1.88, P < .001) and ipratropium (OR 2.03, 95% CI 1.34-3.07, P = .001). Tiotropium also improved dyspnea (measured with the Transitional Dyspnea Index) compared to placebo (OR 1.96, 95% CI 1.58-2.44, P < .001) and ipratropium (OR 2.10, 95% CI 1.28-3.44, P = .003). Tiotropium decreased the likelihood of an exacerbation (OR 0.83, 95% CI 0.72-0.94, P = .004) and related hospitalizations (OR 0.89, 95% CI 0.80-0.98, P = .02) but not serious adverse events (OR 1.06, 95% CI 0.97-1.17, P = .19), compared to placebo. The cumulative incidence of dry mouth was 7.4% with tiotropium, compared to 3.9% with ipratropium, 1.6% with salmeterol, and 2.0% with placebo.. In stable COPD, tiotropium showed superior efficacy in improving quality of life and dyspnea, compared to placebo and ipratropium. However, tiotropium's differences with salmeterol were less clear.

Topics: Adrenergic beta-Agonists; Adult; Bronchodilator Agents; Hospitalization; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

The long-acting bronchodilator tiotropium and single inhaler combination therapy of inhaled corticosteroids and long-acting beta(2)-agonists are both commonly used for maintenance treatment of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of using tiotropium and combination therapy together for the treatment of chronic obstructive pulmonary disease are unclear.. To assess the relative effects of inhaled corticosteroid and long-acting beta(2)-agonist combination therapy in addition to tiotropium compared to tiotropium or combination therapy alone in patients with chronic obstructive pulmonary disease.. We searched the Cochrane Airways Group Specialised Register of trials (July 2010) and reference lists of articles.. We included parallel, randomised controlled trials of three months or longer, comparing inhaled corticosteroid and long-acting beta(2)-agonists combination therapy in addition to inhaled tiotropium against tiotropium alone or combination therapy alone.. We independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.. Three trials (1021 patients) were included comparing tiotropium in addition to inhaled corticosteroid and long-acting beta(2)-agonist combination therapy to tiotropium alone. The duration, type of combination treatment and definition of outcomes varied. The limited data led to wide confidence intervals and there was no significant statistical difference in mortality, participants with one or more hospitalisations, episodes of pneumonia or adverse events. The results on exacerbations were heterogeneous and were not combined. The mean health-related quality of life and lung function were significantly different when combination therapy was added to tiotropium, although the size of the average benefits of additional combination therapy were small, St George's Respiratory Questionnaire (MD -2.49; 95% CI -4.04 to -0.94) and forced expiratory volume in one second (MD 0.06 L; 95% CI 0.04 to 0.08).One trial (60 patients) compared tiotropium plus combination therapy to combination therapy alone. The results from the trial were insufficient to draw firm conclusions for this comparison.. To date there is uncertainty regarding the long-term benefits and risks of treatment with tiotropium in addition to inhaled corticosteroid and long-acting beta(2)-agonist combination therapy on mortality, hospitalisation, exacerbations of COPD and pneumonia. The addition of combination treatment to tiotropium has shown improvements in average health-related quality of life and lung function.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Therapy, Combination; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Bronchodilation with a long-acting muscarinic antagonist (LAMA) or long-acting β(2)-agonist is central to the management of chronic obstructive pulmonary disease (COPD). Tiotropium, the first LAMA available for use in COPD, has been shown to be an effective bronchodilator and is generally safe and well tolerated. However, tiotropium has limitations that include a high incidence of dry mouth, slow onset of action and, in some studies, a part of the patient population did not achieve clinically significant bronchodilation. It also remains unclear whether tiotropium reduces progressive deterioration of lung function in patients with COPD. An ideal LAMA would provide clinically meaningful bronchodilation, deliver symptom relief, prevent disease progression, improve exercise tolerance and health status, prevent and treat complications and exacerbations and reduce mortality risk. A 24-h duration of action, rapid onset of action and a good safety and tolerability profile are also desirable. The once-daily LAMA, NVA237 (glycopyrronium bromide), may meet some of these characteristics. NVA237 has high selectivity for the muscarinic type-3 (M(3)) receptor which might potentially result in a higher therapeutic index than tiotropium, which is less selective for M(3). Phase II studies showed that NVA237 once daily provides clinically significant 24-h bronchodilation with a rapid onset of action and a favourable safety and tolerability profile. Phase III studies are ongoing that will assess the long-term safety and efficacy of NVA237.

Topics: Bronchodilator Agents; Delayed-Action Preparations; Glycopyrrolate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Scopolamine Derivatives; Tiotropium Bromide

Primary care specialists provide first-line care of chronic obstructive pulmonary disease (COPD), characterized by progressive, partially reversible airflow limitation induced mainly by smoking. Spirometry and questionnaires are important for COPD diagnosis, staging and prognosis. Smoking cessation, immunizations, pulmonary rehabilitation and self-management action plans comprise nonpharmacologic COPD management. The Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) and Towards a Revolution in COPD Health (TORCH) megatrials provide evidence for maintenance pharmacotherapy to reduce exacerbations and improve patient symptoms and health-related quality of life. Although the primary outcomes--lung function decline (UPLIFT®) and mortality (TORCH)--were negative, long-acting bronchodilators in both trials reduced exacerbation rates and improved health status. Tiotropium added to usual care (in UPLIFT®) and salmeterol/fluticasone therapy (in TORCH) improved key patient-centered outcomes with no significant mortality risk or excess in serious cardiac adverse events associated with the study drugs. These results provide strong evidence of efficacy and acceptable safety profiles of maintenance pharmacotherapies in patient-centered outcomes and support combination drug regimens in patients with moderate to very severe COPD.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Prognosis; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) encompasses a group of diseases characterized by chronic airway obstruction. This broad diagnostic umbrella includes several clinical phenotypes that overlap and respond differently to each type of therapeutic intervention. Roflumilast is a drug belonging to the new therapeutic class of phosphyldiesterase-4 (PDE4) inhibitors and can be considered the first drug to be developed for a specific COPD phenotype (COPD associated with chronic bronchitis). In preclinical models, roflumilast has shown potent antiinflammatory action against a wide variety of cells and inflammatory mediators, as well as against the etiopathogenic mechanisms of COPD. The present article reviews the evidence generated during the clinical development of roflumilast, with special emphasis on studies evaluating the drug in a context similar to that of routine clinical practice.

Topics: Adrenergic beta-2 Receptor Agonists; Aminopyridines; Anti-Inflammatory Agents; Benzamides; Bronchodilator Agents; Cyclopropanes; Drug Therapy, Combination; Humans; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

To systematically review the risk of mortality associated with long term use of tiotropium delivered using a mist inhaler for symptomatic improvement in chronic obstructive pulmonary disease.. Medline, Embase, the pharmaceutical company clinical trials register, the US Food and Drug Administration website, and ClinicalTrials.gov for randomised controlled trials from inception to July 2010.. Trials were selected for inclusion if they were parallel group randomised controlled trials of tiotropium solution using a mist inhaler (Respimat Soft Mist Inhaler, Boehringer Ingelheim) versus placebo for chronic obstructive pulmonary disease; the treatment duration was more than 30 days, and they reported data on mortality. Relative risks of all cause mortality were estimated using a fixed effect meta-analysis, and heterogeneity was assessed with the I(2) statistic.. Five randomised controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality (90/3686 v 47/2836; relative risk 1.52, 95% confidence interval, 1.06 to 2.16; P = 0.02; I(2) = 0%). Both 10 µg (2.15, 1.03 to 4.51; P = 0.04; I(2) = 9%) and 5 µg (1.46, 1.01 to 2.10; P = 0.04; I(2) = 0%) doses of tiotropium mist inhaler were associated with an increased risk of mortality. The overall estimates were not substantially changed by sensitivity analysis of the fixed effect analysis of the five trials combined using the random effects model (1.45, 1.02 to 2.07; P = 0.04), limiting the analysis to three trials of one year's duration each (1.50, 1.05 to 2.15), or the inclusion of additional data on tiotropium mist inhaler from another investigational drug programme (1.42, 1.01 to 2.00). The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 124 (95% confidence interval 52 to 5682) based on the average control event rate from the long term trials.. This meta-analysis explains safety concerns by regulatory agencies and indicates a 52% increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease.

Topics: Administration, Inhalation; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is a syndrome including a group of obstructive diseases showing both similar features and marked differences. At present, clinicians try to describe various COPD phenotypes reflecting different characteristics of the patients which can be useful in respect of COPD course, prognosis and effective treatment. The article is devoted to approaches to COPD phenotypes definition, gives descriptions of some possible phenotypes and analyses clinical trials of modern COPD treatment modalities in different phenotypes.

Topics: Bronchodilator Agents; Clinical Trials as Topic; Humans; Phenotype; Prognosis; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Data have highlighted the potential bias introduced by withdrawal of inhaled corticosteroids at randomization in chronic obstructive pulmonary disease trials examining inhaled corticosteroids. Analyses were conducted to determine whether this was true of inhaled anticholinergic withdrawal in tiotropium trials.. A pooled analysis of randomized, double-blind, placebo-controlled, parallel-group tiotropium trials of at least six months' duration was performed. Trials had similar inclusion and exclusion criteria. Exacerbation definition was standardized. Patients were divided into two groups, ie, D (anticholinergics discontinued at randomization, previously prescribed) and ND (anticholinergics not discontinued, not previously prescribed).. Demographics were balanced between the D (n = 5846) and ND (n = 6317) groups, except for higher cumulative smoking (56 pack-years versus 48 pack-years), lower forced expiratory volume in one second (FEV(1))/forced vital capacity (43% versus 48%), and lower baseline FEV(1) (35.8% predicted versus 42.4% predicted) in the D group. In both groups, tiotropium reduced the risk for an exacerbation (hazard ratio [HR] = 0.83, P < 0.0001 [D] versus 0.79, P < 0.0001 [ND]) and a hospitalized exacerbation (HR = 0.85, P = 0.0467 versus 0.79, P = 0.0094). Tiotropium reduced the number of exacerbations per patient-year (rate ratio [RR] = 0.82, P < 0.0001 [D] versus RR = 0.80, P < 0.0001 [ND]) and associated hospitalizations per patient-year (RR = 0.88, P = 0.015 [D] versus RR = 0.74, P < 0.0001 [ND]).. Tiotropium reduced exacerbations in patients who did and did not have anticholinergics discontinued upon randomization in clinical trials.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Evidence-Based Medicine; Female; Forced Expiratory Volume; Hospitalization; Humans; Kaplan-Meier Estimate; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Long-acting bronchodilators comprising long-acting beta(2)-agonists and the anticholinergic agent tiotropium are commonly used, either on their own or in combination, for managing persistent symptoms of chronic obstructive pulmonary disease. Patients with severe chronic obstructive pulmonary disease who are symptomatic and who suffer repeated exacerbations are recommended to add inhaled corticosteroids to their bronchodilator treatment. However, the benefits and risks of adding inhaled corticosteroid to tiotropium and long-acting beta(2)-agonists for the treatment of chronic obstructive pulmonary disease are unclear.. To assess the relative effects of adding inhaled corticosteroids to tiotropium and long-acting beta(2)-agonists treatment in patients with chronic obstructive pulmonary disease.. We searched the Cochrane Airways Group Specialised Register of trials (February 2011) and reference lists of articles.. We included parallel group, randomised controlled trials of three months or longer comparing inhaled corticosteroid and long-acting beta(2)-agonist combination therapy in addition to inhaled tiotropium against tiotropium and long-acting beta(2)-agonist treatment for patients with chronic obstructive pulmonary disease (COPD).. Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.. One trial (293 patients) was identified comparing tiotropium in addition to inhaled corticosteroid and long-acting beta(2)-agonist combination therapy to tiotropium plus long-acting beta(2)-agonist. The study was of good methodological quality, however it suffered from high and uneven withdrawal rates between the treatment arms. There is currently insufficient evidence to know how much difference the addition of inhaled corticosteroids makes to people who are taking tiotropium and a long-acting beta(2)-agonist for COPD.. The relative efficacy and safety of adding inhaled corticosteroid to tiotropium and a long-acting beta(2)-agonist for chronic obstructive pulmonary disease patients remains uncertain and additional trials are required to answer this question.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Delayed-Action Preparations; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

The primary aim of pharmachotherapy in COPD is improvement of exertional dyspnea and quality of life through its bronchodilator effects. However, there is emerging evidence that pharmacotherapy may reduce exacerbations, alleviate annual decline of pulmonary function, and even favorably affect mortality, thus changing natural history of COPD. The large-scaled randomized clinical trials, such as TORCH, UPLIFT, have revealed that combination of long acting beta2 agonist (LABA) and inhaled corticosteroids (ICS), LABA/ICS, and/or tiotropium alone may have such effects. In addition, carbocisteine, which is a mucolytic and anti-oxidant agent, has been shown to reduce exacerbations in COPD. Future directions on pharmacotherapy are personalized medicine based on phenotyping of the disease and development of new agents which may cure airway inflammation in COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Current guidelines ERS, ATS, GOLD recommend use of one or more inhaler long-acting bronchodilators to alleviate symptoms and reduce risk of exacerbations for the symptomatic patients with moderate to severe in stabile COPD. Since parasympathetic activity is the dominant reversible component of airway obstruction in COPD, anticholinergic agent became first-line treatment. Exacerbations of COPD are associated with progression of disease. Clinical trials have confirmed that tiotropium is superior to salmeterol in preventing COPD exacerbations in patients with moderate to very severe COPD with history of exacerbations. Tiotropium also resulted in a significant reduction in the decline in post-bronchodilator FEV1, suggesting possible disease modification in younger patients with COPD. The safety data review does not indicate an increased risk for death or cardiovascular morbidity during tiotropium treatment in patients with COPD. Tiotropium was associated with a reduction in the risk of all-cause mortality.

Topics: Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

In chronic obstructive pulmonary disease (COPD) airways inflammation is associated in more advanced stages with systemic inflammation. COPD-associated systemic inflammation syndrome is defined currently with rather non-specific biomarkers such as C-reactive protein (CRP) but there are also other 'organ-specific' biomarkers such as surfactant protein-D which are still not well characterized but might represent more appropriate and reliable alternatives to the non-specific biomarkers. Inhaled therapies are the mainstay in stable COPD and they were demonstrated to reduce airway inflammation and more recently in the case of inhaled corticosteroids alone or combined with long-acting beta-2 agonists to reduce systemic inflammation as well. This paper focuses on current and potential biomarkers of systemic inflammation in COPD and on the systemic anti-inflammatory effects of inhaled therapies in stable COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Biomarkers; C-Reactive Protein; Cholinergic Antagonists; Drug Therapy, Combination; Fibrinogen; Humans; Inflammation; Interleukin-6; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Receptors, Adrenergic, beta-2; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Tumor Necrosis Factor-alpha; Uteroglobin

This article reviews findings from recently published randomized controlled trials and systematic reviews to provide an up-to-date assessment of the efficacy and safety of tiotropium, the only currently available long-acting muscarinic antagonist, when used alone or in conjunction with other respiratory medications in the treatment of chronic obstructive pulmonary disease (COPD).. Results of recent clinical trials support findings from earlier trials in patients with moderate to very severe COPD demonstrating significant benefits of tiotropium compared to placebo, including sustained increases in lung function, reductions in exacerbations and risk of exacerbation-related hospitalizations, and improvement in health status. These benefits were particularly noted in the 4-year UPLIFT study that included 5993 COPD patients, including a large percentage with moderate severity. Whereas the cardiovascular safety of tiotropium has been questioned, results of the UPLIFT trial and a recent pooled analysis of data from 30 trials of tiotropium demonstrated that tiotropium is associated with reductions in the risk of all-cause mortality, cardiovascular mortality and cardiovascular events.. Recent findings confirm the benefits of tiotropium in COPD management and provide reassurance regarding its safety. Moreover, the recent UPLIFT trial provides supportive evidence for the efficacy of tiotropium in COPD patients already receiving treatment with long-acting inhaled beta-agonists and inhaled corticosteroids, suggesting advantages of 'triple' therapy in advanced disease. Further, well designed, adequately powered studies should explore the potential advantages and disadvantages of various combinations of currently available long-acting respiratory medications in COPD, particularly in different clinical phenotypes of this heterogeneous disease.

Topics: Cholinergic Antagonists; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The prevention and relief of symptoms by regular use of bronchodilators is central to the pharmacological management of chronic obstructive pulmonary disease (COPD).. The aim of this article is to review the effects of inhaled muscarinic antagonists in the treatment of stable COPD.. An update of the clinical studies performed with the long-acting inhaled muscarinic antagonist (LAMA) tiotropium bromide in patients with COPD is given. In recent years, combinations of a LAMA and a long-acting inhaled beta2-agonist (LABA), and 'triple therapy' consisting of a LAMA, a LABA, and an inhaled steroid are being developed. Issues of safety of inhaled anticholinergics in COPD are discussed and a short overview of new LAMAs being developed for COPD is given.. The importance of anticholinergic drug treatment in COPD was largely advanced by the development of the first LAMA, tiotropium bromide. The vast experience obtained with tiotropium bromide has paved the way for new LAMAs such as aclidinium bromide and glycopyrrolate (NVA-237).

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Androstadienes; Bronchodilator Agents; Clinical Trials as Topic; Delayed-Action Preparations; Drug Evaluation, Preclinical; Drug Therapy, Combination; Drugs, Investigational; Fluticasone; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

Several long-term studies designed to assess pharmacological treatments for Chronic Obstructive Pulmonary Disease (COPD) have been published recently. Only such long-term studies allow an accurate analysis of the effect of treatments on criteria of effectiveness such as survival or decline in pulmonary function. A review of these studies is opportune.. The high drop out rate, which is not a random event, leads to serious methodological problems that are of importance in the interpretation of these studies. Post hoc analysis of both the TORCH and UPLIFT trials suggest a positive effect of long-acting bronchodilators on survival. Up to now, no treatment has convincingly demonstrated an effect on the rate of decline of FEV(1). The treatments evaluated lead to a decrease in exacerbation rates and an improvement in quality of life although the effects of inhaled corticosteroids are subject to methodological concerns. The treatments are all well tolerated.. The design of future studies should avoid the withdrawal of treatments at enrolment into a study in order to limit the number of drop outs.. Long-term studies have made important progress in the knowledge, not only of the effects of the treatments assessed but also of the methodological issues which need to be addressed.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Budesonide; Combined Modality Therapy; Drug Therapy, Combination; Female; Fluticasone; Humans; Ipratropium; Long-Term Care; Male; Middle Aged; Prednisone; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide; Triamcinolone

The course of COPD is punctuated by acute exacerbations that are associated with an increase in the morbidity and mortality related to this chronic disease and may contribute to its rate of progression. Therefore, preventing and treating exacerbations are major goals of COPD management. The role of tiotropium in the prevention of exacerbations has been investigated in several placebo-controlled randomized clinical trials varying in duration from 3 months to 4 years in patients with moderate to very severe COPD. In all of these trials, tiotropium has uniformly reduced the proportion of patients experiencing at least one exacerbation and delayed the time to the first exacerbation compared with placebo. In the longer trials (> or =6 months' duration) tiotropium has also reduced the exposure-adjusted incidence rate of exacerbations. In trials of at least 1 year in duration, tiotropium either significantly reduced the risk of hospitalization for an exacerbation and/or the proportion of patients with an exacerbation-related hospitalization. In a meta-analysis that included 15 trials of tiotropium vs either placebo (n = 13) and/or a long-acting beta-agonist (LABA; n = 4), tiotropium significantly reduced the odds of experiencing an exacerbation compared to placebo as well as a LABA. The potential additive benefits of tiotropium to those of a LABA and/or inhaled corticosteroid in reducing exacerbations require further investigation. The mechanism whereby tiotropium reduces exacerbations is not due to an anti-inflammatory effect but more likely relates to its property of causing a sustained increase in airway patency and reduction in hyperinflation, thereby counteracting the tendency for respiratory insults to worsen airflow obstruction and hyperinflation. For the management of acute exacerbations, an increase in short-acting inhaled bronchodilators is recommended as needed, while the potential role of long-acting bronchodilators, such as tiotropium, in conjunction with short-acting agents, is unclear and warrants further study.

Topics: Bronchodilator Agents; Comorbidity; Hospitalization; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Combination therapy (inhaled corticosteroids and long-acting beta(2)-agonists) and tiotropium are both used in the treatment of chronic obstructive pulmonary disease (COPD). There is uncertainty about the relative benefits and harms of these treatments.. To assess the relative effects of inhaled combination therapy and tiotropium on patients with COPD.. We searched the Cochrane Airways Group Specialised Register of trials (March 2010) and reference lists of articles. We also contacted authors of the studies.. We included only parallel, randomised controlled trials comparing inhaled combination corticosteroid and long-acting beta(2)-agonist against inhaled tiotropium bromide.. Two authors independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. Discrepancies were resolved through discussion.. One large two year trial (INSPIRE) and two smaller, shorter trials (Dawber 2005; SCO40034) were found. The results from these trials were not pooled. The number of withdrawals from each arm of the INSPIRE trial was large and imbalanced and outcome data was not collected for patients who withdrew, raising concerns about the reliability of data from this study.In INSPIRE, there were more deaths on tiotropium than on fluticasone/salmeterol (Peto OR 0.55; 95% CI 0.33 to 0.93). This was a statistically significant difference, however the number of withdrawals from each of the arms was eleven times larger than the observed number of deaths for participants on fluticasone/salmeterol and seven times larger for participants on tiotropium. There were more all cause hospital admissions in patents on fluticasone/salmeterol than those on tiotropium in INSPIRE (Peto OR 1.32; 95% CI 1.04 to 1.67). There was no statistically significant difference in hospital admissions due to exacerbations, the primary outcome of INSPIRE. There was no significant difference in exacerbations in patients on fluticasone/salmeterol compared to tiotropium. Exacerbations requiring treatment with oral corticosteroids were less frequent in patients on fluticasone/salmeterol (Rate Ratio 0.81; 95% CI 0.67 to 0.99). Conversely exacerbations requiring treatment with antibiotics were more frequent in patients treated with fluticasone/salmeterol (Rate Ratio 1.19; 95% CI 1.02 to 1.38). There were more cases of pneumonia in patients on fluticasone/salmeterol than those on tiotropium (Peto OR 2.13; 95% CI 1.33 to 3.40). Confidence intervals for these outcomes do not reflect the additional uncertainty arising from unknown outcome data for patients who withdrew.. Since the proportion of missing outcome data compared to the observed outcome data is enough to induce a clinically relevant bias in the intervention effect, the relative efficacy and safety of combined inhalers and tiotropium remains uncertain. Further large, long-term randomised controlled trials comparing combination therapy to tiotropium are required, including adequate follow-up of all participants randomised (similar to the procedures undertaken in TORCH and UPLIFT). Additional studies comparing alternative inhaled LABA/steroid combination therapies with tiotropium are also required.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Humans; Patient Dropouts; Pneumonia; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

The Understanding Potential Long-term Improvements in Function with Tiotropium (UPLIFT) trial was a global 4-year randomized placebo-controlled clinical trial that evaluated the long-term impact of tiotropium bromide 18 microg once daily on the accelerated age-related decline in pre- and post-bronchodilator forced expiratory volume in 1 s (FEV(1); co-primary end points). Secondary end points included lung function at serial clinic visits, health-related quality of life, exacerbations, exacerbation-related hospitalizations, mortality, safety and tolerability. The study was carried out in 5992 patients (75% male, mean age 65 years, 30% current smokers) with moderate-to-very severe chronic obstructive pulmonary disease who were permitted to receive prescribed treatment with long-acting beta(2)-agonists and/or inhaled corticosteroids in addition to the study drug. While the results failed to show an effect of tiotropium on the primary end points (rate of decline in pre- and post-bronchodilator FEV(1)), they did show improvements in lung function and health-related quality of life that were maintained throughout the study and a reduction in the risk of exacerbations and related hospitalizations. Tiotropium also reduced all-cause mortality in patients on treatment over the 4-year trial period and reduced lower respiratory and cardiovascular morbidity, including respiratory failure and myocardial infarction. Adverse events were consistent with the drug's known anticholinergic pharmacology.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Aged; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Hospitalization; Humans; Lung; Male; Middle Aged; Multicenter Studies as Topic; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

Anticholinergic agents are of noteworthy value in the treatment of chronic obstructive pulmonary disease (COPD), but concerns have been raised about a possible association between their use and cardiovascular (CV) morbidity and mortality. In this review, we have examined whether and why an anticholinergic agent, and in particular tiotropium, might cause CV risks.. We first examine the potential pharmacological mechanisms that justify the CV risk with an anticholinergic agent, and then the main clinical trials, observational (cohort or case-control) studies, descriptive reviews and meta-analyses that have looked at the CV risks associated with long-term tiotropium, which are available in MEDLINE, EMBASE and Cochrane Controlled Trials Register databases, using the following MeSH, full text and keyword terms: tiotropium bromide OR Spiriva AND COPD OR chronic obstructive pulmonary disease.. The almost absolute confidence that there is no real increased risk for death or CV morbidity during treatment with this inhaled anticholinergic agent in patients with COPD because of the results of a large 4-year trial and a robust and extensive analysis of > 19,000 patients participating in placebo-controlled tiotropium clinical trials. Nonetheless, because high-risk patients such as those with coronary artery disease, heart failure, cardiac arrhythmia, hypoxemia requiring daytime oxygen therapy and a creatinine > 2 mg/dl were excluded from Phase III clinical trials, it is impossible to exclude these patients from an increased risk of drug-related cardiac events in a real-world setting.. Despite the recently raised concerns about an excess risk of CV adverse events with inhaled short-acting anticholinergic agents, the risk:benefit ratio of tiotropium bromide appears still favorable, although it is not known whether high-risk patients are at an increased risk of drug-related CV events.

Topics: Administration, Inhalation; Animals; Cardiovascular Diseases; Case-Control Studies; Cholinergic Antagonists; Clinical Trials as Topic; Cohort Studies; Comorbidity; Disease Susceptibility; Dogs; Heart; Humans; Meta-Analysis as Topic; Multicenter Studies as Topic; Parasympathetic Nervous System; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Risk; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium has been shown to reduce exacerbations and improve quality of life for patients with chronic obstructive pulmonary disease (COPD), a lung disease characterized by a persistent and progressive airflow limitation.. To present a systematic literature review of the cost effectiveness of treatment with tiotropium compared with other currently used treatments for COPD.. A systematic search was performed via PubMed, the Cochrane database, and EMBASE from 2002 to 2009. Methods and results by study design and by country were compared.. Seventeen studies were included in the review. Study designs were characterized as follows: modeling based on clinical trial data, and empirical analysis based on either clinical trial or observational data. Comparing monotherapy regimens (12 studies), all study designs found that treatment with tiotropium was associated with lower costs for hospitalisation and other non-drug services. Total costs, including the costs of maintenance drugs, were lower with tiotropium in some, but not all, of the studies. Tiotropium was shown to be cost effective based on commonly accepted benchmark values. Limitations of the review included the wide variety of outcome measures used in different studies, the limited number of observational database studies for monotherapy, and limited data for combination therapy regimens.. The main conclusions of the economic evaluations derived from clinical trial data at the time of product approval and from later observational data reflecting clinical use are similar: use of tiotropium monotherapy is associated with lower hospital and other non-drug costs and better health outcomes and is either cost saving or cost effective compared with other maintenance monotherapies.

Topics: Bronchodilator Agents; Clinical Trials as Topic; Cost-Benefit Analysis; Humans; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Scopolamine Derivatives; Tiotropium Bromide

Population ageing is a new challenge for physicians because of the clinical complexity of the elderly. Although geriatric pharmacology is an emerging issue, very little is known and the choice of different treatments for the very elderly is still an important question. Chronic obstructive pulmonary disease is one of the most common chronic diseases throughout the world affecting prevalently older people. Despite the increasing burden of chronic obstructive pulmonary disease in older people, underdiagnosis and undertreatment in this age group are still common problems. Some patients are frail as they have impaired homeostatic mechanisms, deteriorated physiological systems, and limited functional reserve. Pharmacotherapeutic decisions should be combined with a careful assessment of comorbidity, polypharmacy, and age-related changes in pharmacokinetics and pharmacodynamics in order to minimize adverse drug events, drug-drug or drug-disease interactions, and nonadherence to treatment. There are few studies that specifically examine age as a factor influencing the pharmacokinetics and pharmacodynamics of inhaled therapies, the cornerstone of treatment for chronic obstructive pulmonary disease. This review provides a summary of age-related physiological changes and their impact on pharmacokinetics and pharmacodynamics, with particular regard to the drugs implicated in chronic obstructive pulmonary disease treatment, in order to optimize drug therapy.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aging; Albuterol; Bronchodilator Agents; Glucocorticoids; Humans; Medication Adherence; Polypharmacy; Pulmonary Disease, Chronic Obstructive; Respiratory Muscles; Respiratory Physiological Phenomena; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

While several studies have examined adherence to controller medications for the treatment of COPD, few systematic reviews have taken the translational step to identifying important and necessary areas for further research. The objective of this study was to review data on the outcomes of adherence to various controller therapies in patients with COPD in an effort to help prescribers understand adherence properties for each therapy.. This is a systematic review of studies investigating adherence to an array of controller pharmaceutical regimens. The studies were obtained from PubMed during 2008 and 2009 using the following key words: chronic obstructive pulmonary disease, COPD, adherence, controller medication, and persistence. Only articles encompassing adherence or persistence data to controller medications and published after 1990 were utilized.. After the search results were filtered for only the articles that pertained to adherence or persistence measurements in COPD, 35 articles remained; and finally, discounting those articles not published in English, articles which did not compare treatments for COPD, as well as those which were review articles, ten applicable articles remained. Each of these found low levels of medication adherence and/or persistence among patients receiving medications for COPD. Patients receiving fluticasone/salmeterol (FSC) and tiotropium (TIO) for treatment showed the highest adherence among all controller medications. Patients who were married, older, and white were more likely to adhere to their medications.. Characteristics of the medication used (i.e. dosing schedule, formulation, etc.) as well as patient characteristics affect the adherence/persistence to medications for the treatment of COPD. Further patient education is necessary in order to effectively improve disease management and patient outcomes in COPD. There is a need for future research and educational efforts to improve adherence in COPD and more clearly identify specific behavioral and treatment characteristics associated with specific COPD medications that can facilitate adherence.

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Fluticasone; Humans; Medication Adherence; Patient Satisfaction; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Self Administration; Tiotropium Bromide; Treatment Outcome

International guidelines recommend long-acting bronchodilators in patients who remain symptomatic despite adequate treatment with short-acting bronchodilators. The purpose of this study is to estimate the effect of tiotropium, a long-acting anticholinergic inhalant, on exacerbation and hospitalisation frequency.. Electronic databases (Medline, Embase, INAHTA, CRD databases, and the Cochrane Library) were searched for randomised controlled trials, comparing tiotropium to placebo, or other bronchodilators. Outcomes were the exacerbation frequency and hospitalisation frequency. Data were pooled using the generic inverse variance method for continuous outcomes.. Nine studies reported comparisons with placebo (n = 8), ipratropium (short-acting anticholinergic inhalant, n = 1), and salmeterol (long-acting β₂-agonist inhalant, n = 1). Only two studies reported adequate concealment of allocation. Tiotropium reduces the number of exacerbations per patient year by 0.31 (95% CI 0.46- 0.17) compared to placebo, and by 0.23 (95% CI 0.31- 0.15) compared to ipratropium. A significant difference in exacerbation frequency between tiotropium and salmeterol was found (-0.16; 95% CI -0.29 - -0.03) based on approximations of the results of one study.The number of hospitalisations is reduced by 0.04 (95% CI 0.08- 0.01) per patient year compared to placebo and by 0.06 (95% CI -0.09 - -0.03) per patient year compared to ipratropium.. Statistically significant but clinically small effects were found for tiotropium compared to placebo and ipratropium. The comparison with salmeterol is significant for exacerbation frequency but not for hospitalisation frequency. Publication bias may be present.

Topics: Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Hospitalization; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) greatly affects quality of life (QoL). Although QoL is a key concern for the patient, primary endpoints in most clinical trials are objective measures of disease progression.. A systematic review of double-blind randomised controlled trials was undertaken to identify data relating to the effect of tiotropium on QoL in patients with COPD.. A total of 24 publications met the inclusion criteria. Compared with placebo, in the majority of studies tiotropium statistically significantly improved the St George's Respiratory Questionnaire (SGRQ) total score, although improvement beyond the accepted minimum clinically important difference (MCID) of 4 units was only achieved in three studies, all of which were of less than nine months' duration. Tiotropium also statistically significantly improved the Transition Dyspnoea Index (TDI) focal score, equating to clinically meaningful improvements, in almost all the studies that assessed TDI. In general, higher proportions of patients receiving tiotropium achieved clinically meaningful responses. The addition of other therapies (dual therapy, triple therapy) to tiotropium provided benefits that exceeded the SGRQ MCID and provided further benefit with regard to the TDI.. Tiotropium improves QoL for patients with COPD requiring long-acting bronchodilators, with other additional therapies providing further benefits, depending on the population.

Topics: Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Five different types of muscarine-sensitive receptors were identified until now. In routine practice, the nonselective antagonist of cholinoreceptors are replaced by ipratropium bromide that is selectively blocking M1, M2, and M3 subtypes with the same affinity to each of them. However, the blockage of M2 subtype leads to bronchoconstriction and is accompanied by inhibition of M3 receptors in bronchial smooth muscles. The new drug tiotropium bromide selectively inhibits only the M1 and M3 types of receptors and does not affect the M2 subtype. This drug is administered only once a day, which is very important in clinical practice. Thus tiotropium bromide is the drug of choice for basic therapy of COPD.

Topics: Animals; Bronchi; Bronchoconstriction; Bronchodilator Agents; Humans; Muscarinic Antagonists; Muscle, Smooth; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

Patients with chronic obstructive pulmonary disease (COPD) and associated bronchitis are at higher risk of exacerbations, which are a major cause of morbidity and impaired quality of life. Moreover, exacerbations are associated with more rapid disease progression and higher mortality. The typical symptoms of chronic bronchitis (chronic cough and sputum production) are correlated with inflammatory markers in COPD. Roflumilast is an anti-inflammatory drug belonging to the novel therapeutic class of phosphodiesterase-4 inhibitors and is the first drug to be developed for the treatment of a specific COPD phenotype (COPD associated with chronic bronchitis). The results of clinical trials indicate that, in patients with COPD associated with chronic bronchitis and a history of exacerbations, roflumilast improves pulmonary function and reduces the symptoms and frequency of exacerbations requiring medical intervention. This effect is maintained when regular treatment with a long-acting bronchodilator or an inhaled corticosteroid is added.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Aged; Albuterol; Aminopyridines; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzamides; Bronchitis; Bronchodilator Agents; Chronic Disease; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; Forced Expiratory Volume; Humans; Mice; Middle Aged; Multicenter Studies as Topic; Muscarinic Antagonists; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Rats; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Weight Loss

Chronic obstructive pulmonary disease (COPD) is one of the most important respiratory diseases, characterized by its multicomponent complexity, with chronic inflammation, increased airway resistance and exacerbations. Several drugs are currently available for its treatment, which act on distinct targets. Bronchodilators, especially prolonged-action bronchodilators, are the most potent and there are two groups: beta-2 mimetics and anticholinergics. Inhaled corticosteroids are the main anti-inflammatory drugs but have modest efficacy and their use is reserved for patients with severe disease and frequent exacerbations and/or asthma traits. Associating these three drugs can improve symptom control, improve quality of life and reduce the number of exacerbations. The present article reviews the evidence supporting this triple combination, as well as published studies.

Topics: Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Clinical Trials as Topic; Delayed-Action Preparations; Drug Therapy, Combination; Ethanolamines; Fluticasone; Forced Expiratory Volume; Formoterol Fumarate; Humans; Multicenter Studies as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The long acting inhaled muscarinic antagonist tiotropium (Spiriva) improves lung function in patients with COPD. In addition, tiotropium reduces exacerbation frequency, dyspnoea and improves exercise capacity. As the latter has been associated with airway inflammation then this suggests that, in addition to the well-known anti-bronchoconstrictor effect, tiotropium might also display anti-inflammatory properties. With our current state of knowledge, however, it is not necessary to postulate an anti-inflammatory effect for tiotropium (Spiriva), rather inhibition of smooth muscle constriction with subsequent effects on lung hyperinflation (and possibly pulmonary circulation) can explain the effects on exacerbation frequency, dyspnoea and exercise capacity. Recent reports suggest that tiotropium can inhibit viral activation of inflammation and vagal nerve stimulation, suggesting a mechanism by which tiotropium can inhibit viral induction of exacerbations in COPD.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Bronchodilator Agents; Humans; Inflammation; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Virus Diseases

Chronic obstructive pulmonary disease (COPD) is a progressive disease with increasing incidence and mortality. Tiotropium is an inhaled long-acting anti-cholinergic for the maintenance treatment of COPD.. To review biochemical and pharmacokinetic data on tiotropium and discuss in the context of tiotropium's efficacy and safety in COPD.. Review of previously done pharmacokinetic studies performed by the manufacturer of tiotropium. Data obtained through peer-reviewed publications and regulatory websites.. The long duration of action with tiotropium is owing to prolonged, competitive binding to M(3) muscarinic receptors. Tiotropium is poorly absorbed following inhalation, which largely limits side effects. Metabolism of absorbed drug is minimal and excretion is largely through the kidneys. Tiotropium is efficacious and well tolerated by patients with COPD.

Topics: Administration, Inhalation; Animals; Bronchodilator Agents; Humans; Protein Binding; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

Frequent exacerbations of chronic obstructive pulmonary disease (COPD) are associated with impaired quality of life, and hospital admissions for exacerbations account for a large proportion of the expenditure of COPD. An important objective when treating COPD is to reduce the frequency of exacerbations. Studies published in the last few years have increased our knowledge on how to prevent exacerbations, but a number of questions remain unanswered. Tiotropium, inhaled steroids and long-acting inhaled beta agonists reduce the frequency of exacerbations, but further studies are necessary to determine if combining tiotropium with the other inhaled medicines is more effective than using them separately. There is evidence that mucolytics and prophylactic antibiotics reduce exacerbations, but there is uncertainty how these treatments should be used. Both influenza and pneumococcal vaccination are recommended in guidelines, although evidence for the latter remains controversial. Other interventions including oral bacterial extracts and self-management programmes warrant further study.

Topics: Acute Disease; Administration, Inhalation; Adrenal Cortex Hormones; Anti-Bacterial Agents; Bacteria; Bronchodilator Agents; Expectorants; Humans; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Vaccination

Tiotropium is the only long-acting inhaled anticholinergic bronchodilator currently available in China, but information about its clinical effect in this population is limited. This meta-analysis assessed the efficacy and safety of tiotropium in Chinese patients with stable COPD.. An electronic search of the literature was undertaken to identify randomized controlled trials (RCTs) of tiotropium in Chinese patients, which were then assessed for inclusion in a meta-analysis. The efficacy and safety of tiotropium was compared with placebo and ipratropium, using the outcomes of FEV(1), FEV(1)%, symptoms, frequency of exacerbations, adverse events and safety.. Eleven RCTs recruiting 1006 patients were included in the meta-analysis. Compared with both placebo and ipratropium, tiotropium significantly improved FEV(1)[weighted mean difference (WMD) = 304 mL, 95% CI 271-337], FEV(1)% (WMD = 8.35%, 95% CI 5.40-11.31) and symptoms [relative risk (RR) = 2.00, 95% CI 1.61-2.49]. Tiotropium significantly reduced the risk of exacerbations (RR = 0.07, 95% CI 0.01-0.54) compared with placebo, and there was a non-significant reduction in the risk of exacerbations compared with ipratropium (RR = 0.70, 95% CI 0.13-3.75). Tiotropium was well tolerated with a similar safety profile to placebo and ipratropium (RR = 1.16, 95% CI 0.76-1.77, P = 0.49).. Tiotropium improved pulmonary function and symptoms, reduced exacerbations and was well tolerated and safe. On the basis of its efficacy and safety profile, tiotropium appears to be a reasonable first-line choice for the management of Chinese patients with stable COPD. Additional long-term RCTs are required to further evaluate the efficacy and safety of tiotropium.

Topics: Bronchodilator Agents; China; Forced Expiratory Volume; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

To assess the effect of tiotropium 18 mcg once daily on chronic obstructive pulmonary disease (COPD) exacerbations and exacerbation-related hospitalisations using a patient-level pooled analysis.. All completed randomised, placebo-controlled, parallel-group tiotropium trials with a duration of >or=24 weeks were included (n=9). An exacerbation was defined in each study as >or=2 respiratory symptoms lasting >or=3 days, and requiring treatment with antibiotics and/or systemic steroids and/or hospitalisation.. Compared with placebo (2,862 patients), tiotropium (3,309 patients) significantly reduced by 21% both the risk of COPD exacerbation (95% confidence interval [CI] 0.73-0.86; p<0.0001) and the risk of exacerbation-associated hospitalisation (95% CI 0.65-0.96; p=0.015). Time to first exacerbation and first associated hospitalisation were increased. The protective effect of tiotropium was consistent regardless of age, gender, inhaled corticosteroid use and disease severity.. This analysis provides further confirmatory evidence that tiotropium reduces the risk of exacerbation and associated hospitalisation.

Topics: Adult; Aged; Bronchodilator Agents; Double-Blind Method; Female; Hospitalization; Humans; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Asthma; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lungs in which airways inflammation related mainly to smoking causes progressive airflow obstruction and chronic respiratory symptoms such as dyspnea or cough. COPD therapy in stable state is mainly inhalatory with bronchodilators and inhaled corticosteroids and the regimen depends on disease severity. Inhaled bronchodilators are the mainstay of maintenance therapy in COPD whether given alone or added to other inhaled medications. Current therapeutic guidelines are based on data from studies assessing long-term impact of such therapies on outcome measures such as lung function, survival, exacerbations or health-related quality of life (HRQoL). This is a review discussing the data regarding to inhaled bronchodilators with a focus on a long-acting anticholinergic, tiotropium bromide.

Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Time Factors; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is associated with progressive airflow obstruction and is characterized by a high risk of morbidity and mortality. With early detection and treatment, the natural history of this disease may be improved. So far, bronchodilator therapy is the most important treatment for COPD. Tiotropium is a bronchodilator of recent introduction.. To discuss the clinical data on the safety and efficacy of tiotropium, a very long-acting antimuscarinic drug, available at present.. The Cochrane trial database, Medline, Embase, were searched systematically, and approximately 20 respiratory journals and conference abstracts were searched manually. Language of publication was limited to English. included tiotropium, COPD, anticholinergic, safety and adverse events.. A large body of evidence is available at present on the safety and efficacy of tiotropium in COPD, with dry mouth being the most common adverse event. Reviews of serious adverse event data in the literature have reported that tiotropium is safe and that the incidence of these events is the same as with placebo. Tiotropium is a convenient treatment for COPD with a good clinical efficacy and safety profile.

Topics: Animals; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Influencing the progression of COPD has long been an elusive goal of drug therapy. Directly or indirectly, this has again been investigated in two of the largest, long-term drug trials in COPD: Towards a Revolution in COPD Health (TORCH) and Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT). Neither trial achieved statistical significance in their respective primary outcomes; however, both make considerable contributions to understanding of how the progression of COPD may be influenced. The objective of this article is to review the data from these different trials with a view to what can be learnt about the management of COPD. The long-term improvements in lung function, health-related quality of life, and possibly survival from the use of long-acting bronchodilators in these trials suggest an influence on progression of the disease. With the more optimistic view of benefits from drug treatment of COPD that these trials provide, a review of prescribing practices is warranted.

Topics: Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Double-Blind Method; Drug Combinations; Evidence-Based Medicine; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Research Design; Scopolamine Derivatives; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

There are safety concerns regarding the use of anticholinergics in the COPD patient population. The purpose of this review was to evaluate the cardiovascular risk of regular use of inhaled tiotropium bromide in patients with COPD of any severity.. Systematic searches were conducted in MEDLINE, EMBASE, the Cochrane Controlled Trials Register, manufactures' trial register, and FDA databases, without language restriction. Primary outcomes were a composite of major adverse cardiovascular events, cardiovascular mortality, and nonfatal myocardial infarction (MI) or stroke during the treatment period. Relative risks (RR) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I2 statistic.. Nineteen randomized controlled trials (18,111 participants) were selected. There was no difference in the incidence of adverse cardiovascular events (RR=0.96; 95% CI, 0.82-1.12, I2=6%). Among individual components of the composite outcome, tiotropium did not significantly increase the risk of cardiovascular death (RR=0.93; 95% CI, 0.73-1.20, I2=1%), nonfatal MI (RR=0.84; 95% CI, 0.64-1.09, I2=0%), and nonfatal stroke (RR=1.04; 95% CI, 0.78-1.39, I2=0%). A smoking history of > or = 55 pack-years presented a trend to a higher rate of cardiovascular adverse events in patients receiving tiotropium.. Compared with control (placebo or salmeterol), tiotropium did not significantly increase the risk of adverse major cardiovascular events among COPD patients. Subgroup analysis suggested that smoking history can modify the risk of cardiovascular adverse events.

Topics: Administration, Inhalation; Bronchodilator Agents; Humans; Myocardial Infarction; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Scopolamine Derivatives; Stroke; Tiotropium Bromide

Exacerbations are the most frequent cause of medical visits, hospital admissions and death among patients with chronic obstructive pulmonary disease (COPD). Tiotropium bromide is a long-acting bronchodilator that has demonstrated clinical efficacy in significantly improving the FEV(1) and health-related quality of life (HRQL) in patients with COPD. The prolonged and persistent bronchodilation achieved with tiotropium may reduce the exacerbation and COPD-related hospitalisation rates. The effect of tiotropium treatment on the incidence of exacerbations has been determined (as a secondary outcome) in registration trials. There are studies designed specifically to demonstrate the effect of tiotropium on the reduction in the frequency of exacerbations. Two of these studies of 6-month and 1-year duration demonstrated an additional significant benefit in the reduction of exacerbations and hospitalisations. The recent UPLIFT trial included 5993 patients followed for 4 years and, compared with control, tiotropium significantly delayed time-to-first exacerbation (16.7 versus 12.5 months) and time-to-first hospitalisation for exacerbations (lower risk of hospitalisation; HR, 0.86 [95% CI = 0.78-0.95]; p = 0.002). Tiotropium also reduced the mean number of exacerbations by 14% (rate per patient-year, 0.73 versus 0.85; HR, 0.86 [95% CI = 0.81-0.91]; p < 0.001). It is important to highlight that the control group in the UPLIFT trial consisted of patients with usual treatment for COPD, which included inhaled corticosteroids and/or long-acting beta-2 agonists in up to 62% of cases at baseline and up to 73% of cases at any time during follow-up. The new clinical trials have demonstrated a significant reduction in exacerbations and hospitalisations, even in patients treated with other drugs that can potentially prevent exacerbations.

Topics: Bronchodilator Agents; Clinical Trials as Topic; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

To assess the comparative efficacy of pharmacologic agents for the maintenance treatment of chronic obstructive pulmonary disease (COPD).. Traditional and mixed-treatment comparison (MTC) meta-analyses of randomized controlled trials.. A total of 31,020 patients with COPD from 43 trials.. A systematic literature search of various databases (through October 2007) was performed to identify randomized controlled trials of long-acting beta(2)-agonists, tiotropium, inhaled corticosteroids, and/or combination therapy with an inhaled corticosteroid and a long-acting beta(2)-agonist in patients with COPD. Forty-three trials were included. Both meta-analyses were used to evaluate the occurrence of one or more episodes of COPD exacerbation, overall mortality, and patient withdrawal rates. With MTC analysis, long-acting beta(2)-agonists, tiotropium, inhaled corticosteroids, and combination inhaled corticosteroid-long-acting beta(2)-agonist therapy each decreased the odds of having an exacerbation by 16%, 31%, 15%, and 24%, respectively, compared with placebo. Moreover, tiotropium use reduced the odds of having at least one exacerbation by 18% compared with long-acting beta(2)-agonists and by 19% compared with inhaled corticosteroids alone. Each of the four drug classes was associated with significant odds reductions in patient withdrawals (26-41%) compared with placebo, and both tiotropium and combination therapy significantly decreased the odds of patient withdrawals compared with long-acting beta(2)-agonists or inhaled corticosteroids alone. Only combination therapy was associated with a mortality benefit, showing a 29% reduction compared with placebo and a 25% reduction compared with long-acting beta(2)-agonists alone. Compared with combination therapy, tiotropium use reduced exacerbations by 9% and increased mortality by only 4%. These findings did not demonstrate significant changes in the sensitivity or subgroup analyses, which were performed to evaluate the effect of heterogeneity among the included studies.. Combination inhaled corticosteroid-long-acting beta(2)-agonist therapy was associated with the greatest positive effect on outcomes in patients with COPD. Of the bronchodilator monotherapies, tiotropium was associated with lower odds of having a COPD exacerbation or withdrawal from a study compared with long-acting beta(2)-agonists.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Bronchodilator Agents; Delayed-Action Preparations; Drug Therapy, Combination; Humans; Patient Compliance; Patient Dropouts; Placebos; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD.. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study was a randomised, double-blind, placebo-controlled trial undertaken in 487 centres in 37 countries. 5993 patients aged 40 years or more with COPD were randomly assigned to receive 4 years of treatment with either once daily tiotropium (18 microg; n=2987) or matching placebo (n=3006), delivered by an inhalation device. Randomisation was by computer-generated blocks of four, with stratification according to study site. In a prespecified subgroup analysis, we investigated the effects of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease. Primary endpoints were the yearly rates of decline in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and in postbronchodilator FEV(1), beginning on day 30 until completion of double-blind treatment. The analysis included all patients who had at least three measurements of pulmonary function. This study is registered with ClinicalTrials.gov, number NCT00144339.. 2739 participants (mean age 64 years [SD 9]) had GOLD stage II disease at randomisation (tiotropium, n=1384; control, n=1355), with a mean postbronchodilator FEV(1) of 1.63 L (SD 0.37; 59% of predicted value). 1218 patients in the tiotropium group and 1157 in the control group had three or more measurements of postbronchodilator pulmonary function after day 30 and were included in the analysis. The rate of decline of mean postbronchodilator FEV(1) was lower in the tiotropium group than in the control group (43 mL per year [SE 2] vs 49 mL per year [SE 2], p=0.024). For prebronchodilator pulmonary function, 1221 patients in the tiotropium group and 1158 in the control group had three or more measurements and were included in the analysis. The rate of decline of mean prebronchodilator FEV(1) did not differ between groups (35 mL per year [SE 2] vs 37 mL per year [SE 2]; p=0.38). Health status, measured with the St George's Respiratory Questionnaire, was better at all timepoints in the tiotropium group than in the control group (p

Topics: Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Health Status; Humans; Linear Models; Male; Middle Aged; Patient Admission; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Severity of Illness Index; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

Bronchodilators are central in symptomatic management of all stages of COPD. For patients whose COPD is not sufficiently controlled by monotherapy, combining an inhaled anticholinergic and a ss(2)-agonist is a convenient way of delivering treatment and obtaining better lung function and improved symptoms. Formoterol (beta(2)-agonist) and tiotropium (anticholinergic) are long-acting bronchodilators with different mechanisms of action. Formoterol has a fast onset and a bronchodilator effect of approximately 12 h, while tiotropium has a 24-h bronchodilator effect and is given once daily. Currently, there is no documentation that tiotropium is superior to formoterol or the contrary, but a combination of tiotropium and formoterol is more effective than single drugs alone in inducing bronchodilation and a bronchodilator-mediated symptom benefit in patients suffering from COPD. Once-daily or twice-daily formoterol, added to tiotropium, are both better than tiotropium alone, but the published evidence suggests twice-daily formoterol is the best add-on option.

Topics: Adrenergic beta-Agonists; Animals; Cholinergic Antagonists; Drug Therapy, Combination; Ethanolamines; Forced Expiratory Volume; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

For many years, chronic obstructive pulmonary disease (COPD) was considered a disease of fixed airflow obstruction for which there was no good treatment. Out of desperation and frustration, health care providers extrapolated from asthma to COPD, and standard asthma therapy was adopted without evidence for efficacy. In recent years, we have gained a better understanding of the pathophysiologic differences between asthma and COPD, and prospective controlled trials have provided a rationale for therapy. Smoking cessation is critically important, both as primary prevention and as an effective way to slow the decrease in lung function in patients with established disease. beta(2)-Adrenergic and anticholinergic agonists improve lung function and relieve symptoms in most patients. Tiotropium improves exercise tolerance and quality of life and reduces exacerbations and hospitalizations. The increase in lung function seen with tiotropium is sustained with continued use over at least 3 to 4 years. Inhaled corticosteroids decrease exacerbations and improve quality of life, and their effect seems greatest in patients with lower lung function and in exacerbation-prone patients. There is no evidence that inhaled corticosteroids alone affect mortality, despite the reduction in exacerbations and increased risk of pneumonia. In some patient populations, inhaled fluticasone, salmeterol, or the combination might slow the rate of loss of lung function. Rather than reflexively using effective asthma therapy in the patient with COPD, current and future therapy for COPD is increasingly evidence based and targeted to specific inflammatory pathways that are important in patients with COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Antagonists; Albuterol; Androstadienes; Antioxidants; Asthma; Bacterial Vaccines; Bronchodilator Agents; Clinical Trials as Topic; Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Viral Vaccines

The prevalence of chronic airways diseases such as chronic obstructive pulmonary disease and asthma is increasing. They lead to symptoms such as a cough and shortness of breath, partially through bronchoconstriction. Inhaled anticholinergics are one of a number of treatments designed to treat bronchoconstriction in airways disease. Both short-acting and long-acting agents are now available and this review highlights their efficacy and adverse event profile in chronic airways diseases.

Topics: Asthma; Cholinergic Antagonists; Chronic Disease; Cost-Benefit Analysis; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium is a long-acting inhaled anticholinergic developed for the treatment of chronic obstructive pulmonary disease (COPD) and has been available since 2002. We sought to update an evaluation of the safety of tiotropium in the HandiHaler formulation as significant clinical trial data have become available over time.. Pooled analysis of adverse event reporting from phase III and IV tiotropium HandiHaler clinical trials with the following characteristics was performed: randomized, double-blind, parallel group, placebo-controlled design, tiotropium 18 microg once-daily dosing, COPD indication, duration of at least four weeks. Incidence rates by treatment group, rate differences (tiotropium-placebo), and 95% confidence intervals were determined.. Twenty-six trials were identified involving 17,014 patients. Mean age was 65 years, mean forced expiratory volume in one second was 1.16 L (41% predicted), 76% men. Total exposure to study drug was 11,958 patient-years (tiotropium) and 10,578 patient-years (placebo). Tiotropium was associated with a reduced risk (expressed as rate difference [95% confidence interval] per 100 patients-years at risk) for an adverse event (-17.5 [-22.9, -12.2]), serious adverse event (-1.41 [-2.81, -0.00]) and a fatal event (-0.63 [-1.14, -0.12]). A reduced risk was present for adverse events that were cardiac (-0.79 [-1.48, -0.09]), lower respiratory (-14.2 [-17.0, -11.5]) and for a composite endpoint of major adverse cardiovascular events (-0.45 [-0.85, -0.05]). Typical expected inhaled anticholinergic effects such as dry mouth, constipation, and urinary difficulties were observed in the safety database.. The safety data review does not indicate an increased risk for death or cardiovascular morbidity during tiotropium treatment in patients with COPD.

Topics: Aged; Cholinergic Antagonists; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Several clinical trials have evaluated the benefits associated with adding an inhaled corticosteroid (ICS) to a long-acting bronchodilator in the treatment of severe or very severe (stage III or IV) chronic obstructive pulmonary disease (COPD).. We conducted a meta-analysis to elucidate the benefits and risks associated with adjunctive ICS treatment in patients with severe or very severe COPD.. A systematic literature search of MEDLINE, EMBASE, and the Cochrane Collaboration's Central Register of Controlled Clinical Trials (from initiation through April 2008) was conducted by 2 investigators working independently. A search strategy using key medical subject headings and text key words was performed using the Cochrane Collaboration's Highly Sensitive Search Strategy for MEDLINE and the McMaster University Health Information Research Unit EMBASE search strategy. To be included in this meta-analysis, studies had to be randomized controlled trials; compare the use of ICS in combination with long-acting beta-agonists (LABAs) or tiotropium with long-acting bronchodilator monotherapy; include only subjects with COPD and forced expiratory volume in 1 second (FEV(1)) <80% and an FEV(1)/forced vital capacity ratio <70%; follow up patients for a minimum of 24 weeks; and report data on either mortality or exacerbations. We evaluated 3 efficacy end points (exacerbations, mortality, and change in St. George's Respiratory Questionnaire [SGRQ] score), 2 tolerability end points (pneumonia and oral candidiasis), and study withdrawals. Rate ratios and relative risks (RRs) were calculated using a random effects model. Statistical heterogeneity was addressed using the Q statistic and I(2) value. The Egger weighted regression statistic and visual inspection of funnel plots were used to assess publication bias.. A total of 9 studies met the inclusion criteria (N = 7,992 subjects). Seven trials provided exacerbation rates and 8 trials provided data on overall mortality. Change in SGRQ score from baseline was reported in 6 trials while pneumonia and oral candidiasis were reported in 5 and 6 studies, respectively. The incidence of patient withdrawal was reported in 8 studies. Exacerbations (rate ratio, 0.82; 95% CI, 0.72-0.92) and SGRQ score (weighted mean difference, -1.98 points; 95% CI, -2.56 to -1.40) were reduced with adjunctive ICS treatment but mortality was not affected (rate ratio, 0.86; 95% CI, 0.73-1.02). Both pneumonia (RR, 1.68; 95% CI, 1.28-2.21) and oral candidiasis (RR, 2.93; 95% CI, 1.94-4.42) were increased with adjuvant ICS treatment. Patient study withdrawal for any reason (RR, 0.83; 95% CI, 0.74- 0.93) was less likely with adjuvant ICS treatment. On visual inspection of the funnel plots, publication bias could not be ruled out for either efficacy or tolerability end point analysis. However, inspection of the Egger weighted regression statistic suggested the low likelihood of publication bias for all end points.. Addition of an ICS to a LABA was associated with a reduced risk for exacerbations but an increased risk for pneumonia and oral candidiasis compared with long-acting bronchodilator monotherapy in this meta-analysis of 9 randomized controlled trials. While measured patient-perceived health and well-being increased to a statistically significant level, this did not translate into a clinically meaningful level for all patients with combination treatment. Lower risk of study withdrawal was observed in adjuvant ICS patients. The benefits and risks associated with adjunctive ICS treatment will need to be assessed when making decisions regarding its use.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Bronchodilator Agents; Drug Therapy, Combination; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown.. To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke.. Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers' trial registries with no date restrictions.. Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events.. The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I(2) statistic.. After a detailed screening of 103 articles, 17 trials enrolling 13,645 [corrected] patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 134 of 6984 [corrected] patients (1.9%) [corrected] receiving inhaled anticholinergics and 83 of 6661 [corrected] patients (1.2%) receiving control therapy (RR, 1.60 [corrected] [95% confidence interval {CI}, 1.22-2.10]; [corrected] P < .001, I(2) = 0%). Among individual components of the primary end point, inhaled anticholinergics significantly increased the risk of MI (RR, 1.52 [95% CI 1.04-2.22]; [corrected] P = .03, I(2) = 0%) and cardiovascular death (RR, 1.92 [95% CI, 1.23-3.00]; P = .004, [corrected] I(2) = 0%) without a statistically significant increase in the risk of stroke (RR, 1.46 [95% CI, 0.81-2.62]; P = .20, I(2) = 0%). All-cause mortality was reported in 146 [corrected] of the patients treated with inhaled anticholinergics (2.1%) and 108 [corrected] of the control patients (1.6%) (RR, 1.29 [95% CI, 1.00-1.65]; P = .05, I(2) = 0%) [corrected] A sensitivity analysis restricted to 6 [corrected] long-term trials (>6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95% CI, 1.27-2.35]; [corrected] P < .001, I(2) = 0%).. Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

Topics: Administration, Inhalation; Cardiovascular Diseases; Cholinergic Antagonists; Humans; Ipratropium; Myocardial Infarction; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk; Scopolamine Derivatives; Stroke; Tiotropium Bromide

COPD is a chronic disease and, like many other chronic diseases, there is no treatment to reverse the severity of the disease except for lung transplant. To date, no inhaled medications have been shown to improve survival. Tiotropium bromide is a long-acting inhaled anticholinergic drug for the treatment of COPD that can improve lung function, reduce symptoms and exacerbations, and improve quality of life with once-daily dosing. It was initially approved and marketed in several countries in Europe in 2002 and then approved in the US in 2004. Tiotropium is generally well tolerated with dry mouth being the main adverse effect. Other adverse effects include constipation, tachycardia, blurred vision, urinary retention and increased intraocular pressure. Despite the recently raised concerns about an excess risk of cardiovascular adverse events with inhaled anticholinergic agents, the risk/benefit ratio of tiotropium appears still favorable given the favorable safety profile demonstrated in the UPLIFT study. However, caution should be advised in patients at high risk for cardiovascular disease given the paucity of data in such patients.

Topics: Administration, Inhalation; Bronchodilator Agents; Cardiovascular Diseases; Cholinergic Antagonists; Humans; Medication Adherence; Patient Satisfaction; Pulmonary Disease, Chronic Obstructive; Quality of Life; Risk Assessment; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Bronchoconstriction; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Disease exacerbations are an important aspect of COPD, because they affect its course and are associated with higher lung function decline. On the other hand, data obtained by biopsies have demonstrated that the progression of COPD is related to an increasing impairment of small airways. We sought to evaluate the small airway impairment (FEF25-75) in two groups of COPD patients (each group had 37 subjects) in relation to the frequency of exacerbations and the effectiveness of treatment with tiotropium bromide on the small airway impairment. The mean number of exacerbations was 3.6/year and 1.38/year in frequent and in infrequent exacerbators, respectively (p < 0.001). The mean value of FEF25-75 at baseline was 624 mL and 865 mL in frequent and in infrequent exacerbators respectively (p = 0.002). The changes in respiratory parameters versus baseline showed increases in mean FEV1, FVC, and FEF25-75 in both groups but only the increase in FEF25-75 in frequent exacerbators was statistically significantly (p = 0.013). During the 3-month period of the study the mean number of exacerbations was 0.66 in frequent and 0.12 in infrequent exacerbators. These findings indicate that COPD patients with frequent exacerbations have a higher impairment of small airways. Treatment with tiotropium in COPD subjects with frequent exacerbations proved to be effective in improving small airway impairment.

Topics: Acute Disease; Aged; Aged, 80 and over; Bronchodilator Agents; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Topics: Aged, 80 and over; Bronchodilator Agents; Forced Expiratory Volume; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Smoking; Spirometry; Tiotropium Bromide; Tomography, X-Ray Computed

Current guidelines recommend the use of inhaled tiotropium in patients with stable chronic obstructive pulmonary disease (COPD). However, this statement is based on a relatively small number of randomized controlled trials (RCTs) and related systematic reviews. This review was undertaken to incorporate the more recent evidence available about the effectiveness of tiotropium bromide compared with placebo, iptratropium bromide or long-acting beta-agonists (LABAs), for the treatment of stable COPD patients.. Medline, EMBASE, CINAHL, and the Cochrane Controlled Trials Register (to February 2006) were searched to identify all published RCTs. We also searched bibliographies of relevant articles.. Data from 13 RCT (6078 subjects, 80% male) showed that tiotropium reduced COPD-related exacerbations (OR=0.76; 95% CI: 0.68-0.87) and hospital admissions (OR=0.59; 95% CI: 0.47-0.73) compared with placebo. Also, tiotropium showed statistically significant improvement in lung function, including trough, average, and peak FEV(1) and FVC from baseline, compared with placebo and ipratropium. The administration of inhaled tiotropium lead to 30% reduction in COPD-related admissions (OR= 0.67; 95% CI: 0.46-0.98) compared with LABAs. Finally, increases in FEV(1) and FVC from baseline were significantly larger with tiotropium than with LABAs.. This review clearly supports the beneficial effects of the use of tiotropium in stable moderate-to-severe COPD patients, and increases the evidence in favor of the superiority of tiotropium on LABAs.

Topics: Adrenergic beta-Agonists; Bronchodilator Agents; Female; Forced Expiratory Volume; Hospitalization; Humans; Ipratropium; Male; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

The Global Obstructive Lung Disease (GOLD) guidelines suggest the potential use of combination bronchodilator therapy in patients with stage II or higher chronic obstructive pulmonary disease (COPD). Guidelines from the American Thoracic Society also mention that certain combinations of bronchodilators may prevent exacerbations. Combinations of several agents may benefit patients with COPD not only by improving lung function, but also by decreasing exacerbation rates and improving overall symptoms. A MEDLINE search was conducted to gather published data and clinical trial reports regarding the clinical effect of combining bronchodilators in the treatment of COPD. Agents such as oxitropium, which is not available in the United States, were not included in the analysis. Although the data are somewhat limited, trials suggest many potential benefits for combination bronchodilator therapy in patients with COPD. Information on combining long-acting anticholinergic drugs with long-acting beta2-agonists is scarce, but the combination of two long-acting agents may provide additional benefits by improving patient compliance with prescribed regimens. More studies evaluating outcomes in patients with COPD may help solidify the potential benefits of combination inhaled bronchodilator therapy.

Topics: Administration, Inhalation; Albuterol; Bronchodilator Agents; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Anticholinergics have been used to treat obstructive respiratory disease for many years from historical preparations of the deadly nightshade genus, to the more recent developments ofipratropium, oxitropium, and tiotropium. The medical treatment of airways obstruction has focused on achieving maximal airway function through bronchodilators. Of the two main bronchodilators, beta2-agonists are often the first treatment choice although there is evidence of equivalence and some suggestions of the superiority of anticholinergics in chronic obstructive pulmonary disease (COPD). The following review looks at the background of anticholinergics, their pharmacological properties, and the evidence for use with suggestions for their place in the treatment of COPD.

Topics: Cholinergic Antagonists; Exercise Tolerance; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Quality of Life; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium is a potent, long-acting, selective anticholinergic bronchodilator. Treatment with tiotropium produces sustained improvements in lung function, particularly FEV1 (peak, trough, average, and area under the curve) compared with either placebo or ipratropium in patients with moderate to severe COPD. Preliminary evidence suggests that treatment with tiotropium may slow the rate of decline in FEV1, but this finding awaits confirmation. Tiotropium reduces lung hyperinflation, with associated improvements in exercise capacity. Tiotropium, compared with either placebo or ipratropium, improves a variety of patient-centered outcomes, including subjective dyspnea ratings and HRQL scores. Tiotropium reduces the frequency of COPD exacerbations and of hospitalizations due to exacerbations, but has not been shown to reduce all-cause mortality. Compared with the long-acting bronchodilators, tiotropium provides incrementally better bronchodilation, but it is not clearly superior in terms of patient-centered outcomes. Tiotropium has a good safety profile; however patients with severe cardiac disease, bladder outlet obstruction, or narrow angle glaucoma were excluded from all studies. Medico economic analyses suggest that treatment with tiotropium may also be cost-effective, primarily by reducing costs associated with hospitalizations.

Topics: Adrenergic beta-Agonists; Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials as Topic; Cost-Benefit Analysis; Drug Costs; Drug Therapy, Combination; Exercise; Forced Expiratory Volume; Humans; Lung; Patient Selection; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) accounts for a major workload in both primary and secondary care. It is characterised by progressive airflow obstruction which does not fully reverse to inhaled or oral pharmacotherapy. The diagnosis should be considered in any current or former smoker who has symptoms of breathlessness, wheeze, cough, sputum production and impaired exercise tolerance. From a pharmacological perspective, short-acting bronchodilators (anti-cholinergics and beta(2)-agonists) play a vital role in immediate relief of symptoms. However, in patients with persistent symptoms and exacerbations, long-acting bronchodilator therapy is advocated for regular use. Tiotropium is a newly introduced long-acting anti-cholinergic which facilitates once daily administration. This evidence based review article discusses the use of long acting bronchodilators in COPD with a particular emphasis on the putative benefits of tiotropium.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Topics: Adrenergic beta-Agonists; Airway Resistance; Albuterol; Anti-Inflammatory Agents; Beclomethasone; Bronchodilator Agents; Drug Monitoring; Ethanolamines; Exercise Tolerance; Forced Expiratory Volume; Formoterol Fumarate; Humans; Inflammation; Plethysmography, Whole Body; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide; Treatment Outcome

Anticholinergic agents have important uses as bronchodilators for the treatment of obstructive airway diseases, both asthma and, more particularly, chronic obstructive pulmonary disease (COPD). Those in approved clinical use are synthetic quaternary ammonium congeners of atropine, and include ipratropium bromide, oxitropium bromide, and tiotropium bromide, each of which is very poorly absorbed when given by inhalation. Ipratropium and oxitropium have relatively short durations of action (4-8 h). They have been widely used for many years, either alone or in combination with short-acting beta-adrenergic agents such as albuterol and fenoterol, for both maintenance treatment of stable disease and for acute exacerbations of airway obstruction. Tiotropium, which was introduced in the early 2000s, has a duration of action of at least 1-2 days making it suitable for once-daily maintenance treatment of COPD. All of the above agents have a wide therapeutic margin and are safe and well tolerated by patients.

Topics: Asthma; Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials as Topic; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Acute Disease; Adrenergic beta-Agonists; Cholinergic Antagonists; Disease Progression; Drug Combinations; Dyspnea; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Long-acting beta(2) agonists are an effective and convenient treatment for chronic obstructive pulmonary disease (COPD), but do not significantly improve lung function. The long-acting anticholinergic tiotropium, which can be taken once daily, decreases exertional dyspnoea and increases endurance by reducing hyperinflation. The role in COPD of the combination of a long-acting beta(2) agonist and a glucocorticoid in a single inhaler remains unclear. The minimum duration of an effective pulmonary rehabilitation program that includes exercise training is 6 weeks. Long-term treatment with inhaled glucocorticoids may reduce the rate of decline in lung function, but the effect is small. Aminophylline should no longer be routinely used in acute exacerbations of COPD. Non-invasive positive pressure ventilation (NPPV) reduces mortality and hospital stay in patients with acute hypercapnic ventilatory failure; it is also an effective weaning strategy for patients who require intubation. Further studies are required to clarify the role of NPPV in the long-term management of stable COPD.

Topics: Administration, Inhalation; Administration, Oral; Adrenergic beta-Agonists; Asthma; Australia; Bronchodilator Agents; Diagnosis, Differential; Drug Combinations; Evidence-Based Medicine; Expectorants; Glucocorticoids; Humans; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Risk Factors; Scopolamine Derivatives; Social Support; Tiotropium Bromide; Vaccination

Chronic obstructive pulmonary disease (COPD) is a common disease with a global impact in terms of morbidity and mortality. Patients usually consult their doctor because of symptoms, and among those, dyspnea at rest or under exercise is one of the most common. The sensation of dyspnea is experienced differently among individuals with COPD and may be based on diverse factors, such as muscle fatigue, patient perception, or trapped volumes. Treatment algorithms for COPD emphasize a stepwise approach to therapy depending on the severity of the disease, which, for reasons of convenience, is primarily based on spirometric impairment. Drugs that alter bronchial smooth muscle tone and increase inspiratory capacity have clinical efficacy for the dyspneic patient, most likely based on their effect on lung function, whereas the effects of antiinflammatory therapy with inhaled corticosteroids is more difficult to explain. The following short review aims to give an overview of the available clinical information of clinical trials performed over the last couple of years.

Topics: Adrenergic beta-Agonists; Albuterol; Cholinergic Antagonists; Dyspnea; Humans; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Anticholinergics are widely used for the treatment of COPD, and to a lesser extent for asthma. Primarily used as bronchodilators, they reverse the action of vagally derived acetylcholine on airway smooth muscle contraction. Recent novel studies suggest that the effects of anticholinergics likely extend far beyond inducing bronchodilation, as the novel anticholinergic drug tiotropium bromide can effectively inhibit accelerated decline of lung function in COPD patients. Vagal tone is increased in airway inflammation associated with asthma and COPD; this results from exaggerated acetylcholine release and enhanced expression of downstream signaling components in airway smooth muscle. Vagally derived acetylcholine also regulates mucus production in the airways. A number of recent research papers also indicate that acetylcholine, acting through muscarinic receptors, may in part regulate pathological changes associated with airway remodeling. Muscarinic receptor signalling regulates airway smooth muscle thickening and differentiation, both in vitro and in vivo. Furthermore, acetylcholine and its synthesizing enzyme, choline acetyl transferase (ChAT), are ubiquitously expressed throughout the airways. Most notably epithelial cells and inflammatory cells generate acetylcholine, and express functional muscarinic receptors. Interestingly, recent work indicates the expression and function of muscarinic receptors on neutrophils is increased in COPD. Considering the potential broad role for endogenous acetylcholine in airway biology, this review summarizes established and novel aspects of muscarinic receptor signaling in relation to the pathophysiology and treatment of asthma and COPD.

Topics: Acetylcholine; Animals; Asthma; Bronchodilator Agents; Cell Differentiation; Cell Proliferation; Fibroblasts; Humans; Lung; Lymphocytes; Mucus; Muscarinic Antagonists; Muscle, Smooth; Neutrophils; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Signal Transduction; Tiotropium Bromide

Topics: Animals; Bronchodilator Agents; Humans; Lung; Parasympatholytics; Pulmonary Disease, Chronic Obstructive; Quality of Life; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

The goals of COPD management according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline are: prevention of disease progression, relief of symptoms, improvement of exercise tolerance and the quality of life, prevention and treatment of exacerbations and complications, and reduction of mortality and adverse effects. These correspond to the goals formulated in the Dutch 'National transmural agreements on COPD'. Bronchodilators play a key role in the pharmacological treatment and with the availability of tiotropium, a long-acting anticholinergic bronchodilator, it has become important to decide at what moment this is indicated in COPD management. In comparative studies, tiotropium was an effective long-acting bronchodilator that had a favourable effect not only on lung function but also on the other parameters indicated in the GOLD guideline. When maintenance treatment with bronchodilators is needed, one should consider a long-acting bronchodilator. In view of the additive positive effects, tiotropium is the bronchodilator of choice. In case of severe symptoms, a combination of tiotropium with a long-acting beta2-sympathicomimetic agent is recommended.

Topics: Bronchodilator Agents; Disease Progression; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

A systematic review was undertaken to evaluate the efficacy of tiotropium, a long acting anticholinergic drug, on clinical events, symptom scales, pulmonary function, and adverse events in stable chronic obstructive pulmonary disease (COPD).. A systematic search was made of the Cochrane trials database, MEDLINE, EMBASE, CINAHL, and a hand search of 20 respiratory journals. Missing data were obtained from authors and the manufacturer. Randomised controlled trials of > or =12 weeks' duration comparing tiotropium with placebo, ipratropium bromide, or long acting beta2 agonists (LABA) were reviewed. Studies were pooled to yield odds ratios (OR) or weighted mean differences with 95% confidence intervals (CI).. Nine trials (8002 patients) met the inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.73; 95% CI 0.66 to 0.81) and related hospitalisation (OR 0.68; 95% CI 0.54 to 0.84) but not pulmonary (OR 0.50; 95% CI 0.19 to 1.29) or all-cause (OR 0.96; 95% CI 0.63 to 1.47) mortality compared with placebo and ipratropium. Reductions in exacerbations and hospitalisations compared with LABA were not statistically significant. Similar patterns were evident for quality of life and symptom scales. Tiotropium yielded greater increases in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) from baseline to 6-12 months than did placebo, ipratropium, and LABA. Decline in FEV1 over 1 year was 30 ml (95% CI 7 to 53) slower with tiotropium than with placebo and ipratropium (data were not available for LABA). Reports of dry mouth and urinary tract infections were increased with tiotropium.. Tiotropium reduced COPD exacerbations and related hospitalisations, improved quality of life and symptoms, and may have slowed the decline in FEV1. Long term trials are warranted to evaluate the effects of tiotropium on decline in FEV1 and to clarify its role compared with LABA.

Topics: Acute Disease; Bronchodilator Agents; Double-Blind Method; Dyspnea; Forced Expiratory Volume; Hospitalization; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Forced expiratory volume in 1 second (FEV1) has served as an important diagnostic measurement of chronic obstructive pulmonary disease (COPD) but has not been found to correlate with patient-centered outcomes such as exercise tolerance, dyspnea, or health-related quality of life. It has not helped us understand why some patients with severe FEV1 impairment have better exercise tolerance compared with others with similar FEV1 values. Hyperinflation, or air trapping caused by expiratory flow limitation, causes operational lung volumes to increase and even approach the total lung capacity (TLC) during exercise. Some study findings suggest that a dyspnea limit is reached when the end-inspiratory lung volume encroaches within approximately 500 mL of TLC. The resulting limitation in daily physical activity establishes a cycle of decline that includes physical deconditioning (elevated blood lactic acid levels at lower levels of exercise) and worsening dyspnea. Hyperinflation is reduced by long-acting bronchodilators that reduce airways resistance. The deflation of the lungs, in turn, results in an increased inspiratory capacity. For example, the once-daily anticholinergic bronchodilator tiotropium increases inspiratory capacity, 6-minute walk distance, and cycle exercise endurance time, and it decreases isotime fatigue or dyspnea. Pulmonary rehabilitation and oxygen therapy both reduce ventilatory requirements and improve breathing efficiency, thereby reducing hyperinflation and improving exertional dyspnea. Thus, hyperinflation is directly associated with patient-centered outcomes such as dyspnea and exercise limitation. Furthermore, therapeutic interventions--including pharmacotherapy and lung volume--reduction surgery--that reduce hyperinflation improve these outcomes.

Topics: Bronchodilator Agents; Dyspnea; Exercise; Exercise Tolerance; Health Status; Humans; Inspiratory Capacity; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Severe exacerbations of chronic obstructive pulmonary disease (COPD) are morbid events with slow recovery periods. They consume substantial healthcare resources, and they may cause a more rapid reduction in lung function over time. Quality of life (QOL) deteriorates in patients who experience exacerbations, and the more frequent the exacerbations, the more rapid the decline in QOL. Hospitalizations due to exacerbations account for up to 70% of the cost of medical care for patients with COPD. Patients with more severe COPD have more hospitalizations compared with those with less severe disease. A number of therapeutic interventions reduce the number of exacerbations and hospitalizations due to respiratory disease. The long-acting anticholinergic bronchodilator tiotropium, influenza vaccination, and possibly case management appear to reduce need for hospitalization substantially. COPD management should include drugs and other interventions that reduce the frequency of exacerbations and minimize their negative impact on the clinical course of the disease.

Topics: Acute Disease; Bronchodilator Agents; Clinical Trials as Topic; Disease Progression; Health Status; Humans; Influenza Vaccines; Patient Admission; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Severity of Illness Index; Surveys and Questionnaires; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease in which patients experience a progressive decline in lung function. Based on clinical evidence, the management of COPD should focus on (1) earlier diagnosis; (2) risk reduction through smoking cessation, decreased exposure to inhaled irritants, and immunization against respiratory pathogens; (3) symptom reduction with pharmacotherapy and pulmonary rehabilitation; (4) decreasing complications by reducing exacerbations and improving pulmonary function; and (5) improving health-related quality of life (HRQOL). Smoking cessation has been shown to slow lung function decline and to reduce mortality--including deaths due to lung cancer, other respiratory disease (including COPD), and cardiovascular disease. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the American Thoracic Society and European Respiratory Society (ATS/ERS) guidelines advocate interventions according to the severity of COPD and recommend initiation of maintenance long-acting bronchodilator therapy in patients with moderate disease. However, recent evidence from a post hoc analysis of randomized controlled trials of tiotropium suggests that initiation of long-acting bronchodilator therapy at earlier stages of disease may also provide improvements in lung function and HRQOL. The results of ongoing long-term studies may soon provide evidence that in addition to relieving symptoms and improving patient HRQOL, specific pharmacologic therapies may also alter the clinical course of COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; Bronchodilator Agents; Clinical Trials as Topic; Drug Therapy, Combination; Forced Expiratory Volume; Health Status; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide

In chronic obstructive pulmonary disease (COPD), the rate of decline in forced expiratory volume in 1 second (FEV1) and progression to disability and death are accelerated. COPD management goals include preventing or slowing the progressive loss of lung function, relieving symptoms, improving exercise tolerance and the patient's health status, preventing and treating exacerbations and complications, minimizing side effects of treatment, and reducing mortality. Although lung function is important for diagnosis of COPD and classification of its severity, clinicians and patients are also very interested in symptoms, ability to function, and general well-being (health status). Consequently, increasing attention is being given to these patient-centered outcomes. It is possible to modify patient-centered outcomes; however, it remains to be seen whether doing so can also alter the natural course of the disease and reduce mortality. Two long-term clinical trials--Towards a Revolution in COPD Health (TORCH) and Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT)--will help to answer the question of whether pharmacologic interventions are effective in changing the clinical course of COPD. The TORCH study examines the long-term effects of combination therapy with an inhaled long-acting beta-agonist (salmeterol) and a corticosteroid (fluticasone) on reduction of all-cause mortality over 3 years. The 4-year UPLIFT study examines the effects of maintenance treatment with the once-daily anticholinergic bronchodilator tiotropium on the yearly rate of decline in trough FEV1 and the yearly rate of decline in FEV1 90 minutes after maximal or near-maximal bronchodilator administration. This article examines the rationale for each of these studies and provides an overview of study methodology as well as preliminary demographic data.

Topics: Acute Disease; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Dyspnea; Female; Fluticasone; Forced Expiratory Volume; Health Status; Humans; Male; Middle Aged; Patient Admission; Patient-Centered Care; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

Marketing approval of pharmaceutical products is often based on data from several thousand subjects or fewer. Evaluation of safety is greatly enhanced by augmenting the safety database with postapproval studies.. We conducted a pooled analysis of adverse event data from 19 randomized, double-blind, placebo-controlled trials with tiotropium in patients with obstructive lung disease. We computed incidence rates and rate ratios (RRs) for various reported adverse event end points of interest. Patients contributed person-time to the analysis as long as they were in the study until 30 days after treatment (tiotropium, placebo), or until they had the event of interest, whichever came first. Studies were pooled using the Mantel-Haenszel estimator, and we used 95% confidence intervals (CIs) to assess the precision of effect estimates.. The pooled trial population includes 4,435 tiotropium patients and 3,384 placebo patients contributing 2,159 person-years of exposure to tiotropium and 1,662 person-years of exposure to placebo. Dyspnea, dry mouth, COPD exacerbation, and upper respiratory tract infection were the most commonly reported events. There was a higher relative risk of dry mouth in the tiotropium group (RR, 3.60; 95% CI, 2.56 to 5.05). There was a lower risk of dyspnea (RR, 0.64; 95% CI, 0.50 to 0.81) and COPD exacerbation (RR, 0.72; 95% CI, 0.64 to 0.82) in patients receiving tiotropium compared to patients receiving placebo. Other results of interest are as follows: (1) all-cause mortality (RR, 0.76; 95% CI, 0.50 to 1.16); (2) cardiovascular mortality (RR, 0.57; 95% CI, 0.26 to 1.26); and (3) respiratory mortality (RR, 0.71; 95% CI, 0.29 to 1.74). The relative risk of urinary retention was 10.93 (95% CI, 1.26 to 94.88).. Pooling of adverse event data from preapproval and postapproval tiotropium clinical trials increase the precision of effect estimates and supports the present safety profile of tiotropium.

Topics: Adverse Drug Reaction Reporting Systems; Aged; Bronchodilator Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Product Surveillance, Postmarketing; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Therapy with bronchodilators forms the pharmacologic foundation of the treatment of patients with COPD. Bronchodilators can significantly lessen dyspnea, increase airflow, improve quality of life, and enhance exercise performance. While bronchodilators decrease airway resistance and lessen dynamic hyperinflation in patients with COPD, they have not been shown to alter the rate of decline in FEV1 over time, or improve patient survival. Fairly recently, a long-acting, once-daily anticholinergic medication, tiotropium bromide, has been developed which may improve symptom management in COPD patients. This paper reviews anticholinergic pharmacologic therapy for patients with COPD focusing on tiotropium bromide, and discusses treatment strategies based on disease stage. It is important to recognize that while bronchodilators improve symptoms, a multimodality treatment approach including respiratory and rehabilitative therapy, nutrition services, psychosocial counseling, and surgical care, is often necessary for the best possible care of patients with COPD.

Topics: Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

This article reviews findings from recently published randomized controlled clinical trials to address the question whether a long-acting inhaled bronchodilator should be the initial choice for maintenance therapy in patients with stable, symptomatic chronic obstructive pulmonary disease (COPD).. Results of recent clinical trials suggest that a long-acting inhaled bronchodilator, either once-daily tiotropium or twice-daily salmeterol or formoterol, has advantages over a regularly-scheduled short-acting anticholinergic inhaled bronchodilator (ipratropium) as initial maintenance therapy in patients with at least moderate, stable, symptomatic COPD (forced expired volume in 1 second

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Bronchodilator Agents; Chemistry, Pharmaceutical; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Theophylline; Tiotropium Bromide; Treatment Outcome

Tiotropium is a new anticholinergic therapy for chronic obstructive pulmonary disease (COPD) that differs from ipratropium by its functional relative selectivity for muscarinic receptor subtypes and which allows once-per-day dosing.. To determine the efficacy of tiotropium on clinical endpoints such exacerbations and hospitalisations, symptom scales and pulmonary function compared to placebo and other bronchodilators used for stable COPD.. Randomised controlled trials (RCTs) were identified from the Cochrane Airways Review Group Specialised Register, a compilation of systematic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and hand searching of 20 respiratory journals. Bibliographies from included studies and reviews were searched. The date of the last search was October 2004.. Randomised clinical trials comparing tiotropium with placebo, ipratropium bromide, or long-acting ss2-agonists for greater than, or equal to, one month's duration.. Two reviewers independently extracted data. Missing data were obtained from authors or the manufacturer of tiotropium. The data were analysed using the Cochrane Review Manager RevMan 4.2. Studies were pooled to yield weighted mean differences (WMD) or odds ratios (OR) and reported using 95% confidence intervals (CI).. From 69 identified references, nine RCTs (6,584 patients) met inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.74; 95% CI 0.66 to 0.83) and related hospitalisations (OR 0.64; 95% CI 0.51 to 0.82) compared to placebo or ipratropium. When applied to an annual baseline risk of 45% for exacerbations and 10% for hospitalisation, the number of patients needed to treat with tiotropium for one year were 14 (95% CI 11 to 22) to prevent one exacerbation and 30 (95% CI 22 to 61) to prevent one hospitalisation compared to placebo and ipratropium. Reductions in these endpoints compared to long-acting ss2-agonists were not statistically significant. Similar patterns were evident for quality-of-life and symptom scales. Increases in FEV1 and FVC from baseline were significantly larger with tiotropium than with placebo, ipratropium and long-acting ss2-agonists over 6 to 12 months. The decline in trough FEV1 from steady state was 30 ml (95% CI 7 to 53 ml) less with tiotropium than with placebo or ipratropium over one year; no data on decline in FEV1 from steady state were available for long-acting ss2-agonists. Dry mouth was increased by tiotropium.. Tiotropium reduced COPD exacerbations and related hospitalisations compared to placebo and ipratropium. It also improved health-related quality-of-life and symptom scores among patients with moderate and severe disease, and may have slowed decline in FEV1. Additional long-term studies are required to evaluate its effect on mortality and change in FEV1 to clarify its role in comparison to, or in combination with, long-acting ss2-agonists and to assess its effectiveness in mild and very severe COPD.

Topics: Administration, Inhalation; Cholinergic Antagonists; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Topics: Administration, Inhalation; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium bromide is a new inhaled anticholinergic agent approved for once-daily, long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).. This article reviews the pharmacology, pharmacokinetic and pharmacodynamic properties, clinical efficacy, tolerability, and cost of tiotropium therapy in patients with COPD.. The MEDLINE (1966-October 2004), Iowa Drug Information Service (1966-October 2004), and International Pharmaceutical Abstracts (1970-November 2004) databases were searched for original research and review articles published in English. The search terms were tiotropium, Ba 679 BR, and HandiHaler. Reference lists from these articles were also consulted, as was selected information provided by the manufacturer of tiotropium. All relevant identified studies were included in the review, with preference given to Phase II/III trials. Pharmacoeconomic studies were limited to those conducted in the United States.. Tiotropium is a nonselective anticholinergic agent that exhibits kinetic receptor selectivity for the muscarinic M1 and M3 receptors. After inhalation, tiotropium has an onset of action within 30 minutes, a peak effect within 3 to 4 hours, and a > or = 24-hour duration of action that allows once-daily dosing. In clinical trials, patients receiving tiotropium 18 microg QD had significant improvements in trough, peak, and mean forced expiratory volume in 1 second (FEV1), dyspnea, and health-related quality of life, as well as fewer COPD exacerbations and hospitalizations, compared with patients receiving placebo and ipratropium (all, P < 0.05). Improvement in FEV1 was also significantly greater in patients who received tiotropium compared with those who received salmeterol (P < 0.05), although the number of exacerbations and extent of health resource use were comparable between groups. Dry mouth was the most commonly reported adverse effect. One analysis found tiotropium to be cost-effective compared with ipratropium.. Tiotropium offers several advantages over ipratropium in the management of COPD. Long-term (> 1 year) studies are necessary to determine the impact of tiotropium on disease progression and life expectancy.

Topics: Adult; Bronchodilator Agents; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage and administration, and formulary considerations of tiotropium are discussed.. Tiotropium, a long-acting inhaled anticholinergic, recently received approval from the Food and Drug Administration for the management of chronic obstructive pulmonary disease (COPD). In patients with COPD, increased parasympathetic nervous system activity leads to bronchoconstriction and mucus secretion. Tiotropium induces relaxation of the airway smooth muscle, as does ipratropium, but differs in receptor association and dissociation rates, allowing for once-daily administration. After inhalation, tiotropium reaches maximal plasma concentrations within five minutes, but clinical improvements in forced expiratory volume in one second (FEV(1)) are maintained over 24 hours. Clinical trials of tiotropium with placebo, ipratropium, and salmeterol have demonstrated the efficacy of tiotropium in improving FEV(1) and forced vital capacity values and health-related quality of life. The most commonly observed adverse effect is dry mouth. No increase in adverse effects was observed when tiotropium was administered concomitantly with other drugs for COPD, including sympathomimetic bronchodilators and oral and inhaled corticosteroids. The combination of tiotropium and other anticholinergics has not been studied and is not recommended. The recommended dosage of tiotropium is the inhalation of an 18-mug capsule with a HandiHaler breath-actuated inhalation device once daily.. Tiotropium appears to be at least as effective as currently available alternatives in the treatment of patients with COPD who require daily bronchodilator treatment. Its simplified dosing and tolerable adverse-effect profile can potentially lead to enhanced patient compliance.

Topics: Administration, Inhalation; Cholinergic Antagonists; Delayed-Action Preparations; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

To review the scientific literature evaluating the efficacy and tolerability of tiotropium bromide, a new bronchodilator indicated for treatment of chronic obstructive pulmonary disease (COPD).. Articles were identified through searches of MEDLINE (1966-January 2005) using the key words tiotropium, BA 679 BR, chronic obstructive pulmonary disease, and anticholinergic agents. Additional citations were identified from bibliographies of publications cited.. Experimental and observational studies of tiotropium bromide were selected. Trials of the efficacy of the drug in humans were the focus of the review.. Tiotropium bromide is an effective bronchodilator for patients with COPD. It produces clinically important improvements in lung function, symptoms of dyspnea, quality of life, and exacerbation rates compared with placebo. In comparative studies, tiotropium does not appear to be more efficacious than salmeterol or ipratropium.. Tiotropium is an effective inhaled anticholinergic agent that is recommended among preferred long-acting bronchodilators for the chronic management of moderate to very severe COPD. Although similar to ipratropium in efficacy and tolerability, it has the advantage of once-daily dosing.

Topics: Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials as Topic; Cost-Benefit Analysis; Exercise; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

Bronchodilator therapy forms the mainstay of treatment for symptomatic patients with COPD. Long-acting bronchodilators, which maintain sustained airway patency over a 24-hour period, represent an advance in therapy. Tiotropium bromide is a new long-acting inhaled anticholinergic agent with superior pharmacodynamic properties compared with the short-acting anticholinergic, ipratropium bromide. Tiotropium bromide has been consistently shown to have a greater impact than ipratropium bromide on clinically important outcome measures such as health status. The mechanisms of clinical benefit with tiotropium bromide are multifactorial, but improved airway function, which enhances lung emptying and allows sustained deflation of over-inflated lungs, appears to explain improvements in dyspnea and exercise endurance in COPD. Inhaled tiotropium bromide therapy has also been associated with reduction in acute exacerbations of COPD as well as reduced hospitalizations. The safety profile of tiotropium bromide is impressive: dry mouth is the most common adverse event and rarely necessitates termination of the drug. No tachyphylaxis to tiotropium bromide has been demonstrated in clinical trials lasting up to 1 year. There is preliminary information that the combination of long-acting anticholinergics and long-acting beta2-adrenoceptor agonists provides additive physiological and clinical benefits. According to recent international guidelines, long-acting bronchodilators should be considered early in the management of symptomatic patients with COPD in order to achieve effective symptom alleviation and reduction in activity limitation. Tiotropium bromide, because of its once-daily administration and its established efficacy and tolerability profile, has emerged as an attractive therapeutic option for this condition.

Topics: Bronchodilator Agents; Cholinergic Antagonists; Exercise Tolerance; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium is a long-acting anticholinergic bronchodilator, inhaled only once a day, which produces relaxation of airway smooth muscle through antagonism of acetylcholine at M3-muscarinic receptors. Its duration of action is at least 24 h with once daily administration of tiotropium. Several studies have shown its efficacy and its good tolerance in the treatment of patients who are suffering from moderate to very severe chronic obstructive pulmonary disease (COPD). Tiotropium improves spirometric measurements and quality of life, and reduces dyspnea and exacerbation rate in COPD patients.

Topics: Administration, Inhalation; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Bronchodilators form the foundation of symptomatic treatment of COPD. Several long-acting bronchodilators are now available for use in COPD, but publications of large-scale studies of their efficacy have, for the most part, postdated the publication of major clinical guidelines. This article provides a critical review of large (> or =50 patients), double-blind, clinical trials of three long-acting bronchodilators in COPD (the once-daily anticholinergic tiotropium, and the twice-daily beta(2)-agonists formoterol and salmeterol) within the context of the objectives of treatment defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Fourteen published studies were identified, of which 12 studies were published since the release of the GOLD guidelines. All three long-acting bronchodilators were found to effectively improve lung function; however, they differed in their effects on outcomes other than bronchodilation, with salmeterol demonstrating inconsistent efficacy compared with placebo in preventing exacerbations and improving health status, and only tiotropium demonstrating consistent superiority to the short-acting bronchodilator ipratropium. Based on this review, a treatment algorithm for the introduction of long-acting bronchodilators to patients with COPD is proposed, which includes the use of long-acting bronchodilators early in the treatment algorithm.

Topics: Adrenergic beta-Agonists; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Ethanolamines; Formoterol Fumarate; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Cholinergic Antagonists; Clinical Trials as Topic; Humans; Pulmonary Disease, Chronic Obstructive; Receptors, Cholinergic; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Bronchodilator Agents; Drug Costs; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium bromide is a quaternary ammonium compound structurally related to ipratropium and has recently been approved in the US for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic-obstructive pulmonary disease (COPD). It is available in a dry powder form, where 18 microg [corrected] of the drug is inhaled once-daily through a device, the HandiHaler). The potency and long duration of effect of this anticholinergic bronchodilator result primarily from a prolonged blockade of the M1 and M3 muscarinic receptors in the airways and a relatively more rapid dissociation from the M2 receptor (which provides inhibitory feedback). Multiple studies of up to a duration of 1 year have demonstrated its effectiveness as a bronchodilator for COPD, with a trough increase (measured approximately 24 h after administration of the drug) in forced expiratory volume in 1 s of approximately 0.12 l and a peak increase of approximately 0.25 l. Tiotropium inhalation also leads to a significant reduction in static lung volumes in hyperinflated patients with COPD; this probably contributes to the reduction in dyspnoea that is associated with long-term use of this maintenance bronchodilator. Regular use of the drug was associated with clinically meaningful increases in the Transitional Dyspnoea Index, which indicate reductions in dyspnoea associated with daily activities. Improvement in the respiratory-specific health status questionnaire, the St George's Respiratory Questionnaire component and total scores was also documented. Finally, pooled data from two 1-year studies and two 6-month studies documented 20 and 28% reductions in the number of exacerbations per patient per year. Side effects have been relatively minimal, with dry mouth the most common symptom, ranging 6 - 16% of patients and rarely leading to discontinuation of the study drug. Limited comparisons of efficacy with other bronchodilators are available. Once-daily tiotropium has been demonstrated to be clearly superior to ipratropium four times daily as a bronchodilator for COPD. Combined results from two studies comparing once-daily tiotropium to twice-daily inhalation of standard doses of salmeterol, indicate a magnitude of the bronchodilator response similar in the two drugs early in the study. However, by 6 months, the bronchodilator effect of tiotropium was somewhat greater than that of the long-acting beta-agonist. Preliminary data suggest that combining tiotropium with lon

Topics: Administration, Inhalation; Bronchodilator Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Delivery Systems; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium bromide (Spiriva) is a long-acting anticholinergic bronchodilator that maintains bronchodilation for at least 24 hours, allowing once-daily administration. The active moiety is the tiotropium cation (tiotropium); tiotropium bromide 22.5 micrograms is equivalent to 18 micrograms of tiotropium cation. Greater improvements in lung function from baseline (primary endpoint mean trough FEV(1)) were observed with inhaled tiotropium 18 micrograms once daily than with placebo in 6-month and 1-year randomized, double-blind trials in patients with COPD. Tiotropium improved lung function (trough FEV(1) response) more effectively than ipratropium bromide (ipratropium) 40 micrograms four times daily in 1-year clinical trials, and was at least as effective as salmeterol 50 micrograms 12-hourly in 6-month trials. Preliminary data suggest that tiotropium alone or in combination with once-daily formoterol has a greater bronchodilator effect than twice-daily formoterol in patients with COPD. Improvements in patients' perception of health-related quality of life (HR-QOL) or dyspnea were greater with tiotropium than with placebo or ipratropium, and were similar to those with salmeterol. Reductions in the frequency and severity of acute exacerbations and in the use of rescue medication were also greater with tiotropium than with ipratropium or placebo. There was no evidence of tachyphylaxis with tiotropium during 1-year clinical trials. Inhaled tiotropium was generally well tolerated in clinical trials. Apart from dry mouth, the type and incidence of adverse events with tiotropium were similar to those with ipratropium, salmeterol or placebo in patients with COPD. In conclusion, inhaled tiotropium 18 micrograms once daily improved lung function, dyspnea, and HR-QOL, and decreased the incidence of acute COPD exacerbations and the use of rescue medication relative to placebo or ipratropium in clinical trials in patients with COPD. Tiotropium was at least as effective as salmeterol in terms of bronchodilator efficacy and improvements in dyspnea or HR-QOL. With the exception of dry mouth, the tolerability profile of tiotropium was similar to that with placebo, ipratropium, or salmeterol. Consequently, inhaled tiotropium is likely to be a valuable option for first-line, long-term maintenance therapy in the management of bronchoconstriction in patients with symptomatic COPD. Tiotropium bromide has a quaternary ammonium structure and acts as an anticholinergic bronchodilat

Topics: Bronchodilator Agents; Drug Administration Schedule; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Cholinergic nerve fibres arise in the nucleus ambiguus and the dorsal motor nucleus of the vagus nerve in the brainstem. They travel down as the vagus nerve to parasympathetic ganglia placed in the walls of the airways. From these ganglia, short postganglionic fibres innervate airway smooth muscle and the submucosal glands in the lung. Activation of vagal nerve releases acetylcholine at the neuroeffector junctions, where it binds to postsynaptic receptors, resulting in bronchoconstrictions. The resting bronchomotor tone in normal airways has a cholinergic component mediated via muscarinic cholinergic receptors. The human airways have five subtypes of muscarinic cholinergic receptors: the M1 and M3 mediate bronchoconstriction and stimulation of mucus secretion, while M2 control the release of acetylcholine from M1 and M3 receptors through a negative-feedback mechanism. Anticholinergic bronchodilators act by blocking muscarinic receptors. Tiotropium bromide is cutting age anticholinergic bronchodilator. It dissociates more slowly from M1 and M3 than from M2 receptors and subsequently has a long and safety duration of action. In COPD patients tiotropium comparing to placebo, ipratropium and long acting beta agonists significantly improves lung function. It is an effective bronchodilator that reduces dyspnea, COPD exacerbations frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic pulmonary disease therapy.

Topics: Bronchi; Bronchoconstriction; Bronchodilator Agents; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium bromide is a novel, inhaled, once-daily anticholinergic bronchodilator that has recently been approved in the United States for use in patients with COPD. Its unique feature is the persistence of bronchodilation for > 24 h due to prolonged M(3) muscarinic receptor blockade. Tiotropium provides significant improvement in spirometry and lung volumes. Clinically relevant outcomes such as the relief of dyspnea, improvement in the quality of life (health status), and reductions in the frequency and severity of acute exacerbations have been consistently obtained with tiotropium in clinical trials. In head-to-head trials, tiotropium administered once daily resulted in bronchodilation (peak, trough, and area under the curve) that was statistically superior to ipratropium administered four times daily and salmeterol administered twice daily. Clinical outcomes (dyspnea, quality of life, exacerbation frequency) were numerically but not always statistically better with tiotropium than salmeterol. Long-term studies of the combination of tiotropium with adrenergic agents, methylxanthines, or inhaled corticosteroids have not been reported in full. Several 1-year studies demonstrate that the only significant side effect of tiotropium was dryness of the mouth, which occurred in approximately 10 to 16% of patients; it is well tolerated by patients and safe.

Topics: Acute Disease; Animals; Bronchi; Bronchodilator Agents; Cholinergic Antagonists; Dose-Response Relationship, Drug; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Anticholinergics are the bronchodilators of choice in the management of chronic obstructive pulmonary disease (COPD). They work by blocking muscarinic receptors in airway smooth muscle. Cholinergic tone appears to be the only reversible component of COPD. With the discovery of different muscarinic receptor subtypes, the development of more selective anticholinergics is possible. A major advance in this therapeutic area has been the discovery of tiotropium bromide, which has kinetic selectivity for M3 receptors as well as a duration of action of >24 hours. Once-daily administration of tiotropium is well tolerated and has shown significant advantages over ipratropium bromide, given 4 times daily, in the control of COPD.

Topics: Bronchodilator Agents; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The defining feature of chronic obstructive pulmonary disease (COPD) is progressive deterioration in lung function. Measures of lung function are used to confirm the diagnosis, assess the severity of disease, and evaluate the efficacy of interventions. Forced expiratory volume in 1 second (FEV1), determined by spirometry, is the best known of these measures; however, it does not correlate well with dyspnea or exercise capacity, which are important targets for improvement in COPD management. Airflow obstruction in COPD often causes lung hyperinflation, which further inhibits the patient's ability to breathe. The degree of hyperinflation has been shown to correlate well with dyspnea and exercise capacity, but it is less convenient to measure than FEV1. This article briefly reviews the key lung function measurements used in monitoring patients with COPD. To illustrate how these measurements can be used to demonstrate the improvements in lung function elicited by effective bronchodilator therapy, the changes associated with the once-daily, long-acting bronchodilator tiotropium are presented.

Topics: Bronchodilator Agents; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Bronchoconstriction; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Inhaled anticholinergic drugs are considered one of the principal bronchodilator treatments for chronic obstructive pulmonary disease (COPD). Ipratropium bromide is an anticholinergic drug frequently administered for the treatment of COPD. Unfortunately, ipratropium has a short duration of action, requiring administration every 6 hours; this regimen affects adherence to drug therapy. Tiotropium bromide is structurally similar to ipratropium and is under development in the United States. The duration of action of tiotropium is approximately 24 hours, allowing for once-daily dosing. Other than xerostomia being more common with tiotropium than with ipratropium, the safety profiles of these drugs were similar in studied populations. On the basis of its improvements in trough spirometric measurements and improved pharmacokinetic profile compared with that of ipratropium, tiotropium is likely to become the first-line anticholinergic agent in the treatment of patients with COPD.

Topics: Administration, Inhalation; Cholinergic Antagonists; Drug Administration Schedule; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

In 2001, we concluded that patients with symptoms of stable chronic obstructive pulmonary disease (COPD) inadequately controlled by an 'as-required' inhaled short-acting beta 2 agonist can be helped by regular use of an inhaled antimuscarinic bronchodilator or a long-acting beta 2 agonist. Since then, a new antimuscarinic drug [symbol: see text] tiotropium bromide (Spiriva--Pfizer/Boehringer Ingelheim) has been licensed as a once-daily bronchodilator for maintenance treatment of COPD in people aged 18 years or over. Here, we review the evidence for efficacy of tiotropium and discuss its role in the maintenance treatment of COPD.

Topics: Albuterol; Bronchodilator Agents; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Anticholinergic agents have proved to be of particular value in the treatment of COPD, as vagal cholinergic tone appears to be the only reversible component of airway narrowing, opposite to what happens in asthma. Anticholinergics block muscarinic receptors on airway smooth muscle an submucosal gland cells. Three subtypes of muscarinic receptors have been demonstrated in human airways. M1 receptors in parasympathetic ganglia facilitate cholinergic neurotransmission. M3 receptors on airway smooth muscle cells and glands mediate bronchoconstriction and mucus secretion. M2 receptors at cholinergic nerve endings inhibit the release of acetylcholine and therefore act as feedback inhibitory receptors (autoreceptors). Ipratropium bromide is a non-selective muscarinic antagonist and therefore blocks M1, M2 and M3 receptors. Tiotropium is a novel, potent, and long-lasting muscarinic antagonist that has a kinetic selectivity for M1 and M3 receptors because it dissociated very quickly from M2 receptors. Once-daily inhaled tiotropium is a safe and effective bronchodilator useful as a first-line maintenance therapy in COPD.

Topics: Bronchi; Bronchodilator Agents; Humans; Ipratropium; Muscarinic Antagonists; Muscle, Smooth; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

Bronchodilators are the mainstay of therapy for patients with established chronic obstructive pulmonary disease (COPD) but, at present, the majority of patients use short-acting agents. There is increasing evidence that long-acting agents, such as the beta(2)-adrenoceptor agonists salmeterol and formeterol, and the new anticholinergic tiotropium bromide provide a better therapeutic option. In the treatment of COPD, long-acting beta(2)-adrenoceptor agonists (LABAs) given twice daily cause the same degree of bronchodilation as tiotropium bromide given once daily. Combined use of an inhaled LABA with tiotropium bromide should provide important therapeutic benefits, as these drugs have distinct and complementary pharmacological actions in the airways. Although clinical trials of this combination have not been performed, clinical experience with Combivent, a combination of a short-acting beta(2)-adrenoceptor agonist (salbutamol) and a short-acting anticholinergic (ipratropium bromide), in COPD is encouraging because the bronchodilation produced is of a magnitude greater than that of either component alone. However, because LABAs are given twice daily but tiotropium bromide is required only once daily, the challenge is to develop a combined inhaler that can be employed on a daily basis.

Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Albuterol; Anti-Inflammatory Agents; Bronchodilator Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethanolamines; Exercise Tolerance; Formoterol Fumarate; Humans; Mucus; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium is a new anti-cholinergic drug with a long duration of action designed for maintenance treatment of chronic obstructive pulmonary disease (COPD). Tiotropium is the first drug specifically developed for the treatment of COPD, but it is also amongst the most expensive drugs used for this condition. The clinical pharmacology of tiotropium and results from published controlled clinical trials are reviewed. It is concluded that tiotropium seems suitable as a symptomatic treatment for patients with moderate to severe COPD (typically a forced expiratorical volume FEV1 < 50% of the predicted volume), who despite optimal use of short acting bronchodilators still suffer from severe symptoms.

Topics: Cholinergic Antagonists; Delayed-Action Preparations; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Anticholinergics are agents of first choice for the symptomatic treatment of patients with COPD. Tiotropium (Ba 679 BR, Spiriva) is a long-acting inhaled anticholinergic designed for once-daily bronchodilator treatment of COPD. Tiotropium is a selective antagonist of pulmonary M1 and M3 muscarinic receptor subtypes, that produces a long-lasting (24 hours), dose-dependent bronchodilation and bronchoprotection against constrictive stimuli, e. g. methacholine, following inhalation of single doses. Clinical trials with tiotropium in COPD patients over a maximum treatment duration of one year have confirmed a persisting bronchodilator effect of tiotropium compared with placebo and ipratropium, as well as meaningful clinical improvements in lung function, hyperinflation, exercise tolerance, symptom control and quality of life. Moreover, recent trials indicate that treatment with tiotropium also reduces the frequency of COPD exacerbations and hospitalizations. Comparative trials further suggest that the bronchodilator potency of tiotropium may be superior to those of available COPD treatments. Besides a higher incidence of dry mouth, the side effect profile was comparable to ipratropium bromide. In conclusion, present clinical data suggest that tiotropium has the potential of a first-line treatment for patients with COPD.

Topics: Bronchodilator Agents; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Pharmacologic treatment of chronic obstructive pulmonary disease (COPD) has evolved considerably during the past several decades. Initial treatment of the disease was accomplished primarily through antibiotics, mucolytic agents, and nonselective sympathomimetic agents. Up-to-date treatment guidelines stratified according to strength of evidence are published in the National Heart, Lung, and Blood Institute-World Health Organization workshop report on the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Current drug therapy for stable COPD focuses primarily on bronchodilation through inhaled beta2-agonists and anticholinergic agents, immunization, and elimination of smoking as a risk factor. Although many pharmacologic agents are available to treat COPD, no drug has demonstrated effectiveness in halting progression of the disease. Rather, the goal of drug therapy at this time is to maintain control of symptoms and prevent COPD exacerbations. Compared with asthma, research into treatment for COPD has been minimal. However, a long-acting anticholinergic agent, tiotropium, has received approval status by the United States Food and Drug Administration. The drug has been shown to improve spirometric parameters, quality of life, and utilization of health care resources. In addition, several new targets for the treatment of COPD are being studied, and a few agents, including some that theoretically may slow functional decline in patients with COPD, are in development.

Topics: Adrenal Cortex Hormones; Bronchodilator Agents; Clinical Trials as Topic; Humans; Immunotherapy, Active; Oxygen; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide

Prevention and relief of symptoms by regular use of bronchodilators is central to the management of patients with chronic obstructive pulmonary disease (COPD). The bronchodilators in use are beta2-agonists, anticholinergics and theophylline. Since the 1970s the anticholinergic ipratropium bromide has been widely used for the treatment of patients with regular symptoms, but because it has a relatively short duration of action, it needs to be administered four times a day. Tiotropium bromide is a long-acting anticholinergic suitable for once daily administration. It has been developed as a dry powder inhaler for the treatment of patients with COPD. Large clinical trials with administration of the drug for one year have now been published. Compared with placebo and ipratopium bromide, significant and long-lasting bronchodilatation was observed, which was maintained over the year. The bronchodilator effect of tiotropium bromide was accompanied by improvements in other health outcomes. A significant decrease in dyspnoea, improvement in health-related quality of life, and a reduction in the number of COPD exacerbations and hospitalisations were noted. In this review we summarise the clinical development of this compound.

Topics: Bronchodilator Agents; Cross-Over Studies; Delayed-Action Preparations; Double-Blind Method; Forced Expiratory Volume; Humans; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

Topics: Administration, Inhalation; Cholinergic Antagonists; Clinical Trials as Topic; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in the world. In the majority of cases, the disease is the result of years of cigarette smoking. Contributing factors leading to bronchial obstruction in COPD include mucus hypersecretion and an increase in bronchial muscle tone, which is triggered mainly by cholinergic mechanisms. Anticholinergic bronchodilators reduce vagal cholinergic tone, the main reversible component of COPD; hence they are the first-line treatment for bronchial obstruction in COPD. In addition to improving lung function, anticholinergics improve dyspnea, quality of life and exercise tolerance, and they reduce exacerbations. When compared with other bronchodilators, anticholinergics show at least equivalent bronchodilator potency, but with fewer side effects. In addition, due to their unique site of action, anticholinergics can be effectively combined with other bronchodilators. The introduction of new, long-acting anticholinergics is a promising addition to the treatment of COPD and is expected to lead to improved treatment outcomes and improved patient compliance.

Topics: Adrenergic beta-Agonists; Cholinergic Antagonists; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Albuterol; Bronchodilator Agents; Clinical Trials as Topic; Dyspnea; Emotions; Exercise; Follow-Up Studies; Forced Expiratory Volume; Health Status; Humans; Interviews as Topic; Ipratropium; Multivariate Analysis; Placebos; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Scopolamine Derivatives; Surveys and Questionnaires; Time Factors; Tiotropium Bromide

Topics: Asthma; Bronchoconstriction; Bronchodilator Agents; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium bromide (Spiriva, BA679BR, Boehringer Ingelheim) is a novel inhaled, long-acting anticholinergic bronchodilator that is employed as a once-daily maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). Like ipratropium bromide, tiotropium bromide is a quaternary ammonium derivative that binds to muscarinic receptors. However, although tiotropium binds with high affinity to muscarinic receptors of M1-, M2- and M3-subtypes, it dissociates very slowly from M1- and M3-receptors but more rapidly from M2-receptors, thereby giving it a unique kinetic selectivity. To date, the short-acting anticholinergic agents ipratropium and oxitropium bromide have been extensively employed as bronchodilator therapy for patients with COPD. Indeed, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy emphasises the role of bronchodilators in symptomatic management of all stages of COPD. It is encouraging that tiotropium given once daily from a dry powder inhaler at 18 g has been shown to cause greater improvement in lung function and reduction in symptoms than ipratropium bromide given four times daily. Furthermore, clinical studies over a 1-year period have demonstrated that tiotropium has impressive and maintained effects on lung function, symptoms and health-related quality of life, and may also reduce exacerbations. In a recent large scale comparative study over 6 months, tiotropium has been shown to cause superior bronchodilation and symptomatic improvement when compared to twice daily salmeterol in COPD. The only significant reported adverse event is dry mouth, which is found in approximately 10%-15% of subjects, but this is reversible and rarely causes discontinuation of therapy. Based on these promising features, it is likely that tiotropium used alone or in combination with other bronchodilators will emerge as first-line maintenance treatment for patients with airway obstruction due to COPD.

Topics: Administration, Inhalation; Albuterol; Area Under Curve; Asthma; Biological Availability; Bronchodilator Agents; Clinical Trials as Topic; Half-Life; Humans; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Bronchodilators are, at the present time, the mainstay of symptomatic therapy in patients with chronic obstructive pulmonary disease (COPD). Anticholinergics are the first steep in the clinical management of these patients although its short half life constitutes a serious limitation in patients with persistent symptoms. However, there have been some important developments on this area. Tiotropium bromide, used once daily shows several clinical advantages when it is compared with ipratropium bromide or with long acting beta-2 agonists. This suggests than tiotropium bromide could be in coming years one of the first options for the treatment of COPD.

Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials as Topic; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease remains a major health problem for which new and improved treatments are desperately needed. Recent trials strongly suggest that treatments are improving. Longer-acting bronchodilators will be more convenient and may have additional advantages. Combinations of bronchodilators may offer additive effects and, possibly, synergies. Inhaled glucocorticoids, although unable to alter the loss of forced expiratory volume in 1 second when used alone, may reduce exacerbation frequency and health status deterioration and improve mortality. These clinically meaningful goals represent end points not previously targeted in chronic obstructive pulmonary disease drug development. Moreover, inhaled glucocorticoids may offer benefits in combination with long-acting beta-agonists. Finally, new classes of agents such as the phosphodiesterase inhibitors are on the horizon. The prospect for better treatment of chronic obstructive pulmonary disease looks brighter than ever. Caution is required, however. Much of the excitement has been generated by small studies, presented only in abstract form, and as yet unpublished work. Therapeutic recommendations will require publication of appropriately designed and adequately powered clinical trials.

Topics: Albuterol; Bronchodilator Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethanolamines; Female; Follow-Up Studies; Formoterol Fumarate; Glucocorticoids; Humans; Male; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Survival Rate; Tiotropium Bromide; Treatment Outcome

Tiotropium bromide is an anticholinergic bronchodilator that antagonises muscarinic M(1), M(2) and M(3) receptors. It dissociates more slowly from M(1) receptors and, importantly, from M(3) receptors (which are located in bronchial smooth muscle) than from M(2) receptors and subsequently has a long duration of action permitting once-daily administration. In patients with chronic obstructive pulmonary disease (COPD), tiotropium 18microg once daily significantly improved lung function compared with placebo and ipratropium 40microg four times daily in 1-year trials or salmeterol 50microg twice daily in a 6-month study. The incidence of COPD exacerbations decreased and use of rescue medication was lower with tiotropium compared with placebo or ipratropium. There was no evidence of tachyphylaxis during 1-year treatment with tiotropium. Compared with placebo, salmeterol and ipratropium, tiotropium produced significant improvements in patients' perception of dyspnoea and health-related quality of life. Tiotropium is generally well tolerated; dry mouth is the most common drug-related adverse event, occurring in about 10 to 16% of patients in clinical trials.

Topics: Bronchodilator Agents; Clinical Trials as Topic; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Receptors, Muscarinic; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Long-acting bronchodilators (LABD), in general, reduce respiratory symptoms, improve exercise endurance time and pulmonary function in patients with chronic obstructive pulmonary disease (COPD). However, there might be heterogeneity in improvement for several outcomes on an individual level. Therefore, we aimed to profile the multidimensional response in patients receiving tiotropium/olodaterol (T/O) using self-organizing maps (SOM).. This is a secondary analysis of the TORRACTO study: a multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effects of T/O (2.5/5 and 5/5 μg) compared with placebo after 6 and 12 weeks of treatment in patients with COPD. In the current study, we used endurance time, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), inspiratory capacity (IC) at rest and IC at isotime (ICiso) to identify clusters by means of SOM in patients treated with T/O.. Six clusters with distinct response profiles were generated at week 12 in COPD patients receiving T/O (n = 268). Patients in cluster 1 improved significantly on all outcomes, whilst cluster 5 showed strong improvement in endurance time (357s); contrarily, FEV1, FVC, ICrest and ICiso decreased when compared to baseline.. Individual responses on endurance time and pulmonary function after 12 weeks of T/O are heterogeneous. This study identified clusters in COPD patients with markedly different multidimensional response on LABD.

Topics: Bronchodilator Agents; Humans; Inspiratory Capacity; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Tiotropium. In a randomised, double-blind, two-period crossover trial, we recruited adult patients from three hospitals in New Zealand. Patients were excluded if they had a smoking history of >20 pack-years. Patients were assigned to either the tiotropium-placebo or placebo-tiotropium sequence in a 1:1 ratio, using randomly permuted blocks stratified by centre. Participants and investigators were masked to treatment allocation. Eligible patients received tiotropium 18 μg. 90 patients were randomly assigned and 85 completed both treatment cycles. The rate of exacerbations was 2.17 per year under the tiotropium treatment and 2.27 per year under placebo (rate ratio 0.96, 95% CI 0.72-1.27; p=0.77). Tiotropium, compared with placebo, improved forced expiratory volume in 1 s by 58 mL (95% CI 23-92 mL; p=0.002). Adverse events were similar under both treatments.

Topics: Adult; Bronchiectasis; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Real-world evidence is needed to optimize pharmacotherapy for chronic obstructive pulmonary disease (COPD). The effectiveness of inhaled tiotropium/olodaterol according to baseline symptoms and previous COPD treatment and predictors of response were assessed.. Tiotropium/olodaterol improved symptoms and lung function in Japanese COPD patients. Our results support the possible use of tiotropium/olodaterol in treatment-naive patients and those with total CAT scores ≥ 10.. Clinicaltrials.gov Identifier for parent study: NCT02850978.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Forced Expiratory Volume; Humans; Product Surveillance, Postmarketing; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Several studies in COPD have shown a significant and early increase in the risk of cardiovascular mortality attributable to inhaled bronchodilators including long acting β2 agonists (LABAs) and muscarinic antagonists (LAMAs). Cardiac autonomic system impairment may be a potential mechanism involved.. We performed a phase 4, investigator-initiated, prospective, randomized, blinded, cross-over trial (LAB-Card trial - NCT02872090) to evaluate the effect of two LAMAs and one LABA on the cardiac autonomic system in patients with COPD by using three major assessment approaches: heart rate variability (HRV, a predictor of cardiovascular death), baroreflex sensitivity (BRS) and autonomic function (tilt test).. 34 patients attended four visits to receive either tiotropium 18µg, glycopyrronium 44µg, indacaterol 150 µg or placebo (lactose) in a randomized order followed by the assessment of HRV and BRS in supine position and after passive rising. Neither LAMAs (tiotropium or glycopyrronium) nor LABA (indacaterol) induced a higher LF/HF ratio (reflect of sympathetic/parasympathetic balance) measured in supine position at rest compared to placebo (primary outcome). Solely indacaterol induced an increase in heart rate compared to placebo. No significant differences were observed for HRV and BRS between active drugs and placebo in supine position or after passive rising.. We did not found evidence of a deleterious effect of 2 LAMAs and one LABA on the autonomic cardiovascular control in COPD patients. Further investigations are needed to explore mechanisms by which long-acting bronchodilators may increase cardiovascular events in COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Glycopyrrolate; Humans; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Patients with stable chronic obstructive pulmonary disease (COPD) have been observed to benefit from tiotropium bromide. However, there are few studies of tiotropium bromide on sputum and sputum viscosity. To evaluate the effect of tiotropium bromide on mucus hypersecretion, a randomized, double-blind controlled trial was performed.. 120 cases of patients with pulmonary function grade II were divided into two groups, which include the treatment group given tiotropium bromide powder inhalation (18 . Three patients (2 cases in the treatment group and 1 case in the control group) were dropped due to loss of follow-up, and 117 cases of patients were enrolled in this study. After 3 months of treatment, the sputum character score,. Inhaled tiotropium bromide can effectively inhibit the mucus hypersecretion in stable COPD patients, improve the sputum properties and lung function of patients, and improve the quality of life of patients.

Topics: Administration, Inhalation; Ambroxol; Calcium; Computational Biology; Double-Blind Method; Formoterol Fumarate; Humans; Mucus; Muscarinic Antagonists; Orosomucoid; Pulmonary Disease, Chronic Obstructive; Pulmonary Ventilation; Quality of Life; Sputum; Tiotropium Bromide

Overall, treatment with tiotropium/olodaterol significantly increased the time to, and reduced the risk of, CID versus tiotropium (median time to CID 226 versus 169 days; hazard ratio [HR] 0.76 [95% confidence interval 0.68, 0.85]; P < 0.0001). Significant reductions were also observed in patients with low exacerbation history (241 versus 170; HR 0.73 [0.64, 0.83]; P < 0.0001), GOLD 2 patients (241 versus 169; 0.72 [0.61, 0.84]; P < 0.0001) and maintenance-naïve patients (233 versus 171; 0.75 [0.62, 0.91]; P = 0.0030).. In patients with COPD, including patients with low exacerbation history, GOLD 2 patients and maintenance-naïve patients, tiotropium/olodaterol reduced the risk of CID versus tiotropium. These results demonstrate the advantages of treatment optimisation with tiotropium/olodaterol over tiotropium monotherapy.. ClinicalTrials.gov identifier: TONADO. COPD is a complicated disease that deteriorates over time. Worsening of COPD is associated with the lungs working less effectively, a fall in quality of life and a rise in sudden flare-ups of the disease. In this study, we looked at lung function, quality of life and flare-ups together using a measure called “clinically important deterioration” (CID). We looked at 2055 people with COPD to compare the effects of taking two bronchodilators (tiotropium and olodaterol) against taking one bronchodilator (tiotropium alone). Bronchodilators are a type of inhaled medication that relax the muscles in the lungs and widen airways, making it easier to breathe. They have also been shown to reduce sudden flare-ups of COPD. Across a wide range of people with COPD, we found that treatment with tiotropium/olodaterol reduced the risk of a CID compared with tiotropium alone. This includes in those patients at an early stage of disease, who may benefit from finding the best treatment option for them as early as possible.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

In chronic obstructive pulmonary disease (COPD) patients, combination treatment with long-acting muscarinic antagonist (LAMA) and long-acting β2 agonist (LABA) increases forced expiratory volume in one second and reduces symptoms compared to monotherapy. In Japan, three different once-daily fixed-dose combinations (FDCs) have been prescribed since 2015, although a direct comparison of these FDCs has never been performed. The objective of the present study was to compare the effectiveness, preference, and safety of three LAMA/LABA FDCs-glycopyrronium/indacaterol (Gly/Ind), umeclidinium/vilanterol (Ume/Vil), and tiotropium/olodaterol (Tio/Olo)-in patients with COPD.. We enrolled 75 COPD outpatients (male:female ratio, 69:6; 77.4 ± 6.9 years). A prospective, randomized, crossover study was conducted on three groups using three FDCs: Gly/Ind; Ume/Vil; and Tio/Olo. Each medication was administered for 4 weeks before crossover (total 12 weeks). After each FDC administration, a respiratory function test and questionnaire survey were conducted. A comparative questionnaire survey of all three LAMA/LABA FDCs was conducted after 12 weeks (following administration of final FDC).. No significant differences in COPD Assessment Test or modified Medical Research Council dyspnea questionnaire were reported in the surveys completed after each FDC administration; no significant differences in spirometric items were observed. In the final comparative questionnaire survey, patients reported better actual feeling of being able to inhale following Gly/Ind administration compared with Tio/Olo, although no significant differences in adverse events or other evaluations were reported.. The three LAMA/LABA FDCs administered to COPD patients show similar effects and safety, although some minor individual preference was reported. Trial registration This study retrospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000041342, registered on August 6, 2020).

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Benzoxazines; Cross-Over Studies; Disease Progression; Drug Administration Schedule; Drug Combinations; Female; Forced Expiratory Volume; Humans; Japan; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tiotropium Bromide; Treatment Outcome

This Phase II, randomized, parallel group study was conducted as part of US regulatory requirements to identify the most appropriate dose of the long-acting muscarinic antagonist glycopyrronium bromide (GB) for use in a single-inhaler triple-therapy combination with the inhaled corticosteroid beclomethasone dipropionate plus the long-acting β

Topics: Administration, Inhalation; Adult; Bronchodilator Agents; Double-Blind Method; Forced Expiratory Volume; Formoterol Fumarate; Glycopyrrolate; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Pneumonia is one of the most frequently occurring complications after esophagectomy and is associated with increased operative mortality. Chronic obstructive pulmonary disease (COPD) is known to be a risk factor for pulmonary complications and operative mortality. However, in COPD patients preparing for esophagectomy, preventive measures against postoperative pneumonia have not yet been discovered. In this study, we evaluate the effect of perioperative inhaled tiotropium, a long-acting, antimuscarinic bronchodilator used in the management of COPD, on patients with COPD who undergo esophageal cancer surgery.. This study investigates the effect of perioperative inhaled tiotropium on patients with COPD who undergo esophagectomy. It is an open-label, randomized controlled trial conducted in a single center (EPITOPE study). A total of 32 enrolled patients are randomly assigned in a 1:1 ratio to either conventional management or inhalation of tiotropium in addition to the conventional management. Patients included in the intervention group receive tiotropium Respimat 5 μg (two inhalations of 2.5 μg) for at least 2 weeks before the esophagectomy. Following the esophagectomy, tiotropium is re-delivered, starting as early as possible and continuing until the postoperative evaluation (between 30 and 44 days after the operation). The primary outcome is the incidence of pneumonia within 30 days after esophagectomy. Secondary outcomes are the incidence of cardiovascular complications within 30 days after esophagectomy, the incidence of any postoperative complications within 30 days after esophagectomy, pulmonary function (preintervention, preoperative, and postoperative), walking distance in the incremental shuttle walking test (preintervention, preoperative, and postoperative), the incidence of adverse events, and mortality within 30 days after esophagectomy.. The EPITOPE study is the first pilot study on the effects of perioperative inhaled tiotropium on patients with COPD undergoing esophagectomy. After completing this study, we will plan a multicenter RCT with the appropriate outcomes in the future.

Topics: Administration, Inhalation; Esophageal Neoplasms; Esophagectomy; Humans; Pilot Projects; Pneumonia; Postoperative Complications; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

The clinical trial of tiotropium in COPD, UPLIFT, enrolled adults with a mean age of 65 years and moderate-to-severe airflow obstruction, based on criteria from the Global Initiative for Chronic Obstructive Lung Disease (GOLD). For the UPLIFT cohort, however, GOLD-based criteria are not age-appropriate.. Will the use of more age-appropriate criteria for airflow obstruction from the Global Lung Function Initiative (GLI) modify the spirometric classification of the UPLIFT cohort and, in turn, the mortality effect of tiotropium in COPD?. Baseline spirometric classifications were first cross-tabulated by GLI- and GOLD-based criteria. Next, in GLI- and GOLD-based airflow obstruction, modified intention-to-treat analyses evaluated differences in time to death over 4 years, comparing tiotropium vs placebo. Because treatment response may differ by COPD severity, the mortality effect also was evaluated within stratum defined by GLI- and GOLD-based moderate and severe airflow obstruction.. Of 5,898 participants with GOLD-based airflow-obstruction, staged as moderate in 2,739 (46.4%) and severe in 3,156 (53.5%), GLI-based criteria established airflow obstruction in 5,750 (97.5%), staged as moderate in 795 (13.5%) and severe in 4,947 (83.9%). Relative to placebo, tiotropium yielded statistically nonsignificant adjusted hazard ratios (adjHRs) (95% CI) for death of 0.91 (0.80-1.04) and 0.91 (0.79-1.03) in GLI- and GOLD-based airflow obstruction, respectively. However, statistically significant effect modification was observed, but only in GLI-based moderate and severe airflow-obstruction, with tiotropium yielding adjHRs for death of 0.53 (0.34-0.81) and 0.99 (0.86-1.13), respectively. The P value for interaction was .007.. Mortality reduction by tiotropium was only statistically significant in GLI-based moderate airflow-obstruction, a group that was underrepresented in UPLIFT because of severity misclassification by the original GOLD-based enrollment criteria.

Topics: Age Factors; Aged; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Spirometry; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality worldwide and in China. For patients with more severe symptoms, initial treatment with long acting β2-agonists and long-acting muscarinic antagonists combination therapy is recommended. Tiotropium + olodaterol fixed-dose combination (Tio + Olo FDC) is an aqueous solution of tiotropium bromide and olodaterol delivered by the RESPIMAT® Soft Mist™ inhaler for patients with moderate to very severe COPD.. This single site, open-label, phase Ib clinical study assessed the pharmacokinetic (PK) and safety profiles of once-daily Tio + Olo FDC (5 μg/5 μg) after single dose and at steady state in Chinese patients with moderate to severe COPD over 3 weeks. The PK and safety profiles of Japanese and Caucasian populations from 2 independent COPD studies were provided for comparison.. A total of 12 Chinese patients received Tio + Olo FDC. After multiple inhaled administration of Tio + Olo FDC, tiotropium and olodaterol were rapidly absorbed and reached peak plasma concentration at about 5 and 25 min, respectively. The accumulation ratios after multiple administrations were 1.3 and 1.6 for tiotropium and olodaterol in Chinese patients. Tio + Olo FDC was well-tolerated; all AEs were mild.. Tio + Olo FDC (5 μg/5 μg) was rapidly absorbed and had a good safety profile in Chinese patients with COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; China; Drug Combinations; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Comparative effects on physical activity of mono and dual bronchodilators remain unclear in patients with treatment-naïve chronic obstructive pulmonary disease (COPD). We sought to compare the changes in physical activity before and after tiotropium and tiotropium/olodaterol treatment in treatment-naïve COPD patients.. A prospective, multicenter, randomized, open-labeled, and parallel interventional study was conducted. Eighty Japanese patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Spirometry and dyspnea index were assessed, and COPD assessment test (CAT) and the 6-minute walk distance (6MWD) were conducted before and after treatment. Evaluation of physical activity was assessed by a triaxle accelerometer over a 2-week period before and after treatment.. This is the first study to report the impact of dual bronchodilator on physical activity in treatment-naïve COPD patients of Japanese with low BMI.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Exercise; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Older patients with chronic obstructive pulmonary disease (COPD) may be at increased risk of adverse events (AEs) due to decreased protective organ function and increased comorbidities. TONADO® 1 + 2 were replicate, randomized, double-blind, parallel-group, 52-week, Phase III trials comparing the efficacy and safety of tiotropium/olodaterol (5/5 µg) versus the monocomponents via the Respimat® inhaler in patients with moderate-to-very-severe COPD. In this prespecified safety analysis, patients were grouped by age. Of 3100 patients, 1585 (51.1%) were aged <65 years, 1198 (38.7%) 65-<75 years, 309 (10.0%) 75-<85 years, and eight (0.3%) ≥85 years. At baseline, 23.4% had a pre-existing cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diagnosed diabetes. Overall, there was no increase in major adverse cardiac events, other AEs, or serious AEs with tiotropium/olodaterol versus the monocomponents in any age group, supporting the safety of tiotropium/olodaterol in older patients with COPD.

Topics: Age Factors; Aged; Aged, 80 and over; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

The efficacy of long-acting bronchodilators for COPD associated with biomass (BE-COPD) has not been properly evaluated.. To determine the acute effect of indacaterol (IND) 150 μg q.d and tiotropium (TIO) 18 μg q.d. on lung hyperinflation, walking distance (WD) and dyspnea during the six-minute walking test (6MWT) in moderate BE-COPD at 30, 60 and 240 mins post-drug administration.. Randomized, controlled, open-level, crossover noninferiority clinical trial. Forty-two women with BE-COPD were randomly assigned to a bronchodilator sequence: IND-TIO or vice versa.. There were statistically significant changes over time in inspiratory capacity (IC) (. Both IND and TIO showed significant and fast onset improvement in hyperinflation. Therefore, either of them may be recommended as a first line of treatment for COPD associated with BE-COPD.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Biomass; Bronchodilator Agents; Cross-Over Studies; Environmental Exposure; Exercise Test; Female; Forced Expiratory Volume; Humans; Indans; Inspiratory Capacity; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Smoke; Spirometry; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Patients with COPD are less physically active. This post hoc analysis of a randomized, double-blind, active-controlled, crossover trial assessed the efficacy of once-daily tiotropium/olodaterol combination therapy versus tiotropium monotherapy in Japanese patients with COPD.. Patients were provided with a three-axis accelerometer to measure sedentary and active behavior defined as 1.0-1.5 metabolic equivalents (METs), ≥2.0 METs, and ≥3.0 METs, respectively. Of the 182 patients enrolled, 131 satisfied the conditions for the present analysis and were randomized to tiotropium monotherapy (n=62) or tiotropium/olodaterol combination therapy (n=69).. Tiotropium/olodaterol combination therapy significantly reduced the duration of 1.0-1.5 MET activity by 8.64 mins (. Tiotropium/olodaterol combination therapy significantly reduced sedentary time and improved physical activity compared with tiotropium monotherapy. This trial was registered in ClinicalTrials.gov (NCT02629965).

Topics: Administration, Inhalation; Aged; Benzoxazines; Cross-Over Studies; Double-Blind Method; Drug Combinations; Exercise; Female; Forced Expiratory Volume; Humans; Male; Motor Activity; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Sedentary Behavior; Tiotropium Bromide; Treatment Outcome

Hyperinflation has been associated with negative cardiocirculatory consequences in patients with chronic obstructive pulmonary disease (COPD). These abnormalities are likely to worsen when the demands for O. 20 patients (residual volume = 201.6 ± 63.6% predicted) performed endurance cardiopulmonary exercise tests (75% peak) 1 h after placebo or tiotropium/olodaterol 5/5 μg via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Cardiac output was assessed by signal-morphology impedance cardiography. Near-infrared spectroscopy determined quadriceps blood flow (indocyanine green dye) and intra-muscular oxygenation.. Tiotropium/olodaterol was associated with marked lung deflation (p < 0.01): residual volume decreased by at least 0.4 L in 14/20 patients (70%). The downward shift in the resting static lung volumes was associated with less exertional inspiratory constraints and dyspnoea thereby increasing exercise endurance by ~50%. Contrary to our premises, however, neither central and peripheral hemodynamics nor muscle oxygenation improved after active intervention compared to placebo. These results were consistent with those found in a subgroup of patients showing the largest decrements in residual volume (p < 0.05).. The beneficial effects of tiotropium/olodaterol on resting and operating lung volumes are not translated into enhanced cardiocirculatory responses to exertion in hyperinflated patients with COPD. Improvement in exercise tolerance after dual bronchodilation is unlikely to be mechanistically linked to higher muscle blood flow and/or O

Topics: Aged; Aged, 80 and over; Benzoxazines; Bronchodilator Agents; Cardiac Output; Case-Control Studies; Cross-Over Studies; Cross-Sectional Studies; Drug Combinations; Dyspnea; Exercise Test; Exercise Tolerance; Female; Hemodynamics; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Oxygen; Physical Exertion; Placebos; Pulmonary Atelectasis; Pulmonary Disease, Chronic Obstructive; Quadriceps Muscle; Regional Blood Flow; Residual Volume; Spectroscopy, Near-Infrared; Tiotropium Bromide

Effective delivery of inhaled drugs in chronic obstructive pulmonary disease (COPD) depends on patients' ability to correctly use an inhalation device. Nebulized delivery may be appropriate for COPD patients who cannot coordinate breath with inhalation or generate adequate inhalational force. Until recently, long-acting muscarinic antagonists (LAMAs), used for maintenance treatment of COPD, were available for delivery only via handheld inhalers. Lonhala™ Magnair™ (glycopyrrolate inhalation solution) is a LAMA delivered via the eFlow. GOLDEN-5, a phase 3, randomized, open-label trial, evaluated the safety and efficacy of glycopyrrolate/eFlow CS 50 μg twice daily versus tiotropium 18 μg once daily (administered via HandiHaler™) in patients with moderate-to-very severe COPD. Only patients in the glycopyrrolate/eFlow CS group completed a study-specific device use questionnaire, evaluating patients' perceptions about ease of use, confidence in drug delivery, and overall device satisfaction at week 48 or end of study. Responses were summarized by counts and percentages.. Of 620 patients who received glycopyrrolate/eFlow CS, 454 completed the questionnaire (mean age [standard deviation, SD] 63.3 [8.5] years; mean BMI [SD] 28.45 [6.208] kg/m. High levels of satisfaction, confidence, and ease of use were reported with the eFlow CS nebulizer in this study. These findings support the use of the eFlow CS for maintenance treatment of COPD with glycopyrrolate inhalation solution.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Equipment Design; Female; Glycopyrrolate; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Patient Satisfaction; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

Plasma pharmacokinetics permit the assessment of efficacy and safety of inhaled drugs, and possibly their bioequivalence to other inhaled products. Correlating drug product attributes to lung deposited dose is important to achieving equivalence. PUR0200 is a spray-dried formulation of tiotropium that enables more efficient lung delivery than Spiriva. A seven-period, single-dose, crossover study was performed in healthy subjects. PUR0200 formulations differing in dose and aerodynamic particle size were administered in five periods and Spiriva HH in two periods. In one period, Spiriva HH gastrointestinal absorption was blocked with oral charcoal. Tiotropium plasma concentrations were assessed over 8 h after inhalation.. PUR0200 pharmacokinetics were influenced by aerodynamic particle size and the ratio of lung-to-oral deposition, with impactor sized mass (ISM) correlating most strongly with exposure. Formulation PUR0217a (3 μg tiotropium) lung deposition was similar to Spiriva HH (18 μg) with and without charcoal block, but total PUR0200 exposure was lower without charcoal. The C. Pharmacokinetic bioequivalence indicative of lung deposition and efficacy can be achieved by matching the reference product ISM. Due to reduced oral deposition and more efficient lung delivery, PUR0200 results in a lower AUC

Topics: Administration, Inhalation; Adult; Area Under Curve; Bronchodilator Agents; Cross-Over Studies; Dry Powder Inhalers; Female; Gastrointestinal Absorption; Healthy Volunteers; Humans; Male; Mouth Mucosa; Particle Size; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Therapeutic Equivalency; Tiotropium Bromide; Young Adult

The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD).This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index <8. Patients received 6 weeks of tiotropium/olodaterol 5/5 µg and tiotropium 5 µg in a randomised order with a 3-week washout period. The speed for the 3-min CSST was determined for each patient such that an intensity of breathing discomfort ≥4 ("somewhat severe") on the modified Borg scale was reached at the end of a completed 3-min CSST.After 6 weeks, there was a decrease in the intensity of breathlessness (Borg dyspnoea score) at the end of the 3-min CSST from baseline with both tiotropium (mean -0.968, 95% CI -1.238- -0.698; n=100) and tiotropium/olodaterol (mean -1.325, 95% CI -1.594- -1.056; n=101). The decrease in breathlessness was statistically significantly greater with tiotropium/olodaterol

Topics: Administration, Inhalation; Aged; Benzoxazines; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Combinations; Dyspnea; Exercise Test; Exercise Tolerance; Female; Forced Expiratory Volume; Humans; Internationality; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality all over the world. Acute exacerbation of COPD (AECOPD) not only accelerates the progression of disease, but also causes hospital administration and death events. Epidemiologic studies have shown air pollution is a high risk factor of AECOPD. However, there are rare technics or treatment strategies recommended to reduce severe air pollution related AECOPD.. This is a multi-center, prospective, randomized and standard treatment parallel control clinical trial. Seven hundred sixty-four stable COPD patients in group B, C and D according to GOLD 2017 will be recruited and equally divided into two parallel groups, salvational intervention (SI group) and control group (CT group). Original treatments for participants include tiotropium (18μg once q.d), budesonide/formoterol (160μg/4.5μg once or twice b.i.d) or budesonide/formoterol (160μg/4.5μg once or twice b.i.d) with tiotropium (18μg once q.d). The savational intervention for SI group is routine treatment plus budesonide/formoterol (160μg/4.5μg once b.i.d) from the first day after severe air pollution (air quality index, AQI ≥200) to the third day after AQI < 200. CT group will maintain the original treatment. The intervention will last for 2 years. Primary outcome is the frequency of AECOPD per year and the secondary outcomes include the incidence of unplanned outpatient visits, emergency visits, hospitalization, medical cost and mortality associated with AECOPD per year.. The salvational intervention is a novel strategy for COPD management under severe air pollution. Results of the present study will provide reference information to guide clinical practice in reducing the air pollution related exacerbation of COPD.. This study has been registered at www.ClinicalTrials.gov (registration identifier: NCT03083067 ) in 17 March, 2017.

Topics: Adult; Aged; Aged, 80 and over; Air Pollution; Beijing; Bronchodilator Agents; Budesonide; Disease Progression; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Multicenter Studies as Topic; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Regression Analysis; Tiotropium Bromide

To compare the efficacy of inhaled glucocorticoid with or without tiotropium bromide in the treatment of patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS).. An experimental study.. Department of Respiratory Medicine, Wuwei People's Hospital, Gansu Province, China, from October 2016 to October 2017.. A total of 86 ACOS patients were randomly divided into the control group and the observation group, with 43 cases in each group. Control group was given inhaled glucocorticoid. Observation group was treated with tiotropium bromide on the basis of the control group. The asthma control test (ACT) score, chronic obstructive pulmonary disease assessment test (CAT) score, serum high-sensitivity C-reactive protein (hs-CRP) and IL-6 levels were compared.. Before treatment, there was no significant difference in ACT score, CAT score, serum hs-CRP and IL-6 levels between the two groups (p=0.808, 0.612, 0.872 and 0.921, respectively). After treatment, ACT score in observation group was higher than that in control group (p <0.001). CAT score, serum hs-CRP, and IL-6 levels in observation group were lower than those in control group (all p <0.001). The incidence of adverse reactions was lower in observation group than that in control group (p=0.033).. Compared with inhaled glucocorticoid, inhaled glucocorticoid combined with tiotropium bromide treatment can more effectively reduce the serum levels of hs-CRP and IL-6 and is beneficial to control the development of ACOS.

Topics: Administration, Inhalation; Adult; Age Factors; Aged; Asthma; China; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Male; Middle Aged; Prognosis; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Risk Assessment; Sex Factors; Tiotropium Bromide; Treatment Outcome; Undifferentiated Connective Tissue Diseases

During the clinical development of a fixed-dose combination of drugs, it is best practice to conduct dose-finding studies to determine the optimal dose of each component. The aims of this phase II dose-finding study were to confirm the lung function benefit of adding olodaterol to tiotropium, describe the dose-response relationship of olodaterol in combination with tiotropium 5 μg, and compare it with the dose response of olodaterol monotherapy.. In this double-blind, parallel-group trial, patients were randomized to receive either tiotropium 5 μg or a fixed-dose combination of tiotropium 5 μg with olodaterol 2 μg, 5 μg, or 10 μg, delivered once daily via the Respimat. There was a benefit of tiotropium/olodaterol compared with tiotropium monotherapy in FEV. Boehringer Ingelheim International GmbH.

Topics: Aged; Benzoxazines; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Drug Monitoring; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Tiotropium Bromide; Treatment Outcome

Prior replicate 12-week phase 3 trials demonstrated that once-daily doses of revefenacin inhalation solution at 88 μg and 175 μg produced significant bronchodilation over 24 h post dose in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The objective was to characterize the safety profile of revefenacin 88 μg and 175 μg over 52 weeks of treatment.. In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 88 μg or 175 μg in a double-blind manner, or open-label active control tiotropium.. Treatment-emergent adverse events (AEs) were comparable across all treatment groups (n [%] patients; revefenacin 88 μg, 272 [74.7%]; 175 μg, 242 [72.2%]; tiotropium, 275 [77.2%]). Numerically fewer COPD exacerbations (n [%] patients) were observed with revefenacin 175 μg (73 [21.8%]) than with 88 μg (107 [29.4%]) or tiotropium (100 [28.1%]). Serious AEs were comparable with revefenacin 88 μg (58 [15.9%] and tiotropium (58 [16.3%]), but were lower with revefenacin 175 μg (43 [12.8%]), and mortality was low. In patients using revefenacin 88 μg or tiotropium with a concurrent long-acting β-agonist (LABA) product, the incidence of AEs was slightly higher than without concurrent LABA. LABA did not affect the incidence of AEs for patients who received revefenacin 175 μg.. Revefenacin was generally well tolerated over 52 weeks of treatment, and had a safety profile that supports its use as a long-term once-daily bronchodilator for the nebulized treatment of COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzamides; Bronchodilator Agents; Carbamates; Case-Control Studies; Cholinergic Antagonists; Disease Progression; Drug Therapy, Combination; Drug Tolerance; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Safety; Severity of Illness Index; Tiotropium Bromide; Vital Capacity

The cardiovascular safety of revefenacin, an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive lung disease (COPD), was evaluated in phase 3 trials in patients with moderate to very severe COPD. No clinically meaningful changes in 12-lead electrocardiogram recordings were observed with up to 52 weeks of once-daily revefenacin 88 or 175 μg. In a pooled analysis of Studies 0126 and 0127, the incidence of prolonged QT interval corrected for heart rate using the Fridericia correction formula (QTcF; >450 msec) for revefenacin 88 μg (n = 23, 5.6%) and revefenacin 175 μg (n = 23, 5.9%) was similar to that for placebo (n = 22, 5.3%). In Study 0128, the incidence of prolonged QTcF was similar in the revefenacin 175 μg (n = 25, 7.7%) and tiotropium (n = 26, 7.3%) groups and lower in the revefenacin 88 μg (n = 15, 4.2%) group. There were four major adverse cardiac events (MACEs) in Study 0126 (one, two, and one in the placebo, revefenacin 88 μg, and revefenacin 175 μg groups, respectively), no MACEs in Study 0127 and 26 MACEs in Study 0128 (9, 10 and 7 in the revefenacin 88 μg, revefenacin 175 μg and tiotropium groups, respectively). In Study 0128, only one MACE was considered possibly/probably related to revefenacin (atrial fibrillation in the revefenacin 175 μg group). Thus, revefenacin may provide beneficial nebulized therapy for patients with COPD without further elevating their risk of cardiovascular events.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is mainly treated pharmaceutically with bronchodilators. The purpose of this study was to evaluate the clinical benefits of two-times-per-day aclidinium bromide (Acli-BID) compared with once-a-day tiotropium bromide hydrate (Tio-QD) in patients with COPD.. This study was a multicentre, open-label, randomised study.. Fourcentres in Kagawa prefecture, Japan.. Patients who were diagnosed to have COPD Grade 2-3 according to the Global Initiative for Chronic Obstructive Lung Disease 2015 criteria were enrolled.. Patients were randomly assigned to receive Acli-BID or Tio-QD at a 1:1 ratio, and followed for 8 weeks. Acli-BID was administered in the morning and night, and Tio-QD was administered in the night.. Primary outcome was forced expiratory volume in one second area under the curve (FEV. 44 patients were included in this study. FEV. Acli-BID as with Tio-QD could be one of the therapeutic options for patients with COPD to improve pulmonary function. Also, our results suggest that intervention with bronchodilators enhanced physical activity in patients with COPD.. UMIN 000020020.

Topics: Aged; Bronchodilator Agents; Exercise; Female; Forced Expiratory Volume; Humans; Japan; Linear Models; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Tropanes

There is continuing debate about whether to define airflow obstruction by a post-bronchodilator ratio of forced expiratory volume in 1 second (FEV. A total of 17,072 patients were analyzed; of these, 1,807 (10.6%) patients had a ratio greater than or equal to LLN. Patients with a ratio greater than or equal to LLN had similar risks of death from any cause and fatal major adverse cardiovascular (CV) event as those below LLN. Patients with a ratio below LLN had a significantly lower risk of major adverse CV events (hazard ratio = 0.69; 95% confidence interval [CI] = 0.55-0.86; P = 0.001), and had significantly greater risks of moderate to severe exacerbation (rate ratio = 1.48; 95% CI = 1.36-1.61; P < 0.0001) and severe exacerbation (rate ratio = 2.01; 95% CI = 1.68-2.40; P < 0.0001) when compared with patients greater than or equal to LLN. Study outcomes by treatment arm (5 μg tiotropium Respimat vs. 18 μg HandiHaler) were comparable.. Using the LLN to define airflow obstruction would have excluded patients in the Tiotropium Safety and Performance in Respimat study with a higher risk of nonfatal major adverse CV events and a lower risk of exacerbation; study outcomes by treatment arm (2.5 μg/5 μg tiotropium Respimat vs. 18 μg HandiHaler) remained similar. Clinical trial registered with www.clinicaltrials.gov (NCT01126437).

Topics: Administration, Inhalation; Age Factors; Aged; Bronchodilator Agents; Cardiovascular Diseases; Disease Progression; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Outcome Assessment, Health Care; Pulmonary Disease, Chronic Obstructive; Risk Factors; Survival Analysis; Tiotropium Bromide; Vital Capacity

Geographical variations may impact outcomes in chronic obstructive pulmonary disease (COPD). We evaluated differences in baseline characteristics and outcomes between patients enrolled in Latin America compared with the rest of the world (RoW) in the TIOtropium Safety and Performance In Respimat. TIOSPIR. At baseline, patients enrolled in Latin America (n=1000) versus RoW (n=16116) were older, with higher pack-years of smoking history and more exacerbations, but less cardiac history. In this analysis, patients in Latin America versus RoW had an increased risk of death (hazard ratio [HR] [95% confidence interval (CI)]: 1.52 [1.24-1.86]; P<.0001) or moderate-to-severe exacerbation (HR [95% CI]: 1.29 [1.18-1.41]; P<.0001), but a lower risk of severe exacerbation (HR [95% CI]: 0.82 [0.68-0.98]; P=.0333). SAE rates in Latin America were lower versus RoW (incidence rate ratio [IRR] [95% CI]: 0.82 [0.72-0.92]), including cardiac disorders (IRR [95% CI]: 0.68 [0.48-0.97]). Risk of major adverse cardiovascular events were similar (HR [95% CI]: 0.99 [0.71-1.40]; P=.9677).

Topics: Administration, Inhalation; Age Factors; Aged; Aged, 80 and over; Bronchodilator Agents; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Geography, Medical; Global Health; Humans; Latin America; Male; Middle Aged; Nebulizers and Vaporizers; Prognosis; Pulmonary Disease, Chronic Obstructive; Smoking; Tiotropium Bromide

Cardiovascular disease is a frequent comorbidity in patients with COPD. Many physicians, particularly pulmonologists, are reluctant to use β-adrenoceptor blocking agents (β-blockers) in patients with COPD, despite their proven effectiveness in preventing cardiovascular events.. The large (5,162 patients) phase III TONADO 1 and 2 studies assessed lung function and patient-reported outcomes in patients with moderate to very severe COPD receiving long-acting bronchodilator treatment across 1 year. This post hoc analysis characterized lung-function changes, patient-reported outcomes, and safety in the subgroup of patients receiving β-blockers in the studies.. In total, 557 of 5,162 patients (11%) received β-blockers at baseline. Postbronchodilator FEV. Lung function, overall respiratory status, and safety of tiotropium/olodaterol were not influenced by baseline β-blocker treatment in patients with moderate to very severe COPD. Results from this large patient cohort support the cautious and appropriate use of β-blockers in patients with COPD and cardiovascular comorbidity.. ClinicalTrials.gov; No.: NCT01431274 and No. NCT01431287; URL: www.clinicaltrials.gov.

Topics: Adrenergic beta-Antagonists; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

This substudy of a large, randomized, controlled trial (NCT01072396) examined tiotropium (18 μg qd) effects on dynamic hyperinflation during constant work rate treadmill exercise. Areas-under-the-spontaneous expiratory flow-volume (SEFV)-curves were compared in 20 COPD patients and 16 age-matched untreated controls, using rectangular area ratio (RAR) between peak intrabreath and end-expiratory flow. Seven patients exhibited SEFV curve concavity with RAR ≤ 0.5 (RAR

Topics: Aged; Analysis of Variance; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Exercise; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; International Cooperation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Ventilation; Spirometry; Tiotropium Bromide; Vital Capacity

Although COPD exacerbations are known to occur more frequently in winter, there is little information on hospitalizations and cause-specific mortality. This study aimed to examine seasonal variations in mortality and exacerbations in patients with COPD during the TIOtropium Safety and Performance In Respimat. TIOSPIR was conducted in 43 northern (n=15,968) and 7 southern (n=1,148) hemisphere (n=1,148) countries. The median duration of treatment was 835 days, with a mean follow-up of 2.3 years. Among 19,494 exacerbations, there were clear seasonal differences (winter, 6,646 [34.1%]; spring, 4,515 [23.2%]; summer, 3,198 [16.4%]; autumn, 5,135 [26.3%]). Exacerbations peaked in early winter (December in the northern hemisphere and June in the southern hemisphere), respiratory hospitalizations in midwinter, and respiratory deaths in early spring.. Although winter poses a 2-fold hazard for COPD exacerbations vs summer, respiratory deaths peak in early spring. These data suggest that seasonal intensification of preventive treatments may impact COPD morbidity and mortality.. NCT01126437.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cause of Death; Cholinergic Antagonists; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Risk Factors; Seasons; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Combinations of long-acting bronchodilators are recommended to reduce the rate of chronic obstructive pulmonary disease (COPD) exacerbations. It is unclear whether combining olodaterol, a long-acting beta-agonist, with tiotropium, a long-acting anti-muscarinic, reduces the rate of exacerbations compared with tiotropium alone.. This 52-week, double-blind, randomised, parallel-group, active-controlled trial randomly assigned (1:1) patients with COPD with a history of exacerbations using a randomised block design to receive tiotropium-olodaterol 5 μg-5 μg or tiotropium 5 μg once daily. Patients using inhaled corticosteroids continued this therapy. Treatment was masked to patients, investigators, and those involved in analysing the data. The primary endpoint was the rate of moderate and severe COPD exacerbations from the first dose of medication until 1 day after last drug administration. The primary analysis included all randomly assigned patients who received any dose of study medication but were not from a site excluded due to on-site protocol violations. The trial is registered with ClinicalTrials.gov, number NCT02296138.. Overall, 9009 patients were screened from 818 centres in 51 countries. We recruited 7880 patients between Jan 22, 2015 and March 7, 2016 (mean age 66·4 years [SD 8·5], 5626 [71%] were men, mean FEV. Combining tiotropium and olodaterol did not reduce exacerbation rate as much as expected compared with tiotropium alone.. Boehringer Ingelheim International GmbH.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Smokers; Tiotropium Bromide; Treatment Outcome

Bronchodilation and exercise training (ExT) improve exercise tolerance in patients with chronic obstructive pulmonary disease (COPD); however, behavior modification is required to impact daily physical activity (PA).. To assess whether tiotropium/olodaterol, with or without ExT, would improve exercise endurance time (EET) and PA compared with placebo in patients participating in a self-management behavior-modification (SMBM) program.. This was a 12-week, randomized, partially double-blind, placebo-controlled, parallel-group trial in patients with COPD (PHYSACTO; NCT02085161). All patients were enrolled into SMBM and randomized 1:1:1:1 to once-daily placebo, tiotropium 5 μg, tiotropium/olodaterol 5/5 μg, or tiotropium/olodaterol 5/5 μg plus 8 weeks ExT. EET, measured by endurance shuttle walk test after 8 weeks, was the primary endpoint. Additional endpoints assessed downstream effects on PA (measured via accelerometry), and activity-related dyspnea and difficulty (using validated patient-reported questionnaires).. SMBM plus tiotropium/olodaterol, with or without ExT, significantly improved EET at Week 8 versus SMBM plus placebo (treatment ratio vs. placebo: with ExT, 1.46; 95% confidence interval, 1.20-1.78; P = 0.0002; without ExT, 1.29; 95% confidence interval, 1.06-1.57; P = 0.0109). No significant increases in steps per day from baseline were observed over SMBM plus placebo at Week 12 (increase of 1,098) when other therapies were added. Adding tiotropium/olodaterol, with or without ExT, to SMBM reduced activity-related dyspnea versus placebo, whereas adding tiotropium/olodaterol plus ExT reduced activity-related difficulty.. Tiotropium/olodaterol, with or without ExT, improved EET in patients with COPD taking part in an SMBM program. Combination bronchodilation, with or without ExT, did not provide additional increases in objective PA compared with SMBM alone but did reduce PA-related dyspnea and difficulty. Clinical trial registered with www.clinicaltrials.gov (NCT02085161).

Topics: Accelerometry; Adult; Aged; Behavior Therapy; Benzoxazines; Bronchodilator Agents; Combined Modality Therapy; Double-Blind Method; Drug Combinations; Exercise; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

There are no studies on withdrawal of inhaled corticosteroids in patients on long-term triple therapy in the absence of frequent exacerbations.. To evaluate the efficacy and safety of direct de-escalation from long-term triple therapy to indacaterol/glycopyrronium in nonfrequently exacerbating patients with chronic obstructive pulmonary disease (COPD).. This 26-week, randomized, double-blind, triple-dummy study assessed the direct change from long-term triple therapy to indacaterol/glycopyrronium (110/50 μg once daily) or continuation of triple therapy (tiotropium [18 μg] once daily plus combination of salmeterol/fluticasone propionate [50/500 μg] twice daily) in nonfrequently exacerbating patients with moderate-to-severe COPD. Primary endpoint was noninferiority on change from baseline in trough FEV. In patients with COPD without frequent exacerbations on long-term triple therapy, the direct de-escalation to indacaterol/glycopyrronium led to a small decrease in lung function, with no difference in exacerbations. The higher exacerbation risk in patients with ≥300 blood eosinophils/μl suggests that these patients are likely to benefit from triple therapy. Clinical trial registered with www.clinicaltrials.gov (NCT 02603393).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone-Salmeterol Drug Combination; Glucocorticoids; Glycopyrrolate; Humans; Indans; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Tiotropium Bromide; Treatment Outcome

Little is known about the recovery patterns from acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in newly diagnosed or maintenance treatment-naïve patients with COPD. This study describes the course of AECOPD in these patients at the time of treatment for the symptoms of acute respiratory tract infection (RTI).. This study was a secondary analysis of data from a 12-week, randomized clinical trial (TICARI 1) testing the efficacy and safety of once-daily tiotropium 18 µg maintenance therapy versus placebo in newly diagnosed or maintenance treatment-naïve COPD patients with acute RTI symptoms for ≤7 days. Patients received standard care for AECOPD and RTI. Due to under-recruitment, the trial ended early and hence was underpowered to detect treatment differences. Data were pooled and exacerbation recovery patterns examined by using the EXAcerbation of Chronic Pulmonary Disease Tool (EXACT), forced expiratory volume in 1 second, rescue medication use, COPD Assessment Test™, Functional Assessment of Chronic Illness Therapy-Short Form, and Work Productivity and Activity Impairment Questionnaire: Respiratory Symptoms.. Of 140 patients, 73.6% had a prior COPD diagnosis without maintenance therapy; 80.0% had moderate-to-severe airflow obstruction. In addition to study drug, 40.0% were prescribed pharmacologic therapy (corticosteroids [34.3%], antibiotics [16.4%], and short-acting β. A substantial portion of newly diagnosed or maintenance treatment-naïve patients with COPD experience relapse or persistent symptoms following a clinic visit for AECOPD with symptoms of RTI. Whether initiating maintenance therapy could improve outcomes and reduce exacerbation risk requires further study.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bronchodilator Agents; Disease Progression; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Early Termination of Clinical Trials; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Respiratory Tract Infections; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; United States; Work Capacity Evaluation

PUR0200 is a tiotropium bromide formulation engineered with the iSPERSE dry powder delivery technology. PUR0200 is being developed as a bioequivalent alternative to tiotropium bromide, delivered using Spiriva® HandiHaler® (HH). We investigated the bronchodilator effects, pharmacokinetics and safety of PUR0200 in patients with chronic obstructive pulmonary disease (COPD).. This was a randomized, placebo-controlled, crossover study using different PUR0200 doses and the comparator tiotropium HH. In vitro aerodynamic particle size distribution (aPSD) characterization of PUR0200 and tiotropium HH are presented. The main endpoints included forced expiratory volume in 1 s (FEV. The increased fine-particle fraction of PUR0200 demonstrated by testing using the next-generation impactor increased the proportion of drug available for lung deposition compared with the tiotropium HH. There was a numerical dose-response effect for PUR0200 on FEV. PUR0200 treatment caused bronchodilation in COPD patients that was similar in magnitude to that caused by tiotropium HH. This enabled a similar clinical effect on lung function to be achieved with PUR0200 using a lower metered dose of tiotropium compared with tiotropium HH.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Dry Powder Inhalers; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Spirometry; Therapeutic Equivalency; Tiotropium Bromide; Treatment Outcome

Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment.. Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment.

Topics: Administration, Inhalation; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

The DYNAGITO study was a Phase IIIb, randomized, double-blind, multicenter, active-controlled, parallel-group, 52-week study designed to determine the efficacy and safety of tiotropium and olodaterol combination therapy (TIO+OLO 5/5 μg) versus tiotropium monotherapy (TIO 5 μg) for reducing moderate-to-severe exacerbations of COPD. This is a prespecified analysis of the DYNAGITO data in Japanese patients.. Enrolled patients had a diagnosis of COPD with at least one moderate-to-severe exacerbation in the previous 12 months. Of the total 7,880 treated patients in the DYNAGITO study, 461 (TIO+OLO 5/5 μg: n=226, TIO 5 μg: n=235) were Japanese. The primary endpoint was the annualized rate of moderate-to-severe COPD exacerbations. The key secondary endpoint was the time to first moderate-to-severe COPD exacerbation, and other secondary endpoints included the annualized rate of exacerbations leading to hospitalization, time to first COPD exacerbation leading to hospitalization, and all-cause mortality. Safety data were analyzed descriptively.. Combination therapy with TIO+OLO resulted in a 29% lower rate of moderate-to-severe COPD exacerbations relative to TIO monotherapy (rate ratio 0.71; 99% CI: 0.46, 1.10;. In a prespecified subgroup analysis of Japanese patients in the DYNAGITO study, combination therapy with TIO+OLO was more effective than TIO in reducing exacerbations. Both treatments were well tolerated.

Topics: Administration, Inhalation; Aged; Benzoxazines; Bronchodilator Agents; Cause of Death; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Hospitalization; Humans; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

We investigated the short-term bronchodilator effects of RPL554 (an inhaled dual phosphodiesterase 3 and 4 inhibitor) combined with other bronchodilators in chronic obstructive pulmonary disease patients with reversibility (>150 mL to short-acting bronchodilators).Study 1 was a six-way, placebo-controlled crossover study (n=36) with single doses of RPL554 (6 mg), salbutamol (200 µg), ipratropium (40 µg), RPL554 (6 mg)+salbutamol (200 µg), RPL554 (6 mg)+ipratropium (40 µg) or placebo. Study 2 was a three-way crossover study (n=30) of tiotropium (18 µg) combined with RPL554 (1.5 or 6 mg) or placebo for 3 days. Forced expiratory volume in 1 s (FEV

Topics: Administration, Inhalation; Aged; Albuterol; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Ipratropium; Isoquinolines; Lung; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pyrimidinones; Tiotropium Bromide; Treatment Outcome; United Kingdom

Use of inhaled corticosteroids (ICS) increases the risk of pneumonia in chronic obstructive pulmonary disease (COPD), but the magnitude of risk with different ICS remains unclear.. A post hoc analysis of the 4-year UPLIFT® trial to assess whether pneumonia risk differed by type of ICS (fluticasone propionate [FP], other ICS, or no ICS) in permanent users (defined by use until end of study) or in users at baseline (sensitivity analysis).. For the permanent-users analysis, 825 patients receiving FP throughout the trial, 825 patients receiving other ICS and 825 patients not receiving ICS were matched on relevant baseline features 1:1:1. A significantly greater risk of pneumonia was observed for FP versus no ICS: the hazard ratio (HR) for risk of pneumonia was 1.33 (95% confidence interval [CI] 1.00, 1.75; p = 0.046) and the rate ratio (RR) was 1.58 (95% CI 1.05, 2.37; p = 0.028). A greater risk was also found for FP versus other ICS: HR 1.28 (95% CI 0.97, 1.68; p = 0.078) and RR 1.48 (95% CI 1.00, 2.19; p = 0.049). A higher proportion of patients on FP were hospitalized with pneumonia (7.9%) versus other ICS (6.7%) or no ICS (5.9%). Whilst other ICS use was associated with the highest number of fatal pneumonia events, the total number of fatal pneumonia incidents was low. A similar pattern was observed in the sensitivity analyses, which included 4002 patients on different treatments at baseline (FP, other ICS, and no ICS) and considered potential switches during the study.. The results support existing evidence of an increased pneumonia risk with FP use compared with other ICS and no ICS use in patients with COPD. Healthcare professionals should evaluate the risk-benefit ratio of using ICS when making treatment decisions with their patients.. Post hoc analysis of UPLIFT®. ClinicalTrials.gov number: NCT00144339 . Retrospectively registered September 2, 2005.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone; Humans; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Research Design; Risk Factors; Tiotropium Bromide

Tiotropium bromide has been widely used in clinical practice, while theophylline is another treatment option for chronic obstructive pulmonary disease (COPD). However, only a few relevant studies have investigated the long-term outcomes and efficacy of both in patients with COPD. We evaluated the effects of tiotropium and low-dose theophylline on stable COPD patients of groups B and D.. Eligible participants (n = 170) were randomized and received either tiotropium 18 µg once daily with theophylline 100 mg twice daily (Group I) or tiotropium 18 µg once daily (Group II) for 6 months. COPD assessment test (CAT), modified Medical Research Council (mMRC) dyspnea scores and pulmonary function tests were measured before randomization and during the treatment.. After 6 months of treatment, the CAT scores in both groups decreased significantly (11.41 ± 3.56 and 11.08 ± 3.05, p < 0.0001). The changes of CAT (p = 0.028) and mMRC scores (p = 0.049) between the two groups differed after 1 month of treatment. In Group I, forced expiratory flow after 25% of the FVC% predicted (MEF. Tiotropium combined with low-dose theophylline significantly improved the symptoms and general health of patients with stable COPD of groups B and D after 6 months of follow-up. Additionally, this therapy also improved the indicators of small airway function.. Chinese Clinical Trial Registry (Registry ID: ChiCTR1800019027).

Topics: Aged; Bronchodilator Agents; Drug Therapy, Combination; Dyspnea; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Theophylline; Tiotropium Bromide

UMEC/VI was associated with small improvements in QALYs (+ 0.029) over a 3-year time horizon, compared with TIO/OLO, alongside cost savings of €393/patient. The ITT scenario analysis and sensitivity analyses had similar results. All probabilistic simulations resulted in UMEC/VI being less costly and more effective than TIO/OLO.

Topics: Aged; Benzoxazines; Benzyl Alcohols; Chlorobenzenes; Cost-Benefit Analysis; Cross-Over Studies; Drug Combinations; Female; Humans; Male; Middle Aged; National Health Programs; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Single-Blind Method; Spain; Tiotropium Bromide

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with loss of lung function and poor outcomes for patients. However, there are limited data on the time course of changes in forced expiratory volume in 1 s (FEV. Eight hundred and eighty-eight patients in the WISDOM study had a moderate/severe exacerbation after the complete ICS withdrawal visit; 360 of them contributed at least one FEV. Mean lung function starts to decline prior to the first reported symptoms of an exacerbation, and does not recover to pre-exacerbation levels 8 weeks after the event.. WISDOM (ClinicalTrials.gov number, NCT00975195 ).

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Spirometry; Tiotropium Bromide

Limited data are available for the efficacy of triple therapy with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We compared treatment with extrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; fixed triple) with tiotropium, and BDP/FF plus tiotropium (open triple).. For this double-blind, parallel-group, randomised, controlled trial, eligible patients had COPD, post-bronchodilator forced expiratory volume in 1 s (FEV. Between Jan 21, 2014, and March 18, 2016, 2691 patients received fixed triple (n=1078), tiotropium (n=1075), or open triple (n=538). Moderate-to-severe exacerbation rates were 0·46 (95% CI 0·41-0·51) for fixed triple, 0·57 (0·52-0·63) for tiotropium, and 0·45 (0·39-0·52) for open triple; fixed triple was superior to tiotropium (rate ratio 0·80 [95% CI 0·69-0·92]; p=0·0025). For week 52 pre-dose FEV. In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV. Chiesi Farmaceutici SpA.

Topics: Administration, Inhalation; Adult; Aged; Beclomethasone; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Glycopyrrolate; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

The long-term safety and efficacy of a novel Co-Suspension™ Delivery Technology glycopyrrolate (GP)/formoterol fumarate (FF) 18/9.6 μg fixed-dose combination metered dose inhaler (GFF MDI) were investigated in a 28-week safety extension study (PINNACLE-3, NCT01970878) of two randomized controlled Phase III trials (PINNACLE-1 and -2; NCT01854645 and NCT01854658) in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD).. Subjects completing 24 weeks' treatment with GFF MDI, GP MDI, FF MDI (all twice-daily) or open-label tiotropium 18 μg (once-daily) in PINNACLE-1 or -2 were randomly selected to continue treatment for 28 weeks. The target enrollment for PINNACLE-3 was 850 subjects. Safety and efficacy were evaluated over 52 weeks.. Of 3274 subjects randomized to active treatment in PINNACLE-1 or -2, 892 entered PINNACLE-3. Incidences of adverse events, serious adverse events and major adverse cardiovascular events were similar across treatment groups with no unexpected safety findings. For change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV. Results confirmed the long-term safety and tolerability of GFF MDI 18/9.6 μg twice-daily in subjects with moderate-to-very severe COPD. Improvements in efficacy endpoints were also sustained over 52 weeks.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Drug Therapy, Combination; Drug Tolerance; Dyspnea; Female; Forced Expiratory Volume; Formoterol Fumarate; Glycopyrrolate; Humans; Male; Metered Dose Inhalers; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Smoking; Tiotropium Bromide; Treatment Outcome

In this pooled analysis, we compared the effect of indacaterol/glycopyrronium (IND/GLY) by sex versus other commonly used chronic obstructive pulmonary disease (COPD) treatments and placebo. Male and female patients with moderate-to-very-severe COPD who had participated in six randomized controlled trials were included in the analysis. Baseline demographics and disease characteristics were analyzed by sex, and any differences noted. The effects of IND/GLY versus salmeterol/fluticasone (SFC), glycopyrronium, tiotropium and placebo, on lung function and the patient-reported outcomes (health status, dyspnea, rescue medication use and symptoms) were assessed by sex after 26 weeks treatment. The analysis population comprised 4719 men and 1389 women. Most baseline parameters differed significantly between men and women. Nonetheless, despite these differences in baseline characteristics, IND/GLY significantly improved lung function versus placebo (p < 0.0001) and all active comparators (p < 0.01) in men and women. Overall, IND/GLY showed better improvement in dyspnea and health status compared with all other treatments in both sex. Greater reduction of rescue medication use was observed with IND/GLY versus placebo and other treatments (all p < 0.01 expect IND/GLY versus SFC). Although some variability was observed, improvements in health status, dyspnea, rescue medication use and symptoms were generally larger in women than in men. Irrespective of sex, IND/GLY provided superior efficacy to monotherapy or SFC in both men and women. Small differences in efficacy response by sex were observed, which should be evaluated further in prospective clinical studies. Nevertheless, the benefits observed with IND/GLY confirm dual bronchodilator as the preferred therapy in patients with moderate-to-very-severe COPD regardless of sex.

Topics: Aged; Bronchodilator Agents; Drug Combinations; Dyspnea; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Glucocorticoids; Glycopyrrolate; Health Status; Humans; Indans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Severity of Illness Index; Sex Factors; Tiotropium Bromide; Vital Capacity

A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo. This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study.. Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 μg twice daily (BID), tiotropium 18 μg once daily (QD), or placebo, for 6 weeks. Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed.. In all, 277 symptomatic patients were included in this post hoc analysis. Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV. In this post hoc analysis of symptomatic patients with moderate to severe COPD, aclidinium 400 μg BID provided additional improvements compared with tiotropium 18 μg QD in: 1) bronchodilation, particularly during the nighttime, 2) daily COPD symptoms (E-RS), 3) early-morning and nighttime symptoms, and 4) early-morning limitation of activity.

Topics: Activities of Daily Living; Aged; Bronchodilator Agents; Circadian Rhythm; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes

An extrafine formulation of the long-acting muscarinic antagonist glycopyrronium bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate - a "fixed triple". This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 μg versus placebo; Part 2: repeat-dose (7-day), four-period crossover, GB 12.5, 25 or 50 μg twice daily (BID) versus placebo, with an open-label extension in which all patients received tiotropium 18 μg once daily. On the morning of Day 8 in all five periods, patients also received formoterol 12 μg. In study Part 1, 27 patients were recruited. All GB doses significantly increased from baseline forced expiratory volume in 1 second (FEV

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Albuterol; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; England; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Ipratropium; Lung; Male; Middle Aged; Muscarinic Antagonists; Particle Size; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

Objective Among elderly patients with chronic obstructive pulmonary disease (COPD), there are some patients who cannot inhale tiotropium via Respimat

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Over Studies; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Terbutaline; Tiotropium Bromide

Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD.. In a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 μg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV. Of 841 patients who underwent randomization, 388 patients in the tiotropium group and 383 in the placebo group were included in the full analysis set. The FEV. Tiotropium resulted in a higher FEV

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide

The use of long-acting bronchodilators is an essential component of the management of chronic obstructive pulmonary disease (COPD). The GOLDEN 5 Phase III, randomized, active-controlled, open-label study was conducted to evaluate the long-term safety and tolerability of a nebulized glycopyrrolate formulation (SUN-101) delivered via the investigational eFlow. Subjects were randomized in a 4:3 ratio to nebulized glycopyrrolate 50 μg twice daily (BID) or tiotropium 18 μg once daily (OD) and treated for 48 weeks. Subjects represented the general COPD population with real-world characteristics including severe disease, presence of comorbidities, and receiving background COPD therapy. Primary endpoints were the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs. Secondary endpoints included the number of subjects with major adverse cardiovascular events (MACE); change from baseline in trough forced expiratory volume in 1 s (FEV. 1086 subjects received at least one dose of study drug. The overall incidence of TEAEs was comparable for subjects treated with glycopyrrolate (69.4%) or tiotropium (67.0%). Serious TEAEs occurred at similar rates in both treatment groups (glycopyrrolate, 12.3%; tiotropium, 10.5%). The most frequent TEAEs were COPD exacerbation/worsening and cough. Discontinuation due to TEAEs was higher in the glycopyrrolate group (10.0%) than the tiotropium group (2.8%) and related, in part, to the open-label study design, prior use of long-acting muscarinic antagonists and aerosol-airway interactions. Fewer subjects in the glycopyrrolate group experienced MACE (glycopyrrolate, n = 3 [0.5%]; tiotropium, n = 8 [1.7%]). Nebulized glycopyrrolate treatment resulted in improvements in trough FEV. Treatment with nebulized glycopyrrolate was well tolerated over 48 weeks with the most common adverse events being COPD worsening and cough. The overall and cardiac safety and tolerability profile and improvements in pulmonary function and patient-reported health outcomes support the use of nebulized glycopyrrolate as a maintenance treatment for moderate-to-very-severe COPD.. NCT02276222.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cough; Female; Forced Expiratory Volume; Gastrointestinal Diseases; Glycopyrrolate; Headache; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections; Severity of Illness Index; Tiotropium Bromide; Vital Capacity

The difference in efficacy of long-acting muscarinic antagonists (LAMAs) and long-acting β. Thirty stable patients were enrolled and randomly divided into two groups following baseline measurements. One group was treated with 5 μg tiotropium (Respimat inhaler) for 4 weeks following a 4-week treatment with 150 μg indacaterol, while the other group was treated with indacaterol for 4 weeks following a 4-week treatment with tiotropium. For both groups, these treatments were followed by a combination of the two drugs for 4 weeks. Pulmonary function tests, including DLH evaluated by metronome-paced incremental hyperventilation and exercise tolerance evaluated by the shuttle-walk test, were performed at the end of each treatment period.. In total, 23 patients completed this study. Both tiotropium and indacaterol alone significantly increased forced expiratory volume in 1 second, exercise tolerance, and improved health status. Tiotropium significantly improved DLH, but indacaterol did not. The combination therapy resulted in further improvements in lung function and exercise tolerance, but not in DLH.. The efficacy of tiotropium in inhibiting DLH following metronome-paced incremental hyperventilation may be superior to that of 150 μg indacaterol, although the effects on airflow obstruction were the same, and the combination therapy showed further improvement in airflow obstruction, but not in DLH.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Cross-Over Studies; Drug Therapy, Combination; Exercise Tolerance; Female; Forced Expiratory Volume; Humans; Indans; Japan; Lung; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Recovery of Function; Time Factors; Tiotropium Bromide; Treatment Outcome

This study aimed to compare rapid improvements in respiratory function and symptoms following single inhalation of formoterol (FOM) dry power inhaler (DPI) or tiotropium bromide (TIO) DPI in patients with chronic obstructive pulmonary disease (COPD).. Fifty-two outpatients with COPD (GOLD stage 2 or 3) received either a single inhalation of FOM DPI (9 μg via a Turbuhaler. Forced expiratory volume in 1 second (FEV1) significantly improved 15min after both FOM (p=0.002) and TIO (p=0.026). Respiratory resistance at 5Hz (R5) and resonant frequency indices significantly decreased 10min (p=0.007) and 3min (p=0.034) after inhaling FOM and remained reduced at 120min. Low frequency reactant indices at 5Hz (X5) significantly increased at 30min (p=0.012) VAS significantly correlated with FEV1 (r=-0.371, p=0.007), X5 (r=-0.304, p=0.029), and low-frequency reactance area (AX; r=0.305, p=0.028) in FOM, but not in TIO. Borg scale scores significantly correlated with FEV1% (r=-0.398, p=0.004), R5 (r=-0.379, p=0.006), respiratory resistance at 20Hz (R20; r=0.321, p=0.020), and R5-R20 (r=0.377, p=0.006) in FOM, but not in TIO.. FOM is more effective than TIO at rapidly improving pulmonary function and symptoms in patients with COPD.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchodilator Agents; Cross-Over Studies; Delayed-Action Preparations; Dosage Forms; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Respiration; Respiratory Function Tests; Time Factors; Tiotropium Bromide; Treatment Outcome

There is currently no measure to predict a treatability of long-acting β-2 agonist (LABA) or long-acting muscarinic antagonist (LAMA) in patients with chronic obstructive pulmonary disease (COPD). We aimed to build prediction models for the treatment response to these bronchodilators, in order to determine the most responsive medication for patients with COPD.. We performed a prospective open-label crossover study, in which each long-acting bronchodilator was given in a random order to 65 patients with stable COPD for 4 weeks, with a 4-week washout period in between. We analyzed 14 baseline clinical traits, expression profiles of 31,426 gene transcripts, and damaged-gene scores of 6,464 genes acquired from leukocytes. The gene expression profiles were measured by RNA microarray and the damaged-gene scores were obtained after DNA exome sequencing. Linear regression analyses were performed to build prediction models after using factor and correlation analyses.. Using a prediction model for a LABA, traits found associated with the treatment response were post-bronchodilator forced expiratory volume in 1 second, bronchodilator reversibility (BDR) to salbutamol, expression of three genes (. Adding the expressions of genes and damaged-gene scores to the clinical traits may improve the predictability of treatment response to long-acting bronchodilators.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Clinical Decision-Making; Cross-Over Studies; Female; Forced Expiratory Volume; Gene Expression Profiling; Humans; Indans; Lung; Male; Middle Aged; Models, Genetic; Muscarinic Antagonists; Oligonucleotide Array Sequence Analysis; Patient Selection; Precision Medicine; Predictive Value of Tests; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quantitative Trait, Heritable; Quinolones; Republic of Korea; Time Factors; Tiotropium Bromide; Transcriptome; Treatment Outcome

Dual bronchodilator therapy is reserved as a second-line treatment in patients with chronic obstructive pulmonary disease (COPD) and provides benefits in lung function and health status versus monotherapy. The aim of this study was to determine whether early initiation of a dual bronchodilator versus monotherapy reduced the risk of deterioration in COPD.. This post hoc pooled analysis investigated the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg/day compared with tiotropium (TIO) 18 mcg/day in a maintenance-naïve (MN) subgroup of patients relative to the intent-to-treat (ITT) population from three 6-month active comparator studies (n = 1747). Other treatment arms (UMEC/VI 125/25, VI 25 and UMEC 125) comprised 850 patients in total but were not included in this analysis. The primary endpoint was trough forced expiratory volume in 1 s (FEV. Early use of dual-bronchodilator therapy has superior efficacy on lung function and may reduce the risk of short-term deterioration compared to monotherapy in symptomatic patients with COPD.. GSK analysis 202066 (NCT01316900/DB2113360, NCT01316913/DB2113374, NCT01777334/ZEP117115).. This study was funded by GSK.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tiotropium Bromide; Treatment Outcome

Long-acting bronchodilators, including anticholinergics glycopyrronium and tiotropium, are central to symptomatic management of chronic obstructive pulmonary disease (COPD). In patients with moderate to severe COPD, glycopyrronium has demonstrated comparable efficacy to open-label and single-blinded tiotropium, but with faster onset of bronchodilation. The FAST study assessed the efficacy of glycopyrronium compared with tiotropium in serial spirometry and body plethysmography assessments to further characterize the earlier onset of action associated with glycopyrronium.. In this German multicentre, randomised, double-blinded, double-dummy, cross-over study, patients with moderate-to-severe COPD received single-dose of glycopyrronium 44 μg and tiotropium 18 μg via the Breezhaler. Of the 152 patients randomised, 99.3% completed the study. After inhalation of the single dose, glycopyrronium demonstrated superiority over tiotropium in early bronchodilation as assessed by improvement in FEV. Glycopyrronium was superior to tiotropium in terms of early bronchodilation. Although both glycopyrronium and tiotropium showed similar improvements in static lung volume parameters, glycopyrronium reduced specific airway resistance faster than tiotropium, which could in part explain the earlier FEV. ClinicalTrials.govNCT01922271.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Germany; Glycopyrrolate; Humans; Inspiratory Capacity; Male; Middle Aged; Plethysmography, Whole Body; Pulmonary Disease, Chronic Obstructive; Residual Volume; Severity of Illness Index; Spirometry; Time Factors; Tiotropium Bromide

Long-term safety, particularly cardiovascular safety, is of special interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting β. This analysis comprised 3100 patients with moderate to very severe COPD, treated for ≤1 year, including 784 patients with cardiovascular co-morbidities. AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities. The incidence and nature of events were consistent with the disease under study and a 1-year trial duration. 494/3100 patients contributed to an adjudicated analysis of SAEs: 260 had respiratory-related, 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs. Incidences of these SAEs were comparable between treatments. There was no evidence of any increased risk for the combination compared to the monotherapy groups.. These data provide confidence for clinicians that tiotropium/olodaterol 5/5 μg can be safely administered once-daily to patients with moderate to very severe COPD long-term, including those with significant cardiovascular co-morbidity.. ClinicalTrials.gov, Nos.: NCT01431274, NCT01431287.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Cardiovascular Diseases; Comorbidity; Double-Blind Method; Drug Combinations; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Incidence; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Chronic obstructive pulmonary disease is associated with significant morbidity and mortality. Trials of maintenance chronic obstructive pulmonary disease treatments focus on improvement in lung function and reductions in exacerbations, while patients are much more concerned about symptoms and health status. Our aim was to investigate the effects of tiotropium + olodaterol on patient-reported health outcomes, breathlessness and night-time rescue medication use in patients with chronic obstructive pulmonary disease, compared to placebo, tiotropium or olodaterol monotherapy. Two pairs of replicate, phase III studies of 12 (OTEMTO 1 + 2) and 52 weeks' (TONADO 1 + 2) duration were evaluated, in which patients received either tiotropium + olodaterol 2.5/5 or 5/5 μg, tiotropium 2.5 or 5 μg, olodaterol 5 μg or placebo, all delivered once daily via Respimat inhaler. Patient-reported outcomes included breathlessness assessed by transition dyspnoea index focal score, health status assessed by St George's Respiratory Questionnaire total score and night-time rescue medication use at 12 or 24 weeks. Outcomes from the pooled study data are reported. Overall, 1621 and 5162 patients were treated in the OTEMTO and TONADO trials, respectively. Significantly larger improvements in St George's Respiratory Questionnaire and transition dyspnoea index focal scores were observed and a greater proportion of patients were responders to therapy (based on minimum clinically important differences in St George's Respiratory Questionnaire and transition dyspnoea index) with tiotropium + olodaterol compared to either monotherapy or to placebo. Tiotropium + olodaterol 5/5 µg significantly reduced night-time rescue medication usage.. COMBINED INHALER PROVES EFFECTIVE: Results from four in-depth studies show that a combined inhaler is very effective for treatment of moderate to severe chronic lung disease. Alleviating the symptoms of chronic obstructive pulmonary disease (COPD), particularly sleep disturbance, is crucial to enhancing patients' quality of life. Gary Ferguson at the Pulmonary Research Institute of Southeast Michigan, together with other scientists across the USA and Germany, analysed data from four large-scale studies to evaluate the efficacy of STIOLTO Respimat, a combination of two bronchodilators-tiotropium, and olodaterol, which tackle airway obstruction and breathlessness, improving long-term lung function. They found that the new drug combination triggered significant improvements in patients' quality of life and levels of breathlessness. Use of night-time rescue medication in patients on STIOLTO Respimat was considerably reduced. A greater number of patients responded positively to the combined inhaler than to monotherapy.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Dyspnea; Female; Forced Expiratory Volume; Health Status; Humans; Male; Middle Aged; Patient Reported Outcome Measures; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Vital Capacity

Long-acting bronchodilator monotherapy (long-acting β. This 12-week, randomized, multicenter, open-label, phase IV study aims to show that the once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 μg fixed-dose LABA/LAMA combination results in an improved lung function in symptomatic patients with mild-to-moderate COPD who switch from once-daily tiotropium 18 μg. The study aims to enroll a total of 404 symptomatic patients in Korea with mild-to-moderate COPD who received tiotropium for at least 12 weeks prior to the study initiation. The primary objective of this study is to demonstrate the superiority of IND/GLY over tiotropium in terms of trough forced expiratory volume in 1 second (FEV. This study intends to establish the use of LABA/LAMA combination therapy in symptomatic patients with mild-to-moderate COPD by demonstrating the superiority of IND/GLY over tiotropium monotherapy.. ClinicalTrials.gov, NCT02566031 . Registered on 10 August 2015.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Cholinergic Antagonists; Clinical Protocols; Drug Administration Schedule; Drug Combinations; Drug Substitution; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Lung; Male; Pulmonary Disease, Chronic Obstructive; Quinolones; Recovery of Function; Republic of Korea; Research Design; Severity of Illness Index; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The efficacy and safety of once-daily tiotropium+olodaterol (T+O) (2.5/5µg or 5/5µg) for treating chronic obstructive pulmonary disease (COPD) have been demonstrated in the large, multinational, randomized, Phase III studies TONADO. Patients were randomized to 52 weeks of double-blind treatment with once-daily T+O (2.5/5 or 5/5µg) or O (5µg) monotherapy via the Respimat. The incidence of adverse events (AEs) was comparable in the T+O 2.5/5µg (75.0%), T+O 5/5µg (85.4%), and O 5µg (80.5%) groups, with drug-related AEs being reported in 5.0%, 7.3%, and 4.9% of patients, respectively. Serious AEs were reported in 14 patients (11.5%). The change from baseline in forced expiratory volume in 1s (FEV. No safety concerns for long-term T+O treatment were identified in Japanese patients with COPD. A numerical improvement in lung function was observed with T+O treatment compared to O monotherapy.

Topics: Administration, Inhalation; Adult; Aged; Asian People; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Time Factors; Tiotropium Bromide; Treatment Outcome

Triple combination therapy with tiotropium plus budesonide/formoterol has improved lung function and reduced exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) in Western countries, but no such data exist for East Asian patients. This study aimed to evaluate the efficacy and tolerability of adding budesonide/formoterol to tiotropium compared with tiotropium alone in East Asian patients with severe/very severe COPD.. This 12-week, randomized, parallel-group, multicentre, open-label study was conducted in East Asia. After a 14-day run-in period during which patients received tiotropium 18 μg once daily, patients were randomized to tiotropium (18 μg once daily) + budesonide/formoterol (160/4.5 μg 2 inhalations twice daily) or tiotropium alone (18 μg once daily). The primary endpoint was change from baseline in pre-dose forced expiratory volume in 1 s (FEV1 ) to the mean of values measured at Weeks 1, 6 and 12.. Pre-dose FEV1 significantly increased from baseline with tiotropium plus budesonide/formoterol (n = 287) versus tiotropium alone (n = 291) (5.0% vs 0.6%; treatment difference: 4.4% (95% CI: 1.9-6.9), P = 0.0004). Triple therapy also reduced the COPD exacerbation rate by 40.7% (P = 0.0032) and prolonged time to first exacerbation (38.6% risk reduction, P = 0.0167) versus tiotropium alone and markedly improved health-related quality of life (HRQoL), measured using the St George's Respiratory Questionnaire. Incidence of adverse events was 26% for both groups.. In East Asian patients with severe/very severe COPD, adding budesonide/formoterol to tiotropium was associated with significant improvements in FEV1 and HRQoL and lower COPD exacerbation rates. Treatment was generally well tolerated.. NCT01397890 at Clinicaltrials.gov.

Topics: Aged; Asia, Eastern; Bronchodilator Agents; Budesonide, Formoterol Fumarate Drug Combination; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Severity of Illness Index; Symptom Flare Up; Tiotropium Bromide; Treatment Outcome

Patients with chronic obstructive pulmonary disease (COPD) have poor sleep quality as a result of various alterations in oxygenation parameters and sleep macro- and micro-architecture. There is a shortage of data to support the efficacy of long-acting inhaled anticholinergic agents in improving these adverse effects, which are known to have a negative impact on clinical outcomes. We aimed to compare the tiotropium Respimat Soft Mist Inhaler and the HandiHaler in terms of their effects on sleeping oxygen saturation (SaO2) and sleep quality in patients with COPD.. In a randomized, open-label, parallel-group trial involving 200 patients with mild to moderate COPD (resting arterial oxygen tension >60 mmHg while awake), we compared the effects of 6 months' treatment with the two devices on sleeping SaO2 and sleep quality. Overnight polysomnography and pulmonary function testing were performed at baseline and after 6 months' treatment.. A total of 188 patients completed the trial. Both groups showed significant improvement in minimum sleep SaO2 and time of sleep spent with SaO2 below 90 (TST90) compared to baseline. The patients using the Respimat had significantly better TST90 than did those using the HandiHaler. Sleep disturbance was highly variable in these patients, but the sleep stage durations were significantly better in the Respimat group.. Sleeping SaO2 can be improved by tiotropium delivered using either the HandiHaler device or the Respimat Soft Mist Inhaler. However, the patients who used the Respimat device had significantly better TST90 and sleep architecture parameters.

Topics: Adult; Aged; Female; Humans; Lung Volume Measurements; Male; Middle Aged; Nasal Sprays; Nebulizers and Vaporizers; Oxygen; Polysomnography; Pulmonary Disease, Chronic Obstructive; Sleep; Tiotropium Bromide

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Drug Therapy, Combination; Fluticasone; Forced Expiratory Volume; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Severity of Illness Index; Tiotropium Bromide; Withholding Treatment

Fluticasone furoate/vilanterol (FF/VI) is a novel, once-daily, inhaled corticosteroid/long-acting β2-agonist combination approved for the treatment of COPD and asthma. We compared the safety and efficacy of FF/VI and tiotropium (TIO) in subjects with moderate-to-severe COPD with greater risk for comorbid cardiovascular disease (CVD).. This randomized, blinded, double-dummy, parallel-group study compared a once-daily morning dose of FF/VI 100/25 mcg delivered via ELLIPTA™ with TIO 18 mcg via HandiHaler(®) for 12 weeks in subjects with diagnosed COPD, forced expiratory volume in 1 second (FEV1) 30%-70% predicted, and CVD or CVD risk. The primary endpoint was change from baseline in 24-hour weighted mean FEV1 on Day 84. Other efficacy endpoints included time to onset of bronchodilation, trough FEV1, other spirometry measures, rescue medication use, symptoms, quality of life (St George's Respiratory Questionnaire-COPD [SGRQ-C]), and health status (COPD Assessment Tests [CAT]) measures. Safety endpoints included cardiovascular monitoring, cortisol excretion, COPD exacerbations, and adverse events, including prespecified drug effects.. Both FF/VI and TIO improved the 24-hour weighted mean FEV1 from baseline after 12 weeks with no significant difference between treatments. Other endpoints favored FF/VI for time to onset of bronchodilation, rescue medication use, dyspnea, SGRQ-C and CAT scores, or favored TIO for change from baseline in forced vital capacity and inspiratory capacity. Pneumonia occurred more frequently in the FF/VI group, and two TIO-treated subjects died following cardiovascular events. Other safety measures were similar between groups, and cardiovascular monitoring did not reveal increased CVD risk.. Both FF/VI and TIO were efficacious in improving lung function in subjects with COPD and comorbid CVD or CVD risk factors, with minor differences in efficacy and safety profiles.

Topics: Administration, Inhalation; Adult; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Cardiovascular Diseases; Chlorobenzenes; Drug Combinations; Drug Monitoring; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Symptom Assessment; Tiotropium Bromide; Treatment Outcome

Long-acting muscarinic antagonists confer improvements in spirometry when used in addition to inhaled corticosteroids and long-acting beta-agonists (ICS/LABA) in COPD. The dual objectives of this proof of concept study were to evaluate trough effects of tiotropium (TIO) or aclidinium (ACL) when used as triple therapy and to assess if impulse oscillometry (IOS) might be more sensitive than spirometry in detecting subtle differences in bronchodilator response.. Patients with moderate to severe COPD already taking ICS/LABA were randomized to receive add-on therapy in cross-over fashion with either TIO 18 µg od or ACL 322 µg bid for 2-3 weeks each. Measurements of IOS, spirometry, 6-min walk test, St George's Respiratory Questionnaire (SGRQ) and Baseline/Transition Dyspnoea Index (TDI) were made at baseline and after chronic dosing at trough (12 h for ACL and 24 h for TIO), in addition to domiciliary diurnal spirometry.. 13 patients were completed: mean age 69 years, FEV1 52 % predicted, FEV1/FVC 0.48, and R5 202 % predicted. There were no differences in any visit-based trough IOS or spirometry outcomes comparing TIO versus ACL. Resonant frequency but not total airway resistance at 5 Hz (R5) significantly improved from baseline with both treatments while peripheral airway resistance (R5-R20) significantly improved with ACL. Visit-based FEV1, and forced and relaxed vital capacity were also significantly improved from baseline with both treatments. There were no significant differences in diurnal FEV1 and FEV6 profiles between treatments. 6-min walk distance and post-walk fatigue significantly improved from baseline with ACL, while post-walk dyspnea improved with TIO. SGRQ symptom score significantly improved to a similar degree with both treatments. TDI significantly improved with ACL versus TIO by 1.54 units.. We observed comparable bronchodilator efficacy at trough with TIO and ACL when used as triple therapy in COPD, while IOS was no more sensitive than spirometry.

Topics: Adult; Aged; Aged, 80 and over; Airway Resistance; Bronchoconstriction; Bronchodilator Agents; Cross-Over Studies; Drug Therapy, Combination; Exercise Test; Exercise Tolerance; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Oscillometry; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Scotland; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes; Vital Capacity

Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD. Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk. This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.. The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.. This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat(®) and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler(®) for 6 weeks. The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0-12) relative to the baseline after 6 weeks.. Tiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0-12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively). Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0-24).. Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate. Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD.

Topics: Administration, Inhalation; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Monitoring; Female; Fluticasone; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome

Several small studies found night-time awakenings due to COPD symptoms were associated with decreased health status. In this study, night-time awakenings in patients with COPD were examined and effects of tiotropium therapy evaluated.. This study was a post hoc, exploratory, pooled analysis of twin, multicenter, double-blind, randomized, placebo-controlled, parallel-group trials. Patients with stable moderate-to-severe COPD were randomized to tiotropium HandiHaler® (n = 550) or placebo (n = 371) and followed for 13 weeks. During a 2-week, pre-treatment baseline period and for 13 weeks on treatment, self-reported night-time awakenings due to COPD symptoms, rescue medication (albuterol) use, and morning and evening peak expiratory flow rate (PEFR) were recorded daily. Nightly, COPD-related awakenings were scored: 0 = no awakenings; 1 = 1 awakening; 2 = 2-3 awakenings; or 3 = awake most of the night. Health-related quality-of-life (HRQoL) and energy-fatigue questionnaires were completed at baseline and during treatment.. Patients were aged 65.2 ± 8.7 years (mean ± SD), with a mean pre-bronchodilator FEV1 of 36.1 ± 13.5 % predicted normal at baseline. Data for night-time awakenings and albuterol use were available for 543 (99 %) patients on tiotropium and 352 (95 %) on placebo. At baseline, 280 (51.5 %) patients on tiotropium and 179 (50.1 %) on placebo reported ≥1 COPD-related night-time awakening per week. Over the 13-weeks' treatment, tiotropium was associated with fewer night-time awakenings, with mean ± SE overall awakening scores per week of 0.356 ± 0.006 compared with 0.421 ± 0.007 for placebo (p < 0.001); means were significantly lower for tiotropium versus placebo in patients with baseline awakenings (p < 0.001), but not for those without baseline awakenings. COPD-related night-time awakenings were associated with increased nocturnal rescue medication use and lower HRQoL ratings in both treatment arms. Following start of treatment, tiotropium decreased patients' use of rescue medication compared with placebo, and morning and evening adjusted means for PEFR were higher for tiotropium compared with placebo.. Tiotropium is associated with decreased COPD-related night-time awakenings. Night-time awakenings are associated with increased nocturnal rescue medication use and may be a surrogate marker of symptom control in patients with COPD.

Topics: Administration, Inhalation; Aged; Albuterol; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Placebo Effect; Pulmonary Disease, Chronic Obstructive; Sleep Wake Disorders; Tiotropium Bromide; Treatment Outcome; United States

The fixed-dose, long-acting bronchodilator combination of umeclidinium/vilanterol (UMEC/VI) has not previously been compared with a combination of a long-acting muscarinic antagonist and long-acting β2-agonist in patients with chronic obstructive pulmonary disease (COPD).. This 12-week, randomized, blinded, triple-dummy, parallel-group, non-inferiority study compared once-daily UMEC/VI 62.5/25 mcg with once-daily tiotropium (TIO) 18 mcg + indacaterol (IND) 150 mcg in patients with moderate-to-very-severe COPD. The primary endpoint was the trough forced expiratory volume in 1 s (FEV1) on day 85 (predefined non-inferiority margin -50 mL), and the secondary endpoint was the 0- to 6-h weighted mean (WM) FEV1 on day 84. Other efficacy endpoints [including rescue medication use, the Transition Dyspnea Index (TDI) focal score, and the St. George's Respiratory Questionnaire (SGRQ) score] and safety endpoints [adverse events (AEs), vital signs, and COPD exacerbations] were also assessed.. Trough FEV1 improvements were comparable between treatment groups [least squares (LS) mean changes from baseline to day 85: UMEC/VI 172 mL; TIO + IND 171 mL; treatment difference 1 mL; 95 % confidence interval (CI) -29 to 30 mL], demonstrating non-inferiority between UMEC/VI and TIO + IND. The treatments produced similar improvements in the trough FEV1 at other study visits and the 0- to 6-h WM FEV1 (LS mean changes at day 84: UMEC/VI 235 mL; TIO + IND 258 mL; treatment difference -23 mL; 95 % CI -54 to 8 mL). The results for patient-reported measures (rescue medication use, TDI focal score, and SGRQ score) were comparable; both treatments produced clinically meaningful improvements in TDI and SGRQ scores. The incidence of AEs and COPD exacerbations, and changes in vital signs were similar for the two treatments.. UMEC/VI and TIO + IND, given once daily, provided similar improvements in lung function and patient-reported outcomes over 12 weeks in patients with COPD, with comparable tolerability and safety profiles.. ClinicalTrials.gov study ID NCT02257385; GSK study no. 116961.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Humans; Indans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease is generally progressive and associated with reduced physical activity. Both pharmacological therapy and exercise training can improve exercise capacity; however, these are often not sufficient to change the amount of daily physical activity a patient undertakes. Behaviour-change self-management programmes are designed to address this, including setting motivational goals and providing social support. We present and discuss the necessary methodological considerations when integrating behaviour-change interventions into a multicentre study.. PHYSACTO is a 12-week phase IIIb study assessing the effects on exercise capacity and physical activity of once-daily tiotropium+olodaterol 5/5 µg with exercise training, tiotropium+olodaterol 5/5 µg without exercise training, tiotropium 5 µg or placebo, with all pharmacological interventions administered via the Respimat inhaler. Patients in all intervention arms receive a behaviour-change self-management programme to provide an optimal environment for translating improvements in exercise capacity into increases in daily physical activity. To maximise the likelihood of success, special attention is given in the programme to: (1) the Site Case Manager, with careful monitoring of programme delivery; (2) the patient, incorporating patient-evaluation/programme-evaluation measures to guide the Site Case Manager in the self-management intervention; and (3) quality assurance, to help identify and correct any problems or shortcomings in programme delivery and ensure the effectiveness of any corrective steps. This paper documents the comprehensive methods used to optimise and standardise the behaviour-change self-management programme used in the study to facilitate dialogue on the inclusion of this type of programme in multicentre studies.. The study has been approved by the relevant Institutional Review Boards, Independent Ethics Committee and Competent Authority according to national and international regulations. The results of this study will be disseminated through relevant, peer-reviewed journals and international conference presentations.. NCT02085161.

Topics: Adult; Aged; Australia; Benzoxazines; Bronchodilator Agents; Canada; Combined Modality Therapy; Double-Blind Method; Europe; Exercise Test; Exercise Therapy; Female; Humans; Male; Middle Aged; New Zealand; Pulmonary Disease, Chronic Obstructive; Quality of Life; Research Design; Self Care; Tiotropium Bromide; Treatment Outcome; United States; Walking

Blood eosinophil counts might predict response to inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. We used data from the WISDOM trial to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn.. WISDOM was a 12-month, randomised, parallel-group trial in which patients received 18 μg tiotropium, 100 μg salmeterol, and 1000 μg fluticasone propionate daily for 6 weeks and were then randomly assigned (1:1) electronically to receive either continued or reduced ICS over 12 weeks. We did a post-hoc analysis after complete ICS withdrawal (months 3-12) to compare rate of exacerbations and time to exacerbation outcomes on the basis of blood eosinophil subgroups of increasing cutoff levels. The WISDOM trial is registered at ClinicalTrials.gov, number NCT00975195.. In the 2296 patients receiving treatment after ICS withdrawal, moderate or severe exacerbation rate was higher in the ICS-withdrawal group versus the ICS-continuation group in patients with eosinophil counts (out of total white blood cell count) of 2% or greater (rate ratio 1·22 [95% CI 1·02-1·48]), 4% or greater (1·63 [1·19-2·24]), and 5% or greater (1·82 [1·20-2·76]). The increase in exacerbation rate became more pronounced as the eosinophil cutoff level rose, with significant treatment-by-subgroup interaction reached for 4% and 5% only. Similar results were seen with eosinophil cutoffs of 300 cells per μL and 400 cells per μL, and mutually exclusive subgroups.. Blood eosinophil counts at screening were related to the exacerbation rate after complete ICS withdrawal in patients with severe to very severe COPD and a history of exacerbations. Our data suggest that counts of 4% or greater or 300 cells per μL or more might identify a deleterious effect of ICS withdrawal, an effect not seen in most patients with eosinophil counts below these thresholds.. Boehringer Ingelheim.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Eosinophils; Female; Fluticasone; Humans; Leukocyte Count; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome; Withholding Treatment

The long-acting muscarinic antagonist tiotropium bromide is approved in many countries as maintenance therapy for chronic obstructive pulmonary disease (COPD). Tiotropium is available as a dry-powder formulation delivered via HandiHaler(®) (18 μg once daily) and is now also approved as an aqueous solution delivered via the Respimat(®) Soft Mist™ Inhaler (5 μg once daily, 2 puffs of 2.5 µg). Several studies have compared the efficacy of tiotropium HandiHaler (18 μg once daily) with different doses of Respimat. We aimed to compare available bronchodilator efficacy data of once-daily Respimat 1.25, 2.5, 5, 10, 20 µg, and HandiHaler 18 µg to investigate which dose of tiotropium delivered by Respimat is the closest match to tiotropium HandiHaler.. Evaluation of six clinical trials (duration from 3 weeks to 2-3 years) that included lung function measures (trough forced expiratory volume in 1 s and trough forced vital capacity) as key outcomes.. In the six trials, bronchodilator efficacy of Respimat 5 μg and HandiHaler 18 μg was similar; however, reduced bronchodilator efficacy was observed with lower doses of Respimat (1.25 and 2.5 μg).. These findings support the use of the marketed once-daily dose of Respimat 5 μg for the maintenance treatment of patients with COPD.. Boehringer Ingelheim.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Monitoring; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

The long-acting muscarinic antagonists umeclidinium (UMEC) and tiotropium (TIO) are approved once-daily maintenance therapies for COPD. This study investigated the efficacy and safety of UMEC versus TIO in COPD.. This was a 12-week, multicenter, randomized, blinded, double-dummy, parallel-group, non-inferiority study. Patients were randomized 1:1 to UMEC 62.5 μg plus placebo or TIO 18 μg plus placebo. The primary end point was trough forced expiratory volume in 1 second (FEV1) at day 85 (non-inferiority margin -50 mL; per-protocol [PP] population). Other end points included weighted mean FEV1 over 0-24 and 12-24 hours post-dose. Patient-reported outcomes comprised Transition Dyspnea Index score, St George's Respiratory Questionnaire total score, and COPD Assessment Test score. Adverse events were also assessed.. In total, 1,017 patients were randomized to treatment. In the PP population, 489 and 487 patients received UMEC and TIO, respectively. In the PP population, change from baseline in trough FEV1 was greater with UMEC versus TIO at day 85, meeting non-inferiority and superiority margins (difference: 59 mL; 95% confidence interval [CI]: 29-88; P<0.001). Similar results were observed in the intent-to-treat analysis of trough FEV1 at day 85 (53 mL, 95% CI: 25-81; P<0.001). Improvements in weighted mean FEV1 over 0-24 hours post-dose at day 84 were similar with UMEC and TIO but significantly greater with UMEC versus TIO over 12-24 hours post-dose (70 mL; P=0.015). Clinically meaningful improvements in Transition Dyspnea Index and St George's Respiratory Questionnaire were observed with both treatments at all time points. No differences were observed between UMEC and TIO in patient-reported outcomes. Overall incidences of adverse events were similar for UMEC and TIO.. UMEC 62.5 μg demonstrated superior efficacy to TIO 18 μg on the primary end point of trough FEV1 at day 85. Safety profiles were similar for both treatments.

Topics: Cholinergic Antagonists; Double-Blind Method; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tiotropium Bromide; Treatment Outcome

Increased sputum production is an important feature of COPD, in which a large amount of secretions stagnated in the respiratory lumen may aggravate airflow limitation, impair airway mucociliary transport, and cause recurrent respiratory infection and, hence, acute exacerbations of the diseases. There is evidence that airway mucus hypersecretion is associated with the severity and prognosis of COPD, but the symptoms are generally difficult to treat.. In an open, non-controlled study, we examined the effect of the anticholinergic agent tiotropium on airway mucus hypersecretion in 22 COPD patients. After a 4-week run-in period, the patients received 18 μg of tiotropium once daily delivered through the handihaler for 8 weeks, while symptoms and their impact associated with sputum were scored according to cough and sputum assessment questionnaire (CASA-Q). At week 0 and week 8, spirometry was performed before and 30 min after the administration of albuterol. To test the effect of tiotropium on airway mucociliary transport, nasal clearance time was measured. To evaluate airway mucus production, solid composition of the sputum (dry/wet weight ratio) was measured.. Treatment with tiotropium increased both prebronchodilator FEV1 and postbronchodilator FEV1. Tiotropium decreased cough symptom scores and provided with favorable influences on sputum-related symptoms, and none of the patients complained of worsening of the symptoms judging from the CASA-Q score. Both solid composition of the sputum and mucin contents decreased and nasal clearance time was shortened from 29.4 ± 5.1 to 20.6 ± 4.1min (p < 0.05) during the 8-week treatment.. Tiotropium decreases symptoms associated with sputum in COPD patients, an effect that may be related to the inhibition of airway mucus hypersecretion and improvement of airway mucociliary clearance.

Topics: Aged; Bronchodilator Agents; Cough; Female; Humans; Male; Mucociliary Clearance; Mucus; Pulmonary Disease, Chronic Obstructive; Spirometry; Sputum; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

Morning symptoms associated with COPD have a negative impact on patients' quality of life. Long-acting bronchodilators with rapid onset may relieve patients' symptoms. In the Symptoms and Pulmonary function in the moRnING study, we prospectively compared the rapid onset bronchodilator profile of glycopyrronium (GLY) and tiotropium (TIO) during the first few hours after dosing in patients with moderate-to-severe COPD.. Patients were randomized (1:1) to receive either once-daily GLY (50 μg) or TIO (18 μg) and corresponding placebos in a cross-over design for 28 days. The primary objective was to demonstrate the superiority of GLY versus TIO in area under the curve from 0 to 4 hours (AUC0-4h) forced expiratory volume in 1 second (FEV1) after the first dose. The secondary objective was to compare GLY versus TIO using the patient reported outcomes Morning COPD Symptoms Questionnaire 3 hours post-inhalation.. One-hundred and twenty-six patients were randomized (male 70.2%; mean age 65.7 years) and 108 patients completed the study. On Day 1, GLY resulted in significantly higher FEV1 AUC0-4h after the first dose versus TIO (treatment difference [Δ], 0.030 L, 95% confidence interval 0.004-0.056, P=0.025). Improvements in morning COPD symptoms from baseline at Days 1 and 28 were similar between GLY and TIO. Post hoc analysis of the FEV1 AUC0-4h by time point on Day 1 showed significant improvements in patients receiving GLY versus TIO at 5 minutes (Δ=0.029 L, P=0.015), 15 minutes (Δ=0.033 L, P=0.026), and 1 hour (Δ=0.044 L, P=0.014). Safety results were comparable between both treatments.. The SPRING study demonstrates the superiority of GLY versus TIO in terms of superior bronchodilation in the first 4 hours after administration, thus extending the clinical data that support a faster onset of action of GLY versus TIO.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Circadian Rhythm; Cross-Over Studies; Drug Administration Schedule; Europe; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Patient Reported Outcome Measures; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recovery of Function; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The TIOtropium Safety and Performance In Respimat (TIOSPIR) trial showed similar safety and exacerbation efficacy profiles for tiotropium Respimat and HandiHaler in patients with COPD. The TIOSPIR results for patients in Asia are presented here.. TIOSPIR evaluated once-daily tiotropium Respimat 5 and 2.5 µg with HandiHaler 18 µg in patients with COPD. Primary endpoints included time to death and time to first COPD exacerbation. Safety and exacerbation efficacy profiles were determined for the Asian region, and for Asia (all treatment arms pooled) versus the rest of the world (RoW).. In Asia (n = 2356), time to death was similar for Respimat 5 and 2.5 µg versus HandiHaler 18 µg (hazard ratio (HR) (95% CI): 0.96 (0.67, 1.38) and 1.23 (0.87, 1.73)). Risk of COPD exacerbation was similar for Respimat 5 µg, but increased for 2.5 µg versus HandiHaler 18 µg (HR (95% CI): 0.99 (0.85, 1.15) and 1.17 (1.00, 1.35)). Time to death in Asia and RoW was similar (HR (95% CI): 1.15 (0.99, 1.35)). Time to first COPD exacerbation was longer (HR (95% CI): 0.84 (0.78, 0.89)) and exacerbation rates were lower in Asia, but severe exacerbations were more frequent than in the RoW. Risk of major adverse cardiovascular events was similar for both regions.. Similar safety and exacerbation efficacy profiles were observed for tiotropium Respimat 5 µg and HandiHaler 18 µg in patients with COPD from Asia, analogous to the global analysis. Asian patients had lower risk of, and fewer exacerbations overall, but a higher proportion of severe exacerbations than in the RoW.

Topics: Administration, Inhalation; Aged; Albuterol, Ipratropium Drug Combination; Asia; Bronchodilator Agents; Double-Blind Method; Drug Monitoring; Female; Forced Expiratory Volume; Humans; Maintenance Chemotherapy; Male; Middle Aged; Mortality; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

The efficacy and safety of once-daily tiotropium + olodaterol (T+O) maintenance treatment was demonstrated in the large, multinational, replicate, randomized, Phase III, Tonado(®) 1 (NCT01431274) and 2 (NCT01431287) studies in patients with moderate to very severe COPD. However, there may be racial differences in the effects of T+O on lung function in patients with COPD.. In this Tonado(®) subgroup analysis, we assessed efficacy and safety of T+O in Japanese participants.. Versus the overall population, the 413 Japanese patients randomized and treated were slightly older, with more men, lower body mass index, lower baseline St George's Respiratory Questionnaire (SGRQ) scores, fewer current smokers, but with higher pack-year smoking history. A lower proportion of Japanese patients used inhaled corticosteroids, short-acting muscarinic antagonists, or short- or long-acting β-adrenergic agonists at baseline, but use of long-acting muscarinic antagonists was higher. At Week 24, mean improvements with T+O 5/5 μg in forced expiratory volume in 1 second area under the curve from 0-3 hours response were 151 mL versus olodaterol and 134 mL versus tiotropium 5 μg; mean improvements with T+O 2.5/5 μg were 87 mL versus olodaterol and 70 mL versus tiotropium 2.5 μg. Mean improvements with T+O 5/5 μg in trough forced expiratory volume in 1 second were 131 mL versus olodaterol and 108 mL versus tiotropium 5 μg; mean improvements with T+O 2.5/5 μg were 60 mL versus olodaterol and 47 mL versus tiotropium 2.5 μg. SGRQ scores improved from baseline to a greater extent with both doses of T+O versus monotherapies. Responses were similar in the overall population. Adverse-event incidence was generally balanced across treatment groups.. Consistent with results from the overall population, T+O 5/5 μg was superior to each monotherapy for lung function and SGRQ in the Japanese sub-population of patients with COPD in Tonado(®).

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Equipment Design; Female; Forced Expiratory Volume; Humans; Japan; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

This study formed part of the dose selection for a glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination formulated using novel Co-Suspension™ Delivery Technology and delivered via a metered dose inhaler (GFF MDI). The study aimed to confirm the optimal dose of GP to formulate with FF 9.6 μg in the fixed-dose combination product, GFF MDI.. This multicenter, randomized, double-blind, chronic-dosing, balanced incomplete block, crossover study (NCT01587079) compared five doses of GFF MDI (18/9.6, 9/9.6, 4.6/9.6, 2.4/9.6 and 1.2/9.6 μg, twice daily [BID]) with its monocomponents FF MDI 9.6 μg and GP MDI 18 μg (both BID) and open-label tiotropium (18 μg once daily) as the active control. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV. These findings further support selection of GP 18 μg as the optimal dose to combine with FF MDI 9.6 μg for advancement into Phase III clinical trials of GFF MDI.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Cholinergic Antagonists; Cross-Over Studies; Double-Blind Method; Drug Combinations; Dry Powder Inhalers; Female; Forced Expiratory Volume; Formoterol Fumarate; Glycopyrrolate; Humans; Male; Metered Dose Inhalers; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Improving health-related quality of life (HRQoL) in COPD patients is an important pharmacotherapeutic objective. This study investigated the extent, consistency, and durability of tiotropium maintenance therapy impact on HRQoL in moderate-to-very severe COPD.. Patients received once-daily tiotropium 18 μg (n = 5244) or placebo (n = 4799) via HandiHaler. Adjusted mean total score differences between treatments for change from baseline were significant (p < 0.05) in favor of tiotropium in 10/13 trials at 6 months and in 8/9 trials at 1 year. In all trials, estimated differences in responder rates between treatments favored tiotropium (significant [p < 0.05]: 5/13 trials at 6 months; 8/9 trials at 1 year). Net benefit favored tiotropium and cumulative improvement rates were consistently greater and deterioration rates consistently lower for tiotropium versus placebo.. Tiotropium maintenance therapy significantly and consistently improved HRQoL in moderate-to-very severe COPD patients in a durable manner. These results may provide a benchmark for assessing benefits on HRQoL of other COPD treatments.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Female; Forced Expiratory Volume; Health Status; Humans; Male; Meta-Analysis as Topic; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Severity of Illness Index; Smoking; Tiotropium Bromide; Treatment Outcome; Vital Capacity

To compare the bronchodilator efficacy of 18 μg once-daily tiotropium inhalation administered via Discair. Fifty-eight patients with moderate-to-severe COPD were enrolled in this randomized, active-controlled, parallel-group, open-label, Phase IV non-inferiority trial. Patients were randomly assigned to a test group (n=29, inhalation with Discair) or a reference group (n=29, inhalation with HandiHaler). The primary efficacy parameter was the average maximum change in forced expiratory volume in 1 second (FEV. The test inhaler was non-inferior to the reference inhaler in terms of maximum change in FEV. Our findings show that the Discair was non-inferior to the HandiHaler. More specifically, these devices had similar clinical efficacy in terms of time-dependent response over 24 h for patients with moderate-to-severe COPD.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cholinergic Antagonists; Dry Powder Inhalers; Equipment Design; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome; Turkey; Vital Capacity

Current guidelines recommend combining long-acting bronchodilators with different modes of action in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). We evaluated the effects of airway dimensions and pulmonary function with tiotropium plus indacaterol versus Advair(®).. Subjects (n = 46) were randomized to receive tiotropium (18 μg once daily) plus indacaterol (150 μg once daily) or Advair(®) (50/250 μg twice daily) for 16 weeks. Airway geometry was determined by quantitative computed tomography (luminal area, Ai; total area of the airway, Ao; wall area, WA; and percentage wall area, WA/Ao and wall thickness, T). Spirometry (forced expiratory volume in 1 s, FEV1; forced vital capacity, FVC and inspiratory capacity, IC) and St. George's Respiratory Questionnaire (SGRQ) were evaluated.. Tiotropium plus indacaterol significantly increased CT-indices including Ai corrected for body surface area (Ai/BSA), and decreased WA/BSA, WA/Ao and T/√BSA compared with Advair(®) (p < 0.05, respectively). In physiological parameters, mean difference in IC was significantly higher under treatment with tiotropium plus indacaterol than Advair(®) (p < 0.05). The changes in Ai/BSA, WA/BSA, WA/Ao and T/√BSA were significantly correlated with changes in IC (r = 0.535, p = 0.011; r = -0.688, p < 0.001; r = -0.555, p = 0.002 and r = -0.542, p = 0.007; respectively). There were more significant improvements in SGRQ scores after treatment with tiotropium plus indacaterol than Advair(®).. These findings suggest that dual bronchodilation with tiotropium plus indacaterol is superior in airway geometry and lung function compared with Advair(®) in COPD.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Glucocorticoids; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Spirometry; Surveys and Questionnaires; Tiotropium Bromide

Topics: Aged; Cohort Studies; Delayed-Action Preparations; Female; France; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Risk; Tiotropium Bromide

Combination therapy with a long-acting antimuscarinic agent and a long-acting β2-agonist are recommended in chronic obstructive pulmonary disease (COPD) if control is not adequate with one long-acting bronchodilator alone. We evaluated the effects of indacaterol and tiotropium combination therapy, including the effects of adding indacaterol to tiotropium (indacaterol add-on group) and adding tiotropium to indacaterol (tiotropium add-on group).. We recruited 79 patients with COPD already treated with tiotropium or indacaterol. We undertook pulmonary function tests, the COPD assessment test (CAT), and the multi-frequency forced oscillation technique (to measure respiratory resistance and reactance) before and after 8 weeks of indacaterol and tiotropium combination therapy.. The median age was 72.1 years and the mean forced expiratory volume in 1 s (FEV1) as a proportion of predicted was 57.2 ± 18.3%. After 8 weeks of combination therapy, FEV1 and %predicted FEV1 had increased significantly. There was no change in CAT score. For respiratory impedance, combination therapy improved resistance at 5 Hz (R5) and resistance at 20 Hz (R20) in the whole-breath, inspiratory and expiratory phases, and resonant frequency (Fres) in the inspiratory phase. The indacaterol add-on group (43 patients) and tiotropium add-on group (36 patients) showed improvements in FEV1 and %predicted FEV1 over monotherapy, although the CAT score fell significantly in the indacaterol add-on group (p = 0.005).. Indacaterol and tiotropium combination therapy improved airflow limitation and respiratory resistances. Adding indacaterol to tiotropium, or tiotropium to indacaterol, had similar effects on airflow limitation.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Bronchodilator Agents; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Studies have shown that tiotropium once daily reduces lung hyperinflation and dyspnea during exercise and improves exercise tolerance in patients with COPD. Mechanisms underlying the effects of the muscarinic receptor antagonist tiotropium on COPD have not been fully understood.. In this study, we investigated whether improvement in neural respiratory drive is responsible for reducing dyspnea during exercise and improving exercise tolerance in COPD.. Twenty subjects with severe COPD were randomized into two groups: no treatment (Control, n = 10, 63.6 ± 4.6 years, FEV1 29.6 ± 13.3%pred) or inhaled tiotropium 18 μg once daily for 1 month (n = 10, 66.5 ± 5.4 years, FEV1 33.0 ± 11.1%pred). All subjects were allowed to continue their daily medications other than anti-cholinergics during the study. Constant cycle exercise with 75% of maximal workload and spirometry were performed before and 1 month after treatment. Diaphragmatic EMG (EMGdi) and respiratory pressures were recorded with multifunctional esophageal catheter. Efficiency of neural respiratory drive, defined as the ratio of minute ventilation (VE) and diaphragmatic EMG (VE/EMGdi%max), was calculated. Modified British Medical Research Council Dyspnea Scale (mMRC) was used for the evaluation of dyspnea before and after treatment.. There was no significant difference in spirometry before and after treatment in both groups. Diaphragmatic EMG decreased significantly at rest (28.1 ± 10.9% vs. 22.6 ± 10.7%, P < 0.05) and mean efficiency of neural respiratory drive at the later stage of exercise increased (39.8 ± 2.9 vs. 45.2 ± 3.9, P < 0.01) after 1-month treatment with tiotropium. There were no remarkable changes in resting EMGdi and mean efficiency of neural respiratory drive post-treatment in control group. The score of mMRC decreased significantly (2.5 ± 0.5 vs. 1.9 ± 0.7, P < 0.05) after 1-month treatment with tiotropium, but without significantly difference in control group.. Tiotropium significantly reduces neural respiratory drive at rest and improves the efficiency of neural respiratory drive during exercise, which might account for the improvement in exercise tolerance in COPD.

Topics: Aged; Dyspnea; Exercise Test; Exercise Tolerance; Forced Expiratory Volume; Humans; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Spirometry; Tiotropium Bromide

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.

Topics: Administration, Inhalation; Aged; Benzoxazines; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Internationality; Male; Maximum Tolerated Dose; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Severity of Illness Index; Spirometry; Tiotropium Bromide; Treatment Outcome

QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD.. This multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% to <80% predicted) to QVA149 110/50 µg o.d. or TIO 18 µg o.d.+ FOR 12 µg twice daily (1:1) for 26 weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety.. Of the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: -0.69 units; 95% CI -2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68 mL, 95% CI 37 mL to 100 mL; p<0.001) and FVC (+74 mL, 95% CI 24 mL to 125 mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%).. QVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD.. NCT01120717.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

In vitro Andersen cascade impactor-sized mass (ISM) and aerodynamic fine particle mass (FPM) <5 μm for tiotropium and salmeterol combined in a novel inhalation powder formulation containing 7.5 μg tiotropium/25 μg salmeterol (TSHH) were similar (within ±15%) to reference products containing 18 μg of tiotropium (Spiriva® HandiHaler®) (TioHH) and 50 μg of salmeterol (Serevent® Diskus®) (SalD). The pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of the novel fixed-dose TSHH formulation administered once daily was compared with the single-agent therapies TioHH (once daily [qd]) and SalD (twice daily [bid]) and with the jointly administered combination of TioHH (qd) plus SalD (bid) in a randomized, 22-week, open-label, four-way crossover study in 50 patients with chronic obstructive pulmonary disease (COPD). For tiotropium, TSHH and TioHH were bioequivalent based on mean steady-state plasma area under the plasma concentration-time curves (AUC), while the urinary excretion amount was higher for TSHH and not bioequivalent to TioHH. Tiotropium peak plasma concentrations at steady state (C max,ss) were 40% higher with TSHH. For salmeterol, substantial differences were observed in plasma AUCs and Cmax,ss. No significant differences in 8-h forced expiratory volume in 1 s or forced vital capacity were detected for the TSHH (qd) against the combination of TioHH (qd) with SalD (bid). Maintenance therapy with tiotropium plus salmeterol as TSHH or as the jointly administered reference products is superior to either agent alone, safe, and well tolerated in COPD patients. In vitro results were not predictive of clinical PK findings for both tiotropium and salmeterol for the TSHH dry powder inhaler product.

Topics: Administration, Inhalation; Area Under Curve; Bronchodilator Agents; Cross-Over Studies; Drug Combinations; Dry Powder Inhalers; Female; Forced Expiratory Volume; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Therapeutic Equivalency; Tiotropium Bromide

The optimal use of various therapeutic combinations for moderate/severe chronic obstructive pulmonary disease (COPD) is unclear. The GLISTEN trial compared the efficacy of two long-acting anti-muscarinic antagonists (LAMA), when combined with an inhaled corticosteroid (ICS) and a long-acting β2 agonist (LABA).. This randomised, blinded, placebo-controlled trial in moderate/severe COPD patients compared once-daily glycopyrronium (GLY) 50 µg, once-daily tiotropium (TIO) 18 µg or placebo (PLA), when combined with salmeterol/fluticasone propionate (SAL/FP) 50/500 µg twice daily. The primary objective was to determine the non-inferiority of GLY+SAL/FP versus TIO+SAL/FP on trough FEV1 after 12 weeks. An important secondary objective was whether addition of GLY to SAL/FP was better than SAL/FP alone.. 773 patients (mean FEV1 57.2% predicted) were randomised; 84.9% completed the trial. At week 12, GLY+SAL/FP demonstrated non-inferiority to TIO+SAL/FP for trough FEV1: least square mean treatment difference (LSMdiff) -7 mL (SE 17.4) with a lower limit for non-inferiority of -60 mL. There was significant increase in week 12 trough FEV1 with GLY+SAL/FP versus PLA+SAL/FP (LSMdiff 101 mL, p<0.001). At 12 weeks, GLY+SAL/FP produced significant improvement in St George's Respiratory Questionnaire total score versus PLA+SAL/FP (LSMdiff -2.154, p=0.02). GLY+SAL/FP demonstrated significant rescue medication reduction versus PLA+SAL/FP (LSMdiff -0.72 puffs/day, p<0.001). Serious adverse events were similar for GLY+SAL/FP, TIO+SAL/FP and PLA+SAL/FP with an incidence of 5.8%, 8.5% and 5.8%, respectively.. GLY+SAL/FP showed comparable improvements in lung function, health status and rescue medication to TIO+SAL/FP. Importantly, addition of GLY to SAL/FP demonstrated significant improvements in lung function, health status and rescue medication compared to SAL/FP.. NCT01513460.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Australia; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Glycopyrrolate; Health Status; Humans; Male; Middle Aged; New Zealand; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

Preclinical studies suggested that aclidinium and glycopyrronium might have a faster onset of action than tiotropium. In this study we assessed the onset of action of aclidinium and glycopyrronium versus tiotropium, all administered at the approved clinical doses, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and in human isolated bronchi by using different concentrations. Sixteen COPD patients inhaled single doses of aclidinium 400µg, glycopyrronium 50μg and tiotropium 18µg and FEV1 was measured to assess their onset of action. In human isolated bronchi the time to evoke half maximal relaxation of transmural stimulation was tested from 10nM to 1µM for each drug. Nine, eight and twelve patients did not achieve 15% increase of FEV1 after inhalation of aclidinium, glycopyrronium and tiotropium, respectively. Aclidinium (15.6±7.5min) and glycopyrronium (17.9±10.4min) enhanced 15% FEV1 more rapidly than tiotropium (42.5±19.4min), with no significant difference (P>0.05). In isolated airways, glycopyrronium elicited a dose-dependent onset of action (10nM: 8.2±1.3min, 100nM: 7.1±2.1min, 1μM: 3.4±0.4min) that was faster compared to that induced by aclidinium (1μM: 6.4±0.5min) and tiotropium (1μM: 8.4±1.1min) (P<0.05), that halved the contractile tone only at the highest concentration. Bronchodilation induced by aclidinium and glycopyrronium was faster than that induced by tiotropium, but since our analysis was restricted to the acute effect of these LAMAs and the inhaled doses were not isoeffective, the real differences in their impact on the onset of bronchodilation will be definitely determined after a long-term challenge of these treatments at isoeffective doses in COPD patients.

Topics: Administration, Inhalation; Bronchi; Bronchoconstriction; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; In Vitro Techniques; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes

This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination (FDC) of the long-acting muscarinic antagonist tiotropium and the long-acting β2-agonist olodaterol in patients with chronic obstructive pulmonary disease.. This was a randomised, double-blind, placebo-controlled, Phase III trial with an incomplete crossover design. Patients received four of the following six treatment options for 6 weeks each: placebo, olodaterol 5 μg, tiotropium 2.5 μg, tiotropium 5 μg, tiotropium + olodaterol FDC 2.5/5 μg and tiotropium + olodaterol FDC 5/5 μg, all delivered via the Respimat(®) inhaler. The primary end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC0-24) response after 6 weeks of treatment; key secondary end points were FEV1 AUC from 0 to 12 h and AUC from 12 to 24 h, and further end points included lung-volume parameters measured using body plethysmography (subset of patients), measures of peak and trough FEV1, and incidence of adverse events.. A significant improvement in FEV1 AUC0-24 response was observed with tiotropium + olodaterol 5/5 μg and 2.5/5 μg versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 μg versus placebo was 0.280 L (p < 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 μg were 0.115 L versus olodaterol 5 μg, 0.127 L versus tiotropium 2.5 μg and 0.110 L versus tiotropium 5 μg (p < 0.0001 for all comparisons). Secondary end points supported these data. No safety concerns were identified.. Overall, this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olodaterol over tiotropium or olodaterol alone, with no observed difference in tolerability. ClinicalTrials.gov number: NCT01559116.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Time Factors; Tiotropium Bromide; Treatment Outcome

Tiotropium is an anticholinergic bronchodilator for symptom relief and reducing exacerbations with an established safety profile in patients with chronic obstructive pulmonary disease (COPD). Using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study, we re-evaluated the safety of tiotropium HandiHaler® in patients who experienced recent myocardial infarction (MI), heart failure or unstable rhythm disorder during the study.. A post-hoc analysis of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, was conducted in patients who had experienced cardiac arrhythmia, MI or cardiac failure during UPLIFT® and who completed the study. Descriptive analyses were performed.. Most patients experiencing cardiac events, for which they would have been excluded at baseline, remained in the trial. Kaplan-Meier analyses revealed a trend to later occurrence of cardiac SAEs with tiotropium HandiHaler® versus placebo. Patients who experienced a cardiac event and continued in UPLIFT® were not found to be at subsequently increased risk of all-cause mortality or cardiac SAEs with tiotropium treatment. Evaluation of deaths by major adverse cardiac events composite endpoints also showed that patients treated with tiotropium were not at increased risk of mortality or cardiac SAEs compared with placebo.. Risk of cardiac events, mortality or SAEs was not increased by tiotropium in patients experiencing cardiac events for which they would have been excluded at study baseline. The findings support the cardiac safety of tiotropium HandiHaler® in patients with COPD.

Topics: Bronchodilator Agents; Cardiovascular Diseases; Double-Blind Method; Female; Humans; Male; Mortality; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Tiotropium Bromide

According to current GOLD strategy, patients with COPD classified as groups A and B may be treated with inhaled bronchodilators, either long-acting β2-agonist (LABA) or long-acting muscarinic antagonist (LAMA). However, there is little guidance on which class of agent is preferred and a lack of prospective data to differentiate the two.. In this study, we performed post-hoc analyses of pooled data from two prospective, controlled clinical trials comparing the LABA indacaterol and LAMA tiotropium in 1422 patients with moderate airflow limitation and no history of exacerbations in the previous year. This population fits the definitions of GOLD A and B groups and could be further stratified by symptom severity using Baseline Dyspnea Index (i.e. modeling GOLD A or B) and inhaled corticosteroid (ICS) use at baseline. Outcomes measured after 12 weeks of treatment were lung function (forced expiratory volume in 1 s; FEV1), health status (St George's Respiratory Questionnaire; SGRQ), symptoms (Transition Dyspnea Index; TDI) and rescue medication use.. In 'GOLD A' patients not receiving ICS, differences favored indacaterol versus tiotropium (trough FEV1 0.05 L; rescue medication use -0.41 puffs/day; TDI total score 0.94 points; SGRQ total score -3.13 units, all p < 0.01). In 'GOLD B, no ICS' patients, compared with tiotropium, indacaterol treatment increased trough FEV1 (0.055 L, p < 0.05) and permitted a larger reduction in rescue medication use (-0.81 puffs/day, p = 0.004). In all patients, and in patients not using ICS, differences favored indacaterol for all variables.. Our findings suggest that patients in GOLD groups A and B may experience greater benefits with indacaterol than with tiotropium.

Topics: Bronchodilator Agents; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Forced Expiratory Flow Rates; Humans; Indans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinolones; Tiotropium Bromide; Treatment Outcome

Among patients with chronic obstructive pulmonary disease (COPD), the frequency and severity of past exacerbations potentiates future events. The impact of current therapies on exacerbation frequency and severity in patients with different exacerbation risks is not well known.. A post hoc analysis of patients at low (≤1 exacerbation [oral steroids/antibiotics requirement] and no COPD-related hospitalization in the year preceding trial entry) or high (≥2 exacerbations [oral steroids/antibiotics requirement] or ≥1 COPD-related hospitalization[s] in the year preceding trial entry) exacerbation risk, from the Prevention of Exacerbations with Tiotropium in Chronic Obstructive Pulmonary Disease (POET-COPD(®)) database.. Compared with salmeterol, tiotropium significantly increased time to first COPD exacerbation (hazard ratio 0.84; 95% confidence interval [CI] 0.76-0.92; p = 0.0002) and reduced the number of COPD exacerbations (rate ratio 0.90; 95% CI 0.81-0.99; p = 0.0383) in patients at high exacerbation risk. With treatment, the risk of remaining in the high-risk exacerbator subgroup was statistically lower with tiotropium versus salmeterol (risk ratio [RR] 0.89; 95% CI 0.80-1.00; p = 0.0478). For low-risk patients, time to first COPD exacerbation and number of COPD exacerbations were numerically lower with tiotropium versus salmeterol. With treatment, the risk of transitioning from a low to a high exacerbation risk was lower with tiotropium versus salmeterol (RR 0.87; 95% CI 0.71-1.07; p = 0.1968).. This analysis confirms the higher efficacy of tiotropium versus salmeterol in prolonging time to first COPD exacerbation and reducing number of exacerbations in patients both at low and high exacerbation risk.. Boehringer Ingelheim and Pfizer.. ClinicalTrials.gov NCT00563381.

Topics: Adrenal Cortex Hormones; Aged; Anti-Bacterial Agents; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Hospitalization; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

The once-daily long-acting muscarinic antagonist (LAMA) tiotropium and once-daily long-acting β2-agonist (LABA) olodaterol have been studied as a once-daily fixed-dose combination (FDC) in patients with chronic obstructive pulmonary disease (COPD). Two large, 52-week, double-blind, parallel-group studies in patients with moderate-very severe COPD demonstrated that tiotropium + olodaterol significantly improved lung function and symptoms versus the monocomponents. This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity.. 5162 patients were randomized and treated with olodaterol 5 µg, tiotropium 2.5 µg, tiotropium 5 µg, tiotropium + olodaterol 2.5/5 µg, or tiotropium + olodaterol 5/5 µg (all once daily via Respimat(®) inhaler). Primary efficacy (lung-function) end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) and trough FEV1 responses (i.e., change from baseline). Pooled data are presented for the following subgroups: prior maintenance treatment with LAMA or LABA, Global initiative for chronic Obstructive Lung Disease (GOLD) 2 (predicted FEV1 50% to <80%) and 3 (30% to <50%)/4 (<30%), sex, age, and prior use of inhaled corticosteroids.. Tiotropium + olodaterol FDC improved lung function over the monocomponents in patients with GOLD 2 and 3-4 disease, irrespective of prior LAMA or LABA maintenance therapy; most comparisons between FDCs and their respective monocomponents were statistically significant (P < 0.05). FEV1 AUC0-3 and trough FEV1 responses for the individual treatments were generally greater in patients with less severe COPD at baseline.. Tiotropium + olodaterol 5/5 µg significantly improved FEV1 AUC0-3 and trough FEV1 in all GOLD severity groups compared to olodaterol 5 µg and tiotropium 5 µg alone, irrespective of whether patients had received prior LAMA or LABA maintenance treatment. Improvements from baseline in lung function were generally greater in patients with less severe disease.. Boehringer Ingelheim.. ClinicalTrials.gov numbers, NCT01431274 and NCT01431287.

Topics: Adrenergic beta-Agonists; Aged; Benzoxazines; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide

To investigate the efficacy and safety of domestic tiotropium inhalation capsule in patients with chronic obstructive pulmonary disease (COPD) with multi-center randomized clinical trial.. Patients with stable slight to moderate COPD were randomized into trial group (n=109) with tiotropium 18 pg Qd or control group (n =111) with ipratropium 40 µg Qid for a treatment of four weeks. The spirometry and scoring questionaire were recorded at different visits during the treatment. Rescue medication consumption and adverse events were recorded. Results Forced expiratory volume in 1 s (FEV1) of both groups increased obviously 30 min and 3 h after first dosing. After four weeks treatments, FEV, and forced vital capacity (FVC) in both groups were improved obviously, and the improvement in tiotropium group was significantly higher than that ipratropium group. COPD symptom scores were significantly reduced in both groups, and the improvement in tiotropium group was significantly better than that in ipratropium group. There was no significant difference in rescue medication consumption between the two groups. The ratios of adverse events were 22. 02% and 15. 32% in tiotropium and ipratropium group, respectively (P=0. 23).. Domestic tiotropium inhalation capsule is efficient and safe in the treatment of COPD.

Topics: Bronchodilator Agents; Forced Expiratory Volume; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Surveys and Questionnaires; Tiotropium Bromide

The forced oscillation technique (FOT) can measure respiratory mechanics and has attracted attention in chronic obstructive pulmonary disease (COPD). We aimed to evaluate the effects of only indacaterol and tiotropium monotherapies on airflow limitation and respiratory impedance. Pulmonary function tests, COPD assessment test (CAT), and multifrequency FOT with MostGraph-01 were performed at the beginning and after 8 weeks of treatment with indacaterol or tiotropium. The resistance index, resistance at 5 Hz (R5), resistance at 20 Hz (R20), reactance index, reactance at 5 Hz (X5), resonant frequency (Fres), and low-frequency reactance area (ALX) were determined at whole-breath, inspiratory, and expiratory phases. Eighty-two patients (mean age: 73 years; mean forced expiratory volume in 1 second (FEV1): 61.6%±19.0% predicted) were randomized to indacaterol or tiotropium treatment. Both bronchodilators improved airflow limitation, with mean trough improvements in FEV1 of 165 mL and 80 mL in the indacaterol and tiotropium groups, respectively. The CAT score decreased in the indacaterol group (P<0.001; 11.2±6.6 to 7.5±5.6). Compared with tiotropium, indacaterol significantly improved FEV1, percent predicted FEV1, and CAT score (P=0.042, P=0.008, and P=0.027, respectively). For respiratory impedance, indacaterol and tiotropium changed R5, X5, Fres, and ALX at whole-breath, inspiratory, and expiratory phases. In the indacaterol group, the changes in R5, R5-R20, X5, Fres, and ALX were significantly correlated with the changes in FEV1. The use of the FOT may enable the evaluation of the effects of bronchodilators in addition to FEV1-indicated therapeutic effects in COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Airway Resistance; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Indans; Japan; Lung; Male; Middle Aged; Muscarinic Antagonists; Oscillometry; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Quinolones; Respiratory Function Tests; Respiratory Mechanics; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Tiotropium + olodaterol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease (COPD). The OTEMTO 1 and 2 studies investigated the effects of tiotropium + olodaterol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD.. In these two replicate, double-blind, parallel-group, placebo-controlled trials, patients were randomised to receive tiotropium + olodaterol 5/5 μg, 2.5/5 μg, tiotropium 5 μg or placebo for 12 weeks, via the Respimat(®) inhaler. Primary end points were St George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response and trough FEV1 response.. In OTEMTO 1 and 2, tiotropium + olodaterol 5/5 μg improved SGRQ total score by 4.89 (95% confidence interval [CI] -6.90, -2.88) and 4.56 (95% CI -6.50, -2.63) units versus placebo (both p < 0.0001), and 2.49 (95% CI -4.47, -0.51; p < 0.05) and 1.72 (95% CI -3.63, 0.19) units versus tiotropium 5 μg. Tiotropium + olodaterol 2.5/5 μg significantly improved SGRQ score compared to placebo. Both doses significantly improved FEV1 AUC0-3 response compared to placebo and tiotropium 5 μg. Tiotropium + olodaterol 5/5 and 2.5/5 μg also significantly improved trough FEV1 response compared to placebo (both studies) and separated from tiotropium 5 μg in OTEMTO 2. Adverse-event incidence was similar between treatment groups.. Tiotropium + olodaterol improved lung function and quality of life compared to placebo and tiotropium 5 μg.. ClinicalTrials.gov: NCT01964352 and NCT02006732.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Tiotropium Bromide

Tiotropium Safety and Performance in Respimat® (TIOSPIR®) compared the safety and efficacy of tiotropium Respimat® and tiotropium HandiHaler® in patients with chronic obstructive pulmonary disease (COPD). A prespecified spirometry substudy compared the lung function efficacy between treatment groups.. TIOSPIR® was a large-scale, long-term (2.3-year), event-driven, randomized, double-blind, parallel-group trial of 17,135 patients with COPD. In the spirometry substudy, trough forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured at baseline and every 24 weeks for the duration of the trial.. The substudy included 1370 patients who received once-daily tiotropium Respimat® 5 μg (n = 461), 2.5 μg (n = 464), or tiotropium HandiHaler® 18 μg (n = 445). Adjusted mean trough FEV1 (average 24-120 weeks) was 1.285, 1.258, and 1.295 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups (difference versus HandiHaler® [95 % CI]: -10 [-38, 18] mL for Respimat® 5 μg and, -37 [-65, -9] mL for Respimat® 2.5 μg); achieving noninferiority to tiotropium HandiHaler® 18 μg for tiotropium Respimat® 5 but not for 2.5 μg (prespecified analysis). Adjusted mean trough FVC was 2.590, 2.544, and 2.593 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups. The rates of FEV1 decline over 24 to 120 weeks were similar for the three treatment arms (26, 40, and 34 mL/year for the tiotropium Respimat® 5-μg, 2.5-μg, and HandiHaler® 18-μg groups). The rate of FEV1 decline in GOLD I + II patients was greater than in GOLD III + IV patients (46 vs. 23 mL/year); as well as in current versus ex-smokers, in patients receiving combination therapies at baseline versus not, and in those experiencing an exacerbation during the study versus not.. The TIOSPIR® spirometry substudy showed that tiotropium Respimat® 5 μg was noninferior to tiotropium HandiHaler® 18 μg for trough FEV1, but Respimat® 2.5 μg was not. Tiotropium Respimat® 5 μg provides similar bronchodilator efficacy to tiotropium HandiHaler® 18 μg with comparable rates of FEV1 decline. The rate of FEV1 decline varied based on disease severity, with a steeper rate of decline observed in patients with moderate airway obstruction.. NCT01126437.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Combining long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) is beneficial in chronic obstructive pulmonary disease (COPD), as the two classes of bronchodilator have complementary modes of action. The optimal dose for the fixed-dose combination of the LAMA tiotropium and the LABA olodaterol needed to be determined. In this phase II trial, the dose response of tiotropium on top of olodaterol was investigated in a free-dose combination, while other phase II studies have explored different doses of olodaterol on top of tiotropium, with both drugs delivered using the Respimat(®) inhaler.. This was a double-blind incomplete crossover trial in which 233 patients with moderate or severe COPD were randomized to receive four out of eight free-dose combinations of olodaterol (5 or 10 µg) and tiotropium (1.25, 2.5, or 5 µg) or placebo for 4 weeks each. Primary end point was trough forced expiratory volume in 1 s (FEV1) change from baseline (response) after 4 weeks.. Addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 5 µg increased mean trough FEV1 response by 0.054, 0.065, and 0.084 L, respectively; addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 10 µg increased mean trough FEV1 response by 0.051, 0.083, and 0.080 L, respectively. All treatments were well tolerated and incidence of adverse events was similar with all treatments.. Overall, a dose response for tiotropium on top of both doses of olodaterol was observed, with increasing improvements in trough FEV1 compared to olodaterol alone as the tiotropium dose was increased.. Boehringer Ingelheim.. ClinicalTrials.gov number, NCT01040403.

Topics: Aged; Benzoxazines; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Tiotropium, a long-acting inhaled anticholinergic drug, has been widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, the issue of whether perioperative tiotropium improves postoperative outcomes for gastric cancer patients with COPD remains unclear. Thus, the aim of this study was to determine the efficacy of perioperative tiotropium intervention for gastric cancer patients with COPD.. Eighty-four gastric cancer patients with mild-to-moderate COPD were randomly assigned to receive perioperative pulmonary rehabilitation alone (control group) or pulmonary rehabilitation with 18 µg of tiotropium once daily (tiotropium group). The patients in the tiotropium group received tiotropium for more than 1 week before surgery and for 2 weeks after surgery. Spirometry was performed prior to group assignment and at 2 weeks after surgery. Postoperative complications, forced expiratory volume in 1 second, forced vital capacity, and the ratio of forced expiratory volume in second to forced vital capacity (%) were compared between the two groups.. There were no significant differences between the two groups in terms of age, body mass index, smoking, gastrectomy incision, operation time, and bleeding volume (all P>0.05). Postoperative complications and pulmonary functions did not differ significantly between the control and tiotropium groups. A subgroup analysis of gastric cancer patients with moderate COPD showed that perioperative tiotropium intervention significantly decreased the rate of postoperative complications compared with the control group (P=0.046). However, even after gastrectomy, many patients with mild COPD in both the control and tiotropium groups showed improved pulmonary function.. Although perioperative tiotropium intervention had no significant effects in gastric cancer patients with mild COPD, it may be beneficial in those with moderate COPD. Therefore, the next prospective study should further evaluate perioperative tiotropium intervention for gastric cancer patients with moderate-to-severe COPD.

Topics: Aged; Bronchodilator Agents; Drug Monitoring; Female; Gastrectomy; Humans; Male; Perioperative Care; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Severity of Illness Index; Stomach Neoplasms; Tiotropium Bromide; Treatment Outcome

Patients with chronic obstructive pulmonary disease (COPD) who were naive to anticholinergics before the TIOtropium Safety and Performance In Respimat (TIOSPIR) trial may reflect patients seen in practice, in particular in primary care. In addition, investigating safety in these patients avoids the potential bias in patients who previously received anticholinergics and may be tolerant of their effects.. The aim of this study was to evaluate whether patients naive to anticholinergic therapy who were treated with tiotropium Respimat 2.5 or 5 μg had different safety and efficacy outcomes than patients treated with tiotropium HandiHaler 18 μg.. A post hoc analysis of patients who were not receiving anticholinergics before TIOSPIR (N=6,966/17,135) was conducted. Primary end points were risk of death from any cause and risk of COPD exacerbation. Secondary outcomes included severe exacerbation and major adverse cardiovascular events (MACE). Additional analysis of exacerbations was carried out in anticholinergic-naive patients with moderate (GOLD II) disease.. Anticholinergic-naive patients had less severe disease than the total TIOSPIR population. Discontinuations because of anticholinergic side effects were infrequent (0.9% overall). Similar to the primary study, patients in the tiotropium Respimat groups had no difference in the risk of death or risk of any or severe exacerbation than patients treated with tiotropium HandiHaler. Risk of MACE was similar across the Respimat and HandiHaler groups. Rates of exacerbations in the subgroup of patients with moderate disease were similar across the Respimat and HandiHaler groups.. Tiotropium Respimat and HandiHaler have similar safety and efficacy profiles in patients who are naive to anticholinergic therapy.

Topics: Administration, Inhalation; Aged; Cholinergic Antagonists; Double-Blind Method; Dry Powder Inhalers; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Triple therapy using salmeterol/fluticasone propionate (FP) and tiotropium bromide is commonly used to treat chronic obstructive pulmonary disease (COPD), but sparse efficacy data exist in COPD patients with fewer symptoms and with a lower dose of inhaled corticosteroid in Japanese patients. The effects of of salmeterol/fluticasone propionate 50/250 μg (SFC250) twice daily plus tiotropium 18 μg (TIO) once daily and individual treatments on lung function were compared.. Fifty three Japanese COPD patients participated in this randomized, double-blind, double-dummy, Williams square design crossover study. Lung function was assessed by plethysmography and spirometry.. The primary endpoint of postdose specific airway conductance area under the curve (AUC0-4h) on day 28 was significantly higher following SFC250 + TIO (0.854) compared with TIO (0.737, 15.8%) and SFC250 (0.663, 28.8%) alone. SFC250 + TIO significantly improved trough forced expiratory volume in 1 second from baseline versus TIO (0.161 L, P<0.001) and SFC250 (0.103 L, P=0.008). SFC250 + TIO significantly improved residual volume compared with TIO (P<0.001) and SFC250 (P=0.003) on day 28. Nonsignificant improvements were seen in trough inspiratory capacity, total lung capacity, and thoracic gas volume. There was no mean change seen in rescue medication.. Triple therapy using SFC250 + TIO was well tolerated and gave a greater improvement in bronchodilation compared with TIO and SFC250 alone in Japanese patients with COPD. There was improvement in few symptoms, but no mean change was seen in patient-reported outcomes measured by rescue medication use.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Area Under Curve; Bronchodilator Agents; Cholinergic Antagonists; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Japan; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Plethysmography; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Recovery of Function; ROC Curve; Severity of Illness Index; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

This post hoc analysis of TIOtropium Safety and Performance In Respimat (TIOSPIR) evaluated safety and exacerbation efficacy in patients with stable (≥ 2 months) use of tiotropium HandiHaler 18 µg (HH18) prior to study entry, to evaluate whether there was a difference in risk for patients who switched from HH18 to tiotropium Respimat 2.5 µg (R2.5) or 5 g (R5).. TIOSPIR (n=17,135) was an international, Phase IIIb/IV, randomised, double-blind, parallel-group, event-driven trial.. Patients from TIOSPIR with chronic obstructive pulmonary disease (COPD) and postbronchodilator ratio of forced expiratory volume in 1 s to forced vital capacity ≤ 0.70, receiving HH18 before study entry, were analysed (n=2784).. Patients were randomised to once-daily tiotropium R2.5 (n=914), R5 (n=918) or HH18 (n=952) for 2-3 years.. time to death (safety) and time to first COPD exacerbation (efficacy).. number of exacerbations and time to first major adverse cardiovascular event (MACE).. Baseline characteristics were similar in all groups. Respimat had a similar mortality risk versus HH18 (vital status follow-up, HR; 95% CI R2.5: 0.87; 0.64 to 1.17; R5: 0.79; 0.58 to 1.07) with no significant differences in the risk and rates of exacerbations and severe exacerbations across treatment groups. Risk of MACE and fatal MACE was similar for Respimat versus HH18 (HR; 95% CI MACE R2.5: 0.73; 0.47 to 1.15; R5: 0.69; 0.44 to 1.08; fatal MACE R2.5: 0.57; 0.27 to 1.19; R5: 0.67; 0.33 to 1.34). Overall risk of a fatal event (on treatment) was lower for R5 versus HH18 (HR; 95% CI R2.5: 0.78; 0.55 to 1.09; R5: 0.62; 0.43 to 0.89).. This analysis indicates that it is safe to switch patients from tiotropium HandiHaler to tiotropium Respimat, and that the efficacy is maintained over the switch.. NCT01126437; Post-results.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Equipment Design; Female; Forced Expiratory Volume; Humans; International Cooperation; Kaplan-Meier Estimate; Male; Middle Aged; Nebulizers and Vaporizers; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Risk Factors; Tiotropium Bromide; Treatment Outcome

Bronchodilators form the main stay of treatment for COPD. When symptoms are not adequately controlled with one bronchodilator, addition of another bronchodilator is recommended. We have recently developed a combination of tiotropium and formoterol in a single pressurized metered dose inhaler (pMDI) (Cipla Ltd., India). The aim of this study was to compare the bronchodilator effects of a single dose of 18 mcg of tiotropium versus a single dose of a combination of 18 mcg tiotropium plus 12 mcg formoterol administered via a pMDI in subjects with moderate-to-severe COPD.. 44 COPD subjects were enrolled in this randomized, double-blind, multi-centre, cross-over study. 18 mcg tiotropium and 18 mcg tiotropium plus 12 mcg formoterol were administered via pressurized metered dose inhalers on two separate days. FEV(1), FVC and Inspiratory capacity (IC) were measured before, 15, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24 h after the study drugs were administered.. Compared with tiotropium alone, a combination of tiotropium plus formoterol showed a faster onset of bronchodilator response (p < 0.01 for FEV(1) and FVC), a greater mean maximum change in FEV(1) (p = 0.01) and FVC (p = 0.008) and greater AUC(0-24h) values for FEV(1), FVC and IC. Trough FEV(1) and FVC values were also greater in the combination group.. A combination of tiotropium plus formoterol administered via a single inhaler produced a superior bronchodilator response than tiotropium alone over a period of 24 h.

Topics: Administration, Inhalation; Adult; Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

Bronchodilators have been reported to influence regional lung ventilation in patients with chronic obstructive pulmonary disease (COPD), which may change regional lung sound distribution. Vibration response imaging (VRI) is a lung imaging system for the assessment of breath sounds.. To evaluate the effects of a short-acting β2-agonist (SABA) on the regional distribution of lung sounds in COPD patients.. A double-blind crossover trial was performed to compare the treatment of COPD patients with an SABA (20 µg of inhaled procaterol) versus a placebo. The percentage of regional lung sound energy [quantitative lung data (QLD)] was evaluated with VRI. VRI, spirometry, and impulse oscillometry (IOS) were performed immediately before and 30 min after SABA administration.. Ten male patients (69.6 ± 14.2 years of age, percentage predicted forced expiratory volume in 1 s: 43.8 ± 16.9%) were evaluated. The use of an SABA produced significant functional improvements in the spirometric and IOS measurements. Among the homogeneous emphysema patients (n = 7), the upper-lung QLD decreased (from 24.2 ± 5.8 to 18.8 ± 6.1%, p < 0.05) and the lower-lung QLD increased (from 37.9 ± 12.7 to 46.1 ± 14.3%, p < 0.05) following SABA inhalation. However, the significant redistribution of the regional lung QLD to the lower-lung field was not observed in 2 of the 3 inhomogeneous emphysema patients.. The additional use of an SABA by COPD patients improved their pulmonary function, which was accompanied by changes in regional lung air flow. The distribution of emphysematous lesions and the bronchial reactivity to SABA appeared to affect the redistribution of the lung sounds following bronchodilator administration.

Topics: Adult; Aged; Aged, 80 and over; Albuterol; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Sounds; Salmeterol Xinafoate; Scopolamine Derivatives; Theophylline; Tiotropium Bromide; Tomography, X-Ray Computed; Vibration

In chronic obstructive pulmonary disease (COPD), there is a poor correlation between forced expiratory volume in 1 s (FEV1) and dyspnea following bronchodilator use. Better correlations have been observed between inspiratory lung function parameters (ILPs) and dyspnea, which drives our interest in ILPs. However, the acute and prolonged effects of long-acting bronchodilators and oral corticosteroids on ILPs have not been well investigated. Therefore, the aim of this study was to investigate the effects of these treatments on the ILPs, FEV1, dyspnea (visual analog scale (VAS)) and clinical COPD questionnaire (CCQ).. Twenty-eight stable COPD patients had their ILPs and FEV1 measured both before and 2 h after the use of a single dose of 18 mcg bronchodilator tiotropium and 50 mcg salmeterol. Thereafter, the patients were randomized to 2 weeks of treatment with 30 mg oral prednisolone once daily or oral placebo in combination with daily treatment with these two bronchodilators. Four weeks after the cessation of the randomized treatment, the ILPs and FEV1 were again measured. After each intervention, any change in the VAS score was assessed.. With both bronchodilators, significant improvements in ILPs were demonstrated (p < 0.005), with the exception of changes in ILPs inspiratory capacity (IC) and forced inspiratory flow at 50% of the vital capacity (FIF50) after tiotropium inhalation. After 2 weeks of treatment with prednisolone, significant differences were found for ILP forced inspiratory volume in 1 s (FIV1) and FEV1 compared with placebo. These differences were no longer present 4 weeks after the cessation of prednisolone. Significant relationships between ILPs and VAS scores were only found after 2 weeks of treatment with prednisolone or placebo.. After a single dose of long-acting bronchodilator salmeterol, significant improvements are observed in all ILPs and in FIV1 and PIF after tiotropium. Two weeks of oral corticosteroid treatment improved the FIV1 and FEV1. The dyspnea VAS score was only significantly correlated with the ILPs after 2 weeks of oral corticosteroid treatment.

Topics: Administration, Oral; Aged; Aged, 80 and over; Albuterol; Bronchodilator Agents; Delayed-Action Preparations; Double-Blind Method; Dyspnea; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Inspiratory Capacity; Male; Middle Aged; Prednisolone; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Surveys and Questionnaires; Time Factors; Tiotropium Bromide

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD.

Topics: Aged; Bronchodilator Agents; Cholinergic Antagonists; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Powders; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Solutions; Tiotropium Bromide; Treatment Outcome

We evaluated the effect of QVA149, a dual bronchodilator combining indacaterol and glycopyrronium, on direct patient-reported dyspnoea in patients with moderate-to-severe chronic obstructive pulmonary disease. In this multicentre, blinded, double-dummy, three-period crossover study, 247 patients were randomised to once-daily QVA149 110/50 μg, placebo or tiotropium 18 μg. Superiority of QVA149 versus placebo (primary objective) and tiotropium (secondary objective) was assessed for improvement in dyspnoea via the self-administered computerised (SAC) version of the Baseline and Transition Dyspnoea Index after 6 weeks. Secondary end-points included lung function, rescue medication use and safety. After 6 weeks, the SAC Transition Dyspnoea Index total score was significantly higher with QVA149 versus placebo (least squares mean (LSM) treatment difference 1.37, p<0.001) and tiotropium (LSM treatment difference 0.49, p=0.021). QVA149 provided significant improvements in lung function, with higher forced expiratory volume in 1 s area under the curve from 0-4 h post-dose versus placebo and tiotropium at day 1 and week 6 (all p<0.001). Rescue medication use was significantly lower with QVA149 versus placebo (p<0.001) and tiotropium (p=0.002). All treatments were well tolerated. Once-daily QVA149 provided superior improvements in patient-reported dyspnoea and lung function versus placebo and tiotropium. These benefits were associated with improvements in other symptoms and reduced use of rescue medication.

Topics: Adult; Aged; Area Under Curve; Bronchodilator Agents; Cross-Over Studies; Drug Combinations; Dyspnea; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Male; Middle Aged; Powders; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

Two once-daily long-acting muscarinic antagonists (LAMAs) are currently available for the treatment of chronic obstructive pulmonary disease (COPD) - tiotropium and glycopyrronium. Previous studies have compared glycopyrronium with open-label tiotropium. In the GLOW5 study, we compare glycopyrronium with blinded tiotropium.. In this blinded, double-dummy, parallel group, 12-week study, patients with moderate-to-severe COPD were randomized 1:1 to glycopyrronium 50 μg once daily or tiotropium 18 μg once daily. The primary objective was to demonstrate the non-inferiority of glycopyrronium versus blinded tiotropium with respect to trough forced expiratory volume in 1 second (FEV1) following 12 weeks of treatment (non-inferiority margin: -50 mL). Secondary objectives were to evaluate glycopyrronium versus tiotropium for other spirometric outcomes, breathlessness (Transition Dyspnea Index; TDI), health status (St George's Respiratory Questionnaire; SGRQ), daily rescue medication use, COPD exacerbations and COPD symptoms over 12 weeks of treatment.. 657 patients were randomized (glycopyrronium: 327; tiotropium: 330); 96% (630 patients) completed the study. Least squares mean trough FEV1 for both glycopyrronium and tiotropium was 1.405 L at Week 12, meeting the criterion for non-inferiority (mean treatment difference: 0 mL, 95% CI: -32, 31 mL). Glycopyrronium demonstrated rapid bronchodilation following first dose on Day 1, with significantly higher FEV1 at all time points from 0-4 h post-dose versus tiotropium (all p < 0.001). FEV1 area under the curve from 0-4 h (AUC0-4h) post-dose with glycopyrronium was significantly superior to tiotropium on Day 1 (p < 0.001) and was comparable to tiotropium at Week 12. Glycopyrronium demonstrated comparable improvements to tiotropium in TDI focal score, SGRQ total score, rescue medication use and the rate of COPD exacerbations (all p = not significant). Patients on glycopyrronium also had a significantly lower total COPD symptom score versus patients on tiotropium after 12 weeks (p = 0.035). Adverse events were reported by a similar percentage of patients receiving glycopyrronium (40.4%) and tiotropium (40.6%).. In patients with moderate-to-severe COPD, 12-week blinded treatment with once-daily glycopyrronium 50 μg or tiotropium 18 μg, provided similar efficacy and safety, with glycopyrronium having a faster onset of action on Day 1 versus tiotropium.

Topics: Double-Blind Method; Drug Administration Schedule; Female; Glycopyrrolate; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The effect of β2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol.. We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381.. 5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0·0130) and Gly16Gly (p=0·0018) genotypes (proportion of patients with at least one exacerbation was 32·3% in Arg16Arg, 39·8% in Arg16Gly, and 42·1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0·0164; Arg16Arg p=0·0316; proportion of patients with at least one exacerbation was 28·3% in Arg16Arg, 31·6% in Arg16Gly, and 39·2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0·0198; not Arg16Gly p=0·64; proportion of patients with at least one exacerbation was 35·9% in Arg16Arg, 46·7% in Arg16Gly, and 44·8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events.. Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting β-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of β-adrenergic polymorphisms and their association with clinical features of COPD.. Boehringer Ingelheim and Pfizer.

Topics: Acute Disease; Albuterol; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Pulmonary Disease, Chronic Obstructive; Receptors, Adrenergic, beta-2; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

QVA149 is a novel, inhaled, once-daily dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237), for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the effects of QVA149 on exercise tolerance, hyperinflation, lung function and lung volumes versus placebo and tiotropium.. Patients with moderate-to-severe COPD were randomized to QVA149 110/50 μg, placebo or tiotropium 18 μg once daily in a blinded, 3-period crossover study for 3 weeks. The primary endpoint was exercise endurance time at Day 21 for QVA149 versus placebo.. Eighty-five patients were randomized; 86% completed the study. QVA149 significantly improved exercise endurance time at Day 21 compared with placebo (least squares mean treatment difference 60 s [p = 0.006]). No significant improvements in exercise endurance time at Day 21 between QVA149 and tiotropium were found. Dynamic inspiratory capacity (IC) at exercise isotime, trough forced expiratory volume in 1 s, residual volume and functional residual capacity showed significant improvements with QVA149 from Day 1 of treatment that were maintained throughout the study. The safety profiles were similar across groups.. In patients with moderate-to-severe COPD, once-daily QVA149 significantly improved exercise endurance time compared with placebo which was associated with sustained reductions of lung hyperinflation as indicated by significant improvement in IC at rest and during exercise.. ClinicalTrials.gov NCT01294787.. Dual bronchodilation with QVA149 decreases lung hyperinflation and improves exercise tolerance and lung function in patients with moderate-to-severe COPD.

Topics: Adult; Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Exercise Tolerance; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Lung Volume Measurements; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Owing to the high and increasing morbidity and mortality, chronic obstructive pulmonary disease (COPD) has become a major public health problem worldwide. Although the majority of patients with COPD are in the early stages, little attention has been paid to them, in particular regarding to early intervention. Tiotropium bromide can significantly relieve symptoms and reduce the incidence of acute exacerbations of COPD. Therefore, we hypothesise that therapy with tiotropium bromide will benefit patients with COPD with early-stage disease.. A randomised, double-blinded, placebo-controlled, parallel-group, multicentre clinical trial (Tiotropium In Early COPD study, Tie-COPD study) is being conducted to evaluate the efficacy and safety of long-term intervention with tiotropium in patients with COPD with early-stage disease. A total of 839 patients with COPD who satisfied the eligibility criteria were randomly assigned (1:1) to receive a once daily inhaled capsule of either tiotropium bromide (18 μg) or matching placebo for 2 years. Measurements will include forced expiratory volume in 1 s, health-related quality of life, grade degree of breathlessness related to activities, COPD exacerbations and pharmacoeconomic analysis.. This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University. Recruitment started in November 2011 and ended in October 2013, with 839 patients randomised. The treatment follow-up of participants with Tie-COPD is currently ongoing and is due to finish in November 2015. The authors will disseminate the findings in peer-reviewed publications, conferences and seminar presentations.. ClinicalTrials.gov (NCT01455129).

Topics: Bronchodilator Agents; China; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Pulmonary Disease, Chronic Obstructive; Quality of Life; Spirometry; Tiotropium Bromide; Treatment Outcome

Combining a long-acting muscarinic antagonist with a long-acting β₂-agonist has been shown to be pharmacologically useful in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the effectiveness of the dual bronchodilator therapy on airway dimensions in COPD.. Patients (n = 54) were randomly assigned to receive tiotropium (18 μg once daily), indacaterol (150 μg once daily) or tiotropium plus indacaterol for 16 weeks. Quantitative computed tomography (CT), pulmonary function and health status (St. George's Respiratory Questionnaire) were measured.. Compared with tiotropium or indacaterol alone, combination therapy resulted in a significant decrease in percentage wall area (WA%) and wall thickness, corrected for body surface area, and an increase in luminal area (Ai/BSA). Concurrent treatment was superior to monotherapy in physiological indices, including forced vital capacity, forced expiratory volume in 1 s (FEV₁) and inspiratory capacity. The changes in WA% and Ai/BSA were significantly correlated with changes in FEV₁ (r = -0.44, P < 0.01 and r = 0.37, P < 0.01). There were more significant improvements in SGRQ scores after treatment with combined therapy than with either treatment alone.. Concurrent therapy with tiotropium and indacaterol is effective for COPD patients to promote reduction in airway wall thickness, bronchodilation, and improvements in lung function compared with a single inhaler.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Drug Therapy, Combination; Female; Health Status; Humans; Indans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Respiratory Function Tests; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Tomography, X-Ray Computed; Treatment Outcome

Combination long-acting bronchodilator treatment might be more effective than long-acting bronchodilator monotherapy for the treatment of chronic obstructive pulmonary disease (COPD). We aimed to compare the efficacy and safety of umeclidinium (UMEC) plus vilanterol (VI) with tiotropium (TIO) monotherapy, UMEC monotherapy, or VI monotherapy in patients with moderate to very severe COPD.. In two multicentre, randomised, blinded, double-dummy, parallel-group, active-controlled trials, eligible patients (current or former smokers aged 40 years or older with an established clinical history of COPD) were randomly assigned in 1:1:1:1 ratio to UMEC 125 μg plus VI 25 μg, UMEC 62·5 μg plus VI 25 μg, TIO 18 μg, and either VI 25 μg (study 1) or UMEC 125 μg (study 2). All study drugs were used once daily for 24 weeks. TIO was delivered via the HandiHaler inhaler and all other active treatments were delivered via the ELLIPTA dry powder inhaler. Random assignment (by a validated computer-based system) was done by centre and was not stratified. All patients and physicians were masked to assigned treatment during the studies. The primary efficacy endpoint of both studies was trough forced expiratory volume in 1 s (FEV1) on day 169, which was analysed in the intention-to-treat population. Both studies are registered with ClinicalTrials.gov, numbers NCT01316900 (study 1) and NCT01316913 (study 2).. 1141 participants were recruited in study 1, and 1191 in study 2. For study 1, after exclusions, 208, 209, 214, and 212 patients were included in the intention-to-treat analyses for TIO monotherapy, VI monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. For study 2, 215, 222, 215, and 217 patients were included in the intention-to-treat analyses for TIO monotherapy, UMEC monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. In both studies, we noted improvements in trough FEV1 on day 169 for both doses of UMEC plus VI compared with TIO monotherapy (study 1, UMEC 125 μg plus VI 25 μg: 0·088 L [95% CI 0·036 to 0·140; p=0·0010]; study 1, UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·141; p=0·0006]; study 2, UMEC 125 μg plus VI 25 μg: 0·074 L [0·025 to 0·123; p=0·0031]; study 2, UMEC 62·5 μg plus VI 25 μg: 0·060 L [0·010 to 0·109; nominal p=0·0182]). Both doses of UMEC plus VI also improved trough FEV1 compared with VI monotherapy (UMEC 125 μg plus VI 25 μg: 0·088 L [0·036 to 0·140; p=0·0010]; UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·142; p=0·0006], but not compared with UMEC 125 μg monotherapy (UMEC 125 μg plus VI 25 μg: 0·037 L [-0·012 to 0·087; p=0·14]; UMEC 62·5 μg plus VI 25 μg: 0·022 L [-0·027 to 0·072; p=0·38]). All treatments produced improvements in dyspnoea and health-related quality of life; we noted no significant differences in symptoms, health status, or risk of exacerbation between UMEC plus VI and TIO. The most common on-treatment, severe-intensity adverse event in both studies was acute exacerbation of COPD (1-4 [<1-2%] patients across treatment groups in study 1 and 1-6 [<1-3%] patients in study 2). We recorded five to 15 (2-7%) on-treatment serious adverse events across treatment groups in study 1, and nine to 22 (4-10%) in study 2. We noted no substantial changes from baseline in vital signs, clinical laboratory findings, or electrocardiography findings in any of the treatment groups.. Combination treatment with once-daily UMEC plus VI improved lung function compared with VI monotherapy and TIO monotherapy in patients with COPD. Overall our results suggest that the combination of UMEC plus VI could be beneficial for the treatment of moderate to very severe COPD.. GlaxoSmithKline.

Topics: Administration, Inhalation; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

The benefits of pharmacotherapy with tiotropium HandiHaler 18 μg for patients with chronic obstructive pulmonary disease (COPD) have been previously demonstrated. However, few data exist regarding the treatment of moderate disease (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II).. To determine whether tiotropium improves lung function/patient-reported outcomes in patients with GOLD stage II COPD naive to maintenance therapy.. A randomised 24-week double-blind placebo-controlled trial of tiotropium 18 μg once daily (via HandiHaler) was performed in maintenance therapy-naive patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 and post-bronchodilator FEV1 ≥50 and <80%.. A total of 457 patients were randomised (238 tiotropium, 219 placebo; mean age 62 years; FEV1 1.93 l (66% predicted)). Tiotropium was superior to placebo in mean change from baseline in post-dose FEV1 area under the curve from 0 to 3 h (AUC0-3h) at week 24 (primary endpoint): 0.19 vs. -0.03 l (least-squares mean difference 0.23 l, P<0.001). FVC AUC0-3h, trough and peak FEV1 and FVC were significantly improved with tiotropium versus placebo (P<0.001). Compared with placebo, tiotropium provided numerical improvements in physical activity (P=NS). Physician's Global Assessment (health status) improved (P=0.045) with less impairment on the Work Productivity and Activity Impairment questionnaire (P=0.043) at week 24. The incidence of exacerbations, cough, bronchitis and dyspnoea was lower with tiotropium than placebo.. Tiotropium improved lung function and patient-reported outcomes in maintenance therapy-naive patients with GOLD stage II COPD, suggesting benefits in initiating maintenance therapy early.

Topics: Activities of Daily Living; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Health Status; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

Umeclidinium (UMEC) is an inhaled long-acting muscarinic antagonist approved in the US and EU for the once-daily (QD) treatment of chronic obstructive pulmonary disease (COPD); it is not indicated for the treatment of asthma. To fully characterize the dose-response relationship of UMEC in patients with COPD, a pooled analysis of data from two randomized, placebo-controlled, cross-over, dose-ranging studies was performed, evaluating UMEC at doses of 15.6-1000 mcg QD and 15.6-250 mcg twice daily (BID). The primary endpoint was trough forced expiratory volume in one second (FEV(1)) at the end of each study's treatment period (Day 8/Day 15). A population model-based analysis using total daily UMEC dose was used for the primary analysis comparing QD and BID dosing. A physiological effect (E(max)) model was optimal in defining the relationship between UMEC dose and the primary endpoint, demonstrating a clear monotonic dose response over QD and BID dosing regimens. UMEC doses ≥62.5 mcg QD were differentiated from lower doses and BID dosing did not provide benefit over QD dosing. The potency (ED(50)) estimate was 33 mcg with QD dosing. These data indicate that UMEC 62.5 mcg and 125 mcg QD provide lung function benefits that warrant further investigation for the treatment of COPD.

Topics: Aged; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Scopolamine Derivatives; Tiotropium Bromide

Inhaled therapies reduce risk of chronic obstructive pulmonary disease (COPD) exacerbations, but their effect on mortality is less well established. We hypothesized that heterogeneity in baseline mortality risk influenced the results of drug trials assessing mortality in COPD.. The 5706 patients with COPD from the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study that had complete clinical information for variables associated with mortality (age, forced expiratory volume in 1 s, St George's Respiratory Questionnaire, pack-years and body mass index) were classified by cluster analysis. Baseline risk of mortality between clusters, and impact of tiotropium were evaluated during the 4-yr follow up.. Four clusters were identified, including low-risk (low mortality rate) patients (n = 2339; 41%; cluster 2), and high-risk patients (n = 1022; 18%; cluster 3), who had a 2.6- and a six-fold increase in all-cause and respiratory mortality compared with cluster 2, respectively. Tiotropium reduced exacerbations in all clusters, and reduced hospitalizations in high-risk patients (p < 0.05). The beneficial effect of tiotropium on all-cause mortality in the overall population (hazard ratio, 0.87; 95% confidence interval, 0.75-1.00, p = 0.054) was explained by a 21% reduction in cluster 3 (p = 0.07), with no effect in other clusters.. Large variations in baseline risks of mortality existed among patients in the UPLIFT® study. Inclusion of numerous low-risk patients may have reduced the ability to show beneficial effect on mortality. Future clinical trials should consider selective inclusion of high-risk patients.

Topics: Aged; Bronchodilator Agents; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Factors; Scopolamine Derivatives; Survival Rate; Tiotropium Bromide

Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting β2-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers.. In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of a proprietary glycopyrronium (GP) MDI were evaluated compared with Placebo MDI and open-label tiotropium (TIO) in study patients with COPD. Thirty-three study patients were enrolled and received single-dose administration of 4 of the 6 treatments (Placebo MDI, TIO 18 μg, or GP MDI at 14.4, 28.8, 57.6, and 115.2 μg ex-actuator) with an interval of 1 to 3 weeks between doses. The primary efficacy endpoint was peak change in forced expiratory volume in 1 second (FEV1).. All 4 doses of GP MDI showed statistically superior efficacy compared with Placebo MDI for peak FEV1 (differences of 146 to 248 mL; P<.001), with a clear dose ordering of the response. Statistically significant differences compared with Placebo MDI were noted at almost all doses for the secondary FEV1 parameters (P ≤ .049) except 24-hour trough FEV1 at 28.8 μg. All doses were safe and well tolerated in this study; the most frequently reported adverse event was dry mouth (0-14.3% across doses; 9.5% for Placebo MDI, and 9.1% for TIO).. This study demonstrated superior bronchodilatory efficacy of GP MDI compared with Placebo MDI at all doses tested, and no serious adverse events were reported. This study supports the further evaluation of GP MDI in study patients with COPD. In addition, these findings indicate that the correct dosage of glycopyrronium is no more than 115.2 μg total daily dose, or 57.6 μg twice daily based on comparisons with the active comparator.. This clinical trial was registered on ClinicalTrials.gov, Identifier: NCT00871182.

Topics: Adult; Aged; Area Under Curve; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Male; Metered Dose Inhalers; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Xerostomia

There are only a few reports of the use of impulse oscillation system (IOS) for the evaluation of COPD treatment. In this study, we applied IOS and spirometry to evaluate the effectiveness of fluticasone propionate and salmeterol (SFC) combined with tiotropium (TIO) in COPD patients. Following a 4-week run-in period with TIO (18 μg once daily) treatment, COPD patients were randomized to SFC (250/50 μg twice daily; SFC+TIO group, n=25), or TIO alone (TIO group, n=31). Pulmonary functions were recorded by IOS and spirometry before and after the study period. The SFC+TIO group showed significant improvements in inspiratory resistance at 5 Hz and resonant frequency, as well as in FVC and FEV1, after the 12-week treatment (p<0.05). Since there were no significant correlations between improvements in IOS measurements and FVC or FEV1, IOS may provide a physiological point of view that is different from spirometry and seemed to be applicable as an additional assessment tool targeting COPD patients.

Topics: Aged; Albuterol; Bronchodilator Agents; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Oscillometry; Outcome Assessment, Health Care; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Surveys and Questionnaires; Tiotropium Bromide

Increased arterial stiffness as measured by aortic pulse wave velocity (aPWV) predicts cardiovascular events and mortality and is elevated in patients with COPD. Prior investigation suggests that a long-acting β-agonist (LABA)/inhaled corticosteroid (ICS) lowers aPWV in patients with baseline aPWV ≥ 11 m/s. This study compared the effect of the ICS/LABA fluticasone furoate/vilanterol (FF/VI), 100/25 μg, delivered via the ELLIPTA dry powder inhaler, with tiotropium bromide (TIO), 18 μg, on aPWV.. This multicenter, randomized, blinded, double-dummy, parallel-group, 12-week study compared FF/VI and TIO, both administered once daily. The primary end point was aPWV change from baseline at 12 weeks. Safety end points included adverse events (AEs), vital signs, and clinical laboratory tests.. Two hundred fifty-seven patients with COPD and aPWV ≥ 11 m/s were randomized; 87% had prior cardiovascular events and/or risk. The mean difference in aPWV between FF/VI and TIO at week 12 was not significant (P = .484). Because the study did not contain a placebo arm, a post hoc analysis was performed to show that both treatments lowered aPWV by an approximate difference of 1 m/s compared with baseline. The proportion of patients reporting AEs was similar with FF/VI (24%) and TIO (18%). There were no changes in clinical concern for vital signs or clinical laboratory tests.. No differences on aPWV were observed between FF/VI and TIO. However, further studies with a placebo arm are required to establish definitively whether long-acting bronchodilators lower aPWV. Both treatments demonstrated an acceptable tolerability profile.. ClinicalTrials.gov; No.: NCT01395888; URL: www.clinicaltrials.gov.

Topics: Administration, Inhalation; Aged; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulse Wave Analysis; Respiratory Function Tests; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Vascular Stiffness

To further assess the safety profile of the fixed-dose combination of indacaterol and glycopyrronium (QVA149) and its monocomponents; we investigated the impact of individual patient-level factors and time by integrating the patient-level safety data from the QVA149 clinical programme with relevant information from the independent indacaterol and glycopyrronium safety databases.. Data from 11,404 patients with chronic obstructive pulmonary disease (COPD) were pooled from 14 clinical studies of QVA149, indacaterol and glycopyrronium of ≥3 month's duration with at least two of the treatment groups: QVA149 110/50 μg, glycopyrronium 50 μg, indacaterol 150 μg, placebo or tiotropium 18 μg. Overall hazard ratio (HR) was assessed between the active treatments and placebo and in various subgroups related to severity of airways obstruction, inhaled corticosteroid use, cardiovascular risk factors, sex, age and body mass index for death, serious cases of cardio- and cerebrovascular (CCV) events, major adverse cardiovascular events (MACEs), pneumonia, COPD exacerbations requiring hospitalisation or atrial flutter/fibrillation (AF/F).. The HR for QVA149 versus placebo showed no significant increase in the overall risk for death (HR [95% confidence interval]: 0.93 [0.34-2.54]); CCV events (0.60 [0.29-1.24]); MACE (1.04 [0.45-2.42]); pneumonia (1.10 [0.54-2.25]); COPD exacerbations (0.60 [0.40-0.91]); and AF/F (1.03 [0.49-2.18]). Similar results were observed for indacaterol, glycopyrronium and tiotropium versus placebo for overall risk and in analysed subgroups.. There was no increase in the risk for the investigated safety endpoints for the fixed-dose combination QVA149, and it had a comparable safety profile as its monocomponents and tiotropium versus placebo.

Topics: Aged; Bronchodilator Agents; Drug Combinations; Drug Therapy, Combination; Female; Glycopyrrolate; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Tiotropium is the first bronchodilator to be studied systematically in cystic fibrosis (CF). We investigated whether any intrinsic or extrinsic factors affected pharmacokinetic (PK) parameters of inhaled tiotropium delivered by Respimat(®) in adults and children with CF. Tiotropium PK in patients with CF was compared with that of healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). This pooled analysis summarizes the PK parameters of inhaled tiotropium Respimat(®) across 9 early- and late-phase trials involving 27 healthy volunteers (1 trial), 409 patients with CF (3 trials), and 281 patients with COPD (5 trials). Patients with CF aged 5 to 11, 12 to 17, and ≥ 18 years had similar tiotropium plasma concentrations (geometric mean C(0.083,ss,norm): 2.22 pg/mL/μg; not determined for patients aged <5 years). The fraction excreted unchanged in the urine was 3.4-fold lower for patients aged 0.4 to <5 years than for those aged 5 to 11 years (fe(0-4,ss): 1.19% vs 4.09%). Tiotropium PK parameters were similar between CF patients and COPD patients.

Topics: Adolescent; Adult; Age Factors; Aged; Bronchodilator Agents; Case-Control Studies; Child; Child, Preschool; Cystic Fibrosis; Double-Blind Method; Humans; Infant; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Young Adult

We previously reported a progressive decline in absolute responses of FEV1 and FVC to a near-maximal dose of 2 different short-acting bronchodilators over 4 years. Since varying host factors and the method of expressing the response may impact the time trend of acute bronchodilator responses, we now examined the potential influence of salient host characteristics on changes in bronchodilator responses over time expressed in different ways.. As part of the 4-year, placebo-controlled Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, pre- and post-bronchodilator spirometry was performed at baseline and 1 month and every 6 months thereafter. Post-bronchodilator values for FEV1 and FVC were analyzed for subjects completing at least the 1 year visit (Placebo - N = 2463; Tiotropium - N = 2579), stratified by GOLD stage, age, gender and smoking status and expressed as absolute, relative (%) and % predicted changes from pre-bronchodilator values. Annual changes in bronchodilator response were estimated using linear mixed effects models.. For all subjects analyzed, FEV1 and FVC bronchodilator responses showed progressive and highly significant (p < 0.0001) declines over 4 years. Declines were generally larger in patients with severe/very severe than mild/moderate airflow obstruction, in older patients (≥65 yrs) and in former than continuing smokers.. Acute FEV1 and FVC responses to bronchodilators decline significantly over time in COPD patients, whether expressed as absolute, relative or % predicted changes, potentially impacting on the clinical responses to bronchodilator therapy as well as on the annual rate of decline in post-bronchodilator lung function. Clinicaltrials.gov number: NCT00144339.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome

This study focused on repeatability data and minimal important difference (MID) estimates of the endurance shuttle walking test (ESWT). 255 chronic obstructive pulmonary disease patients (forced expiratory volume in 1 s 54.7±13.2% predicted) completed four ESWTs at different times during the 8-week study: two under baseline conditions with tiotropium (1 week apart), one after a single dose and one after 4 weeks of either fluticasone propionate/salmeterol combination or placebo in addition to tiotropium. 97 patients performed all the tests with a portable metabolic system. Reproducibility of test performance and cardiorespiratory response was investigated with the data obtained on the first two ESWTs. The mean differences between the first two ESWT performances (-6.7±72.2 s and -7.3±113.1 m for endurance time and walking distance, respectively) were not statistically significant. The between-test end-exercise and isotime values for each cardiorespiratory parameter were not significantly different from each other. With the exception of arterial oxygen saturation by pulse oximetry, the repeatability of cardiorespiratory adaptations to ESWT was also confirmed with strong Pearson and intraclass correlation coefficients. Finally, changes of 56-61 s and 70-82 m in endurance time and distance walked, respectively, were perceived by patients. This study provides methodological information supporting the reliability of the ESWT and suggests MID estimates for this test.

Topics: Aged; Androstadienes; Anthropometry; Bronchodilator Agents; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Scopolamine Derivatives; Tiotropium Bromide; Walking

Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchodilators has not been fully explored.. In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric findings, health status, and dyspnea were also monitored.. As compared with continued glucocorticoid use, glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95% confidence interval (CI) with respect to the first moderate or severe COPD exacerbation (hazard ratio, 1.06; 95% CI, 0.94 to 1.19). At week 18, when glucocorticoid withdrawal was complete, the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group (P<0.001); a similar between-group difference (43 ml) was seen at week 52 (P=0.001). No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group.. In patients with severe COPD receiving tiotropium plus salmeterol, the risk of moderate or severe exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT00975195.).

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Withholding Treatment

Indacaterol is a long-acting beta-2 agonist for once-daily treatment of COPD. We evaluated the effects of indacaterol 150 μg on lung hyperinflation compared with placebo and open-label tiotropium 18 μg. We measured physical activity during treatment with indacaterol 150 μg and matched placebo.. We performed a randomized, three-period, cross-over study (21 days of treatment separated by two wash-out periods of 13 days) with indacaterol 150 μg or matching placebo and tiotropium 18 μg. Lung function was assessed by body plethysmography and spirometry. Physical activity was measured for one week by a multisensory armband at the end of both treatment periods with indacaterol/matched placebo. The primary endpoint was peak inspiratory capacity at the end of each treatment period.. 129 patients (mean age, 61 years; mean post-bronchodilator FEV1, 64%), were randomized and 110 patients completed the study. Peak inspiratory capacity was 0.22 L greater with Indacaterol at day 21 compared to placebo (p < 0.001). Similar results were observed for tiotropium. Both bronchodilators also significantly improved other parameters of lung hyperinflation compared with placebo. All parameters of physical activity were significantly increased during treatment with indacaterol versus placebo.. Indacaterol 150 μg improved lung hyperinflation in patients with moderate COPD, which was associated with an increase of physical activity.. ClinicalTrials.gov registration number: NCT01012765.

Topics: Actigraphy; Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Indans; Inspiratory Capacity; Male; Middle Aged; Motor Activity; Plethysmography, Impedance; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Bronchodilator therapy represents a potentially valuable therapeutic option to increase exercise tolerance and enhance lung function in mild to moderate chronic obstructive pulmonary disease (COPD).. To determine effects of tiotropium on pulmonary hyperinflation and exercise tolerance in patients with symptomatic Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 and 2 COPD who experienced inspiratory capacity decrease greater than or equal to 100 ml during incremental and constant work rate treadmill exercise.. This 22-week, randomized, double-blind, two-period crossover study evaluated the efficacy of once-daily tiotropium bromide (18 μg) versus placebo in patients with GOLD 1 and 2 COPD. Primary endpoint was between-group (tiotropium vs. placebo) difference in inspiratory capacity at isotime (i.e., at the time the shortest test ended) during constant work rate treadmill exercise from baseline to the end of a 6-week treatment period. Key secondary endpoints included differences in exercise duration and exertional dyspnea. Safety was assessed by recording adverse events.. Study population comprised 48 patients with GOLD 1 COPD and 78 patients with GOLD 2 COPD. Resting inspiratory capacity significantly improved with tiotropium versus placebo in the overall (P < 0.0001), GOLD 1 (P = 0.0183), and GOLD 2 (P < 0.0001) groups. Isotime inspiratory capacity was significantly enhanced during exercise in the overall (P = 0.0087) and GOLD 2 (P = 0.0494) groups after tiotropium versus placebo. Tiotropium versus placebo significantly enhanced exercise duration in the GOLD 2 group (P = 0.0070) but not in the GOLD 1 or overall patient groups. In the overall group, increase in exercise duration seen with tiotropium was well correlated with the increase in isotime inspiratory capacity (r = 0.463, P < 0.0001).. Resting and exercise hyperinflation were ameliorated by bronchodilator therapy with tiotropium in the overall GOLD 1 plus 2 COPD group. Exercise tolerance was enhanced in GOLD 2, but not GOLD 1, COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01072396).

Topics: Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Exercise Tolerance; Female; Humans; Inspiratory Capacity; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

The 2013 GOLD classification system for COPD distinguishes four stages: A (low symptoms, low exacerbation risk), B (high symptoms, low risk), C (low symptoms, high risk) and D (high symptoms, high risk). Assessment of risk is based on exacerbation history and airflow obstruction, whatever results in a higher risk grouping. The previous system was solely based on airflow obstruction. Earlier studies compared the predictive performance of new and old classification systems with regards to mortality and exacerbations. The objective of this study was to compare the ability of both classifications to predict the number of future (total and severe) exacerbations and mortality in a different patient population, and to add an outcome measure to the comparison: lung function decline.. Patient-level data from the UPLIFT trial were used to analyze 4-year survival in a Weibull model, with GOLD stages at baseline as covariates. A generalized linear model was used to compare the numbers of exacerbations (total and severe) per stage. Analyses were repeated with stages C and D divided into substages depending on lung function and exacerbation history. Lung function decline was analysed in a repeated measures model.. Mortality increased from A to D, but there was no difference between B and C. For the previous GOLD stages 2-4, survival curves were clearly separated. Yearly exacerbation rates were: 0.53, 0.72 and 0.80 for stages 2-4; and 0.35, 0.45, 0.58 and 0.74 for A-D. Annual rates of lung function decline were: 47, 38 and 26 ml for stages 2-4 and 44, 48, 38 and 39 for stages A-D. With regards to model fit, the new system performed worse at predicting mortality and lung function decline, and better at predicting exacerbations. Distinguishing between the sub-stages of high-risk led to substantial improvements.. The new classification system is a modest step towards a phenotype approach. It is probably an improvement for the prediction of exacerbations, but a deterioration for predicting mortality and lung function decline.. ClinicalTrials.gov NCT00144339 (September 2, 2005).

Topics: Bronchodilator Agents; Disease Progression; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Risk Assessment; Scopolamine Derivatives; Survival Rate; Tiotropium Bromide

Combining bronchodilators with different mechanisms of action may improve efficacy and reduce risk of side effects compared to increasing the dose of a single agent in chronic obstructive pulmonary disease (COPD). We investigated this by combining two long-acting bronchodilators: once-daily muscarinic antagonist tiotropium and once-daily β2-agonist olodaterol.. Two replicate, double-blind, randomized, 12-week studies (ANHELTO 1 [NCT01694771] and ANHELTO 2 [NCT01696058]) evaluated the efficacy and safety of olodaterol 5 μg once daily (via Respimat(®)) combined with tiotropium 18 μg once daily (via HandiHaler(®)) versus tiotropium 18 μg once daily (via HandiHaler(®)) combined with placebo (via Respimat(®)) in patients with moderate to severe COPD. Primary efficacy end points were area under the curve from 0-3 hours of forced expiratory volume in 1 second (FEV1 AUC0-3) and trough FEV1 after 12 weeks (for the individual trials). A key secondary end point was health status by St George's Respiratory Questionnaire (SGRQ) total score (combined data set).. Olodaterol + tiotropium resulted in significant improvements over tiotropium + placebo in FEV1 AUC0-3 (treatment differences: 0.117 L [P<0.001], ANHELTO 1; 0.106 L [P<0.001], ANHELTO 2) and trough FEV1 (treatment differences: 0.062 L [P<0.001], ANHELTO 1; 0.040 L [P=0.0029], ANHELTO 2); these were supported by secondary end points. These effects translated to improvements in SGRQ total scores (treatment difference -1.85; P<0.0001). The tolerability profile of olodaterol + tiotropium was similar to tiotropium monotherapy.. These studies demonstrated that olodaterol (Respimat(®)) and tiotropium (HandiHaler(®)) provided bronchodilatory effects above tiotropium alone in patients with COPD. In general, both treatments were well tolerated.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Equipment Design; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; United States

Combinations of inhaled long-acting bronchodilator therapies such as muscarinic antagonists and β2-agonists may be more effective than monotherapy in the treatment of chronic obstructive pulmonary disease (COPD).. This study was a 24-week, Phase III, multicenter, randomized, blinded, double-dummy, parallel-group study of the once-daily, inhaled, fixed-dose combination of the long-acting muscarinic antagonist umeclidinium bromide and the long-acting β2-agonist vilanterol (UMEC/VI 62.5/25 mcg) versus tiotropium (TIO, 18 mcg). The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Day 169. The secondary endpoint was weighted mean FEV1 over 0–6 h post-dose at Day 168. For key endpoints, a step-down closed testing hierarchy was applied to account for multiplicity. Other efficacy and safety endpoints were assessed.. Statistically significant improvements in trough FEV1 at Day 169 (0.112 L, 95% confidence interval [CI]: 0.081, 0.144; p < 0.001) and weighted mean FEV1 over 0–6 h post-dose at Day 168 (0.105 L, 95% CI: 0.071, 0.140; p < 0.001) were observed for UMEC/VI versus TIO. In addition UMEC/VI improved health-related quality of life, and reduced requirement for the use of rescue medication compared with TIO. The incidence of adverse events was similar between treatment groups.. UMEC/VI was associated with statistically significant and clinically meaningful improvements in lung function versus TIO. UMEC/VI was well tolerated. UMEC/VI 62.5/25 mcg could provide an effective new treatment option for patients with moderate-to-very severe COPD.

Topics: Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinuclidines; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

To compare the efficacy and safety of long-term treatment (48 weeks) with tiotropium bromide (5 µg) via Respimat(®) with placebo in patients with chronic obstructive pulmonary disease (COPD).. A total of 338 patients were randomized in this double-blind, placebo controlled, parallel study. All patients received either tiotropium bromide or placebo. Tiotropium bromide solution 5 µg (2×2.5 µg/puff) or matching placebo was delivered via Respimat(®) at a dosage of once daily for 48 weeks. Co-primary endpoints were trough forced expiratory volume in one second (FEV(1)) and the time to first exacerbation.. Statistically significant improvements of both trough FEV(1) and trough forced vital capacity (FVC) in the tiotropium group were achieved at weeks 4, 24, and 48 compared with those in the placebo group (P < 0.000 1). Tiotropium treatment delayed the time to first exacerbation. The time was 157 days in the tiotropium group and 85 days in the placebo group. A statistically significant difference (P = 0.002 7) in favor of tiotropium was also observed. The total numbers of exacerbation during treatment were 90 and 128 in the tiotropium and placebo groups, respectively. The Poisson regression analysis gave a mean exacerbation rate per patient year exposure of 0.67 in the tiotropium group compared to 0.98 in the placebo group with a rate ratio of 0.69 (95%CI 0.50-0.93, P = 0.016 4). A much larger improvement from baseline in St. George's respiratory questionnaire (SGRQ) total score was observed for the tiotropium group than in the placebo group (P = 0.036 7), SGRQ symptom and activity scores of patients in the tiotropium group were also superior to those of patients receiving placebo. The drugs-related adverse events in the tiotropium and placebo groups were 12 cases and 11 cases, respectively.. Tiotropium significantly improved lung function and quality of life, delayed the time to first exacerbation, reduced the number of exacerbation. Overall, tiotropium was well tolerated.

Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Safety; Scopolamine Derivatives; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

To determine the safety and efficacy of BEA2180, an anticholinergic agent in patients with chronic obstructive pulmonary disease (COPD).. Smokers or ex-smokers ≥40 years with COPD and a postbronchodilator forced expiratory volume in 1 s (FEV1) <80% predicted and FEV1/forced vital capacity ≤70% participated in this multinational, randomised, double-blind, parallel study. Patients received BEA2180 (50, 100 or 200 μg), tiotropium (5 μg) or placebo once daily via Respimat Soft Mist™. The primary endpoint was trough FEV1 after 24 weeks. Secondary endpoints included Transition Dyspnoea Index (TDI) focal score, St George's Respiratory Questionnaire (SGRQ) total score, exacerbations and adverse events.. Patients (n = 2080, 64.5% male) had a mean age of 64.2 years and a baseline FEV1 of 1.2 L. Trough FEV1 at 24 weeks with all BEA2180 doses (0.044-0.087 L) and tiotropium 5 μg (0.092 L) was significantly higher (p < 0.0001) than placebo (-0.034 L) and BEA2180 (200 μg) was noninferior to tiotropium. Mean TDI focal scores were higher with BEA2180 (1.43-1.48) or tiotropium (1.46) versus placebo (0.94; p ≤ 0.01 for all). Mean SGRQ total scores also improved with BEA2180 (40.1-40.7) or tiotropium (39.5) compared with placebo (43.0, p < 0.01 for all). COPD exacerbation rates were reduced for all active treatments, reaching statistical significance for BEA2180 (50 and 200 μg) (p < 0.05, for both).. All study doses of BEA2180 improved lung function, reduced symptoms and exacerbations, and improved health status in COPD; all treatments were well tolerated. Clinical trial identifier: NCT00528996.

Topics: Aged; Bronchodilator Agents; Cholinergic Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Spirometry; Tiotropium Bromide; Treatment Outcome

GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β2-agonism (MABA) properties. This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV1) at 24 h on Days 1 and 14. MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV1 over 24 h. Mean (95% CI) 24 h trough FEV1 (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only. GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.

Topics: Adrenergic beta-2 Receptor Agonists; Adult; Aged; Albuterol; Bronchodilator Agents; Carbamates; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

Tiotropium bromide is an effective therapy for COPD patients. Comparing across programs tiotropium Respimat Soft Mist inhaler was at least as efficacious as tiotropium HandiHaler, however, concerns have been raised about tiotropium's safety when given via Respimat.. The TIOSPIR trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat 5 μg once daily (marketed) and 2.5 μg once daily (investigational) with tiotropium HandiHaler 18 μ once daily (marketed). The hypotheses to be tested are 1). that tiotropium Respimat 5 μg once daily and Respimat 2.5 μg once daily are non-inferior to HandiHaler in terms of all-cause mortality, and 2). that tiotropium Respimat 5 μg once daily is superior to HandiHaler in terms of time to first exacerbation. A spirometry substudy evaluates the bronchodilator efficacy. The trial is a randomized, double-blind, double dummy, event-driven, parallel group study. Participants can use any background treatment for COPD except inhaled anticholinergic agents. The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included. Clinical sites are international and include both primary care as well as specialists.. To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2-3 years.. TIOSPIR will provide precise estimates of the relative safety and efficacy of the Respimat and HandiHaler formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort.

Topics: Administration, Inhalation; Bronchodilator Agents; Female; Humans; Internationality; Male; Metered Dose Inhalers; Prevalence; Pulmonary Disease, Chronic Obstructive; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Disease progression in COPD is associated with a decline in exercise performance over time. We assessed whether tiotropium might mitigate this by determining its effect on treadmill endurance time (ET) over 2 years.. This was a randomized, double-blind, placebo-controlled trial of tiotropium, 18 μg daily, in patients with COPD (FEV1/FVC < 70%; postbronchodilator FEV1 < 65%). The primary end point was ET at 90% of baseline maximum work rate at 96 weeks. Secondary end points were ET at other visits, ET by smoking status, spirometry, and St. George's Respiratory Questionnaire (SGRQ).. A total of 519 patients were randomized (tiotropium 260, placebo 259). Mean age was 65 years, 77% were men, 34% were continuing smokers, and mean FEV1 was 1.25 L (44% predicted). Significantly more patients discontinued placebo (hazard ratio [95% CI], 0.61 [0.44-0.83]). Baseline ET was 301 s (improvement tiotropium/placebo was 13% overall; P = .009; 18% at 48 weeks, P = .004; 13% at 96 weeks, P = .106). In patients with baseline ET between 2 and 10 min (n = 404), improvement at 96 weeks was 19% (P = .04). Current smokers had higher ET with tiotropium vs placebo (P = .018). FEV1/FVC improved with tiotropium (P < .01). SGRQ total score at 96 weeks improved with tiotropium vs placebo by 4.03 units (P = .007).. Treadmill ET was numerically greater over 2 years with tiotropium vs placebo. However, the 96-week difference was not statistically significant. Spirometry and health status also improved with tiotropium over 2 years, attesting to the benefits of long-acting bronchodilator therapy.. ClinicalTrials.gov; No.: NCT00525512; URL: www.clinicaltrials.gov.

Topics: Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Endpoint Determination; Exercise Test; Female; Health Status Indicators; Humans; Male; Middle Aged; Physical Endurance; Placebos; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Smoking; Tiotropium Bromide

This study explores spirometry quality and reproducibility in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT(®)) trial.. Four-year, randomized, double-blind, placebo-controlled, multicenter trial in 5993 patients with chronic obstructive pulmonary disease. Within-test variability of pre- and post-bronchodilator forced expiratory volume in 1 s (FEV(1)) was compared across study visits. Between-test variability of best pre- or post-FEV(1) values between two visits 6 months apart was compared at the start, middle and end of the trial.. Three or more acceptable maneuvers were obtained in 93% of visits. Within-test variability of pre- and post-FEV(1) (mean standard deviation: 0.092 and 0.098 L) decreased during the trial. Between-test variability also decreased: pre-FEV(1) (visit 3-5 = 0.141 ± 0.138 L; visit 9-11 = 0.129 ± 0.121 L; visit 17-19 = 0.121 ± 0.122 L); post-FEV(1) (0.139 ± 0.140, 0.126 ± 0.123, 0.121 ± 0.122 L, respectively), and was dependent on age, sex, smoking status and disease stage, but not on bronchodilator response or study treatment.. Spirometry quality in UPLIFT(®) was good and improved during the trial. Between-test variability across patient subgroups suggests that relevant cut-offs for individual disease monitoring are difficult to establish.. NCT00144339.

Topics: Bronchodilator Agents; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Vital Capacity

This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).. Patients received aclidinium 400 μg twice daily (morning and evening), tiotropium 18 μg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0-24) at week 6. Secondary and additional endpoints included FEV1 AUC12-24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety.. Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0-24 and FEV1 AUC12-24 were significantly increased from baseline with aclidinium (∆ = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (∆ = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (<1.5%) or serious AEs (<3%) occurred in any group.. Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after 6 weeks. Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium. Aclidinium was generally well tolerated.

Topics: Aged; Area Under Curve; Bronchodilator Agents; Circadian Rhythm; Cough; Disease Progression; Double-Blind Method; Dry Powder Inhalers; Dyspnea; Female; Forced Expiratory Volume; Headache; Humans; Male; Middle Aged; Muscarinic Antagonists; Patient Preference; Pharyngitis; Pulmonary Disease, Chronic Obstructive; Respiratory Sounds; Scopolamine Derivatives; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Tropanes; Xerostomia

Assess the cost effectiveness of budesonide/formoterol (BUD/FORM) Turbuhaler(®)+tiotropium (TIO) HandiHaler(®) vs. placebo (PBO)+TIO in patients with chronic obstructive pulmonary disease (COPD) eligible for inhaled corticosteroids/long-acting β2-agonists (ICS/LABA).. The cost-effectiveness analysis was based on the 12-week, randomised, double-blind CLIMB trial. The study included 659 patients with pre-bronchodilator forced expiratory volume in 1 s ≤ 50% and ≥1 exacerbation requiring systemic glucocorticosteroids or antibiotics the preceding year. Patients received BUD/FORM 320/9 μg bid + TIO 18 μg qd or PBO bid + TIO 18 μg qd. Effectiveness was defined as the number of severe exacerbations (hospitalisation/emergency room visit/systemic glucocorticosteroids) avoided. A sub-analysis included antibiotics in the definition of an exacerbation. Resource use from CLIMB was combined with Danish (DKK), Finnish (€), Norwegian (NOK) and Swedish (SEK) unit costs (2010). The incremental cost-effectiveness ratios (ICERs) for BUD/FORM + TIO vs. PBO + TIO were estimated using descriptive statistics and uncertainty around estimates using bootstrapping. Analyses were conducted from the societal and healthcare perspectives in Denmark, Finland, Norway and Sweden.. From a societal perspective, the ICER was estimated at €174/severe exacerbation avoided in Finland while BUD/FORM + TIO was dominant in the other countries. From the healthcare perspective, ICERs were DKK 1580 (€212), €307 and SEK 1573 (€165) per severe exacerbation avoided for Denmark, Finland and Sweden, respectively, while BUD/FORM + TIO was dominant in Norway. Including antibiotics decreased ICERs by 8-15%. Sensitivity analyses showed that results were overall robust.. BUD/FORM + TIO represents a clinical and economic benefit to health systems and society for the treatment of COPD in the Nordic countries. (ClinicalTrials.gov Identifier: NCT00496470).

Topics: Adrenergic beta-2 Receptor Agonists; Adult; Aged; Bronchodilator Agents; Budesonide; Cost of Illness; Cost-Benefit Analysis; Double-Blind Method; Drug Combinations; Drug Costs; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Glucocorticoids; Health Care Costs; Health Resources; Humans; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scandinavian and Nordic Countries; Scopolamine Derivatives; Sick Leave; Tiotropium Bromide; Treatment Outcome

Combined therapy with tiotropium and long-acting beta 2 agonists confers additional improvement in symptoms, lung function and aspects of health-related quality of life (QOL) compared with each drug alone in patients with COPD. However, the efficacy of combined therapy on walking distance, a surrogate measure of daily functional activity and morbidity remains unclear. The aim was, therefore, to quantify the benefit of this therapy on the six minute walk test. Secondary outcomes included change in lung function, symptoms, the BODE index and QOL. In a double-blind, crossover study, 38 participants with moderate to severe COPD on tiotropium were randomised to receive either formoterol or placebo for 6 weeks. Following a 2-week washout period, participants crossed over to the alternate arm of therapy for a further 6 weeks. Thirty-six participants, with an average age of 64.3 years and FEV1 predicted of 53%, completed the study. Combined therapy improved walking distance by a mean of 36 metres [95% CI: 2.4, 70.1; p = 0.04] compared with tiotropium. FEV1 increased in both groups (160 mL combination therapy versus 30 mL tiotropium) with a mean difference of 110 mL (95% CI: -100, 320; p = 0.07) between groups, These findings further support the emerging advantages of combined therapy in COPD. Australian New Zealand Clinical Trials.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Exercise Test; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Walking

Triple inhalation therapy with tiotropium (Tio) and salmeterol/fluticasone propionate combination (SFC) is widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, the effects of triple therapy on airway structural changes remain unknown.. The aim of the study was to assess the effects of Tio, salmeterol (SM), SFC and Tio plus SFC on airway dimensions in COPD.. A randomized, open-label, 4-way study (n = 60) was conducted comparing 16-week treatment periods of Tio (18 μg once daily), SM (50 μg twice daily), SFC (50/250 μg twice daily) and Tio (18 μg once daily) plus SFC (50/250 μg twice daily). Airway dimensions were assessed by a validated CT technique, and airway wall area (WA) corrected for body surface area (BSA), percentage WA (WA%), wall thickness/√BSA and luminal area (Ai)/BSA at the right apical segmental bronchus were measured. Pulmonary function and the St. George's Respiratory Questionnaire (SGRQ) were evaluated.. Tio plus SFC resulted in a significant decrease in WA corrected for BSA and WA% compared with Tio, SM and SFC (p < 0.05 for all). The changes in WA% and Ai/BSA were significantly correlated with changes in forced expiratory volume in 1 s (r = -0.86, p < 0.001, and r = 0.48, p < 0.05, respectively). There were more significant improvements in SGRQ scores after treatment with triple therapy than after the 3 other treatments.. Tio plus SFC therapy is more effective than Tio, SM and SFC for reducing airway wall thickness in COPD.

Topics: Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Exercise Tolerance; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Male; Middle Aged; Physical Endurance; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sympathomimetics; Tiotropium Bromide; Treatment Outcome; Walking

Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo.. In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 μg or 5 μg, as compared with tiotropium HandiHaler at a once-daily dose of 18 μg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 μg or 2.5 μg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 μg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease.. During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 μg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups.. Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.).

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Risk; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

A pharmacokinetic study in an Asian population showed that tiotropium 5 µg via Respimat leads to the same plasma levels compared to 18 µg via HandiHaler. The objective of the trial was to compare the efficacy and safety of longterm treatment (1 year) with tiotropium bromide (5 µg) via Respimat® with placebo in patients with chronic obstructive pulmonary disease (COPD).. A total of 3991 patients were randomized in this double-blind, placebo controlled, parallel group study, while in China 338 patients (309 males, 29 females) received either tiotropium bromide (n = 167) or placebo (n = 171). Tiotropium bromide solution or matching placebo was delivered via Respimat® at a dosage of 5 µg (2×2.5 µg/puff) once daily for 48 weeks. Co-primary endpoints were trough forced expiratory volume in one second (FEV1) and the time to first exacerbation.. Statistically significant improvements in trough FEV1 and trough forced vital capacity (FVC) in the tiotropium group were achieved at weeks 4, 24, and 48 compared with those in the placebo group. A statistically significant difference (P = 0.0027) in favour of tiotropium was also observed for the time to first exacerbation. The total numbers of exacerbations during treatment were 90 and 128 in the tiotropium and placebo groups, respectively, with a rate ratio of 0.69 (P = 0.0164). The difference between the treatment groups in the adjusted mean changes from baseline of St. George Respiratory Questionnaire (SGRQ) total score was -3.9 (95% CI: -7.5, -0.2) and was of statistical significance (P = 0.0367). The incidences of serious adverse events (SAEs) in the tiotropium and placebo groups were 16.2% and 17.0%, respectively. Seven deaths occurred whilst patients were on treatment, four in the tiotropium group and three in the placebo group, all of which were assessed as non-related study drugs by the investigators.. Tiotropium significantly improved lung function and quality of life, delayed the time to first exacerbation, reduced the number of exacerbations. Overall, tiotropium was well tolerated.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The Global initiative for chronic Obstructive Lung Disease (GOLD) Committee has proposed a chronic obstructive pulmonary disease (COPD) assessment framework focused on symptoms and on exacerbation risk. This study will evaluate a symptom and exacerbation risk-based treatment strategy based on GOLD in a real-world setting in Japan. Optimal management of COPD will be determined by assessing symptoms using the COPD Assessment Test (CAT) and by assessing the frequency of exacerbations.. This study (ClinicalTrials.gov identifier: NCT01762800) is a 24-week, multicenter, randomized, double-blind, double-dummy, parallel-group study. It aims to recruit 400 patients with moderate-to-severe COPD. Patients will be randomized to receive treatment with either salmeterol/fluticasone propionate (SFC) 50/250 μg twice daily or with tiotropium bromide 18 μg once daily. Optimal management of patients will be assessed at four-weekly intervals and, if patients remain symptomatic, as measured using the CAT, or experience an exacerbation, they have the option to step up to treatment with both drugs, ie, SFC twice daily and tiotropium once daily (TRIPLE therapy). The primary endpoint of the study will be the proportion of patients who are able to remain on the randomized therapy.. No data are available. This paper summarizes the methodology of the study in advance of the study starting.. The results of this study will help physicians to understand whether TRIPLE therapy is more effective than either treatment strategy alone in controlling symptoms and exacerbations in patients with moderate-to-severe COPD. It will also help physicians to understand the GOLD recommendation work in Japan.

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Androstadienes; Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Double-Blind Method; Drug Combinations; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Japan; Kaplan-Meier Estimate; Lung; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Research Design; Scopolamine Derivatives; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Data examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce.. Post-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint. Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or ≥ 2 exacerbations during study treatment), irrespective of study treatment. A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation.. In total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators. Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses. Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and ≥ 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers. The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality.. The frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival.. NCT00563381; Study identifier: BI 205.389.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Albuterol; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Phenotype; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Regression Analysis; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Survival Rate; Tiotropium Bromide; Treatment Outcome

We evaluated the effect of dual, longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease (COPD).. In this parallel-group study, 2224 patients (aged ≥40 years, Global Initiative for Chronic Obstructive Lung Disease stages III-IV, and one or more moderate COPD exacerbation in the past year) were randomly assigned (1:1:1; via interactive voice response or web system; stratified for smoking status) to once-daily QVA149 (fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg), glycopyrronium 50 μg, or tiotropium 18 μg for 64 weeks. Assignment to QVA149 and glycopyrronium was double-blind; tiotropium was open-label. Efficacy was assessed in all patients randomly assigned to treatment groups who received at least one dose of study drug; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group. The primary objective was to show superiority of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations (defined by worsening symptoms and categorised by treatment requirements) during treatment. This completed trial is registered at ClinicalTrials.gov, NCT01120691.. Between April 27, 2010, and July 11, 2012, 741 patients were randomly assigned to receive QVA149, 741 to receive glycopyrronium, and 742 to receive tiotropium (729, 739, and 737 patients, respectively, analysed for efficacy). QVA149 significantly reduced the rate of moderate to severe exacerbations versus glycopyrronium by 12% (annualised rate of exacerbations 0·84 [95% CI 0·75-0·94] vs 0·95 [0·85-1·06]; rate ratio 0·88, 95% CI 0·77-0·99, p=0·038). Adverse events (including exacerbations) were reported for 678 (93%) of 729 patients on QVA149, 694 (94%) of 740 on glycopyrronium, and 686 (93%) of 737 on tiotropium. Incidence of serious adverse events was similar between groups (167 [23%] patients on QVA149, 179 [24%] on glycopyrronium, and 165 [22%] on tiotropium); COPD worsening was the most frequent serious adverse event (107 [15%] patients on QVA149, 116 [16%] on glycopyrronium, 87 [12%] on tiotropium).. The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium, with concomitant improvements in lung function and health status. These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD.. Novartis Pharma AG.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Drug Monitoring; Female; Glycopyrrolate; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Respiratory Function Tests; Respiratory System; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease (COPD) and a history of at least one moderate to severe exacerbation in the previous 12 months.. In this multicentre, randomised, blinded, double-dummy, parallel group study, we enrolled patients aged 40 years or older with severe COPD and at least one exacerbation within the previous year. We used a computer-generated sequence to randomly allocate patients (1:1; stratified by baseline inhaled corticosteroid use, with the balance of treatments maintained at country level) to receive either indacaterol (150 μg) or tiotropium (18 μg) once-daily for 52 weeks. Our primary and key secondary objectives were to investigate whether indacaterol was non-inferior to tiotropium for trough forced expiratory volume in 1 s (FEV1) at week 12 (primary endpoint), and for rate of exacerbations at week 52 (secondary endpoint). Analysis populations for the primary and key secondary endpoints were per-protocol sets. The safety set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00845728.. Between March 16, 2009, and July 5, 2012, we enrolled and randomly allocated 3444 patients: 1723 to indacaterol and 1721 to tiotropium. At week 12, the estimated least squares mean trough FEV1 difference between the groups was -0.011 L (least squares mean with indacaterol [n=1450] 1.134 L [SE 0.008] vs tiotropium [n=1467] 1.145 L [0.008]; one-sided 97.5% CI lower limit -0.026 L; p<0.0001). The lower limit of the 97.5% CI was above the prespecified non-inferiority margin of -0.055 L, suggesting that indacaterol was non-inferior to tiotropium. Indacaterol did not show non-inferiority in terms of annualised exacerbation rates: 0.79 (indacaterol, n=1529) versus 0.61 (tiotropium, n=1543); ratio 1.29 (one-sided 97.5% CI upper limit 1.44). In the safety set, we recorded no between-group difference in the number of patients who had adverse events (indacaterol 1119 [65%] of 1721 patients vs tiotropium 1065 [62%] of 1718 patients) or serious adverse events (indacaterol, 263 [15%] of 1721 patients vs tiotropium, 255 [15%] of 1718 patients). Respiratory disorders, particularly worsening of COPD, were the most common adverse events (COPD: indacaterol, 747 [43%] of 1721 patients and tiotropium, 665 [39%] of 1718 patients) and serious adverse events (COPD: indacaterol, 147 [9%] of 1721 patients and tiotropium, 121 [7%] of 1718 patients).. Indacaterol and tiotropium provided clinically relevant improvements in lung function with comparable safety profiles. Tiotropium afforded greater protection from exacerbations, although the absolute number of events was small and the difference between treatments is of uncertain clinical importance. The present data offer evidence consistent with current guidelines.. Novartis Pharma AG.

Topics: Adult; Aged; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The aim of this study was to perform a 1-yr trial-based cost-effectiveness analysis (CEA) of tiotropium versus salmeterol followed by a 5-yr model-based CEA. The within-trial CEA, including 7,250 patients with moderate to very severe chronic obstructive pulmonary disease (COPD), was performed alongside the 1-yr international randomised controlled Prevention of Exacerbations with Tiotropium (POET)-COPD trial comparing tiotropium with salmeterol regarding the effect on exacerbations. Main end-points of the trial-based analysis were costs, number of exacerbations and exacerbation days. The model-based analysis was conducted to extrapolate results to 5 yrs and to calculate quality-adjusted life years (QALYs). 1-yr costs per patient from the German statutory health insurance (SHI) perspective and the societal perspective were €126 (95% uncertainty interval (UI) €55-195) and €170 (95% UI €77-260) higher for tiotropium, respectively. The annual number of exacerbations was 0.064 (95% UI 0.010-0.118) lower for tiotropium, leading to a reduction in exacerbation-related costs of €87 (95% UI €19-157). The incremental cost-effectiveness ratio was €1,961 per exacerbation avoided from the SHI perspective and €2,647 from the societal perspective. In the model-based analyses, the 5-yr costs per QALY were €3,488 from the SHI perspective and €8,141 from the societal perspective. Tiotropium reduced exacerbations and exacerbation-related costs, but increased total costs. Tiotropium can be considered cost-effective as the resulting cost-effectiveness ratios were below commonly accepted willingness-to-pay thresholds.

Topics: Aged; Albuterol; Bayes Theorem; Bronchodilator Agents; Cost-Benefit Analysis; Double-Blind Method; Female; Health Care Costs; Humans; Male; Middle Aged; Models, Economic; Probability; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

There is still a need for new agents which improve upon the therapeutic index of tiotropium, the current standard of care for many patients with chronic obstructive pulmonary disease (COPD). We examined in patients with COPD the efficacy of single doses of AZD9164, an M(3)-selective muscarinic antagonist, to identify an appropriate dose-range for future studies. COPD patients (n = 28) inhaled AZD9164 (100, 400 and 1200 μg), tiotropium (18 μg) and placebo at 5 study centre visits (Clinicaltrials.gov identifier NCT00939211). The effects of these test drugs on average (E(av)), peak (E(max)) and trough (E(22-26)) forced expiratory volume in one second (FEV(1)) were assessed, as were systemically-mediated effects and the safety and exposure of single doses of AZD9164. AZD9164 100, 400 and 1200 μg caused increases in FEV(1) to peak effects of 12, 17 and 12% above baseline respectively, following an initial transient and dose-related fall in FEV(1) and associated increase in mild respiratory symptoms such as cough. Bronchodilation was maintained overnight, with minimal FEV(1) decline. AZD9164 400 and 1200 μg produced larger effects than tiotropium on E(22-26) (p < 0.05; both doses) while AZD9164 400 μg also had larger effects on E(max) (p = 0.001) and E(av) (p < 0.05). There were no serious adverse events and statistically significant systemic effects were observed only with AZD9164 1200 μg. AZD9164 may improve upon the therapeutic index of tiotropium, increasing the magnitude and duration of lung function improvements without increasing systemically-mediated adverse events. The initial bronchoconstrictor effect of AZD9164 requires further investigation.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Piperidines; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Receptor, Muscarinic M3; Scopolamine Derivatives; Tiotropium Bromide

The objective of this study was to investigate the effect of tiotropium compared with salmeterol on exacerbations in patients with moderate (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II) chronic obstructive pulmonary disease (COPD) and those naïve to maintenance respiratory therapy in the 1-year Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD(®)) trial (NCT00563381). Time to first exacerbation (primary endpoint) and rates of exacerbations were analyzed using exploratory Cox and Poisson regression (adjusting for time on treatment). Of 7376 randomized patients, 3614 were GOLD stage II (tiotropium n = 1781; salmeterol n = 1833) and 1343 were maintenance therapy naïve (tiotropium n = 672; salmeterol n = 671). Tiotropium significantly increased time to first exacerbation vs. salmeterol in GOLD stage II patients (hazard ratio [HR], 0.88; 95% confidence interval [CI]: 0.79-0.99; p = 0.028) and maintenance therapy naïve patients (HR, 0.79; 95% CI, 0.65-0.97; p = 0.028). Annual exacerbation rates were also significantly lower with tiotropium in the maintenance naïve subgroup compared with salmeterol (rate ratio [RR], 0.77; 95% CI, 0.63-0.94; p = 0.012). In the GOLD stage II subgroup, the rate of hospitalized exacerbations per year was significantly lower with tiotropium than with salmeterol (RR, 0.70; 95% CI, 0.57-0.85; p < 0.001); tiotropium also significantly prolonged time to first hospitalized exacerbation versus salmeterol in this subgroup (HR, 0.66; 95% CI, 0.48-0.91; p = 0.012). In conclusion, results from this prespecified subgroup analysis support the selection of tiotropium as first-choice maintenance therapy for patients with GOLD stage II COPD.

Topics: Adult; Aged; Albuterol; Bronchodilator Agents; Double-Blind Method; Female; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

There is still a lack of data on the seasonality of exacerbations of COPD based on large randomized studies using COPD exacerbations as primary end points. The objective of this study was to assess the seasonal pattern of moderate and severe exacerbations and analyze the influence of associated baseline factors. We also determined the timing of second exacerbations and the potential impact of the 2009 influenza A(H1N1) pandemic on exacerbations.. Analyses of exacerbation rates across treatment groups were adjusted for differing times on treatment by means of descriptive statistics based on the 1-year Prevention of Exacerbations with Tiotropium in COPD (POET-COPD) trial, in which exacerbations were the primary end point.. Of the 7,376 patients who were randomized, a total of 4,411 exacerbations were reported in 2,691 patients. Mean monthly exacerbation rates during winter were 2.16-fold higher than during summer, regardless of baseline characteristics (age, sex, COPD severity, smoking status, BMI, inhaled corticosteroid use, cardiovascular comorbidity, concomitant cardiovascular medication). Second exacerbations after a previous event in October to March occurred 1 month earlier than during the warmer half of the season. The portion of exacerbation-related hospitalizations remained constant throughout the year. Most exacerbations were treated with antibiotics and reached a peak in the colder season. All-cause mortality showed a seasonal pattern similar to exacerbations. The 2009 A(H1N1) pandemic was not associated with an increase in exacerbation rates or deaths.. This analysis presented a marked impact of season on exacerbation outcomes, antibiotic treatment, timing of second exacerbations, and all-cause mortality.

Topics: Aged; Anti-Bacterial Agents; Bronchodilator Agents; Disease Progression; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Seasons; Tiotropium Bromide

The purpose of this study was to clarify the additive efficacy of short-acting β(2)-agonists (SABA) or muscarinic antagonists (SAMA) on dynamic hyperinflation and exercise tolerance in patients with chronic obstructive pulmonary disease (COPD) who had been treated with long-acting bronchodilators. Thirty-two patients with stable COPD who had been treated with long-acting bronchodilators, including long-acting muscarinic antagonists (LAMA), were examined by pulmonary function tests, dynamic hyperinflation evaluated by the method of step-wise metronome-paced incremental hyperventilation, and the incremental shuttle walking test before and after inhalation of SABA or SAMA. The additive efficacy of the two drugs was analyzed. Inhalation of SABA and SAMA improved airflow limitation and dynamic hyperinflation in stable COPD patients who had been treated with LAMA. Inhalation of SABA decreased respiratory resistance and the difference in respiratory resistance at 5 Hz and 20 Hz. On the whole, the additive efficacy of SABA on airflow limitation and dynamic hyperinflation was superior to that of SAMA. Furthermore, inhalation of SABA resulted in relief of breathlessness during exercise and significant improvement in exercise capacity. Inhalation of SABA resulted in significant improvement in exercise tolerance, which may have been due to improvement in dynamic hyperinflation. Single use of SABA before exercise, in addition to regular treatment with LAMA, may therefore be useful in stable COPD patients.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Airway Resistance; Bronchodilator Agents; Drug Administration Schedule; Drug Therapy, Combination; Exercise Test; Exercise Tolerance; Female; Forced Expiratory Volume; Humans; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Respiratory Rate; Scopolamine Derivatives; Tiotropium Bromide

The primary objective of this study was to evaluate the effects of a 3-week treatment with tiotropium on walking capacity in chronic obstructive pulmonary disease (COPD). After familiarisation with study procedures, 36 patients were randomised to receive tiotropium 18 μg once daily or a matching placebo in a double-blind, parallel-group study. Pre- (trough) and 2-h post-dose pulmonary function was measured. An endurance shuttle walk was then completed. The same procedures were repeated after 3 weeks of treatment. Ventilatory parameters were monitored during exercise. At 3 weeks, tiotropium significantly improved walking endurance time in comparison with placebo, with a mean±sd between-group difference of 128±141 s (p=0.017). At 3 weeks, trough values for forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were significantly improved with tiotropium in comparison with placebo. The post-dose response to tiotropium was statistically superior to placebo after the first dose and after 3 weeks of treatment for FEV(1), FVC and inspiratory capacity. Ventilation and tidal volume at the end of walking were significantly improved with tiotropium. 3 weeks of tiotropium resulted in a greater walking endurance in patients with COPD. Improvements in FEV(1), maximal ventilation and tidal volume may contribute to this enhanced exercise capacity.

Topics: Aged; Bronchodilator Agents; Female; Humans; Male; Middle Aged; Physical Endurance; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Walking

Tiotropium has been shown to improve lung function, quality of life, and exacerbations and reduce mortality when compared with placebo in COPD. It remains unclear whether benefits are seen when tiotropium is used in conjunction with inhaled corticosteroids (ICSs) plus long-acting β-agonists (LABAs).. We performed a retrospective cohort study using a National Health Service database of patients with COPD in Tayside, Scotland, between 2001 and 2010 that is linked with databases regarding hospital admissions, pharmacy prescriptions, and death registries. The impact of the addition of tiotropium (Tio) to ICS + LABA therapy on all-cause mortality, hospital admissions for respiratory disease, and emergency oral corticosteroid bursts was evaluated. Adjusted hazard ratios (HRs) were calculated by Cox regression after inclusion of the following covariates: cardiovascular and respiratory disease, diabetes, smoking, age, sex, and deprivation index.. A total of 1,857 patients were given ICS + LABA + Tio, and 996 were given ICS + LABA. Mean follow-up was 4.65 years. The adjusted HR for all-cause mortality for ICS + LABA + Tio vs ICS + LABA was 0.65 (95% CI, 0.57-0.75; P < .001). Adjusted HRs for hospital admissions and oral corticosteroid bursts were 0.85 (95% CI, 0.73-0.99; P = .04) and 0.71 (95% CI, 0.63-0.80; P < .001), respectively.. The study suggests that the addition of tiotropium to ICSs and LABA therapy may confer benefits in reducing all-cause mortality, hospital admissions, and oral corticosteroid bursts in patients with COPD. Triple therapy is widely used in the real-life management of COPD, with only limited scientific support. The study supports the use of triple therapy in COPD and provides a platform for randomized controlled trials specifically addressing this topic.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Cause of Death; Cholinergic Antagonists; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Forced Expiratory Volume; Glucocorticoids; Hospital Mortality; Humans; Male; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Recurrence; Retrospective Studies; Scopolamine Derivatives; Scotland; Survival Rate; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The efficacy and safety of aclidinium bromide bid, a novel, long-acting, muscarinic antagonist, was assessed in patients with moderate to severe COPD.. In this phase IIa randomized, double-blind, double-dummy, crossover trial, patients with moderate to severe COPD received aclidinium 400 μg bid, tiotropium 8 μg once daily, and placebo for 15 days, with a 9- to 15-day washout between treatment periods. Treatments were administered through the Genuair or HandiHaler dry powder inhalers. The primary end point was mean change from baseline in FEV(1) AUC(0-12/12h) (area under the curve where the numbers represent the time period for which data were collected divided by the number of hours over which the data are averaged [eg, 0-12 h postdose divided by 12 h]) on day 15. Secondary end points were changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), peak FEV(1), and COPD symptom scores.. Thirty patients with COPD were randomized, and 27 completed the study. Mean change from baseline in FEV(1) AUC(0-12/12h) at day 15 was significantly greater for aclidinium and tiotropium over placebo (P < .0001). Mean changes from baseline in FEV(1) AUC(12-24/12h), FEV(1) AUC(0-24/24h), morning predose FEV(1), and peak FEV(1) at day 15 were significantly greater for aclidinium and tiotropium over placebo (P < .0001 for all except P < .001 for FEV(1) AUC(12-24/12h) tiotropium vs placebo). Improvements were significantly greater with aclidinium vs tiotropium on day 1 for all of the normalized AUC values of FEV(1) as well as on day 15 for FEV(1) AUC(12-24/12h) (P < .05 for all). COPD symptoms were significantly improved from baseline with aclidinium vs placebo (P < .05) but not with tiotropium.. In patients with COPD, aclidinium 400 μg bid compared with placebo provided clinically meaningful improvements in 24-h bronchodilation that generally were comparable to tiotropium 18 μg daily but with significant differences in favor of aclidinium observed in the average nighttime period. Larger studies with longer treatment duration are ongoing to confirm the efficacy of aclidinium 400 μg bid on bronchodilation and COPD symptoms.. ClinicalTrials.gov; No.: NCT00868231; URL: www.clinicaltrials.gov.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Tropanes

The combination of tiotropium and fluticasone propionate/salmeterol (FSC) is commonly used to treat chronic obstructive pulmonary disease (COPD), but no study had evaluated the effectiveness of tiotropium plus FSC with 250 μg of fluticasone propionate. Our aim was to assess whether tiotropium (18 μg once daily) plus FSC (250/50 μg twice daily) provides better clinical outcomes compared to tiotropium monotherapy.. In this 24-week, randomized, open label, multicenter two-arm parallel study, 479 patients received tiotropium plus FSC (n = 237) or tiotropium alone (n = 242).. After 24 weeks of treatment, the triple-inhaled treatment group had a significant improvement in pre-bronchodilator FEV(1) (L) compared to the tiotropium-only group (0.090 L vs. 0.038 L; P = 0.005). Regarding health-related quality of life, the mean change in total score on the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) was -6.6 points in the tiotropium plus FSC group, but -1.5 points in the tiotropium-only group (P = 0.001). In the subgroup of GOLD stage II patients with COPD, treatment with tiotropium plus FSC also improved FEV(1) compared to tiotropium alone (0.088 L vs. 0.030 L; P = 0.011) and improved the total SGRQ-C score than tiotropium alone (-4.5 points vs. -1.0 points, respectively). This triple-inhaled treatment approach did not induce more adverse events, such as pneumonia.. Over the course of 24 weeks, FSC (250/50 μg twice daily) added to tiotropium provided greater improvement in lung function and quality of life in patients with COPD (FEV(1) ≤ 65%) than tiotropium alone.

Topics: Acute Disease; Aged; Albuterol; Algorithms; Androstadienes; Bronchodilator Agents; Drug Combinations; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Evidence has been provided that high-dose indacaterol (300 μg) can reduce lung hyperinflation in moderate-to-severe chronic obstructive pulmonary disease (COPD).. To study whether low-dose indacaterol (150 μg) also reduces lung hyperinflation in comparison with the recommended dose of tiotropium (18 μg) in moderate COPD.. This was a multicenter, randomized, blinded, 3-period cross-over, placebo-controlled study. Spirometry and lung volumes were measured before and 30, 60, 120, 180 and 240 min after the administration of single-doses of indacaterol, tiotropium, or placebo. The primary end-point was the change in peak inspiratory capacity (IC). The area under the 4-h curve (AUC(0-4)) for IC, 1-s forced expiratory volume (FEV(1)) and forced vital capacity (FVC) were secondary variables.. 49 patients completed the study. On average, peak IC and AUC(0-4) for IC were significantly greater after indacaterol than placebo by 177 mL (p = 0.007) and 142 mL (p = 0.001), respectively. Differences in peak IC and AUC(0-4) for IC between tiotropium and placebo were 120 mL (p = 0.07) and 85 mL (p = 0.052), respectively. Differences between indacaterol and tiotropium were statistically insignificant. Peak IC increased by >20% in 12 patients with indacaterol and 9 with tiotropium (p = 0.001), and by >30% in 8 patients with indacaterol and 3 with tiotropium (p = 0.001). The effects of indacaterol and tiotropium on FEV(1) and FVC were statistically significant vs placebo.. Low-dose indacaterol has a bronchodilator effect that is similar to the recommended dose of tiotropium, but it is slightly superior in reducing lung hyperinflation.. ClinicalTrials.gov number: NCT00999908.

Topics: Aged; Area Under Curve; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; Indans; Inspiratory Capacity; Lung Volume Measurements; Male; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Severity of Illness Index; Spirometry; Time Factors; Tiotropium Bromide; Vital Capacity

Combining maintenance medications with different mechanisms of action may improve outcomes in COPD. In this study we evaluated the efficacy and safety of fluticasone/salmeterol (FSC) (250/50 mcg twice daily) when added to tiotropium (18 mcg once daily) (TIO) in subjects with symptomatic moderate to severe COPD.. This was a 24-week, randomized, double-blind, parallel group, multi-center study. Subjects 40 years or older with cigarette smoking history ≥10 pack-years and with the diagnosis of COPD and post-bronchodilator FEV(1) ≥40 to ≤ 80% of predicted normal and FEV(1)/FVC of ≤0.70 were enrolled. Following a 4-week treatment with open-label TIO 18 mcg once daily, subjects were randomized in a double-blind fashion to either the addition of FSC 250/50 DISKUS twice daily or matching placebo. The primary efficacy endpoint was AM pre-dose FEV(1) and secondary endpoints included other measures of lung function, rescue albuterol use, health status and exacerbations.. The addition of FSC to TIO significantly improved lung function indices including AM pre-dose FEV(1), 2 h post-dose FEV(1), AM pre-dose FVC, 2 h post-dose FVC and AM pre-dose IC compared with TIO alone. Furthermore, this combination was superior to TIO alone in reducing rescue albuterol use. However, there were no significant differences between the treatment groups in health status or COPD exacerbations. The incidence of adverse events was similar in both groups.. The addition of FSC to subjects with COPD treated with TIO significantly improves lung function without increasing the risk of adverse events. NCT00784550.

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Health Status; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; United States

Mortality is an important endpoint in chronic obstructive pulmonary disease (COPD) trials, although accurately determining cause of death is difficult. In the Understanding the Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial, a mortality adjudication committee (MAC) provided systematic, independent and blinded assessment of cause-specific mortality of all 981 reported deaths. Here we describe this process of mortality adjudication and methodological revisions introduced to help standardise the adjudication of two areas recognised to pose particular difficulty; firstly, the classification of fatal COPD exacerbations that occur in the setting of pneumonia and secondly, the categorisation of sudden death. In addition MAC determined cause of death was compared with that reported by site investigators (SIs). MAC-assigned causes of death were: respiratory, 35%; cancer, 25%; cardiovascular, 11%; sudden cardiac death, 4.4%; sudden death, 3.4%; other, 8.8%; unknown, 12.4%. Cancer/cardiac deaths were more common in Global Initiative for Chronic Obstructive Lung Disease stage II, respiratory deaths in stages III and IV. Agreement between MAC and SI regarding cause of death was complete (50.2%), incomplete (18.5%) or none (31.3%). The SI classified deaths as cardiac three-fold more frequently than MAC (incidence rate [IR]/100 patient-years 0.797 vs. 0.257), although IR ratios for cardiac deaths for tiotropium vs. control were similar between SI and MAC. Discrepancies between MAC- and SI-adjudicated causes of death are common, especially increased reporting of cardiac deaths by the SI. Future multicentre COPD trials should plan appropriate infrastructure before study initiation to ensure collection and interpretation of fatal events data.

Topics: Aged; Bronchodilator Agents; Cause of Death; Death, Sudden; Death, Sudden, Cardiac; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Research Design; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

Chronic obstructive pulmonary disease (COPD) is a disease characterized by an airflow limitation that is not fully reversible. β(2)-agonists and anticholinergics represent the most effective therapeutic options. Optoelectronic plethysmography (OEP) is a novel technology, which provides noninvasive steady-state measurements of chest wall kinematics, together with the assessment of the relative contribution of all different thoracic and abdominal compartments to tidal volume.. The aim of this pilot study was to investigate the changes in quiet breathing due to different long-acting bronchodilators (namely, formoterol and tiotropium) administered to COPD patients of different severity.. Eight moderate-to-severe COPD patients were studied according to a randomized crossover design. All subjects received both the long-acting bronchodilators: formoterol (long-acting β(2)-agonist, 24 µg) and tiotropium (long-acting anticholinergic bronchodilator, 18 µg). The effect of bronchodilators on quiet breathing was evaluated by means of OEP at base conditions, and 2 and 7 hours after inhalation.. Both bronchodilators caused changes in the quiet breathing pattern in COPD patients that had previously reported only negligible changes in FEV(1) (ΔFEV(1) = 2.6% after salbutamol). The main changes were observed in increased ventilation per minute, inspiratory and expiratory flow, and decreased breath-by-breath variability. Formoterol induced its main effects during the first 2 hours after inhalation, while tiotropium caused improvements between 2 and 7 hours.. Even though a greater cohort of COPD patients is needed in order to confirm the present results, this pilot study reports a novel piece of evidence concerning the effects of bronchodilators on quiet breathing pattern in severe and very severe COPD patients.

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Cross-Over Studies; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pilot Projects; Plethysmography; Pulmonary Disease, Chronic Obstructive; Respiration; Scopolamine Derivatives; Tiotropium Bromide

We investigated whether exacerbation frequency in chronic obstructive pulmonary disease (COPD) was related to an exponent α which quantifies self-similarity in daily peak expiratory flow (PEF) and is calculated using detrended fluctuation analysis (DFA). We examined data from COPD patients who recorded an increase in respiratory symptoms and post-bronchodilator PEF on daily diary cards. We also investigated PEF data from a double-blind, placebo-controlled trial of the anti-cholinergic agent, tiotropium. In the observational study there were 308 patients with COPD (195 males; mean ± sd age 68.3 ± 8.4 yrs, forced expiratory volume in 1 s (FEV(1)) 1.12 ± 0.46 L, FEV(1) % predicted 44.5 ± 16.4%). The mean ± sd α over the first year was 0.944 ± 0.19 and it was positively related to the frequency of exacerbations per year (p=0.009). In the clinical trial, α was lower in COPD patients randomised to tiotropium, mean ± sd 0.87 ± 0.21 (n=48) than on placebo, mean ± sd 0.95 ± 0.19 (n=52; p=0.035). Power analysis showed that fewer patients would be required for clinical studies with α as the outcome measure than exacerbation frequency. DFA shows that daily PEF in COPD has long-term correlations which are related to exacerbation frequency. Monitoring of PEF and use of α may result in smaller COPD patient sample sizes in trials.

Topics: Aged; Cholinergic Antagonists; Disease Progression; Female; Humans; Male; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

GSK233705 is an inhaled, long-acting muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). This study was performed to see if the addition of GSK233705 to salmeterol would provide greater bronchodilation than salmeterol or tiotropium alone in COPD.. In an incomplete-block, three-period, crossover design, dually responsive patients received three of the following five treatments: GSK233705 20 μg plus salmeterol 50 μg twice-daily; GSK233705 50 μg plus salmeterol 50 μg twice-daily; salmeterol 50 μg or placebo, each twice-daily; and tiotropium 18 μg or placebo once-daily for 7 days. Each treatment period was separated by a 14-day washout. The primary efficacy endpoint was morning (trough) forced expiratory volume in 1 second (FEV(1)) on Day 8, following 7 days of treatment. Secondary endpoints included pulmonary function, plethysmography, pharmacokinetics of GSK233705 and salmeterol, adverse events (AEs), electrocardiograms (ECGs), vital signs, and laboratory parameters.. A total of 47 patients were randomized. The mean % predicted normal postbronchodilator FEV(1) was 55% at screening. Compared with placebo (n = 24), the adjusted mean change from baseline in trough FEV(1) on Day 8 was 215 mL higher with GSK233705 20 μg + salmeterol (n = 23) and 203 mL higher with GSK233705 50 μg + salmeterol (n = 27), whereas with salmeterol (n = 27) and tiotropium (n = 28) the changes were 101 mL and 118 mL higher, respectively. The primary efficacy results were supported by the results from the other secondary lung function assessments. AEs were reported by similar proportions of patients across the treatment groups, with headache the most frequently reported treatment-related AE reported by one subject receiving each of GSK233705 20 μg + salmeterol, tiotropium, and placebo. No significant differences were seen in vital signs, ECGs, or laboratory parameters between the groups.. The addition of GSK233705 to salmeterol in partially reversible COPD patients resulted in greater bronchodilation than salmeterol or tiotropium alone and was well tolerated.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Bronchodilator Agents; Cross-Over Studies; Drug Administration Schedule; Drug Therapy, Combination; Electrocardiography; Europe; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Pilot Projects; Placebos; Plethysmography; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Signs

GOLD stage II COPD encompasses patients with FEV₁ 50-80% predicted. A published trials review suggested that benefits of maintenance therapy are limited to patients with FEV₁ <60% predicted. We previously reported data demonstrating the efficacy of tiotropium in GOLD stage II disease in the 4-year UPLIFT® trial, and present here a further analysis of a sub-category of GOLD stage II patients with post-bronchodilator FEV1 ≥60% predicted from UPLIFT®. Outcomes included pre- and post-bronchodilator spirometry, exacerbations, SGRQ and mortality. Of the 5,992 UPLIFT® cohort, 1,210 (632 tiotropium, 578 control) had baseline post-bronchodilator FEV₁ ≥60% predicted (range 60-78%), mean age was 64 years, 70% were men, and mean SGRQ total score was 39.9 units. Mean annual rate of post-bronchodilator FEV₁ decline was 41 (tiotropium) and 49 (control) mL/year (P = 0.07); corresponding pre-bronchodilator values were 32 and 37 mL/year (P = 0.24). Morning pre-drug FEV₁ and FVC improvements for tiotropium versus control were 87-127 mL and 139-186 ml, respectively (P < 0.001, all time-points). SGRQ total score improvements (tiotropium-control) were 2.0-3.4 units (P < 0.05 for all); a higher percentage of patients had an improvement of ≥4 units with tiotropium (P <0.05). Tiotropium reduced risk for an exacerbation (HR [95% CI] = 0.83 [0.71, 0.96]) and mortality for the 4-year protocol-defined treatment period (HR [95% CI] = 0.66 [0.45, 0.96]). Tiotropium treatment provides clinical efficacy in patients with GOLD stage II disease with an FEV₁ ≥60% predicted, supporting current GOLD guidelines for COPD treatment. (ClinicalTrials.gov number NCT00144339).

Topics: Aged; Bronchodilator Agents; Cohort Studies; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Spirometry; Survival Analysis; Tiotropium Bromide; Treatment Outcome

AZD9668 is a fully reversible, selective, oral inhibitor of neutrophil elastase, a protease implicated in chronic obstructive pulmonary disease (COPD). Efficacy, safety and tolerability of AZD9668 (5, 20 and 60 mg bid) were compared with placebo in a randomised, double-blind, placebo-controlled, 12-week, Phase IIb trial (NCT00949975: approved by an Investigational Review Board), in patients with symptomatic COPD receiving maintenance tiotropium. The primary endpoint was pre-bronchodilator forced expiratory volume in 1 second (FEV₁). Secondary endpoints included forced vital capacity and inspiratory capacity, peak expiratory flow, Breathlessness, Cough and Sputum Scale score, exercise capacity, quality of life (QoL), exacerbation assessments, safety and pharmacokinetics. Exploratory endpoints included inflammatory and tissue degradation biomarkers. A total of 838 patients were randomised to AZD9668 5 mg bid (212 patients), 20 mg bid (206 patients), 60 mg bid (202 patients) or placebo (218 patients). AZD9668 showed no effect on lung function, respiratory signs and symptoms, QoL or biomarkers. At end of treatment, the change in mean pre-bronchodilator FEV₁ for AZD9668 60 mg bid compared with placebo was 0.00L (95% confidence interval: -0.05, 0.04; p = 0.873). Overall, AZD9668 was well tolerated; the numbers of patients with adverse events (AEs), serious AEs and AEs leading to discontinuation were similar in each of the four study groups. AZD9668 60 mg bid showed no clinical benefit and no effect on biomarkers of inflammation or tissue degradation when added to tiotropium in patients with COPD. These results raise important questions for future investigation of anti-inflammatory and disease-modifying agents in patients with COPD.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Biomarkers; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Leukocyte Elastase; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pyridones; Quality of Life; Scopolamine Derivatives; Spirometry; Sulfones; Tiotropium Bromide; Treatment Outcome

Current guidelines recommend treatment with one or more long-acting bronchodilators for patients with moderate or more severe chronic obstructive pulmonary disease (COPD). The authors investigated the approach of dual bronchodilation using indacaterol, a once-daily long-acting β(2) agonist, and the long-acting muscarinic antagonist tiotropium, compared with tiotropium alone.. In two identically designed, double-blind, 12-week studies, patients with moderate to severe COPD were randomised to indacaterol 150 μg once daily or matching placebo. All patients concurrently received open-label tiotropium 18 μg once daily. The primary outcome was standardised area under the curve of forced expiratory volume in 1 s (FEV(1)) from 5 min to 8 h post dose at week 12. The key secondary outcome was 24 h post-dose ('trough') FEV(1) at week 12. Resting inspiratory capacity (IC) was measured in a subgroup.. 1134 and 1142 patients were randomised in studies 1 and 2; 94% and 94% completed. Compared with monotherapy, concurrent therapy increased FEV(1) (area under the curve by 130 and 120 ml, trough by 80 and 70 ml; all p<0.001) and trough IC (by 130 and 100 ml, p<0.01). Cough was more common with indacaterol plus tiotropium (10% and 9%) than with tiotropium alone (4% and 4%). Most cases (∼90%) of cough were mild. Other adverse events were similar for the treatment groups.. Compared with tiotropium monotherapy, indacaterol plus tiotropium provided greater bronchodilation and lung deflation (reflected by increased resting IC). Adverse events were similar between treatments apart from mild cough being more common with indacaterol plus tiotropium. These results support COPD guideline recommendations to combine bronchodilators with different mechanisms of action.. NCT00846586 and NCT00877383.

Topics: Adrenergic beta-Agonists; Adult; Analysis of Variance; Area Under Curve; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Least-Squares Analysis; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Quinolones; Respiratory Function Tests; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

Tiotropium partially relieves exertional dyspnea and reduces the risk of congestive heart failure in chronic obstructive pulmonary disease (COPD) patients. However, its effect on the sympathetic activation response to exercise is unknown.. This study aimed to determine whether tiotropium use results in a sustained reduction in sympathetic activation during exercise.. We conducted a 12-week, open-label (treatments: tiotropium 18 μg or oxitropium 0.2 mg × 3 mg), crossover study in 17 COPD patients. Treatment order was randomized across subjects. The subjects underwent a pulmonary function test and two modes of cardiopulmonary exercise (constant work rate and incremental exercise) testing using a cycle ergometer, with measurement of arterial catecholamines after each treatment period.. Forced expiratory volume in 1 second and forced vital capacity were significantly larger in the tiotropium treatment group. In constant exercise testing, exercise endurance time was longer, with improvement in dyspnea during exercise and reduction in dynamic hyperinflation in the tiotropium treatment group. Similarly, in incremental exercise testing, exercise time, carbon dioxide production, and minute ventilation at peak exercise were significantly higher in the tiotropium treatment group. Plasma norepinephrine concentrations and dyspnea intensity were also lower during submaximal isotime exercise and throughout the incremental workload exercise in the tiotropium treatment group.. Tiotropium suppressed the increase of sympathetic activation during exercise at the end of the 6-week treatment, as compared with the effect of oxipropium. This effect might be attributed to improvement in lung function and exercise capacity and reduction in exertional dyspnea, which were associated with decreases in respiratory frequency and heart rate and reduced progression of arterial acidosis.

Topics: Aged; Cholinergic Agents; Cholinergic Antagonists; Cross-Over Studies; Dyspnea; Exercise Tolerance; Female; Heart Failure; Heart Function Tests; Humans; Male; Physical Exertion; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is characterized by neutrophilic airway inflammation and oxidative stress. Leukotriene B₄ (LTB₄), a potent proinflammatory mediator, is synthesized by 5-lipoxygenase (5-LO), which is activated by the presence of lipid hydroperoxides resulting from oxidative stress on biological membranes. We proposed to evaluate the effect of a four week treatment with two different bronchodilators of common practice in COPD treatment, on the production of reactive oxygen species (ROS), in particular superoxide anions, and of LTB₄ by peripheral blood neutrophils obtained from COPD subjects. 24 subjects among the COPD outpatients were enrolled, and randomized to receive either formoterol (12 μg bid) or tiotropium (18 μg od). Peripheral blood neutrophils were obtained at the start and at the end of the treatment, and production of superoxide anions and of LTB₄ were evaluated as previously published. The results obtained showed a decrease in the unstimulated production of superoxide by isolated neutrophils in both groups, but tiotropium only was effective in modulating the production of LTB₄, while formoterol caused an increased production of superoxide in response to fMLP, when compared to values obtained before treatment. In conclusion, tiotropium showed a better antiinflammatory activity profile when compared to formoterol in a clinical setting, reducing superoxide and LTB₄ production by peripheral neutrophils obtained from COPD subjects.

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Ethanolamines; Female; Formoterol Fumarate; Humans; Leukotriene B4; Lung; Male; Neutrophils; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Superoxides; Tiotropium Bromide

The addition of tiotropium bromide (TIO) to formoterol fumarate (FOR) improves exercise performance in patients with chronic obstructive pulmonary disease (COPD). In this study, we test the hypothesis that the addition of TIO to FOR may improve respiratory muscle performance and oxygen uptake kinetics after exercise in patients with COPD.. Thirty eight patients with COPD were randomized to a 2 week treatment with FOR 12 μg twice a day plus TIO 18 μg once a day (FOR + TIO) or FOR 12 μg twice a day plus placebo (FOR + PLA) once a day, using a double-blind crossover design. Inspiratory muscle. Strength was measured before, immediately after, as well as 2, 5, and 10 min during recovery of exercise. Time to limit of tolerance on a constant work load exercise test and oxygen uptake kinetics during recovery were evaluated before and after intervention.. Only FOR + TIO improved resting (63 ± 10 cm to 84 ± 11 cmH(2)O) and post-exercise (49 ± 7 cm to 84 ± 11 cmH(2)O) maximal inspiratory pressure. Time to limit of tolerance on the constant work load test was increased by FOR + PLA and by FOR + TIO, but the size of the increment was significantly larger with FOR + TIO (40.7 ± 7.6% vs. 84.5 ± 8.2%; p < 0.05). Only FOR + TIO improved oxygen uptake kinetics during recovery (69 ± 21 to 60 ± 18 s). The improvement in maximal inspiratory pressure (0.78, p < 0.001) and in oxygen uptake kinetics (-0.91, p < 0.001) correlated with the change in time to the limit of tolerance.. The addition of TIO to FOR improves inspiratory muscle strength and oxygen uptake kinetics after exercise in COPD patients.

Topics: Administration, Inhalation; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Exercise; Formoterol Fumarate; Humans; Middle Aged; Muscle Strength; Oxygen Consumption; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Respiratory Muscles; Scopolamine Derivatives; Tiotropium Bromide

Data comparing two bronchodilators vs. one bronchodilator plus inhaled corticosteroid (ICS) on hyperinflation and exercise endurance in chronic obstructive pulmonary disease (COPD) are scarce, though these therapeutic strategies are widely used in clinical practice.. We performed a randomized, crossover clinical trial of two × 8 weeks comparing tiotropium (18 μg once daily) + salmeterol (50 μg twice daily) (T + S) to salmeterol + fluticasone (50/500 μg twice daily) (S + F) in COPD (forced expiratory volume in 1 s (FEV(1)) ≤65% predicted, and thoracic gas volume (TGV) ≥120% predicted). Coprimary endpoints were postbronchodilator TGV and exercise endurance time (EET).. In 309 patients, at baseline, prebronchodilator FEV(1) was 1.36 L (46% predicted), TGV was 5.42 L (165% predicted), and EET = 458 s. Relative to S + F, T + S lowered postdose TGV by 182 ± 44 ml after 4 weeks (p < 0.0001) and 87 ± 44 ml after 8 weeks (p < 0.05). EET was nonsignificantly increased following T + S treatment (20 ± 15 s at 4 weeks, 15 ± 13 s at 8 weeks) vs. S + F. BORG dyspnea score at exercise isotime was reduced in favor of T + S.. The two bronchodilators decreased hyperinflation significantly more than one bronchodilator and ICS. This difference was not reflected in EET. (ClinicalTrials.gov number, NCT00530842).

Topics: Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Exercise Test; Exercise Tolerance; Female; Fluticasone; Humans; Lung Volume Measurements; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

The changes in inspiratory capacity (IC) over time in chronic obstructive pulmonary disease (COPD) patients are unknown. The Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial included IC measurements.. IC analysis from UPLIFT® (N = 5992) was performed at 1 and 6 months, and every 6 months through 4 years. Annualized rate of decline in pre- and post-bronchodilator IC and mean differences at each time point were analyzed by mixed-effects models. The relationships between baseline IC and exacerbation rate and mortality were explored using Cox regression analysis.. Baseline characteristics: age, 65 years; 75% men; post-bronchodilator forced expiratory volume in 1 second, 1.32 L (48% predicted); pre- and post-bronchodilator IC, 2.03 and 2.33 L. Mean IC rate of decline (mL/year) was 34 ± 2 (1.7% of baseline) and 50 ± 3 (2.1% of baseline) pre- and post-bronchodilator, respectively, without significant between-group differences. Morning pre-bronchodilator (trough) IC improved with tiotropium versus placebo: 124 mL (1 month), 103 mL (1 year), 107 mL (2 years), 98 mL (3 years), and 97 mL (4 years) (all p < 0.001). Post-bronchodilator improvements were similar between treatment groups. Lower baseline IC values were associated with reduced time to first exacerbation. For the lowest quartile (n = 1413) the values in months were 14.3 (11.7-17.0) for tiotropium and 10.3 (8.8-11.7) for controls (p < 0.01).. IC declines from approximately 34 to 50 mL/year in patients with stage II to IV COPD. Tiotropium treatment does not change the IC decline rate but provides 24-hour improvements in IC sustained over the long term. Trough IC differences suggest that tiotropium provides sustained decrease in end-expiratory lung volume.

Topics: Aged; Bronchodilator Agents; Disease Progression; Female; Forced Expiratory Volume; Humans; Inspiratory Capacity; Longitudinal Studies; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Regression Analysis; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

Topics: Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Disease Progression; Double-Blind Method; Follow-Up Studies; Forced Expiratory Volume; Hospitalization; Humans; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

In a prespecified subgroup analysis of the 4-year trial "Understanding Potential Long-term Impacts on Function with Tiotropium", the efficacy of tiotropium versus control in patients with moderate COPD (GOLD II) was examined and compared with the pooled results of patients with more severe disease (GOLD III/IV).. Randomised, multicentre, double-blind, placebo-controlled, parallel-group study in 5993 patients over a period of 4 years. Patients received either tiotropium 18 µg or placebo once-daily. The study endpoints were the annual FEV1 decline as well as lung function parameters, health status, exacerbations and all-cause mortality.. 46 % of the patients had moderate disease (GOLD II; tiotropium: n = 1384, control group: n = 1355) with a mean postbronchodilator FEV1 of 1.63 (0.37) L (59 % predicted). In these patients with moderate COPD, tiotropium significantly improved the absolute FEV1 values (pre-bronchodilator FEV1: 101 - 119 ml, post-bronchodilator FEV1: 52 - 82 ml, p < 0.001) and the postbronchodilator FEV1 decline compared with the control patients (43 (2) vs. 49 (2) ml/year; p = 0.024). In addition, there was a statistically significant improvement in the annual exacerbation rate (tiotropium: 0.56, control: 0.7; p < 0.0001), the time to first exacerbation (tiotropium: 23.09, control: 17.47 months; p < 0.0001) and health status (tiotropium vs. control: minus 2.7 - 4 units; p < 0.0001) in the tiotropium group. . The results of this subgroup analysis support current guideline recommendations and indicate that already patients with moderate COPD (GOLD stage II) benefit clinically from treatment with tiotropium.

Topics: Adult; Aged; Bronchodilator Agents; Female; Germany; Humans; Male; Middle Aged; Prevalence; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Secondary Prevention; Tiotropium Bromide; Treatment Outcome

To evaluate the cost-utility of adding tiotropium to usual care versus usual care alone for patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in the UK and Belgium.. A four-state Markov model was developed with three disease severity states (moderate, severe, very severe) and death. Severity was based on post-bronchodilator FEV₁ and transitions were based on outcomes of the Understanding Potential Long Term Impacts on Function with Tiotropium (UPLIFT®) trial. Utilities were derived from EQ-5D scores for a subset of UPLIFT® patients. UK costs were evaluated separately for England (E), and for Scotland, Wales and Northern Ireland (SWNI). Belgian (B) costs were obtained from local sources. Uncertainty was assessed by deterministic and probabilistic sensitivity analysis (PSA).. Adding tiotropium to usual care resulted in an incremental cost per patient of €969 (B), £796 (E), and £812 (SWNI), and incremental QALYs of 0.052 (B), and 0.051 (E, SWNI). The four-year incremental cost-effectiveness ratios (ICER) were €18,617 (B), £15,567 (E) and £15,890 (SWNI) per QALY. Probability of tiotropium being cost-effective at £30,000 (€50,000) per QALY gained was greater than 60%.. At willingness to pay thresholds of £(€) 30,000 per QALY gained, adding tiotropium to usual care is cost-effective.

Topics: Bronchodilator Agents; Cost-Benefit Analysis; Disease Progression; Drug Costs; Female; Health Resources; Humans; Male; Markov Chains; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quality-Adjusted Life Years; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

NVA237 (glycopyrronium bromide) is a once-daily long-acting muscarinic antagonist (LAMA) in development for chronic obstructive pulmonary disease (COPD). The GLycopyrronium bromide in COPD airWays clinical Study 2 (GLOW2) evaluated the efficacy and safety of NVA237 in moderate-to-severe COPD over 52 weeks. Patients were randomised 2:1:1 to NVA237 50 μg, placebo or open-label tiotropium 18 μg for 52 weeks. Primary end-point was trough forced expiratory volume in 1 s (FEV(1)) at 12 weeks. 1,066 patients were randomised, 810 completed the study. At week 12, trough FEV(1) increased significantly by 97 mL with NVA237 (95% CI 64.6-130.2; p<0.001) and 83 mL with tiotropium (95% CI 45.6-121.4; p<0.001). Compared with placebo, NVA237 produced significant improvements in dyspnoea (Transition Dyspnoea Index at week 26; p=0.002) and health status (St George's Respiratory Questionnaire at week 52; p<0.001). NVA237 significantly reduced the risk of moderate-to-severe COPD exacerbations by 34% (p=0.001) and the use of rescue medication (p=0.039), versus placebo. NVA237-placebo and tiotropium-placebo differences were comparable for all outcomes. Safety profiles were similar across groups. NVA237 50 μg provided significant improvements in lung function, dyspnoea, health status, exacerbations and rescue medication use, versus placebo, and was comparable to tiotropium. NVA237 can potentially be an alternative choice of LAMA for COPD patients.

Topics: Bronchodilator Agents; Double-Blind Method; Female; Glycopyrrolate; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.

Topics: Administration, Inhalation; Animals; Azetidines; Bronchodilator Agents; Cell Line; Cell Membrane Permeability; CHO Cells; Cricetinae; Cricetulus; Diphenylacetic Acids; Dogs; Female; Guinea Pigs; Hepatocytes; Humans; In Vitro Techniques; Kinetics; Male; Microsomes, Liver; Muscle Relaxation; Muscle, Smooth; Pulmonary Disease, Chronic Obstructive; Radioligand Assay; Rats; Receptor, Muscarinic M3; Recombinant Proteins; Stereoisomerism; Structure-Activity Relationship; Trachea

Pneumonia is an important complication of COPD and is reported more often in patients receiving inhaled corticosteroids (ICSs). Little is known about the clinical course and factors predisposing to pneumonia in patients with COPD. We investigated patient characteristics and symptoms occurring before pneumonia reports in the Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) study.. This was a 2-year, double-blind, double-dummy parallel study of 1,323 patients randomized to salmeterol/fluticasone propionate 50/500 μg bid (SFC) or tiotropium 18 μg once daily (Tio). Baseline demographics, including serum C-reactive protein (CRP) levels, were measured, and daily record cards (DRCs) were completed.. We identified 87 pneumonia reports from adverse event records (SFC=62; Tio=25) in 74 patients (SFC=50; Tio=24), compared with 2,255 exacerbations (SFC=1,185; Tio=1,070). Pneumonia was more common in patients with severe dyspnea and in those with a baseline CRP level>10 mg/L. Numbers of de novo pneumonias (events that were not preceded by symptoms of an exacerbation) were similar between treatment groups, but pneumonia was more likely after either a treated or untreated unresolved exacerbation in patients receiving ICSs (SFC=32; Tio=7). Similar results were seen when analysis was confined to radiologically confirmed events.. Pneumonia is much less frequent than exacerbation in COPD. The excess of events with ICS treatment appears to be associated with protracted symptomatic exacerbations. Earlier identification and treatment of these events to prevent pneumonia merits further investigation.. ClinicalTrials.gov; No.: NCT00361959; Study No.: SC040036; URL: clinicaltrials.gov.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Albuterol; Androstadienes; Bronchodilator Agents; C-Reactive Protein; Double-Blind Method; Female; Fluticasone; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

A recent randomized, double-blind, parallel-group, active-controlled, multicenter study of 255 patients ≥ 40 years of age with chronic obstructive pulmonary disease (COPD) showed that combined formoterol (FOR) and tiotropium (TIO) treatment in patients with COPD significantly improved lung function as well as symptoms and other patient-reported outcomes compared with TIO alone. FOR and TIO are long-acting bronchodilators that represent the β₂-adrenergic agonist and anticholinergic classes, respectively. However, the possible influence of smoking status, inhaled corticosteroid (ICS) use, baseline disease severity, and gender differences on bronchodilator efficacy requires further investigation. Using data from the previously published study mentioned above, a post hoc analysis was performed to examine the efficacy of combined FOR + TIO treatment compared with TIO monotherapy in subgroup analyses of men and women, current and ex-smokers, ICS users and non-ICS users, and patients with moderate and severe/very severe COPD. Efficacy comparisons were based on the changes in forced expiratory volume in 1 s measured 0-4 h after the morning dose (FEV₁ AUC₀₋₄h). After a run-in period, patients were treated for 12 weeks with either FOR 12 μg twice daily (BID) plus TIO 18 μg once daily (QD) in the morning (AM, n = 124) or with FOR placebo BID plus TIO 18 μg QD AM (n = 131). The least squares mean change from baseline in the normalized FEV₁ AUC₀₋₄h was assessed using analysis of covariance. With the exception of treatment differences at week 4 in smokers and subjects with "very severe" COPD, and at weeks 4, 8, and 12 for ICS users and non-ICS users (p values not determined), FOR + TIO was significantly superior (P < 0.05) to TIO alone at all time points (weeks 4, 8, 12, and endpoint), regardless of gender, smoking status, ICS use, or COPD severity. We conclude that coadministered FOR + TIO significantly improves lung function compared with TIO treatment alone in COPD patients regardless of differences in patient subgroups.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Area Under Curve; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sex Factors; Smoking; Tiotropium Bromide

Although salmeterol/fluticasone propionate combination (SFC) therapy has been widely used for the treatment of COPD, the relationship between airway dimensions and improvement in pulmonary function remains unknown. The aim of this study was to compare the effects of SFC in combination with tiotropium (Tio) and Tio alone, on airway dimensions and pulmonary function in COPD patients.. Thirty COPD patients were randomized to receive inhaled Tio (18 µg once daily) or inhaled SFC (50/250 µg twice daily) plus Tio for 12 weeks. Spirometry and CT were performed, and the St. George's Respiratory Questionnaire (SGRQ) was completed, before and after the trial. Airway dimensions were assessed by a validated CT technique, and airway wall area (WA) corrected for body surface area (BSA), percentage wall area (WA%), absolute wall thickness T/√BSA, and luminal area Ai/BSA at the right apical segmental bronchus, were measured.. Treatment with SFC plus Tio significantly decreased WA/BSA (P < 0.05), WA% (P < 0.01) and T/√BSA (P < 0.01), and increased Ai/BSA (P < 0.01), whereas treatment with Tio alone had no effect. The changes in WA/BSA and Ai/BSA were significantly correlated with increases in FEV1 (r = 0.48, P < 0.05, and r = 0.36, P < 0.05, respectively). There were significant improvements in SGRQ scores after treatment with SFC plus Tio.. Airway wall thickening and airway narrowing decreased after treatment with SFC plus Tio, and the changes in airway dimensions were proportional to the improvements in FEV1 . These results suggest that SFC plus Tio is more effective than Tio alone in the management of COPD patients.

Topics: Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchi; Bronchodilator Agents; Drug Combinations; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Humans; Male; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

A new diagnosis of chronic obstructive pulmonary disease (COPD) is often made during the evaluation of patients requiring a surgical intervention for lung cancer. Based on initial impaired lung function, these untreated patients are often considered not fit for lung surgery. There is limited information on the short-term effectiveness of preoperative pharmacologic treatment strategies in patients with newly diagnosed COPD before lung surgery.. A prospective randomized study was conducted comparing 1-week-treatment periods of tiotropium/formoterol/budenoside (GR1) with tiotropium/formoterol (GR2) in conjunction with smoking cessation and chest physiotherapy. No patients had been previously treated for COPD. The primary end point was body plethysmography (forced expiratory volume in 1s (FEV1), forced vital capacity (FVC), and airway resistance (RAW)) at the end of each treatment period. Secondary end points were improvement of ≥ 10% in FEV1 (% predicted) and improvement of the severity of COPD after the 1-week treatment, as well as the rate of pulmonary complications after surgery.. A total of 46 patients were randomized in GR1 (n=24) and GR2 (n=22). Both groups were comparable with regard to age, height, weight, smoking history, baseline body plethysmography (FVC, FEV1, and RAW), and the severity of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) staging, respectively. However, the short-term effects of the treatment with regard to FEV1 (2.0 l vs 1.7 l; p=0.031) and increase of FEV1 (0.31 l vs 0.10 l; p=0.02) were better in GR1. More patients in GR1 had an improvement of ≥ 10% in FEV1 (p=0.004) and improvement of the severity of COPD (p=0.012) after the 1-week treatment. Fewer pulmonary complications (11.1% vs 42.9%, p=0.04) were observed in GR1 after surgery.. Both therapies resulted in an improvement of lung function. There is benefit from adding inhalative budenoside to tiotropium and formoterol in terms of an improvement in FEV1 and the severity of COPD. These beneficial results might lead to less pulmonary complications in the postoperative period.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Airway Resistance; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Carcinoma, Non-Small-Cell Lung; Drug Combinations; Drug Therapy, Combination; Epidemiologic Methods; Ethanolamines; Forced Expiratory Volume; Humans; Lung Neoplasms; Middle Aged; Plethysmography, Whole Body; Pneumonectomy; Preoperative Care; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Novel evaluation of protective effect of tiotropium against induced dynamic hyperinflation (DH) during metronome paced hyperventilation (MPH) in moderate COPD.. Prospective, randomized, double-blind, placebo control, crossover study. Lung function measured pre/post MPH at 30 breaths/min for 20 s in 29 (18 M) COPD patients (GOLD Stage 2) age 70±9 yr (mean ± SD) before and after 30 days of 18 μg tiotropium bromide vs placebo. Lung CT scored for emphysema (ES).. At baseline post 180 μg aerosolized albuterol sulfate, FEV(1): 1.8±0.6 L (69±6% pred) and ≥60% predicted in all, and 14 of 29 had FEV(1) (L) ≥70% predicted with FEV(1)/FVC 58±8%. After 29 days + 23 h post tiotropium (trough) there was significant decrease only in FRC/TLC% (p=0.04); after 30 days + 2 h post tiotropium (peak) significant increase only in FEV(1) (L) (p=0.03) compared to placebo. Results post MPH induced DH at baseline and after 30 days and 2 h post placebo or tiotropium were similar with decrease in IC 0.44±0.06 L (p<0.001). Correlation between ES and increased FEV(1) (L) at peak tiotropium: r=0.19, p=0.96 and decreased FRC/TLC% at trough tiotropium: r=-0.26, p=0.36.. In moderate COPD, tiotropium did not reduce MPH induced DH and reduction in IC. However, at peak tiotropium, there was significant bronchodilation in FEV(1) (L) and at trough a decrease in FRC/TLC% compared to placebo despite varying emphysema.

Topics: Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Hyperventilation; Male; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Tomography, X-Ray Computed

Debate continues as to whether acute bronchodilator responsiveness (BDR) predicts long-term outcomes in COPD. Furthermore, there is no consensus on a threshold for BDR.. At baseline and during the 4-year Understanding Potential Long-term Improvements in Function with Tiotropium (UPLIFT®) trial, patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg. Patients were split according to three BDR thresholds: ≥ 12% + ≥ 200 mL above baseline (criterion A), ≥ 15% above baseline (criterion B); and ≥ 10% absolute increase in percent predicted FEV1 values (criterion C). Several outcomes (pre-dose spirometry, exacerbations, St. George's Respiratory Questionnaire [SGRQ] total score) were assessed according to presence or absence of BDR in the treatment groups.. 5783 of 5993 randomized patients had evaluable pre- and post-bronchodilator spirometry at baseline. Mean age (SD) was 64 (8) years, with 75% men, mean post-bronchodilator FEV1 1.33 ± 0.44 L (47.6 ± 12.7% predicted) and 30% current smokers. At baseline, 52%, 66%, and 39% of patients had acute BDR using criterion A, B, and C, respectively. The presence of BDR was variable at follow-up visits. Statistically significant improvements in spirometry and health outcomes occurred with tiotropium regardless of the baseline BDR or criterion used.. A large proportion of COPD patients demonstrate significant acute BDR. BDR in these patients is variable over time and differs according to the criterion used. BDR status at baseline does not predict long-term response to tiotropium. Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD.

Topics: Aged; Albuterol; Albuterol, Ipratropium Drug Combination; Bronchodilator Agents; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Ipratropium; Lung; Male; Middle Aged; Outcome and Process Assessment, Health Care; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Spirometry; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Lung mucociliary clearance is impaired in patients with chronic obstructive pulmonary disease (COPD). Treatment guidelines recommend that patients with COPD receive maintenance therapy with long-acting beta-agonists and anticholinergic agents.. Twenty-four patients with mild to moderate COPD received formoterol (12 μg, twice daily from Turbuhaler® dry powder inhaler (DPI)) or tiotropium (18 μg, once daily from Handihaler® DPI) for 14 days. They also received single doses of formoterol, tiotropium, salbutamol (200 μg) and placebo. A radioaerosol technique was used to assess the effects on mucus clearance of 14 days treatment with formoterol or tiotropium, as well as single doses of these drugs.. The 4 h whole lung retention of radioaerosol was significantly higher after 14 days treatment with tiotropium (P = 0.016), but not after 14 days treatment with formoterol. However, patients bronchodilated after 14 days treatment with both drugs, so that the deposited radioaerosol may have had an increased distance to travel in order to be cleared by mucociliary action. A single dose of formoterol enhanced radioaerosol clearance significantly compared to other single dose treatments (P < 0.05).. Formoterol (12 μg) enhances mucus clearance in patients with mild to moderate COPD when given as a single dose, and may do so when given for 14 days. Studies of longer duration would be needed in order to assess the effects of the study drugs on mucus clearance when they are used for long-term maintenance therapy.

Topics: Administration, Inhalation; Adult; Aged; Bronchodilator Agents; Cross-Over Studies; Drug Therapy, Combination; Dry Powder Inhalers; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Mucus; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD.. In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year.. A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group.. These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.).

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pneumonia; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

In COPD, improvements in lung mechanics following bronchodilator, measured using the forced oscillation technique (FOT), are more sensitive than spirometry at detecting improvement in lung function following bronchodilator. The relationship between these improvements in lung mechanics and improvements in functional outcomes, such as exertional dyspnoea, following bronchodilator, in COPD is unknown.. 17 COPD subjects were recruited into a double blind placebo controlled randomised cross over study. Dyspnoea was induced using a standardised six-minute walk test (6 MWT), and measured by borg score throughout the test. Measurement of respiratory system conductance (Grs), respiratory system reactance (Xrs), inspiratory capacity (IC) and spirometry were made at baseline and 1 h after a single dose of either 18 μg of tiotropium bromide plus 200 μg salbutamol, or placebo.. Subjects had a mean baseline FEV(1) of 45.5 ± 11.0% predicted. The bronchodilator induced reduction in exertional dyspnoea correlated significantly with the increase in Grs (r(s) = 0.59, p = 0.01) and approached significance with FEV(1) (r(s) = 0.45, p = 0.07) but not with FVC (r(s) = 0.30, p = 0.24), Xrs (r(s) = 0.19, p = 0.47) or IC (r(s) = -0.08, p = 0.78). Increase in Grs was the best and sole predictor of reduction in exertional dyspnoea, explaining 41% of the variance. There was no additional contribution to the model from the increase in FEV(1) or IC.. Bronchodilator induced improvements in exertional dyspnoea in moderate to severe COPD are predicted by improvements in Grs, measured by FOT, independent of improvements in spirometry or hyperinflation. The findings suggest that FOT may be useful for measuring response to bronchodilator in COPD.

Topics: Aged; Aged, 80 and over; Albuterol; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Dyspnea; Exercise Test; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Oscillometry; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Respiratory Mechanics; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Walking

Placebo-controlled clinical trials on COPD are characterized by premature discontinuation. At present, no clear insight into this phenomenon is available.. To obtain better insight into the phenomenon of premature discontinuation.. We analyzed the pattern of discontinuation in the UPLIFT-trial.. Premature discontinuation was substantial and greater in the placebo than in the tiotropium group (45 vs. 37%, p < 0.001). Patients discontinuing were characterized by more severe COPD (p < 0.0001), greater number of pack years (p < 0.002), smaller pre-bronchodilator and post-bronchodilator FEV(1) (p < 0.0001 for both), and worse SGRQ scores (p < 0.0001). Rates of decline of FEV(1) and SGRQ were greater in non-completers (p < 0.0001 for both). The latter differences increased over time indicating that the evolution of variables in time was related to trial completion. The risks of exacerbations and hospitalizations were greater in non-completers. In logistic regression analysis BMI, post-bronchodilator FEV(1), male gender and treatment with tiotropium were positively related to trial completion, whereas age, worse SGRQ, female gender, current smoking and assignment to the placebo group were negatively related.. Assignment to the control group is related to premature discontinuation. Discontinuation was important and selective in this large trial. Pulmonary function, health-related quality of life and smoking are the most important other variables related to discontinuation. The evolution of variables during the trial is also related to discontinuation. Complete follow-up of discontinued patients may provide better insight into the efficacy of medication in future trials.

Topics: Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Female; Humans; Male; Medication Adherence; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions. We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial.. Subgroup analysis from a randomized, double-blinded, placebo-controlled trial of tiotropium 18 µg daily in COPD. Primary end-point was rate of decline in FEV(1) . Secondary end-points included spirometry at individual time points, health-related quality of life (St George's Respiratory Questionnaire), exacerbations and mortality.. Of 5992 patients, 362 were from Asian centres (100 from Japan). Mean age 66 years, 95% men, 13% current smokers, BMI: 21 kg/m(2) ; post-bronchodilator FEV(1) : 44% predicted; St George's Respiratory Questionnaire total score: 44 units. No treatment effect was observed for rate of decline in FEV(1) although annual decline was less in Asian patients. Morning pre-bronchodilator FEV(1) and forced vital capacity improved in Asian patients (P < 0.05). Tiotropium reduced number of exacerbations (rate ratio (95% confidence interval (CI)): 0.73 (0.57-0.94)). Hazard ratios (95%CI) for exacerbations and hospitalized exacerbations (tiotropium/control) were 0.81 (0.62-1.05) and 0.85 (0.61-1.19), respectively. St George's Respiratory Questionnaire total score improved by 1.5-6.1 units (P < 0.05 for months 18, 24, 30 and 36) with tiotropium. Fatal events occurred in 34 tiotropium (18.5%) and 42 control (23.6%) patients.. In COPD patients from Asia, tiotropium improves lung function, improves health-related quality of life and reduces exacerbations over 4 years of treatment.

Topics: Aged; Asia; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Two, once daily (q.d.) inhaled bronchodilators are available for the treatment of chronic obstructive pulmonary disease (COPD): the β(2)-agonist indacaterol and the anticholinergic tiotropium. This blinded study compared the efficacy of these two agents and assessed their safety and tolerability. Patients with moderate-to-severe COPD were randomised to treatment with indacaterol 150 μg q.d. (n=797) or tiotropium 18 μg q.d. (n=801) for 12 weeks. After 12 weeks, the two treatments had similar overall effects on "trough" (24 h post-dose) forced expiratory volume in 1 s. Indacaterol-treated patients had greater improvements in transition dyspnoea index (TDI) total score (least squares means 2.01 versus 1.43; p<0.001) and St George's Respiratory Questionnaire (SGRQ) total score (least squares means 37.1 versus 39.2; p<0.001; raw mean change from baseline -5.1 versus -3.0), and were significantly more likely to achieve clinically relevant improvements in these end-points (indacaterol versus tiotropium odds ratios of 1.49 for TDI and 1.43 for SGRQ, both p<0.001). Adverse events were recorded for 39.7% and 37.2% of patients in the indacaterol and tiotropium treatment groups, respectively. The most frequent adverse events were COPD worsening, cough and nasopharyngitis. Both bronchodilators demonstrated spirometric efficacy. The two treatments were well tolerated with similar adverse event profiles. Compared with tiotropium, indacaterol provided significantly greater improvements in clinical outcomes.

Topics: Adrenergic beta-2 Receptor Antagonists; Aged; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Indans; Male; Medical Records; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Severity of Illness Index; Spirometry; Tiotropium Bromide; Treatment Outcome

We hypothesized that bronchodilator treatment not only improves hyperinflation and endurance capacity but also muscular efficiency in stable chronic obstructive pulmonary disease (COPD). We aimed to demonstrate that tiotropium and salmeterol improve muscular efficiency compared with placebo. Twenty-five COPD patients were studied, including 20 males of mean (standard deviation) age 62 years (7 years) with baseline forced expiratory volume in 1 second of 41% (10%) predicted, and maximal workload of 101 Watt (36 Watt). Subjects were randomized for 6-week treatment with tiotropium 18 μg once daily, salmeterol 50 μg twice daily, or placebo using a double-blind, crossover design. Muscular efficiency and endurance time were measured during cycling at 50% of maximal work load. Resting energy expenditure was measured using a ventilated hood. Muscular efficiency after tiotropium, salmeterol, and placebo treatment was 14.6%, 14.4%, and 14.4%, respectively (P > 0.05), and resting energy expenditure was 1485 kcal/24 hours, 1709 kcal/24 hours, and 1472 kcal/24 hours (P > 0.05), respectively. Endurance time after tiotropium treatment was significantly higher than that after placebo (27.0 minutes versus 19.3 minutes [P = 0.02]), whereas endurance time after salmeterol treatment was not higher than that after placebo (23.3 minutes [P = 0.22]). In this small study, we were not able to demonstrate that bronchodilator therapy improved muscular efficiency. Apparently, reduced costs of breathing relative to total energy expenditure were too small to be detected.

Topics: Aged; Albuterol; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Energy Metabolism; Exercise Test; Exercise Tolerance; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscle, Skeletal; Netherlands; Physical Endurance; Plethysmography; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The addition of transdermal tulobuterol (Tulo) to inhaled tiotropium bromide (Tio) produced beneficial effects on spirometry-assessed parameters of respiratory function, disease-related symptoms and quality of life in patients with chronic obstructive pulmonary disease (COPD).. To compare the effects of Tio plus Tulo versus Tio alone on peripheral airway obstruction and quality of life in Japanese patients with COPD using impulse oscillation system (IOS)-assessed measures.. Patients aged 50-80 years with clinically stable COPD and a forced expiratory volume in 1 s (FEV(1)) that was 30-80% of the predicted value were randomized to receive Tio 18 μg once daily, or combination therapy with Tio 18 μg once daily plus Tulo 2 mg once daily for 4 weeks. Patients then switched treatments for a further 4 weeks.. Sixteen patients completed the study. Tio plus Tulo was associated with significantly greater improvements than Tio in IOS-assessed markers of resistance (R5 and R5-R20), reactance and reactance area, from baseline to week 4. Both treatments significantly improved these markers over the 4-week treatment period, with the exception of R20 for which improvements were not significant. Tio plus Tulo improved symptoms of dyspnea to a significantly greater extent than Tio alone. St. George's Respiratory Questionnaire Score-Total was not significantly different between the two groups, but improvement from baseline in the 'impact' component was significantly greater with Tio plus Tulo than with Tio alone.. Coadministration of transdermal Tulo with inhaled Tio, as well as Tio alone, is associated with beneficial effects on IOS-assessed measures of peripheral airway obstruction in patients with COPD.

Topics: Administration, Cutaneous; Administration, Inhalation; Aged; Aged, 80 and over; Airway Resistance; Bronchodilator Agents; Cross-Over Studies; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Oscillometry; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Scopolamine Derivatives; Terbutaline; Tiotropium Bromide; Transdermal Patch; Treatment Outcome

For optimal efficacy, an inhaler should deliver doses consistently and be easy for patients to use with minimal instruction. The delivery characteristics, patients' correct use, and preference of two single-dose dry powder inhalers (Breezhaler and HandiHaler) were evaluated in two complementary studies. The first study examined aerodynamic particle size distribution, using inhalation profiles of seven patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The second was an open-label, two-period, 7-day crossover study, evaluating use of the inhalers with placebo capsules by 82 patients with mild to severe COPD. Patients' correct use of the inhalers was assessed after reading written instructions on Day 1, and after training and 7 days of daily use. Patients' preference was assessed after completion of both study periods. Patient inhalation profiles showed average peak inspiratory flows of 72 L/minute through Breezhaler and 36 L/minute through HandiHaler. For Breezhaler and HandiHaler, fine particle fractions were 27% and 10%, respectively. In the second study, correct use of Breezhaler and HandiHaler was achieved by > 77% of patients for any step after 7 days; 61% of patients showed an overall preference for Breezhaler and 31% for HandiHaler (P = 0.01).Breezhaler is a low-resistance inhaler suitable for use by patients with a range of disease severities. Most patients used both inhalers correctly after 7 days, but more patients showed an overall preference for the Breezhaler compared with the HandiHaler. These are important factors for optimum dose delivery and successful COPD management.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Aerosols; Aged; Bronchodilator Agents; Canada; Cholinergic Antagonists; Cross-Over Studies; Dry Powder Inhalers; Equipment Design; Female; Humans; Indans; Inhalation; Lung; Male; Middle Aged; Particle Size; Patient Education as Topic; Patient Preference; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; United States

To explore the utility of applying growth mixture models (GMMs) in secondary analyses of clinical trials to identify sources of variability in data reported by patients with COPD.. Analyses were performed on data from two 6-month clinical trials comparing indacaterol and open-label tiotropium or blinded salmeterol and the first six months of a 12-month trial comparing indacaterol and blinded formoterol. Latent growth model (LGM) analyses were conducted to explore the response of the SGRQ Symptoms score from baseline to six months and GMM analyses were evaluated as a method to identify latent classes of differential responders.. Variability in SGRQ Symptom scores was found suggesting subsets of patients with differential response to treatment. GMM analyses found subsets of non-responders in all trials. When the responders were analyzed separately from non-responders, there were increased treatment effects (e.g., symptoms score improvement over six months for whole groups: indacaterol=8-12 units, tiotropium=7 units, salmeterol=9 units, formoterol=11 units. Responder subgroup improvement: indacaterol=9-21 units, tiotropium=7 units, salmeterol=10 units, formoterol=20 units). Responders had significantly different baseline SGRQ Symptom scores, smoking history, age, and mMRC dyspnea scores than non-responders.. Patients with COPD represent a heterogeneous population in terms of their reporting of symptoms and response to treatment. GMM analyses are able to identify sub-groups of responders and non-responders. Application of this methodology could be of value on other endpoints in COPD and in other disease areas.

Topics: Administration, Inhalation; Albuterol; Bronchodilator Agents; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Ethanolamines; Female; Follow-Up Studies; Forced Expiratory Volume; Formoterol Fumarate; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate; Scopolamine Derivatives; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome

The rate of decline in forced expiratory volume in 1 second (FEV1) is representative of the natural history of COPD. Sparse information exists regarding the associations between the magnitude of annualised loss of FEV1 with other endpoints.. Retrospective analysis of UPLIFT® trial (four-year, randomized, double-blind, placebo-controlled trial of tiotropium 18 μg daily in chronic obstructive pulmonary disease [COPD], n = 5993). Decline of FEV1 was analysed with random co-efficient regression. Patients were categorised according to quartiles based on the rate of decline (RoD) in post-bronchodilator FEV1. The St George's Respiratory Questionnaire (SGRQ) total score, exacerbations and mortality were assessed within each quartile.. Mean (standard error [SE]) post-bronchodilator FEV1 increased in the first quartile (Q1) by 37 (1) mL/year. The other quartiles showed annualised declines in FEV1 (mL/year) as follows: Q2 = 24 (1), Q3 = 59 (1) and Q4 = 125 (2). Age, gender, respiratory medication use at baseline and SGRQ did not distinguish groups. The patient subgroup with the largest RoD had less severe lung disease at baseline and contained a higher proportion of current smokers. The percentage of patients with ≥ 1 exacerbation showed a minimal difference from the lowest to the largest RoD, but exacerbation rates increased with increasing RoD. The highest proportion of patients with ≥ 1 hospitalised exacerbation was in Q4 (Q1 = 19.5% [tiotropium], 26% [control]; Q4 = 33.8% [tiotropium] and 33.1% [control]). Time to first exacerbation and hospitalised exacerbation was shorter with increasing RoD. Rate of decline in SGRQ increased in direct proportion to each quartile. The group with the largest RoD had the highest mortality.. Patients can be grouped into different RoD quartiles with the observation of different clinical outcomes indicating that specific (or more aggressive) approaches to management may be needed.. ClinicalTrials.gov number, NCT00144339.

Topics: Aged; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Time Factors; Tiotropium Bromide

This study compared the efficacy and safety of tiotropium bromide inhalation powder (spiriva) and doxofylline oral tablet (doxofylline) in the treatment of chronic obstructive pulmonary disease (COPD). A multi-center, randomized, double-blind, double-dummy, parallel-controlled study involved 127 eligible stable moderate to severe COPD patients treated with inhaled tiotropium dry powder (18 μg/day) or oral doxofylline tablets (0.2 g/time, 2 times a day) for 12 and 24 weeks. Before and after treatment for 12 weeks and 24 weeks, respectively, pulmonary function, 6-min walking distance and dyspnea index were recorded. The results showed that in both tiotropium group and doxofylline groups, after 12-week treatment, FEV(1), FEV(1)/FVC% and 6-min walk distance were significantly higher than those before the medication, while dyspnea index decreased as compared with that before treatment. After 24-week treatment, a slight improvement in the measures was observed as compared with that of 12-weeks treatment, but the difference was not statistically significant. With both 12-week and 24-week treatment, the effect of tiotropium was slightly better than that of doxofylline tablets, with the difference being statistically insignificant. The major adverse events in the tiotropium group and doxofylline group were observed in 9 cases (9.9%) and 12 cases (12.9%), respectively, and no statistically significant difference was found between them. We are led to conclude that both tiotropium at 18 μg a day and doxofylline tablets at 0.2 g/day (two times a day) are effective and safe for the treatment of COPD.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchodilator Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Theophylline; Tiotropium Bromide

The primary aim of pharmachotherapy in COPD is improvement of exertional dyspnea and quality of life through its bronchodilator effects. However, there is emerging evidence that pharmacotherapy may reduce exacerbations, alleviate annual decline of pulmonary function, and even favorably affect mortality, thus changing natural history of COPD. The large-scaled randomized clinical trials, such as TORCH, UPLIFT, have revealed that combination of long acting beta2 agonist (LABA) and inhaled corticosteroids (ICS), LABA/ICS, and/or tiotropium alone may have such effects. In addition, carbocisteine, which is a mucolytic and anti-oxidant agent, has been shown to reduce exacerbations in COPD. Future directions on pharmacotherapy are personalized medicine based on phenotyping of the disease and development of new agents which may cure airway inflammation in COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

UPLIFT (Understanding Potential Long-Term Improvements in Function with Tiotropium), a 4-yr trial of tiotropium in chronic obstructive pulmonary disease, allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy. 5,993 patients were randomised (tiotropium/placebo). Lung function, St George's Respiratory Questionnaire, exacerbations and adverse events were followed. Patients were characterised as continuing smokers (CS), continuing ex-smokers (CE), or intermittent smokers (IS) based on self-reporting smoking behaviour. 60%, 14% and 26% of patients were CE, CS and IS, respectively. The rate of forced expiratory volume in 1 s (FEV(1)) decline for placebo patients was most rapid in CS (-52+/-4, -37+/2 and -23+/2 mL.yr(-1) in CS, IS, and CE, respectively). Tiotropium did not alter FEV(1) decline, but was associated with significant improvements in pre- and post-bronchodilator FEV(1) over placebo that persisted throughout the 4-yr trial for each smoking status (pre-bronchodilator: 127, 55 and 97 mL at 48 months in CS, IS and CE, respectively; p< or =0.0003). Tiotropium reduced exacerbation risk in CS (HR (95% CI) 0.80 (0.67-0.95)), in CE (0.85 (0.79-0.92)) and trended towards significance in IS (0.89 (0.79-1.00)). At 4 yrs, St George's Respiratory Questionnaire for tiotropium patients improved the most in CS (-4.63 units, p = 0.0006) and the least in IS (-0.60 units, p = 0.51), [corrected] compared with control. Tiotropium provided long-term benefits irrespective of smoking status, although differences among categories were observed.

Topics: Aged; Bronchodilator Agents; Cholinergic Antagonists; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Smoking; Time Factors; Tiotropium Bromide; Treatment Outcome

The current mainstream treatment for COPD is bronchodilators alone or in combination. The effects of a beta(2)-agonist, tulobuterol, administered transdermally, have been reported to last for 24h. However, there are no reports on the efficacy of tulobuterol combined with an anticholinergic. In this study, we investigated the efficacy and safety of transdermal tulobuterol combined with inhaled tiotropium in COPD.. After a 2-week run-in period, 103 stable COPD patients aged >or=40 years were randomized into two groups: inhaled tiotropium (18microg, Tio group) or transdermal tulobuterol (2mg) combined with inhaled tiotropium (18microg, Tio+Tulo group) for 8 weeks. Primary endpoints were pulmonary function and severity of dyspnea. The St. George's Respiratory Questionnaire (SGRQ) score was a secondary endpoint.. In both groups, FEV(1) and FVC as well as dyspnea improved significantly after 8 weeks. In a comparison of both groups, percentage changes in IC and morning and evening peak expiratory flow were significantly greater in the Tio+Tulo group than in the Tio group. In addition, significant improvement in SGRQ score was observed in the Tio+Tulo group only. The risk of adverse events related to the study drugs was not increased.. In COPD patients, additional administration of transdermal tulobuterol to inhaled tiotropium produced significant benefits in dyspnea and SGRQ score as well as pulmonary function. These benefits may be due to a reduction in pulmonary hyperinflation resulting from improvement of peripheral airflow obstruction through tulobuterol via the systemic circulation.

Topics: Administration, Cutaneous; Administration, Inhalation; Aged; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Dyspnea; Female; Humans; Japan; Male; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Scopolamine Derivatives; Surveys and Questionnaires; Terbutaline; Tiotropium Bromide; Treatment Outcome

The synergistic interactions between pharmacotherapy and pulmonary rehabilitation has been provided, but it remains to be established whether this may also apply to more severe patients.. We have examined whether tiotropium enhances the effects of exercise training in patients with advanced COPD (FEV(1)

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Combined Modality Therapy; Drug Administration Schedule; Drug Synergism; Dyspnea; Exercise Tolerance; Female; Fluticasone; Humans; Male; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

To compare the efficacy and safety of tiotropium inhaled via Respimat Soft Mist Inhaler, a multidose propellant-free inhaler and HandiHaler, a single-dose dry powder inhaler, in a phase 2 study of Japanese COPD patients.. Patients with FEV(1)10 pack-years received tiotropium once daily via Respimat (5microg) and HandiHaler (18microg) for 4 weeks each in a randomised, double-blind, double-dummy, two-way crossover study. Lung function, adverse events, pharmacokinetics and safety were assessed.. Of 184 patients screened, 134 were evaluable. The trough FEV(1) response on Day 29 showed Respimat to be non-inferior to HandiHaler (mean treatment difference, 0.008L; 95% CI, -0.009 to +0.024L; p<0.001). Peak and average FEV(1) and FVC responses on Day 1 and Day 29 were very similar for the two treatments. Tiotropium plasma levels and excretion kinetics showed a similar profile of systemic exposure for the two formulations of tiotropium. Adverse events were reported by similar numbers of patients on each treatment, i.e. 27.9 and 30.6% in the Respimat and HandiHaler groups, respectively.. In Japanese patients with COPD, tiotropium Respimat 5microg and tiotropium HandiHaler 18microg showed a similar profile of efficacy, safety and pharmacokinetics.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Tiotropium, a long-acting bronchodilator, can be used perioperatively in patients with lung cancer and airway obstruction, although its benefits for the perioperative outcome remain unclear.. We prospectively collected the perioperative data of 44 patients with resectable lung cancer and untreated airway obstruction. Tiotropium was not used before September 2007 (control group, n = 24) but was used routinely thereafter (treated group, n = 20). We estimated a propensity score to adjust comparisons between the groups.. Tiotropium improved preoperative global pulmonary function significantly, especially in four patients. Postoperative outcomes in these major responders were significantly better than those in the remaining minor responders. However, postoperative outcomes were not significantly different between the treated group (n = 15) and the control group (n = 15) matched by a propensity score.. Regardless of its favorable effects on preoperative pulmonary function, we could not establish a significant benefit of tiotropium for postoperative outcomes overall. Nonetheless, our data suggested that tiotropium might have improved the postoperative outcomes of major responders.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchodilator Agents; Female; Humans; Lung Neoplasms; Male; Perioperative Care; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The drug development process can be streamlined by combining the traditionally separate stages of dose-finding (Phase IIb) and confirmation of efficacy and safety (Phase III) using an adaptive seamless design. This approach was used in a clinical study of indacaterol, a novel once-daily (od) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD (chronic obstructive pulmonary disease).. The study comprised a dose-finding stage with dose selection after 14 days of treatment, and a second stage evaluating efficacy and safety during 26 weeks of treatment. The dose-finding stage included seven randomized treatment arms: double-blind indacaterol 75 microg, 150 microg, 300 microg or 600 microg od, the beta(2)-adrenoceptor agonist formoterol 12 microg twice-daily or placebo, or the anticholinergic tiotropium 18 microg od open-label. An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician. The sponsor, investigators and patients remained blinded to the results. The indacaterol doses were selected using pre-set efficacy criteria for trough (24-h post-dose) and early (1-4 h post-dose) bronchodilator effect after 14 days, and all safety data. To qualify for selection, the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol, whichever was the highest value. Selected doses were continued into the second, 26-week stage. The two other indacaterol doses not selected, and formoterol, were discontinued following dose selection.. 801 patients with moderate-to-severe COPD were evaluated. Indacaterol 150 microg was the lowest effective dose, exceeding criteria for trough FEV(1) (reference value 140 mL vs placebo) and FEV(1) AUC(1-4 h) (reference value 220 mL vs placebo). No safety signal was observed with any dose of indacaterol. Thus, indacaterol 150 and 300 microg were selected to continue into the second, 26-week stage.. The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial.

Topics: Adult; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Ethanolamines; Female; Formoterol Fumarate; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Research Design; Respiratory Function Tests; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

The aim of the present study was investigate the long-term effect of tiotropium as first maintenance respiratory medication in chronic obstructive pulmonary disease (COPD). A 4-yr, randomised, multicentre, double-blind, parallel-group, placebo-controlled trial (Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) was conducted. Analysis focused on the effect of tiotropium versus matching placebo in the 810 (13.5%) COPD patients not on other maintenance treatment (long-acting beta-agonists, inhaled corticosteroids, theophyllines or anticholinergics) at randomisation. Spirometry, health-related quality of life (St George's Respiratory Questionnaire (SGRQ) score), exacerbations of COPD and mortality were also analysed. 403 patients (mean+/-sd age 63+/-8 yrs, post-bronchodilator forced expiratory volume in 1 s (FEV(1)) 53+/-12% predicted) received tiotropium and 407 (64+/-8 yrs of age, post-bronchodilator FEV(1) 51+/-12% pred) received placebo. Post-bronchodilator FEV(1) decline was 42+/-4 mL.yr(-1) in the tiotropium group and 53+/-4 mL.yr(-1) in the placebo group (p = 0.026). At 48 months, the morning pre-dose FEV(1) was 134 mL higher in the tiotropium group compared to the placebo group (p<0.001). SGRQ total score declined more slowly in the tiotropium group (difference of 1.05+/-0.34 units.yr(-1); p = 0.002). This was particularly significant for the impact (difference of 1.08+/-0.37 units.yr(-1); p = 0.004) and activity (1.44+/-0.40 units.yr(-1); p<0.001) domains, but not for symptoms (0.26+/-0.50 units.yr(-1); p = 0.6). At 48 months, the difference in total score was 4.6 units (p<0.001) with tiotropium compared to placebo. In patients with COPD who are not on maintenance therapy, tiotropium is associated with significant benefits in disease progression.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Aged; Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Spirometry; Theophylline; Time; Tiotropium Bromide

Clinical information on 24-h spirometric efficacy of combining tiotropium and salmeterol compared to single-agent therapy is lacking in patients with COPD.. A randomized, double-blind, four-way crossover study of 6-week treatment periods comparing combination therapy of tiotropium 18 microg plus qd or bid salmeterol 50 microg versus single-agent therapy. Serial 24-h spirometry (FEV(1), FVC), effects on dyspnea (TDI focal score) and rescue salbutamol use were evaluated in 95 patients.. Tiotropium plus qd salmeterol was superior to tiotropium or salmeterol alone in average FEV(1) (0-24h) by 72 mL and 97 mL (p<0.0001), respectively. Compared to this qd regimen, combination therapy including bid salmeterol provided comparable daytime (0-12h: 12 mL, p=0.38) bronchodilator effects, but significantly more bronchodilation during the night-time (12-24h: 73 mL, p<0.0001). Clinically relevant improvements in TDI focal score were achieved with bronchodilator combinations including salmeterol qd or bid (2.56 and 2.71; p<0.005 versus components). Symptom benefit of combination therapies was also reflected in less need for reliever medication. All treatments were well tolerated.. Compared to single-agent therapy, combination therapy of tiotropium plus salmeterol in COPD provided clinically meaningful improvements in airflow obstruction and dyspnea as well as a reduction in reliever medication.

Topics: Adult; Airway Obstruction; Albuterol; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Dyspnea; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

Gender differences may occur in many chronic diseases. We have examined the influence of gender in chronic obstructive pulmonary disease (COPD) on long-term responses to tiotropium.. Subgroup analysis of data from the Understanding the Potential Long-term Impact of Tiotropium (UPLIFT) trial (4-year, randomized, double-blind, placebo-controlled trial of tiotropium in patients with COPD).. Of 5992 patients, 75% were men and 25% women. Mean age was 65 and 63 years, respectively. Baseline post-bronchodilator forced expiratory volume in 1s (FEV(1))=47% predicted(men) and 49% predicted(women). St George's Respiratory Questionnaire (SGRQ) total score was 44.9 and 48.7units, respectively. At 48 months, improvement in trough FEV(1) over control was 92mL(men) and 77mL(women) (p<0.001 for both), with no differences in the rate of decline (trial primary endpoint). Hazard ratio (HR) (95% confidence interval [CI]) for first exacerbation (tiotropium/placebo) was 0.87(0.81, 0.93)(men) and 0.83(0.74, 0.94)(women). Number of exacerbations (per patient-year) was reduced with tiotropium in men (from 0.82 to 0.71) and women (from 0.92 to 0.77) (p<0.005 for both). HR (95% CI) for a hospitalized exacerbation was 0.89(0.79, 0.99) and 0.77(0.62, 0.94), respectively. HR (95% CI) for mortality during treatment was 0.85(0.72, 0.99)(men) and 0.85(0.62, 1.18)(women). Improvements in SGRQ total score (tiotropium-control) at 1, 2, 3 and 4 years were: -2.8, -2.3, -3.6, -2.4(men) and -2.7, -2.6, -2.6, -2.1(women) (p<0.05 for all).. Long-term treatment of COPD with tiotropium improves lung function, exacerbations and health status in men and women, with similar magnitudes of benefit. Boehringer Ingelheim trial 205.235; ClinicalTrials.gov: NCT00144339.

Topics: Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Scopolamine Derivatives; Sex Factors; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

Lowest receptor occupancy for a drug occurs at trough prior to the next dose. Previous studies have focused on the effects of triple therapy at peak dose intervals using forced expiratory maneuvers. Impulse oscillometry (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to assess inhaled therapies in COPD.. Nineteen patients with COPD (FEV(1)/FVC ratio < 0.7; FEV(1) < 60%) completed a double-blind randomized crossover trial of tiotropium 18 microg/d or placebo for 2 weeks each, with a 1-week washout. Prior to this procedure, there was a nonrandomized 4 week run-in of budesonide/formoterol 200/6 2 puffs bid, which continued throughout the study. Spirometry, IOS, and PLETH were performed both before pre- and post-budesonide/formoterol run-in and at trough following the first and last dose of tiotropium (ie, 24 h posttiotropium and 12 h post-budesonide/formoterol).. Mean +/- SEM for age and FEV(1) were 65 +/- 2 years and 42 +/- 2%, respectively. Following initial budesonide/formoterol, there were no significant changes in spirometry; however, all measures of IOS and PLETH deteriorated (P < .01 for all outcomes). Compared with placebo, tiotropium was additive to budesonide/formoterol after single and chronic dosing measured by FEV(1) (P < .001 and P = .014, respectively) and forced expiratory flow, midexpiratory phase (P = .001; P= .026), whereas specific airway resistance, reactance, resonant frequency, and area under the reactance curve showed additive benefits at a single dose only.. Budesonide/formoterol caused an unexpected worsening of IOS and PLETH outcomes compared with a washed-out baseline in the nonplacebo-controlled run-in. This finding was not observed with spirometry. Subsequent addition of tiotropium improved lung function with all techniques after a single dose and for spirometry after chronic dosing. These paradoxical findings may reflect beta2-adrenoceptor downregulation and muscarinic 3 receptor cross talk. Placebo-controlled studies are required to explore this result.

Topics: Adrenal Cortex Hormones; Aged; Biological Availability; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Cross-Over Studies; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Humans; Male; Middle Aged; Oscillometry; Plethysmography, Whole Body; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

Indacaterol is the first once-daily, long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease (COPD).. To demonstrate greater efficacy of indacaterol versus placebo on FEV(1) at 24 hours post dose (trough) after 12 weeks, to compare efficacy with placebo and tiotropium, and to evaluate safety and tolerability over 26 weeks.. Patients with moderate-to-severe COPD were randomized to double-blind indacaterol 150 or 300 microg or placebo, or open-label tiotropium 18 microg, all once daily, for 26 weeks. The primary efficacy outcome was trough FEV(1) at 12 weeks. Additional analyses (not adjusted for multiplicity) included transition dyspnea index (TDI), health status (St George's Respiratory Questionnaire [SGRQ]), and exacerbations. Serum potassium, blood glucose, and QTc interval were measured.. A total of 1,683 patients (age, 63.3 yr; post-bronchodilator FEV(1), 56% predicted; FEV(1)/FVC, 0.53) were randomized to the four treatment arms. Trough FEV(1) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium (all P < 0.001 vs. placebo). At Week 26, for indacaterol 150/300 microg, respectively, versus placebo, TDI increased (1.00/1.18, P < 0.001) and SGRQ total score decreased (-3.3/-2.4, P < 0.01); corresponding results with tiotropium were 0.87 (P < 0.001) for TDI and (-1.0, P = not significant) for SGRQ total score. The incidence of adverse events, low serum potassium, high blood glucose, and prolonged QTc interval was similar across treatments.. Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD. Clinical trial registered with clinicaltrials.gov (NCT 00463567).

Topics: Administration, Inhalation; Blood Glucose; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Dyspnea; Electrocardiography; Female; Forced Expiratory Volume; Health Status; Humans; Indans; Male; Middle Aged; Potassium; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

NVA237 is a once-daily inhaled long-acting muscarinic antagonist in development for the treatment of COPD. This randomized, double-blind, placebo-controlled, four-period, incomplete block crossover study, with open-label active comparator (tiotropium), assessed the efficacy and safety of NVA237. Patients (>or=40 years; smoking history >or=10 pack-years) with stable moderate-to-severe COPD (post-bronchodilator FEV(1) >or= 30% and <80% predicted, FEV(1)/FVC < 0.7) received NVA237 12.5, 25, 50 or 100 microg, placebo, or tiotropium 18 microg once-daily for 7 days. The primary endpoint was mean trough (23-24 h post-dose) FEV(1) on Day 7. Secondary endpoints included mean trough FEV(1) on Day 1, and FEV(1) and FVC at individual time points post-dose on Days 1 and 7. 83 patients (mean age 64.4 years; male 83.1%; mean COPD duration 6.7 years; mean post-bronchodilator FEV(1) 1.5 L/52.7% predicted) were randomized; 78 completed. Mean trough FEV(1) on Day 7 and Day 1 was significantly higher with all active treatments versus placebo (p < 0.05). NVA237 50 microg, 100 microg and tiotropium showed clinically relevant improvements versus placebo on Day 7 (differences of 131, 142 and 127 mL, respectively; p < 0.0001) and 1 (differences of 121, 135 and 112 mL, respectively; p < 0.0001). On Day 1, but not Day 7, FEV(1) was significantly higher (p < 0.05) with NVA237 50 and 100 microg versus tiotropium from 5 min up to 2 and 4 h post-dose, respectively. All doses of NVA237 and tiotropium were well tolerated. NVA237 once-daily was effective and well tolerated versus placebo, and demonstrated rapid and sustained 24-h bronchodilation. (ClinicalTrials.gov Identifier: NCT00501852).

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

It is currently unclear whether the additive effects of a long-acting beta(2)-agonist (LABA) and the antimuscarinic tiotropium bromide (TIO) on resting lung function are translated into lower operating lung volumes and improved exercise tolerance in patients with chronic obstructive pulmonary disease (COPD).. On a double-blind and cross-over study, 33 patients (FEV(1) = 47.4 +/- 12.9% predicted) were randomly allocated to 2-wk formoterol fumarate 12 microg twice-daily (FOR) plus TIO 18 microg once-daily or FOR plus placebo (PLA). Inspiratory capacity (IC) was obtained on constant-speed treadmill tests to the limit of tolerance (Tlim).. FOR-TIO was superior to FOR-PLA in increasing post-treatment FEV(1) and Tlim (1.34 +/- 0.42 L vs. 1.25 +/- 0.39 L and 124 +/- 27% vs. 68 +/- 14%, respectively; p < 0.05). FOR-TIO slowed the rate of decrement in exercise IC compared to FOR-PLA (Deltaisotime-rest = -0.27 +/- 0.40 L vs. -0.45 +/- 0.36 L, p < 0.05). In addition, end-expiratory lung volume (% total lung capacity) was further reduced with FOR-TIO (p < 0.05). Of note, patients showing greater increases in Tlim with FOR-TIO (16/26, 61.6%) had more severe airways obstruction and lower exercise capacity at baseline. Improvement in Tlim with FOR-TIO was also related to larger increases in FEV(1) (p < 0.05).. Compared to FOR monotherapy, FOR-TIO further improved effort-induced dynamic hyperinflation and exercise endurance in patients with moderate-to-severe COPD. These beneficial consequences were more likely to be found in severely-disabled patients with larger resting functional responses to the combination therapy.. Clinicaltrials.gov Identifier: NCT00680056 [ClinicalTrials.gov].

Topics: Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Dyspnea; Ethanolamines; Exercise Tolerance; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Total Lung Capacity; Treatment Outcome

In this randomised double-blind study, patients >or=40 years old with COPD, a smoking history of >or=10 pack-years, a pre-bronchodilator FEV(1) of

Topics: Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Smoking; Tiotropium Bromide

Two 1-year studies evaluated the long-term efficacy and safety of tiotropium 5 or 10 microg versus placebo, inhaled via the Respimat Soft Mist Inhaler (SMI). The two studies were combined and had 4 co-primary endpoints (trough FEV(1) response, Mahler Transition Dyspnea Index [TDI] and St George's Respiratory Questionnaire scores all at week 48, and COPD exacerbations per patient-year). A total of 1990 patients with COPD participated (mean FEV(1): 1.09 L). The mean trough FEV(1) response of tiotropium 5 or 10 microg relative to placebo was 127 or 150 mL, respectively (both P < 0.0001). The COPD exacerbation rate was significantly lower with tiotropium 5 microg (RR = 0.78; P = 0.002) and tiotropium 10 microg (RR = 0.73; P = 0.0008); the health-related quality of life and Mahler TDI co-primary endpoints were significantly improved with both doses (both P < 0.0001). Adverse events were generally balanced except anticholinergic class effects, which were more frequent with active treatment. Fatal events occurred in 2.4% (5 microg), 2.7% (10 microg), and 1.6% (placebo) of patients; these differences were not significant. Tiotropium Respimat SMI 5 microg demonstrated sustained improvements in patients with COPD relative to placebo and similar to the 10 microg dose but with a lower frequency of anticholinergic adverse events.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

Whilst recent large-scale studies have provided much evidence on the natural history and therapeutic response in patients with chronic obstructive pulmonary disease (COPD), relatively little is known about the effect in younger patients. We report a pre-specified post-hoc analysis of 356 patients with COPD ≤ 50 years old from the four year randomised, double blind placebo controlled Understanding Potential Long Term Impact on Function with Tiotropium (UPLIFT) trial. Inclusion criteria included a post-bronchodilator forced expiratory volume in 1 s (FEV(1)) of ≤70%, FEV(1)/FVC < 0.70, age ≥40 years, and smoking history of ≥10 pack years. Younger patients had a mean FEV(1) of 1.24 L (39% predicted) and an impaired health-related quality of life (St. George's Respiratory Questionnaire (SGRQ)) compared to the entire UPLIFT population. There were 40.2% women and 51.1% current smokers in the younger age group. Tiotropium was associated with a sustained improvement in spirometry and SGRQ. Mean decline in post-bronchodilator FEV(1) was 58 ml/year (placebo) vs. 38 ml/year (tiotropium) (p = 0.01). Corresponding values for pre-bronchodilator FEV(1) were 41 ml/year (placebo) compared with 34 ml/year (tiotropium) (p = 0.34). The hazard ratio (95%CI) for an exacerbation in the younger age group was 0.87(0.68, 1.13)). The rate of exacerbations was reduced by tiotropium (rate ratio (95%CI) = 0.73(0.56, 0.95)). Tiotropium resulted in sustained bronchodilation, improved quality of life, and a decreased exacerbation rate in younger patients. Tiotropium also resulted in a significant reduction in the decline in post-bronchodilator FEV(1), suggesting possible disease modification by tiotropium in younger patients with COPD.

Topics: Bronchodilator Agents; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

ABSTRACT Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the rate of onset of bronchodilation with aclidinium compared with placebo and tiotropium. This was a double-blind, double-dummy, multicenter, crossover study in COPD patients with a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) ≥30% and <60% predicted. On study days, patients received single doses of aclidinium 200 μg, tiotropium 18 μg, or placebo. Serial spirometry was conducted from 10 minutes to 3 hours post-dose. The primary variable was the percentage of patients with an increase in FEV(1) of ≥10% above baseline at 30 minutes post-dose. Other assessments included change from baseline in FEV(1) and dyspnea over 3 hours post-dose. A total of 115 patients entered the study. Significantly more patients had an increase in FEV(1) of ≥10% above baseline at 30 minutes with aclidinium and tiotropium versus placebo (49.5% and 51.8% versus 13.8%; p < 0.0001). At 30 minutes, the relative increase from baseline in FEV(1) was significantly higher for aclidinium and tiotropium versus placebo (12% and 11% versus 3%; p < 0.0001). Aclidinium and tiotropium also significantly increased FEV(1) (p < 0.01) and improved the perception of dyspnea compared with placebo at all measured time points from 10 minutes to 3 hours post-dose. In conclusion, aclidinium provided effective bronchodilation, similar to that seen with tiotropium, with significant improvements compared with placebo observed from 10 minutes post-dose.

Topics: Administration, Inhalation; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes

Indacaterol is a novel, inhaled, once-daily, ultra-long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, double-blind study compared the bronchodilator efficacy of indacaterol with that of placebo and tiotropium in patients with moderate-to-severe COPD.. In an incomplete-block, multi-dose, three-period, crossover design, patients received three of the following four treatments: indacaterol 150 μg, indacaterol 300 μg, tiotropium 18 μg and placebo, each once-daily for 14 days. Each treatment period was separated by a 14-day washout. Study drug was supplied daily by blinded, third party study personnel to maintain blinding of patients and investigators. The primary efficacy variable was trough forced expiratory volume in one second (FEV1) at 24 h post-dose after 14 days. The study was powered to demonstrate non-inferiority of indacaterol to tiotropium for this variable.. A total of 169 patients were randomized (mean age 65 years); 153 (90.5%) completed. Trough FEV1 after 14 days with indacaterol 150 μg and 300 μg was statistically and clinically superior to placebo, with differences (95% CI) of 170 (120-220) and 150 (100-200) mL respectively (both p < 0.001). For this endpoint, both doses of indacaterol not only met the criterion for non-inferiority compared with tiotropium, but also achieved numerically higher values, with differences versus tiotropium of 40 and 30 mL for indacaterol 150 and 300 μg, respectively. At 5 min post-dose on Day 1, the mean FEV1 for both indacaterol doses was significantly higher than placebo (by 120 and 130 mL for indacaterol 150 and 300 μg, respectively; p < 0.001) and tiotropium (by 80 mL for both doses; p < 0.001). Adverse events were reported by similar proportions of patients: 31.4%, 29.5%, 28.3% and 28.5% for indacaterol 150 μg and 300 μg, tiotropium and placebo treatments, respectively.. Once-daily indacaterol provided clinically and statistically significant 24-h bronchodilation. Indacaterol was at least as effective as tiotropium, with a faster onset of action (within 5 min) on the first day of dosing. Indacaterol should prove useful in patients with moderate-to-severe COPD, for whom treatment with one or more classes of long-acting bronchodilator is recommended.. ClinicalTrials.gov: NCT00615459, EudraCT number: 2007-004071-19.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Over Studies; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Time Factors; Tiotropium Bromide

To compare the efficacy and safety between tiotropium capsule and placebo in a 12-week treatment in patients with chronic obstructive pulmonary disease (COPD).. A multi-center, randomized, double-blind, and placebo-control clinical trial was conducted in 205 patients with stable COPD. They were randomized into inhaled tiotropium 18 µg once daily or placebo, lasting for 12 weeks. The spirometry was conducted at baseline, 6 and 12 weeks after treatment.. A total of 205 patients with stable stage I or II COPD were randomized to tiotropium and placebo groups. The improvement rate of clinical symptom in the tiotropium group was 25.2% (26/103) after a 12 week treatment, but that of the control group was 4.9% (5/102). The forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) in the tiotropium group increased (0.2 ± 0.3) L and (19.2 ± 29.1)% after the 12 week therapy, but only (0.0 ± 0.2) L and (0.8 ± 18.2)% in the placebo group. The rate of adverse reaction in the tiotropium group was 7.8% (8/103), but in the placebo group was 12.8% (13/102). The difference between the 2 groups was not significant. All adverse reactions were mild, including dry mouth and sore throat.. This trial confirmed that tiotropium powder 18 µg once daily relieved dyspnea, prevented aggravation and improved pulmonary function, clinical symptoms and life quality. Tiotropium was a safe and effective once-daily anticholinergic bronchodilator as first-line maintenance therapy in COPD.

Topics: Adolescent; Adult; Aged; Bronchodilator Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Young Adult

Because treadmill exercise testing is more representative of daily activity than cycle testing, we developed treadmill protocols to be used in various clinical settings as part of a two-year, multicenter, chronic obstructive pulmonary disease (COPD) trial evaluating the effect of tiotropium on exercise.. We enrolled 519 COPD patients aged 64.6 ± 8.3 years with a postbronchodilator forced expiratory volume in one second (FEV(1)) of 1.25 ± 0.42 L, 44.3% ± 11.9% predicted. The patients performed symptom-limited treadmill tests where work rate (Ẇ) was increased linearly using speed and grade adjustments every minute. On two subsequent visits, they performed constant Ẇ tests to exhaustion at 90% of maximum Ẇ from the incremental test.. Mean incremental test duration was 522 ± 172 seconds (range 20-890), maximum work rate 66 ± 34 watts. For the first and second constant Ẇ tests, both at 61 ± 33 watts, mean endurance times were 317 ± 61 seconds and 341 ± 184 seconds, respectively. The mean of two tests had an intraclass correlation coefficient of 0.85 (P < 0.001). During the second constant Ẇ test, 88.2% of subjects stopped exercise because of breathing discomfort; 87.1% for Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II, 88.5% for GOLD Stage III, and 90.2% for GOLD Stage IV.. The symptom-limited incremental and constant work treadmill protocol was well tolerated and appeared to be representative of the physiologic limitations of COPD.

Topics: Aged; Bronchodilator Agents; Cholinergic Antagonists; Exercise Test; Exercise Tolerance; Feasibility Studies; Female; Forced Expiratory Volume; Germany; Humans; Los Angeles; Lung; Male; Middle Aged; Pilot Projects; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Tiotropium, a once daily inhaled anticholinergic delivered via HandiHaler, provides bronchodilation for >24h and improves patient-centred outcomes. The Respimat Soft Mist Inhaler (SMI), a novel, propellant-free inhaler, has been developed and proposed as an alternative delivery device for use with tiotropium.. In a pre-specified, pooled analysis of two 30-week, double-blind, double-dummy, crossover studies, 207 patients with Chronic Obstructive Pulmonary Disease (COPD) were randomised to receive once daily tiotropium 5 microg or 10 microg (aqueous solution delivered via Respimat SMI), tiotropium 18 microg (inhalation powder via HandiHaler) or placebo. The primary endpoint was trough forced expiratory volume in 1s (FEV(1)) response. Forced vital capacity (FVC), peak expiratory flow rate (PEFR), rescue medication use, safety and pharmacokinetics (in a subgroup of patients) were also assessed.. Both tiotropium doses delivered by Respimat SMI were significantly superior to placebo and non-inferior to tiotropium 18 microg HandiHaler on the primary endpoint (all p<0.0001). All active treatments were significantly superior to placebo (all p<0.0001) and both doses of tiotropium Respimat SMI were non-inferior to tiotropium 18 microg HandiHaler on the secondary spirometry variables and rescue medication use. The systemic exposure was similar between tiotropium 5 microg Respimat SMI and tiotropium 18 microg HandiHaler but was higher for tiotropium 10 microg Respimat SMI. All active treatments were well tolerated.. Tiotropium 5 microg Respimat SMI is comparable with tiotropium 18 microg HandiHaler in terms of efficacy, pharmacokinetics and safety. Respimat SMI is an effective alternative, multi-dose delivery device for tiotropium.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Metabolic Clearance Rate; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The anti-inflammatory effects of salmeterol/fluticasone (SFP), tiotropium/fluticasone (Tio+FP) and tiotropium (Tio) alone were investigated on the inflammatory cells and mediators in sputum induced from chronic obstructive pulmonary disease patients. Subjects were either newly diagnosed or had not taken any medication for 3 months prior to the study. Subjects (n = 99) were randomised (not double blinded) and received either SFP (100/1,000 microg daily), Tio+FP (18/1,000 microg daily) or Tio (18 microg daily) for 12 weeks. Induced sputum and serum C-reactive protein (CRP) were analysed prior to and at the end of treatment. The results showed that treatment with SFP caused a significant reduction in interleukin (IL)-8 and matrix metalloprotease (MMP)-9 in induced sputum, compared with treatment with Tio alone. There were no treatment differences between the SFP and Tio+FP groups in decreasing IL-8 and MMP-9 levels. The reduction in IL-8 showed significant association with the reduction in MMP-9. All treatment groups failed to significantly reduce the numbers of total cells, neutrophils, macrophages and eosinophils in induced sputum; in addition, there were no treatment differences in terms of improvement of forced expiratory volume in one second, forced vital capacity, CRP or quality of life between the three groups. The anti-inflammatory effects of salmeterol/fluticasone probably contribute to the clinical benefits seen in chronic obstructive pulmonary disease patients.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Biomarkers; C-Reactive Protein; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Fluticasone; Humans; Inflammation; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Sputum; Tiotropium Bromide

Current guidelines support using in combination more than one class of long-acting bronchodilator for COPD patients whose symptoms are not controlled by mono-therapy. This 2-week, multi-center (34 sites), randomized, modified-blind, parallel group study evaluated the efficacy and safety of concomitant treatment with nebulized arformoterol (the formoterol(R,R)-isomer) BID and tiotropium DPI QD.. COPD patients (mean FEV(1) 1.37L, 45.4% predicted) were randomized to receive mono-therapy (either arformoterol 15microg BID [n=76] or tiotropium 18microg QD [n=80]), or combined therapy (sequential dosing of arformoterol 15microg BID and tiotropium 18microg QD [n=78]). Changes in pulmonary function, dyspnea, and rescue levalbuterol use were evaluated, as were safety outcomes.. Mean FEV(1)AUC(0-24) (the primary endpoint) improved similarly from baseline for arformoterol (0.10L) and tiotropium (0.08L) treatment groups and greater for the combined therapy group (0.22L; all p-values <0.005). Peak FEV(1), peak FVC, 24-h trough FEV(1), and inspiratory capacity also improved similarly for the mono-therapies and greatest for the combined therapy. Dyspnea (mean transition dyspnea index) improved similarly for arformoterol (+2.3) and tiotropium (+1.8) and greatest with combined therapy (+3.1; p-values <0.05). Levalbuterol use decreased for all treatment groups (range -1.8 to -2.5 actuations/day). All treatments had similar frequency of adverse events.. In this study, the combination of nebulized arformoterol 15microg BID plus tiotropium 18microg DPI QD was the most effective in improving pulmonary function and disease symptoms. Mono-therapy improvement with arformoterol or tiotropium was similar. All three treatments were well tolerated.

Topics: Administration, Inhalation; Aged; Albuterol; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Dyspnea; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The effects of tiotropium, a long-acting anticholinergic drug, were compared with those of the combination of salmeterol, a long-acting beta(2)-agonist, and fluticasone, an inhaled corticosteroid, in patients with COPD.. A 4-month, randomized, open cross-over study of tiotropium, 18 microg once daily, versus salmeterol, 50 microg, plus fluticasone, 200 microg, twice daily, was conducted in patients with COPD. Efficacy was assessed by spirometry and responses to the St George's Respiratory Questionnaire (SGRQ). After 4 months, patients were asked to select their subsequent therapy and indicate the reasons for their selection.. A total of 78 patients completed the study. There were no significant differences in the improvements in FEV(1) or SGRQ scores between the therapies. Similar numbers of patients selected tiotropium (42.3%) and salmeterol plus fluticasone (57.7%). However, those who preferred one of the therapies demonstrated greater improvements in SGRQ scores with that therapy. One subgroup of patients (30.8%) showed greater improvements in dyspnoea and FEV(1) in response to tiotropium, and the other subgroup of patients (35.9%) showed greater improvements in dyspnoea and FEV(1) in response to salmeterol plus fluticasone. Some patients (14.1%) selected salmeterol plus fluticasone because of positive effects on sputum expectoration.. The study was unblinded and the results need to be interpreted with caution. However, tiotropium and salmeterol plus fluticasone had similar overall effects on pulmonary function and SGRQ scores in patients with COPD. Responses to the two therapies were heterogeneous, and the patients who showed greater improvements in FEV(1) or SGRQ scores with one of the therapies preferred it for their subsequent treatment.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Health Status; Humans; Lung; Male; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

Combined use of beta(2)-agonists and anticholinergic bronchodilators may have complementary benefits in patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to compare combination treatment with formoterol (FORM) plus tiotropium (TIO) versus treatment with TIO alone in patients with COPD. In this active-controlled, double-blind, multicenter trial, a total of 255 subjects with diagnosed COPD were randomized to 12 weeks of either a combination of FORM 12 microg twice-daily plus TIO 18 microg once-daily in the morning (QD AM) or monotherapy with TIO 18 microg QD AM. The primary efficacy variable was the area under the curve for forced expiratory volume in 1 second measured 0 to 4 hours after AM dosing (FEV(1) AUC(0-4h)). Significantly greater improvements in the FEV(1) AUC(0-4h) were seen with FORM + TIO (n = 116) versus TIO (n = 124) at all time points. The increase in FEV(1) 5 minutes after the first dose was 180 mL with FORM + TIO versus 40 mL with TIO (p < 0.001). At endpoint, FEV(1) AUC(0-4h) increased 340 mL with FORM + TIO versus 170 mL with TIO (p < 0.001). Improvements in trough FEV(1) with FORM + TIO versus TIO were 180 mL and 100 mL, respectively (p < 0.01). Significantly greater reductions from baseline in symptom scores (p < 0.05) and daytime albuterol use (p < 0.04) were seen at endpoint with combination FORM + TIO versus TIO monotherapy. Both treatments were well tolerated. This study demonstrated that concurrent treatment with FORM + TIO results in greater therapeutic benefits than TIO alone.

Topics: Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Vital Capacity

The UPLIFT study (Understanding Potential Long-term Impacts on Function with Tiotropium) was a double-blind, randomised, international, multicentric, placebo-controlled clinical trial, investigating with tiotropium (Spiriva) the change in the annual rate of decline in FEV1 in chronic obstructive pulmonary disease (COPD). Secondary end points included COPD exacerbation rate with or without hospitalisation, lung function, quality of life and mortality. 5.993 patients were randomized. In this article, we briefly describe the most important results of the study. While tiotropium did not alter the annual rate of decline in FEV1 (pre and postbronchodilatation), it improved lung function and quality of life, and reduced exacerbations and hospitalisations by comparison with control for up to 4 years. Tiotropium also reduced respiratory and cardiac morbidity.

Topics: Aged; Belgium; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Scopolamine Derivatives; Survival Analysis; Tiotropium Bromide; Treatment Outcome

Impulse oscillometry (IOS) is a forced oscillation technique that enables pulmonary functional studies to be performed without requiring strenuous maneuvers. IOS assesses different components of respiratory impedance. The aim of this study was to compare the inspiratory and expiratory IOS parameters in COPD patients. IOS and spirometry were performed in 15 COPD patients and 23 healthy subjects. Thereafter, COPD patients were treated with tiotropium and their pulmonary function was re-evaluated. In COPD patients, the variations in the IOS parameters were significantly larger during expiration than during inspiration. The improvement in R5-20 (the difference between the respiratory resistance at 5 and 20 Hz, which reflects the distal lung resistance) after tiotropium treatment was statistically detected only during inspiration (p=0.008), not during expiration (p=0.139). In conclusion, the expiratory IOS parameters varied more than the inspiratory parameters, particularly in COPD patients-possibly because of flow-limitation during expiration. Thus, the evaluation of IOS parameters may be more accurate during inspiration in COPD patients.

Topics: Adult; Age Factors; Aged; Biological Clocks; Bronchodilator Agents; Exhalation; Humans; Inhalation; Lung Volume Measurements; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Young Adult

Currently available long-acting inhaled bronchodilators (tiotropium, salmeterol, formoterol) have demonstrated beneficial effects on exacerbations in placebo-controlled trials. However, there have been no direct comparisons of these drugs with exacerbations as the primary outcome and consequently COPD treatment guidelines do not indicate a preference for either bronchodilator. Therefore, an international, randomized, double-blind, double-dummy, parallel-group clinical trial has been designed to investigate the comparative efficacy of 2 long-acting bronchodilators tiotropium 18 microg daily and salmeterol 50 microg bid on exacerbations. The trial will include at least 6800 randomized patients with diagnosis of COPD, >or= 10 pack-year history of smoking, post-bronchodilator FEV(1)

Topics: Adrenergic beta-Agonists; Adult; Aged; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Forced Expiratory Volume; Humans; Lung; Middle Aged; Pulmonary Disease, Chronic Obstructive; Research Design; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

In chronic diseases such as chronic obstructive pulmonary disease (COPD), patients may not perceive all of the benefits of drug therapy until withdrawal. Thus, we evaluated the effect of tiotropium withdrawal on clinical variables.. COPD subjects who participated in two identical 1-year, prospective, double-blind, placebo-controlled studies of tiotropium 18 microg once daily who completed a 3-week visit following discontinuation of therapy were included in this analysis. Outcomes measured included dyspnea (transition dyspnea index [TDI]), Peak Expiratory Flow Rate (PEFR), health status (St George's Respiratory Questionnaire [SGRQ]), and rescue beta2-agonist use.. Overall, the tiotropium group exhibited significant improvements in clinical parameters at the end of therapy. Of the entire cohort of 921 patients, 713 patients (77%) completed 3-weeks post-withdrawal evaluation. Patients in the tiotropium group had 1.1 unit worsening in TDI, decreased in PEFR, health status and reduced beta(2)-agonist medication following treatment discontinuation, while the placebo group remained relatively stable.. The withdrawal of tiotropium results in worsening of COPD over a three-week interval. There was no evidence of a rebound effect in response to tiotropium withdrawal.

Topics: Aged; Bronchodilator Agents; Dyspnea; Epidemiologic Methods; Female; Forced Expiratory Volume; Humans; Male; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Withholding Treatment

Current guidelines for the treatment of chronic obstructive pulmonary disease (COPD) recommend the use of long-acting bronchodilators in the maintenance management of COPD. Combining bronchodilators that work through different mechanisms is recommended in patients with continuous symptoms. We conducted this study to confirm and further investigate the efficacy and safety of nebulized formoterol as an add-on therapy to maintenance tiotropium in patients with COPD. This randomized, double-blind, placebo-controlled, parallel-group study (NCT00507234) was conducted at 24 US sites from March to October 2007 in 155 patients aged > or =40 years with post-bronchodilator forced expiratory volume in 1 second (FEV(1)) > or =25% to <65% predicted normal. COPD patients receiving open-label tiotropium bromide 18 microg once daily during a 1- to 2-week run-in period were randomized to receive either formoterol fumarate inhalation solution 20 microg or placebo by nebulization twice daily for 6 weeks while continuing treatment with tiotropium. Outcomes included serial spirometry, inspiratory capacity (IC), baseline dyspnoea index/transition dyspnoea index (BDI/TDI), daily symptom scores, salbutamol (albuterol) use and health status measured by the St George's Respiratory Questionnaire (SGRQ). The primary efficacy endpoint was standardized absolute FEV(1) area under the curve over 3 hours (AUC(0-3)) at week 6. Treatment groups (formoterol plus tiotropium, n = 78; placebo plus tiotropium, n = 77) were comparable at baseline. At 6 weeks, FEV(1) AUC(0-3) was significantly greater in the formoterol group compared with the placebo group (1.57 vs 1.38 L [p < 0.0001]). Similarly, formoterol plus tiotropium improved other lung function measures, including FEV(1), forced vital capacity and post-dose IC at day 1, and maintained efficacy through week 6. Formoterol plus tiotropium decreased rescue albuterol use throughout the study (p < 0.05). Mean TDI, SGRQ and most symptom scores did not differ between the two treatment groups. Overall, 37% of formoterol plus tiotropium recipients experienced adverse events versus 51% of those receiving placebo plus tiotropium. The addition of nebulized formoterol to tiotropium in maintenance treatment of COPD provided clinically meaningful, statistically significant and sustained improvements in pulmonary function without additional adverse effects.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Aged; Albuterol; Area Under Curve; Bronchodilator Agents; Drug Therapy, Combination; Dyspnea; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Budesonide/formoterol and tiotropium are commonly used maintenance treatments for patients with chronic obstructive pulmonary disease. Combining these medications may provide additional benefits.. To assess the efficacy and tolerability of budesonide/formoterol added to tiotropium in patients eligible for inhaled corticosteroid/long-acting beta(2)-agonist combination therapy.. In this 12-week, randomized, double-blind, parallel-group, multicenter study, after a 2-week run-in, 660 subjects (75% male; mean age, 62 yr; FEV(1), 1.1 L; 38% predicted normal), 40 years of age or older, received tiotropium (18 microg once daily) plus either budesonide/formoterol (320/9 microg) (n = 329) or placebo (n = 331) twice daily.. Clinic predose (primary outcome) and postdose FEV(1), predose and postdose forced vital capacity and inspiratory capacity, and health status were measured. Other outcomes included daily measurements taken at home (pre- and postdose morning FEV(1) and peak expiratory flow, morning symptoms and activities, and morning reliever use), severe exacerbations, and tolerability. Over the treatment period, budesonide/formoterol plus tiotropium significantly increased predose FEV(1) by 6% (65 ml) and postdose by 11% (123 and 131 ml at 5 and 60 min postdose, respectively) versus tiotropium alone (both P < 0.001). Other outcomes all significantly improved with budesonide/formoterol plus tiotropium versus tiotropium alone. The number of severe exacerbations decreased by 62% (rate ratio, 0.38; 95% confidence interval, 0.25-0.57; P < 0.001). Both treatments were well tolerated.. In patients with chronic obstructive pulmonary disease, budesonide/formoterol added to tiotropium versus tiotropium alone provides rapid and sustained improvements in lung function, health status, morning symptoms and activities, and reduces severe exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT00496470).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Aged; Aged, 80 and over; Budesonide; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD.. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study was a randomised, double-blind, placebo-controlled trial undertaken in 487 centres in 37 countries. 5993 patients aged 40 years or more with COPD were randomly assigned to receive 4 years of treatment with either once daily tiotropium (18 microg; n=2987) or matching placebo (n=3006), delivered by an inhalation device. Randomisation was by computer-generated blocks of four, with stratification according to study site. In a prespecified subgroup analysis, we investigated the effects of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease. Primary endpoints were the yearly rates of decline in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and in postbronchodilator FEV(1), beginning on day 30 until completion of double-blind treatment. The analysis included all patients who had at least three measurements of pulmonary function. This study is registered with ClinicalTrials.gov, number NCT00144339.. 2739 participants (mean age 64 years [SD 9]) had GOLD stage II disease at randomisation (tiotropium, n=1384; control, n=1355), with a mean postbronchodilator FEV(1) of 1.63 L (SD 0.37; 59% of predicted value). 1218 patients in the tiotropium group and 1157 in the control group had three or more measurements of postbronchodilator pulmonary function after day 30 and were included in the analysis. The rate of decline of mean postbronchodilator FEV(1) was lower in the tiotropium group than in the control group (43 mL per year [SE 2] vs 49 mL per year [SE 2], p=0.024). For prebronchodilator pulmonary function, 1221 patients in the tiotropium group and 1158 in the control group had three or more measurements and were included in the analysis. The rate of decline of mean prebronchodilator FEV(1) did not differ between groups (35 mL per year [SE 2] vs 37 mL per year [SE 2]; p=0.38). Health status, measured with the St George's Respiratory Questionnaire, was better at all timepoints in the tiotropium group than in the control group (p

Topics: Aged; Bronchodilator Agents; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Health Status; Humans; Linear Models; Male; Middle Aged; Patient Admission; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Severity of Illness Index; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated.. In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 microg or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1 s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128.. In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal.. Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients.. Nycomed.

Topics: Administration, Inhalation; Administration, Oral; Aged; Albuterol; Aminopyridines; Analysis of Variance; Benzamides; Bronchodilator Agents; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Regression Analysis; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Smoking; Tiotropium Bromide; Treatment Outcome; Vital Capacity

In the 4-year UPLIFT trial, tiotropium improved lung function and health-related quality of life and decreased exacerbations compared with usual respiratory medications except inhaled anticholinergics in patients with chronic obstructive pulmonary disease (COPD). Mortality and its causes was a secondary endpoint in UPLIFT.. We describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow-up of discontinued patients.. This study involved a randomized, double-blind trial comparing tiotropium with placebo in patients with COPD (>or=40 yr of age; postbronchodilator FEV(1)

Topics: Aged; Cause of Death; Cholinergic Antagonists; Double-Blind Method; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Smoking; Tiotropium Bromide

Ipratropium and albuterol, combined in a single formulation, is widely used as three to four times daily maintenance therapy in COPD. This trial compared tiotropium, once daily, as a potential alternative to patients already taking the ipratropium/albuterol combination.. 676 patients with moderate to very severe stable COPD (mean FEV(1)=39% of predicted) maintained on ipratropium/albuterol were randomized to receive over an 84 day period either tiotropium (18 mcg) each morning, or continue with ipratropium (26 mcg)/albuterol (206 mcg), 2 actuations 4 times daily, using a parallel group, double-blind, double-dummy design. Six-hour spirometry was assessed on study days 1, 22, and 84, along with safety assessments and other efficacy measures.. In terms of primary outcomes, mean trough FEV(1) at 84 days was larger in the tiotropium arm, as compared with the ipratropium/albuterol arm (difference=86 ml; 95% CI, 49 to 123 ml, p<0.0001). The mean FEV(1) AUC(0-6) at 84 days was also larger in the tiotropium arm (difference=17 ml; 95% CI, -21 to 56 ml), this difference being statistically non-inferior to the ipratropium/albuterol arm (p<0.001), but not statistically superior (p=0.37). Other efficacy measures were similar in the two groups. Lower respiratory adverse events were reported in 40 tiotropium patients vs. 52 ipratropium/albuterol patients. Safety reporting was otherwise similar.. Patients previously maintained on the ipratropium/albuterol combination taken four times daily can be switched to tiotropium once daily with the reasonable expectation of at least equivalent bronchodilation during daytime hours and superior bronchodilation during early morning hours.

Topics: Aged; Albuterol; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Ipratropium; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

Evaluation of tiotropium efficacy in patients with mild chronic obstructive pulmonary disease (COPD) defined by the 2003 Swedish Society of Respiratory Medicine guidelines (post-bronchodilator FEV1/FVC <70%; FEV1 >60% predicted).. In this 12-week, randomised, double-blind, placebo-controlled study of tiotropium 18 mcg once daily versus placebo, respiratory function was assessed on Days 1, 15 and 85 (baseline: pre-dose Day 1).. Mean+/-SD baseline FEV1 (% predicted) was 73.4+/-12.5 (tiotropium, n=107; placebo, n=117). Tiotropium significantly improved change from baseline in area under the curve from pre-dose to 2 hours post-dose (AUC0-2 h) FEV1 versus placebo, by 166+/-26 mL (mean+/-SE) at study end (p<0.0001). With tiotropium, there were significant increases in the change in AUC0-2 h FVC versus baseline, and trough FEV1 and FVC, versus placebo, on all test days (p<0.01). Adverse event rates were similar.. Compared with placebo, tiotropium improved lung function in patients with mild COPD.

Topics: Bronchodilator Agents; Double-Blind Method; Dyspnea; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Severity of Illness Index; Spirometry; Tiotropium Bromide; Vital Capacity

Cold air hyperventilation is an indirect challenge (cold air challenge, CACh) with high specificity and low sensitivity in defining asthmatic subjects. A small proportion of chronic obstructive pulmonary disease (COPD) patients present with positive CACh. The aim of this prospective study was to investigate the presence of factors related to cold air challenge (CACh) in COPD patients. Factors examined were FEV(1), FEV(1)/FVC, reversibility after bronchodilation, eosinophils in induced sputum, bronchial hyperresponsiveness to methacholine and the spirometric response to tiotropium compared to placebo. We studied 92 consecutive COPD patients in order to retrieve 15 CACh positive + patients. Fifteen COPD patients with negative CACh [CACh(-)], randomly selected from the initial group, were added in order to retrieve a group of 30 patients. Spearman's correlation coefficient was used in order to evaluate possible significant correlations between CACh values and study parameters. Sixteen percent of our subjects presented CACh+. CACh values were repeatable with an intraclass correlation coefficient between the two measurements 0.980 (95% CI 0.940-0.993). The only significant correlation observed was between Delta FEV(1) after CACh [Delta(C)FEV(1)] and trough FEV(1) values post tiotropium inhalation (r(2) = 0.62, p < 0.0001). When we analyzed the response to tiotropium in the 2 separate groups we found that patients with CACh+ presented significantly lower values of trough FEV(1) compared to those with CACh(-). In conclusion, a small proportion of COPD patients present with bronchial hyperresponsiveness to CACh. The only parameter related to CACh + in our study was a smaller bronchodilating effect of tiotropium.

Topics: Aged; Bronchial Provocation Tests; Bronchodilator Agents; Capnography; Cold Temperature; Forced Expiratory Volume; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide

Little is known about the combination of different medications in chronic obstructive pulmonary disease (COPD). This study determined the cost effectiveness of adding salmeterol (S) or fluticasone/salmeterol (FS) to tiotropium (T) for COPD.. This concurrent, prospective, economic analysis was based on costs and health outcomes from a 52 week randomised study comparing: (1) T 18 microg once daily + placebo twice daily (TP group); (2) T 18 microg once daily + S 25 microg/puff, 2 puffs twice daily (TS group); and (3) T 18 microg once daily + FS 250/25 microg/puff, 2 puffs twice daily (TFS group). The incremental cost effectiveness ratios (ICERs) were defined as incremental cost per exacerbation avoided, and per additional quality adjusted life year (QALY) between treatments. A combination of imputation and bootstrapping was used to quantify uncertainty, and extensive sensitivity analyses were performed.. The average patient in the TP group generated CAN$2678 in direct medical costs compared with $2801 (TS group) and $4042 (TFS group). The TS strategy was dominated by TP and TFS. Compared with TP, the TFS strategy resulted in ICERs of $6510 per exacerbation avoided, and $243,180 per QALY gained. In those with severe COPD, TS resulted in equal exacerbation rates and slightly lower costs compared with TP.. TFS had significantly better quality of life and fewer hospitalisations than patients treated with TP but these improvements in health outcomes were associated with increased costs. Neither TFS nor TS are economically attractive alternatives compared with monotherapy with T.

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Cost-Benefit Analysis; Delayed-Action Preparations; Drug Combinations; Fluticasone; Humans; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Salmeterol Xinafoate; Scopolamine Derivatives; Theophylline; Tiotropium Bromide

Sparse information exists about chronic obstructive pulmonary disease (COPD) outcomes among different ethnic groups. To determine whether the effect of tiotropium on COPD exacerbation differs between African Americans and Caucasians, we performed a post hoc analysis of African-American (n = 150) and Caucasian (n = 1670) subgroups from a previously reported 6-month trial of tiotropium in patients with moderate-to-very-severe COPD. Compared with placebo, tiotropium reduced the likelihood of having at least 1 exacerbation in the entire group (RR, 0.81; 95% CI, 0.66-0.99, P = 0.037) with no statistically significant difference between African-American and Caucasian subgroups (P = 0.34). For African Americans, tiotropium significantly reduced the number of antibiotic days for COPD, hospitalizations for exacerbations, and hospitalization days for COPD. For Caucasians, tiotropium significantly reduced the number of exacerbations, exacerbation days, unscheduled clinic visits for COPD, and hospitalizations for exacerbations. Tiotropium reduced the frequencies of antibiotic days and of COPD hospital days to a significantly greater extent in African Americans compared with Caucasians (P = 0.027 and P = 0.025, respectively). No statistically significant ethnic-related differences were observed in the effect of tiotropium on the frequencies of exacerbations, exacerbation days, systemic corticosteroid days, unscheduled clinic visits, or COPD hospitalizations. Spirometry improved to a similar extent in both subgroups for the entire duration of the 6-month trial. African Americans used fewer respiratory medications than Caucasians in this study. We conclude that tiotropium reduces COPD exacerbations and associated health-care use to a similar extent in African Americans compared with Caucasians.

Topics: Aged; Black or African American; Female; Hospitalization; Humans; Male; Pulmonary Disease, Chronic Obstructive; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide; White People

Clinical manifestations of chronic obstructive pulmonary disease (COPD), including airflow limitation, dyspnea, and activity limitation, ultimately lead to impaired health-related quality of life (HRQoL). This 9-month, randomized, double-blind, multicenter study compared the effect of once-daily tiotropium 18 microg and placebo on HRQoL, spirometric parameters, and exacerbations in 554 patients with moderate-to-severe COPD. HRQoL was assessed using the St. George's Respiratory Questionnaire (SGRQ) and the new 8-item Visual Simplified Respiratory Questionnaire (VSRQ), which is currently being validated. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end (Month 9). Mean +/- SD baseline SGRQ total score was 47.4 +/- 18.1. Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score vs placebo at study end (59.1% vs 48.2%, respectively; p = 0.029). Tiotropium significantly improved spirometric parameters (forced expiratory volume in 1 second [FEV1]: 0.11 +/- 0.02 L vs 0.01 +/- 0.02 L; between-group difference: 0.10 +/- 0.03 L, p = 0.0001) and reduced exacerbations vs placebo. Maintenance treatment with tiotropium provided significant and clinically relevant improvements in HRQoL, as measured by the SGRQ.

Topics: Cholinergic Antagonists; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Flow Rates; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Retrospective Studies; Scopolamine Derivatives; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome

To determine which timing of therapy with formoterol (FOR) and/or tiotropium (TIO) shows the greater and more continuous functional improvement during 24 h in patients with moderate to severe COPD.. In this randomised, blind, crossover study 80 patients with stable COPD (40 moderate and 40 severe) received 5 different bronchodilator 30-day treatments in a random order. Treatments (Tr) were: Tr1: TIO 18 microg once-daily (8 am); Tr2: TIO 18 microg (8 am) + FOR 12 microg (8 pm); Tr3: FOR 12 microg twice-daily (8 am and 8 pm); Tr4: TIO 18 microg (8 am) + FOR 12 microg twice-daily (8 am and 8 pm); Tr5: FOR 12 microg twice-daily (8 am and 8 pm) + TIO 18 microg (8 pm). Spirometries were performed during 24 h (13 steps) on Day1 and Day30. End-points were: gain of FEV(1) (DeltaFEV(1)) from baseline of the Day1 and Day30, AUC (Area Under Curve), Dyspnoea Index, and as-needed use of salbutamol.. Sixty-eight patients completed all treatments. The greater and continuous daily functional improvement was showed during Tr4 and Tr5 (Day1 +135.8 mL and +119.1 mL; Day30 +160.2 mL, and +160.5 mL, respectively). Daily means of DeltaFEV(1) were significantly different between single-drug treatments and combination therapy. Dyspnoea was greater in single-drug treatments. Less use of rescue salbutamol was reported in Tr4 (0.80 puffs/die) and Tr5 (0.71 puffs/die).. In patients with moderate to severe COPD, combination therapy with tiotropium administered in the morning (Tr4) was the most effective; in patients with prevailing night-symptoms, treatment with tiotropium in the evening (Tr5) reduced symptoms and use of salbutamol. Tr5 showed less variability of FEV(1) during the 24 h (CV=0.256). These results are relevant for opening new ways in clinical practice.

Topics: Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Dyspnea; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Although guidelines recommend combining long-acting bronchodilators in COPD, data are limited. We examined the clinical efficacy and safety of formoterol, tiotropium and the combination in patients with COPD. Eight hundred and forty-seven patients with COPD (mean FEV(1) 52% predicted; FEV(1)/FVC 53%) were randomized to receive one of the following four treatments for 24 weeks: formoterol 10 microg b.i.d. plus tiotropium 18 microg o.d.; formoterol 10 microg b.i.d.; tiotropium 18 microg o.d., or placebo. The study was partially blinded (formoterol and placebo). For the primary endpoint, FEV(1) 2h post-dose after 24 weeks, there were small differences in favour of the combination therapy versus formoterol (0.07 L, p=0.044) or tiotropium (0.06 L, p=0.066). All three treatments were superior to placebo (p<0.001). The combination was statistically superior to monotherapy for: the primary endpoint (p=0.044 vs. formoterol); FEV(1) 5 min after the first dose (p<0.001) and at 12 weeks (p<0.05 vs. tiotropium); and peak expiratory flow averaged over the first 6 weeks (p<0.001 vs. both). The three active treatments were significantly more effective than placebo for secondary endpoints: COPD-related 'bad days', symptoms, use of rescue medication and peak expiratory flow, and aspects of health-related quality of life. The overall incidence of adverse events was similar with all active treatments, although COPD-related adverse events were more common with tiotropium. Combined bronchodilator therapy may be a valuable treatment option for patients with COPD.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Electrocardiography; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease (COPD) led us to examine the long-term effects of tiotropium therapy.. In this randomized, double-blind trial, we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs. The patients were at least 40 years of age, with a forced expiratory volume in 1 second (FEV(1)) of 70% or less after bronchodilation and a ratio of FEV(1) to forced vital capacity (FVC) of 70% or less. Coprimary end points were the rate of decline in the mean FEV(1) before and after bronchodilation beginning on day 30. Secondary end points included measures of FVC, changes in response on St. George's Respiratory Questionnaire (SGRQ), exacerbations of COPD, and mortality.. Of a total of 5993 patients (mean age, 65+/-8 years) with a mean FEV(1) of 1.32+/-0.44 liters after bronchodilation (48% of predicted value), we randomly assigned 2987 to the tiotropium group and 3006 to the placebo group. Mean absolute improvements in FEV(1) in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation), as compared with the placebo group (P<0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV(1) before and after bronchodilation were not significant. The mean absolute total score on the SGRQ was improved (lower) in the tiotropium group, as compared with the placebo group, at each time point throughout the 4-year period (ranging from 2.3 to 3.3 units, P<0.001). At 4 years and 30 days, tiotropium was associated with a reduction in the risks of exacerbations, related hospitalizations, and respiratory failure.. In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1). (ClinicalTrials.gov number, NCT00144339.)

Topics: Adult; Aged; Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

To observe the efficacy of combination therapy with inhaled salmeterol/fluticasone and tiotropium in reducing the frequency of acute episodes of symptom exacerbation and improving lung function and health status in chronic obstructive pulmonary disease (COPD).. One hundred and twenty-six patients (M/F: 92/34) with COPD were treated in a randomised, parallel-group, controlled study with salmeterol/fluticasone (50/250 microg) twice daily and tiotropium 18 microg once daily (n = 33, M/F: 23/10); salmeterol/fluticasone (50/250 microg) twice daily (n = 32, M/F: 24/8); or tiotropium 18 microg once daily (n = 32, M/F: 23/9) for 12 months. Patients in the blank control group (n = 29, M/F: 22/7) did not receive any inhaled anticholinergic drugs, long-acting beta(2) agonists or glucocorticoid therapy. Intention-to-treat analysis (n = 161) and per-protocol analysis (n = 126, age 45 - 71 years) were performed.. Three active treatments significantly improved symptoms and health status. The use of rescue medication in the combination group [1 (0 - 7) time, 95% CI] was significantly decreased compared with those in the blank group [2 (0 - 29) times], salmeterol/fluticasone alone [2 (0 - 13) times], tiotropium alone [1 (0 - 11) time], F = 4.914, P < 0.01. The frequency of exacerbations in the combination group was (0.7 +/- 0.5) time, significantly lower than that in the blank group [(1.5 +/- 0.9) times], salmeterol/fluticasone alone [(1.2 +/- 0.6) times], and tiotropium alone [(1.1 +/- 0.5) times], F = 8.513, P < 0.01. The FEV(1) in the combination group after the trial was (1.19 +/- 0.03) L, significantly improved compared to that before treatment (1.09 +/- 0.04) L, a 9.5% increase, which was greater than the blank (0.9%), tiotropium alone (8.2%) and salmeterol/fluticasone alone (6.3%), t = -5.024 to -15.58, P < 0.01.. Combination therapy with salmeterol/fluticasone and tiotropium leads to better control of symptoms and improved lung function, with no greater risk of side-effects, as compared to salmeterol/fluticasone or tiotropium alone in the treatment of COPD.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Cholinergic Antagonists; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Exercise training improves exercise tolerance in chronic obstructive pulmonary disease (COPD). Tiotropium 18 microg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation, one of the pathophysiological factors contributing to exertional dyspnea in COPD patients.. To determine whether tiotropium enhances the effects of exercise training in patients with COPD.. Multicenter, 25 week randomized, double-blind, placebo-controlled, parallel-group study.. Twelve Italian Pulmonary Units practicing pulmonary rehabilitation.. Two hundred thirty four COPD patients (196 males; mean age: 67.4 +/- 7.6; forced expiratory volume at 1 second (FEV1): 41.4 +/- 13.0% predicted) were randomised to tiotropium 18 microg or placebo inhalation capsules taken once daily. Both groups underwent a 8 week pulmonary rehabilitation program (PR) consisting of 3 exercise training session per week.. Baseline, at the end of PR and after 12 weeks, patients completed pulmonary function testing, six minute walking test (6MWT), the Baseline and Transition Dyspnea Index (BDI and TDI), and the St. George's Respiratory Questionnaire (SGRQ).. Relative to placebo, tiotropium had larger trough and post-study drug FEV1 responses on all test days. At the end of and 12 weeks following PR, patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo. Compared to the period immediately prior to PR, the mean improvement in 6MWT was only 29.7 meters (7.1%) for the combined cohort. Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo (p < 0.01). At 12 weeks after PR, TDI focal scores were 2.71 for tiotropium and 2.11 for placebo (p = 0.16). Reduction in all four SGRQ component scores, indicating an improvement in health-related quality of life, was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant. During the study period, there were fewer exacerbations and exacerbation days in the tiotropium group.. Although significant improvements were observed with perceived dyspnea, compared to placebo, the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT.

Topics: Aged; Bronchodilator Agents; Cholinergic Antagonists; Combined Modality Therapy; Double-Blind Method; Dyspnea; Exercise Therapy; Exercise Tolerance; Female; Forced Expiratory Volume; Hospitalization; Humans; Italy; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; Walking

International guidelines recommend the long-acting anticholinergic, tiotropium, or long-acting beta 2-agonists as maintenance therapy in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). The efficacy of long-acting beta(2)-agonists combined with inhaled corticosteroids (ICS) in the treatment of COPD has also been confirmed for severe and very severe COPD, but data comparing tiotropium with the combination of a long-acting beta 2-agonist and an ICS are lacking.. This 6-week multicentre, randomised, double-blind, triple-dummy pilot study compared the bronchodilator effects of tiotropium 18 microg once daily (n=56) vs. the combination of salmeterol 50 microg plus fluticasone 250 microg twice daily (n=51) in patients with moderate-to-very severe COPD. Serial spirometry was performed over 12h after 6 weeks of treatment. The primary endpoint was forced expiratory volume in 1s (FEV1) area under the curve from 0 to 12h (AUC0-12h) on Day 43.. Randomization failed to provide treatment groups with comparable baseline characteristics for smoking history, current smokers, duration of COPD, FEV1, forced vital capacity (FVC) and reversibility. Mean+/-SD FEV1 was 1.31+/-0.47 l in the tiotropium group vs. 1.46+/-0.53 l in the salmeterol plus fluticasone group. Fewer patients in the tiotropium showed a 12% and 200 ml acute increase to short-acting bronchodilators at baseline. However, treatment with tiotropium alone resulted in comparable bronchodilation compared with salmeterol plus fluticasone, as measured by all the spirometric parameters at the end of the 6-week study period. FEV1 AUC0-12h was 1.55+/-0.03 l in the tiotropium group vs. 1.57+/-0.04 l in the salmeterol plus fluticasone groups (p=0.63). Trough (predose) FEV1 was 1.54+/-0.03 l in the tiotropium group vs. 1.46+/-0.03 l in the combination group (p=0.07), and peak FEV(1) was 1.68+/-0.04 l vs. 1.66+/-0.04 l, respectively, (p=0.77). FVC AUC0-12h, trough and peak were also comparable between groups at study end (p>0.05, for all). Further, rescue salbutamol use was similar in the tiotropium and combination groups and both treatment regimens were well tolerated.. Six weeks of treatment with tiotropium resulted in comparable bronchodilation compared with salmeterol plus fluticasone in patients with moderate-to-very severe COPD, despite tiotropium patients having lower lung function and fewer patients considered reversible at baseline. The results of this pilot study will aid planning for further large-scale comparative studies.

Topics: Adult; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Fluticasone-Salmeterol Drug Combination; Humans; Male; Middle Aged; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

This study evaluated whether the effect of tiotropium on the change in trough forced expiratory volume in 1s (FEV1), vs. placebo, is affected by smoking status. In a 3-month, double-blind study in 31 centres in Portugal, 311 (289 completed) patients were randomised to tiotropium 18 microg once daily or placebo. Baseline mean (standard deviation (SD)) FEV1 was 1.11 (0.39) l in the tiotropium group and 1.13 (0.39) l in the placebo group. Patients had an average smoking history of 55 (25.7) pack-years; 80 (26%) were smokers and 224 (74%) were ex-smokers. The primary end-point was change in morning pre-dose (i.e. trough) FEV1 after 12 weeks. Trough FEV1 at 12 weeks was significantly improved with tiotropium vs. placebo: the difference in means was 102 ml, P=0.0011, 95% confidence interval (CI) (41, 164). The difference in means in smokers was 138 ml, P=0.0105, CI (32, 244); in ex-smokers it was 66 ml, P=0.0375, CI (3, 129). The difference between smokers and ex-smokers was not statistically significant (P=0.6982) and may be due to greater variability and differences in disease severity. The significant improvement in lung function in patients treated with tiotropium vs. placebo in both smokers and ex-smokers suggests that tiotropium is an effective and well-tolerated therapy in chronic obstructive pulmonary disease (COPD), regardless of smoking status.

Topics: Aged; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking; Tiotropium Bromide

Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease (COPD).. We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination (salmeterol/fluticasone propionate) 50/500 microg twice daily and the long-acting bronchodilator (tiotropium) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD.. A total of 1,323 patients (mean age, 64 yr, post-bronchodilator FEV1, 39% predicted) were randomized in this 2-year, double-blind, double-dummy parallel study.. Primary endpoint was health care utilization exacerbation rate. Other endpoints included health status measured by St. George's Respiratory Questionnaire (SGRQ), mortality, adverse events, and study withdrawal. Probability of withdrawing from the study was 29% greater with tiotropium than salmeterol/fluticasone propionate (P = 0.005). The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group (rate ratio, 0.967; 95% confidence interval [CI], 0.836-1.119]; P = 0.656). The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium (difference 2.1 units; 95% CI, 0.1-4.0; P = 0.038). Mortality was significantly lower in the salmeterol/fluticasone propionate group; 21 (3%) of patients in this group died compared with 38 (6%) in the tiotropium group (P = 0.032). More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium (P = 0.008).. We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium. More patients failed to complete the study while receiving tiotropium. A small statistically significant beneficial effect was found on health status, with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients. Clinical trial registered with www.clinicaltrials.gov (NCT 00361959).

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Fluticasone-Salmeterol Drug Combination; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Secondary Prevention; Survival Rate; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) and asthma have different diagnostic criteria and treatment paradigms. Both are common and can occur in the same patient. We sought to determine the spirometric effects of tiotropium in COPD patients with concomitant asthma.. A 12-week randomized, double-blind, placebo-controlled, parallel group trial with tiotropium 18 mcg daily was performed. Patients continued usual respiratory medications except for inhaled anticholinergics.. Physician diagnosis of COPD and asthma, age >or= 40 years, smoking >10 pack years, post-bronchodilator forced expiratory volume in 1s (FEV(1))<80% predicted, FEV(1)/forced vital capacity (FVC)<70%, >or= 12%, and >or= 200 ml increase in FEV(1) following inhaled bronchodilator, treatment with inhaled steroids >or= 1 year. Spirometry was measured serially for 6h on days 1, 29 and 85.. Four hundred and seventy-two patients were randomized. Baseline characteristics were balanced. Mean age=59.6 years, 61.4% were men, and FEV(1)=1.55l (53.0% predicted). Improvements at 12 weeks with tiotropium were observed for the primary endpoint FEV(1) area under the curve (AUC) from 0 to 6h (difference=186+/-24 ml, p<0.001) and for morning pre-dose FEV(1) (difference=98+/-23 ml, p<0.001). Significant differences in favor of tiotropium were observed for pre-dose FVC (difference=128+/-34 ml, p<0.001) and FVC AUC 0-6h (difference=232+/-35 ml, p<0.001). Compared to baseline, the mean weekly number of daily puffs of prn salbutamol was reduced by 0.05+/-0.12 puffs/day in the placebo group and by 0.50+/-0.12 puffs/day in the tiotropium group at week 12 (p<0.05).. Patients with COPD and concomitant asthma achieve spirometric improvements with tiotropium along with symptomatic benefit as seen by reduced need for rescue medication.

Topics: Asthma; Bronchodilator Agents; Epidemiologic Methods; Female; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

The aim of these studies was to compare the efficacy and the safety of tiotropium, delivered via Respimat Soft Mist Inhaler (SMI), a novel multi-dose, propellant-free inhaler, with ipratropium pressurized metered-dose inhaler (pMDI) in chronic obstructive pulmonary disease (COPD) patients. Two identical, 12-week, multi-national, randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled studies were performed. COPD patients were randomized to treatment with either inhaled tiotropium (5 or 10 microg) via Respimat SMI administered once daily, ipratropium (36 microg) pMDI QID or placebo. The primary endpoint was the mean trough forced expiratory volume in 1s (FEV(1)) response after 12 weeks of treatment. Secondary endpoints included other spirometry measures and rescue medication use. A total of 719 patients were randomized; the majority were male (69%) with a mean pre-bronchodilator FEV(1) (% predicted) of 40.7%. The mean treatment differences between tiotropium 5 and 10 microg and placebo for the primary endpoint (mean trough FEV(1) response at week 12) were 0.118 and 0.149L, respectively (both P<0.0001). Treatment differences between tiotropium 5 and 10 microg and ipratropium were 0.064L (P=0.006) and 0.095L (P<0.0001). The increases in peak FEV(1), FEV(1) AUC((0-6h)) and FVC for both tiotropium doses were statistically superior to placebo (P<0.01) and higher than ipratropium. All active treatments significantly reduced the rescue medication use compared with placebo, but only tiotropium 10 microg was statistically superior to ipratropium (P=0.04). The incidence of adverse events was comparable across groups. In conclusion, tiotropium 5 and 10 microg daily, delivered via Respimat SMI, significantly improved lung function compared with ipratropium pMDI and placebo.

Topics: Adult; Aged; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Ipratropium; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The combination of salmeterol and fluticasone propionate (SFC) and tiotropium bromide (TIO) are commonly used treatments in chronic obstructive pulmonary disease (COPD) but there are few data on their effectiveness when used together. We compared the effects of SFC 50/500 microg twice daily in addition to TIO 18 microg once daily with the individual treatments alone.. 41 patients with COPD participated in a randomised, double blind, double dummy, three way crossover study with 2 week washout periods between treatments. Lung function assessment included plethysmography and spirometry. The primary end point was post-dose specific airways conductance (sGaw) area under the curve (AUC(0-4 h)) on day 14.. AUC(0-4 h) sGaw was significantly higher on day 14 after SFC+TIO compared with TIO (22%) or SFC alone (27%) (both p<0.001). SFC+TIO significantly improved trough forced expiratory volume in 1 s compared with TIO alone (212 ml, p<0.001) and SFC alone (110 ml, p = 0.017) on day 14. Inspiratory capacity measurements also showed significant benefits for triple therapy over individual components on day 14. Subjects receiving SFC+TIO had clinically relevant improvements in Transition Dyspnoea Index (TDI) total score of 2.2 compared with TIO alone (p<0.001) (but not SFC alone, 0.7; NS) and used significantly less rescue medication (1.0 occasion less daily than TIO (p<0.001) and 0.6 less than SFC (p = 0.01)).. SFC+TIO triple therapy led to greater improvements in bronchodilation compared with TIO and SFC alone. The advantages of triple therapy are observed across a range of physiologically important parameters, including airway conductance and lung volumes. Triple therapy also led to patient related benefits by improving TDI and use of rescue medication.

Topics: Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Lung Volume Measurements; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease (COPD) patients, and depends upon the type and dose of bronchodilator and the timing of administration. Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, a 4-yr randomised double-blind trial evaluating the efficacy of 18 mug tiotropium daily in reducing the rate of decline in lung function. After wash-out of respiratory medications, patients received 80 mug ipratropium followed by 400 mug salbutamol. Spirometry was performed before and 90 min following ipratropium administration. The criteria used for forced expiratory volume in one second (FEV(1)) responsiveness were: >or=12% increase over baseline and >or=200 mL; >or=15% increase over baseline; and >or=10% absolute increase in the percentage predicted value. Of the patients, 5,756 had data meeting the criteria for analysis (age 64.5 yrs; 75% male; baseline FEV(1) 1.10 L (39.3% predicted) and forced vital capacity (FVC) 2.63 L). Compared with baseline, mean improvements were 229 mL in FEV(1) and 407 mL in FVC. Of these patients, 53.9% had >or=12% and >or=200 mL improvement in FEV(1), 65.6% had >or=15% improvement in FEV(1), and 38.6% had >or=10% absolute increase in FEV(1) % pred. The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators.

Topics: Aged; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

Adding a long-acting beta(2)-agonist (LABA) by dry powder inhaler (DPI) to tiotropium provides significantly increased and sustained bronchodilation in chronic obstructive pulmonary disease (COPD) patients over either product alone. To demonstrate similar benefits with a nebulized LABA, a placebo-controlled trial was conducted to evaluate the efficacy and safety of formoterol fumarate inhalation solution in subjects receiving tiotropium as a maintenance treatment for COPD. After a 7-14-day screening period using tiotropium 18 microg once daily, subjects with diagnosed COPD (> or = 25% to <65% predicted FEV(1)) were randomized to receive 20 microg formoterol fumarate inhalation solution twice daily for nebulization plus tiotropium (FFIS/TIO) or nebulized placebo twice daily plus tiotropium (PLA/TIO) for 6 weeks. Efficacy was assessed with spirometry at each visit (Day 1, Week 1, 3, 6), the transition dyspnea index (TDI), and St. George's Respiratory Questionnaire (SGRQ). Baseline characteristics were comparable, including mean FEV(1)% predicted. At Week 6, FEV(1) AUC(0-3) was 1.52 L for FFIS/TIO-treated subjects vs. 1.34 L for PLA/TIO-treated subjects (p<0.0001). The mean TDI scores in the FFIS/TIO and PLA/TIO groups were 2.30 and 0.16, respectively (p=0.0002). SGRQ did not change significantly with 6 weeks treatment, with the exception of FFIS/TIO improvements in symptom score vs. PLA/TIO (p=0.04). More PLA/TIO- than FFIS/TIO-treated subjects experienced AEs (39.7% vs. 22.9%), COPD exacerbations (7.9% vs. 4.5%), and serious AEs (3.2% vs. 1.5%). Nebulized formoterol fumarate in combination with tiotropium provided statistically and clinically significant improvements in bronchodilation and symptom control over tiotropium alone and demonstrated good tolerability.

Topics: Administration, Inhalation; Aged; Area Under Curve; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Lung; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Responsiveness to pharmacologic agents may differ among subpopulations compared with the general population. In patients of African descent, possible differences have been observed for inhaled beta-agonists. However, pharmacologic responsiveness to a long-acting anticholinergic has not been prospectively evaluated.. An 8-week, randomized, placebo-controlled clinical trial was conducted to assess the efficacy of the once-daily, inhaled anticholinergic tiotropium in COPD patients of African descent. African-American COPD patients > or =40 years, FEV(1) < or= 65% predicted, FEV(1)/FVC < or=70% were included. Spirometry (pre-study drug, and 0.5, 1, 2 and 3 hours post-dose) and the University of California, San Diego Shortness of Breath Questionnaire (SOBQ) were performed at baseline and at 4 and 8 weeks. Data on use of rescue medication and on adverse events (including COPD exacerbations) were also collected.. Randomized patients (n = 166) were (mean +/- SD) 62.5 +/- 9.3 years; baseline mean FEV(1) 1.02 +/- 0.37 L (41 +/- 13% predicted); 67.5% were male. A total of 160 patients were eligible for efficacy evaluation. At 8 weeks, mean FEV(1) AUC(0 - 3) response was 180 mL greater with tiotropium (n = 78) than with placebo (n = 82), (p < 0.0001). Difference (tiotropium-placebo) for mean peak FEV(1) response was 182 mL (p < 0.0001) and 122 mL (p = 0.002) for mean trough FEV(1) response. There were no significant differences in SOBQ or use of rescue medication between the groups. No patients in the tiotropium group experienced a COPD exacerbation compared with 12 in patients receiving placebo.. Tiotropium significantly improved pulmonary function in African-American COPD patients.

Topics: Administration, Inhalation; Black or African American; Cholinergic Antagonists; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Powders; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome; United States

It has been documented that tiotropium is less likely to induce oxygen desaturation in stable COPD patients compared to long-acting beta2-agonists (LABAs) and combined administration of a LABA and an inhaled corticosteroid (ICS) reduces the potential for acute effects of LABA on blood-gas tensions. In this study, we have compared the acute effects of tiotropium 18 microg and salmeterol/fluticasone combination (SFC) 50/250 microg on arterial blood gases in 20 patients with stable COPD. Each subject was studied on 2 days, separated from one another by at least 4 days. Blood specimens were taken just before the inhalation and at 15, 30, 60, 180 and 360 min after inhalation of each treatment, and spirometry was performed at the same time points. As expected, both treatments significantly improved FEV1 (greatest changes were 0.20 L, 95% CI: 0.13-0.27 at 360 min after tiotropium; and 0.13 L, 95% CI: 0.06-0.19 at 180 min after SFC). The greatest mean changes from baseline in PaO2 were -1.7 (95% CI: -4.0 to 0.6)mmHg, p=0.134, after tiotropium; -0.8 (95% CI: -2.2 to 0.6)mmHg, after SFC. Both changes were observed after 15 min. Both drugs caused a small decrease in PaCO2 (greater changes: -1.9 (95% CI -3.2 to -0.6)mmHg, p=0.005 at 60 min after tiotropium; and -2.4 (95% CI: -3.5 to -1.3) mmHg, p=0.0002 at 180 min after SFC). These results indicate that both tiotropium and SFC are able to induce a significant long-last bronchodilation without affecting arterial blood gases. Moreover, they confirm that the impact of tiotropium on PaO2 is small and without clinical significance and the addition of a LABA to an ICS can reduce the potentially dangerous acute effect of the LABA on blood gases.

Topics: Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Inflammatory Agents; Bronchodilator Agents; Carbon Dioxide; Cross-Over Studies; Drug Combinations; Fluticasone; Forced Expiratory Volume; Humans; Oxygen; Partial Pressure; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

Recently, there has been interest in interactions of beta(2) adrenergic receptors (beta(2)-AR) and muscarinic acetylcholine receptors (mAChR), which share intracellular signal transduction systems. The aim of the present study was to investigate whether bronchodilator response to tiotropium is influenced by beta(2)-AR genotype in patients with COPD who show poor responsiveness to inhaled beta(2)-agonists.. After a 4-week run-in period, patients with COPD were treated with inhaled tiotropium bromide (18 microg once daily) for 8 weeks. Spirometric measurements and reversibility testing with inhaled beta(2)-AR agonists were performed and health-related quality of life was assessed using the St George's respiratory questionnaire (SGRQ) before and after treatment. Genomic DNA was prepared from peripheral blood and individual genotypes at amino acid 16 of the beta(2)-AR were examined.. Forty-four patients with COPD completed the study. COPD patients with the Arg/Arg genotype (n = 22) had a significant increase in FEV(1) during treatment compared with those without the Arg/Arg genotype (n = 22) (FEV(1), P = 0.009; FEV(1)%, P = 0.006). While all component and total scores on the SGRQ improved significantly in both genetic groups, changes in impact and total scores were significantly greater in patients with Arg/Arg compared with those without (total scores, P = 0.005; impact scores, P < 0.001).. These findings indicate that the homozygous Arg/Arg genotype at amino acid 16 of the beta(2)-AR could affect bronchodilator response to tiotropium in patients with COPD with significant effects on health-related quality of life.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Albuterol; Alleles; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Resistance; Female; Forced Expiratory Volume; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Pulmonary Disease, Chronic Obstructive; Receptors, Adrenergic, beta-2; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

A 6-week, multicenter, randomized, double-blind, parallel-group study was conducted in patients with COPD to compare lung function improvements of tiotropium, 18 microg qd, plus formoterol, 12 microg bid, to salmeterol, 50 microg bid, plus fluticasone, 500 microg bid.. Following a screening visit, subjects entered a run-in period in which they received regular ipratropium. At randomization, patients were assigned to either tiotropium plus formoterol or salmeterol plus fluticasone. After 6 weeks of treatment, a 12-h lung function profile was obtained. The coprimary end points were FEV(1) area under the curve for the time period 0 to 12 h (AUC(0-12)) and peak FEV(1).. A total of 729 patients were screened, and 605 patients were randomized and treated. A total of 592 patients (baseline FEV(1), 1.32 +/- 0.43 L/min [+/-SD]) were included in the analysis. After 6 weeks, the 12-h lung function profiles in the group receiving tiotropium plus formoterol were superior to those in the group receiving salmeterol plus fluticasone (mean difference in FEV(1) AUC(0-12), 78 mL [p = 0.0006]; mean difference in FVC AUC(0-12), 173 mL, p < 0.0001). Also, peak responses were in favor of tiotropium plus formoterol (difference in peak FEV(1), 103 mL [p < 0.0001]; difference in peak FVC, 214 mL [p < 0.0001]), as were FEV(1) and FVC at each individual time point after dose (p < 0.05). Predose FVC was significantly higher with the bronchodilator combination, while predose FEV(1) and rescue medication use did not differ significantly between groups. Both treatments were well tolerated.. Tiotropium plus formoterol was superior in lung function over the day compared to salmeterol plus fluticasone in patients with moderate COPD. Long-term studies in patients with severe COPD are warranted to assess the relative efficacy of different treatment combinations.. Clinicaltrials.gov Identifier: NCT00239421.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Ethanolamines; Female; Fluticasone; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

To elucidate efficacy of a combination almitrine+thiotropium bromide (TB)+pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) of stage II-III complicated with chronic respiratory failure (CRF).. Efficacy of therapy was compared in two groups of patients: group 1 (n = 22) received TB in a dose 18 mcg/day for one year, almitrine in a dose 10 mg/kg/day for 3 months, an 8 week course of PR, group 2 (n = 17) received TB and PR. The treatment efficacy was determined by spirometric parameters of external respiration function, blood gases, dyspnea indices, exercise tolerance assessed by 6-min walk test, quality of life (St. George Hospital Respiratory Questionnaire).. Group 1 patients walked longer distance after a course of PR and 1 year later (by 90.5 +/- 25.4 and 44.5 +/- 10.2 m, respectively, p < 0.05), had reduced desaturation measured by pulsoxym-etry at the end of 6-min walk test, increased PaO2 in baseline under 70 mmHg (by 5.8 +/- 1.2 mmHg, p > 0.05), decreased exacerbation rate per 1 patient a year (by 25%).. Combination treatment with TB, almitrine and PR is indicated for COPD patients with moderate hypoxemia.

Topics: Administration, Inhalation; Almitrine; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Exercise Therapy; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

This dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol, a novel once-daily inhaled beta2-agonist, in subjects clinically diagnosed with COPD. Comparative data with tiotropium were collected. In the double-blind, core period of the study, 635 subjects with COPD (prebronchodilator FEV(1)40% of predicted and > or =1.0L; FEV1/FVC <70%) were randomized to receive indacaterol 50, 100, 200 or 400microg or placebo via multi-dose dry powder inhaler, or indacaterol 400microg via single-dose dry powder inhaler, once daily for 7 days. After completing double-blind treatment and washout, a subset of subjects from each treatment group entered an open-label extension and received tiotropium 18microg once daily for 8 days. The primary efficacy variable was the trough bronchodilator effect: standardized area under the FEV1 curve between 22 and 24h post-dose (FEV1 AUC(22-24h)) on Day 1. Clinically relevant improvements versus placebo in FEV1 AUC(22-24h) were seen for 400 and 200microg doses on Day 1 and all doses on Day 7. All indacaterol doses significantly (P<0.05) increased FEV1 from 5min to 24h post-dose; the 400 and 200microg doses were most effective. All doses were well tolerated. Indacaterol trough FEV1 levels compared favorably with the improvement seen by Day 8 in subjects treated with tiotropium in the open-label extension. The results confirm that indacaterol has a 24-h duration of bronchodilator effect and a fast onset of action in COPD and suggest that indacaterol could be an effective once-daily inhaled beta2-agonist bronchodilator. Indacaterol demonstrated a good overall safety and tolerability profile.

Topics: Administration, Inhalation; Adult; Aged; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Indans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Disease exacerbations are an important aspect of COPD, because they affect its course and are associated with higher lung function decline. On the other hand, data obtained by biopsies have demonstrated that the progression of COPD is related to an increasing impairment of small airways. We sought to evaluate the small airway impairment (FEF25-75) in two groups of COPD patients (each group had 37 subjects) in relation to the frequency of exacerbations and the effectiveness of treatment with tiotropium bromide on the small airway impairment. The mean number of exacerbations was 3.6/year and 1.38/year in frequent and in infrequent exacerbators, respectively (p < 0.001). The mean value of FEF25-75 at baseline was 624 mL and 865 mL in frequent and in infrequent exacerbators respectively (p = 0.002). The changes in respiratory parameters versus baseline showed increases in mean FEV1, FVC, and FEF25-75 in both groups but only the increase in FEF25-75 in frequent exacerbators was statistically significantly (p = 0.013). During the 3-month period of the study the mean number of exacerbations was 0.66 in frequent and 0.12 in infrequent exacerbators. These findings indicate that COPD patients with frequent exacerbations have a higher impairment of small airways. Treatment with tiotropium in COPD subjects with frequent exacerbations proved to be effective in improving small airway impairment.

Topics: Acute Disease; Aged; Aged, 80 and over; Bronchodilator Agents; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Improvements in ventilatory mechanics with tiotropium increases exercise tolerance during pulmonary rehabilitation. We wondered whether tiotropium also increased physical activities outside of pulmonary rehabilitation.. COPD patients participating in 8 weeks of pulmonary rehabilitation were studied in a randomized, double-blind, placebo-controlled trial of tiotropium 18 microg daily (tiotropium = 47, placebo = 44). Study drug was administered for 5 weeks prior to, 8 weeks during, and 12 weeks following pulmonary rehabilitation. Patients completed a questionnaire documenting participation in pre-defined activities outside ofpulmonary rehabilitation during the 2 weeks prior to each visit. Patients who submitted an activity questionnaire at week 4 and on at least one subsequent visit were included in the analysis. For each patient, the number of sessions was multiplied with the duration of each activity and then summed to give overall activity duration.. Patients (n = 46) had mean age of 67 years, mean baseline FEVJ of 0.84 L (33% predicted). Mean (SE) increase in duration of activities (minutes during 2 weeks prior to each visit) from week 4 (prior to PR) to week 13 (end of PR) was 145 (84) minutes with tiotropium and 66 (96) minutes with placebo. The increase from week 4 to week 25 (end of follow-up) was 262 (96) and 60 (93) minutes for the respective groups. Increases in activity duration from week 4 to weeks 17, 21, and 25 were statistically significant with tiotropium. No statistical differences over time were observed within the placebo-treated group and differences between groups were not significant.. Tiotropium appears to amplify the effectiveness of pulmonary rehabilitation as seen by increases in patient self-reported participation in physical activities.

Topics: Aged; Bronchodilator Agents; Double-Blind Method; Exercise; Exercise Tolerance; Female; Follow-Up Studies; Forced Expiratory Volume; Health Behavior; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Self-Assessment; Tiotropium Bromide

Although combination therapy with bronchodilators is recommended for chronic obstructive pulmonary disease (COPD), there is insufficient evidence for the efficacy of some combinations of long-acting bronchodilators.. We investigated the effects of a combination therapy with tiotropium and theophylline in COPD patients.. In a 12-week, open-labeled, parallel-group randomized study, pulmonary functions and dyspnea scores were compared between the combination and theophylline alone therapy at baseline, and 4 and 8 weeks after randomization in COPD.. Sixty-one COPD patients completed the trial (31 combination therapy, 30 theophylline alone; mean age 70 years; 58 males; mean dyspnea score 2.0 and forced expiratory volume in one second (FEV1) 1.5 L [62.5% predicted]). FEV1 in the combination group, but not in the theophylline alone, was significantly increased at 4 (1.56 +/- 0.13 L, p < 0.001) and 8 weeks (1.60 +/- 0.13 L, p < 0.001) from the baseline (1.40 +/- 0.12 L). In the combination group, but not the theophylline alone group, the dyspnea score was significantly improved after 4 (p < 0.01) and 8 weeks (p <0.05) compared with baseline. In 17 patients who did not receive theophylline at screening, treatment with 4 or 8 weeks of theophylline alone did not improve dyspnea score or FEV1.. Addition of tiotropium therapy to theophylline treatment can improve dyspnea and pulmonary function in COPD. Although this study did not assess whether there was any benefit of adding theophylline to patients treated with tiotropium, tiotropium can be a useful addition in COPD already treated with theophylline.

Topics: Aged; Bronchodilator Agents; Drug Therapy, Combination; Dyspnea; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Theophylline; Tiotropium Bromide; Treatment Outcome

The aim of this pilot study was to explore the relative efficacy in terms of improvement in symptoms and lung function of combining fluticasone propionate/salmeterol combination (FSC) and tiotropium in patients with severe-to-very severe stable COPD. Ninety patients were randomized to receive 3 months of treatment in one of three treatment groups: (1) FSC 500/50 microg Diskus, 1 inhalation twice daily+placebo Handihaler 1 inhalation once-daily daily; (2) tiotropium 18 microg Handihaler, 1 inhalation once daily+placebo Diskus, 1 inhalation twice daily; (3) FSC 500/50 microg Diskus, 1 inhalation twice daily+tiotropium 18 microg Handihaler, 1 inhalation once-daily daily. Patients attended the clinic before and after 1 month, 2 months, and 3 months of treatment for evaluations of pulmonary function, and dyspnea, which was assessed using a visual analog scale (VAS). Also the supplemental salbutamol use was measured. Eighty-one patients completed the 3-month treatment period: 26 patients receiving FSC, 26 patients receiving tiotropium, and 29 patients receiving FSC+tiotropium. Patients were withdrawn for COPD exacerbation. Improvements in trough FEV(1) with all treatments medications were observed by the first month when trough FEV(1) had improved significantly above baseline by 74 mL (p<0.05) in the tiotropium group, by 117 mL (p<0.05) in the FSC group and by 115 mL (p<0.05) in FSC+tiotropium group. At the end of the study, trough FEV(1) had improved significantly above baseline by 141 mL (p<0.05) in the tiotropium group, by 140 mL (p<0.05) in the FSC group and by 186 mL (p<0.05) in FSC+tiotropium group. The difference between FSC and tiotropium appeared to decrease, that between FSC and FSC+tiotropium appeared to increase and that between tiotropium and FSC+tiotropium remained almost similar with study duration. Our results suggest that adding FSC and tiotropium may provide benefits in symptomatic patients with severe-to-very severe stable COPD.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Inhaled bronchodilators are first line drugs in the treatment of chronic obstructive pulmonary disease (COPD). Tiotropium bromide is a recently introduced long-acting anticholinergic agent able to reduce dyspnoea and COPD exacerbations and to improve pulmonary function and quality of life. We designed a study to compare the short-term efficacy of tiotropium bromide with that of oxitropium bromide in improving pulmonary function in patients with COPD.. Eighty patients were randomized either to continue oxitropium 800 mcg/day or to receive tiotropium 18 mcg/day. Seventy-six (39 in the tiotropium and 37 in the oxitropium group) completed the study. Plethysmography was performed at baseline and after 72 h in all patients. The changes in functional parameters in the two groups were compared by the Mann-Whitney U-test.. There were no differences between the two groups regarding age (72.5 vs. 74.2 years), male/female ratio (25/14 vs. 23/14) and pulmonary function at baseline. The changes in spirometric parameters were significantly greater in tiotropium- than in oxitropium-treated patients: mean forced expiratory volume in 1s (FEV(1)) increased significantly by 15% vs. 3% (P=0.017), mean FVC by 10.5% vs. 2.2% (P=0.044), and FEF 25, 50, and 75 by 34% vs. 14% (P<0.05), 33% vs. 7% (P<0.05), and 50% vs. 6% (P<0.0001), respectively; mean FRC and RV decreased nonsignificantly by 7.5% and 10% with tiotropium vs. 4.3% and 6.5% with oxitropium, respectively.. The replacement of oxitropium with tiotropium significantly increases pulmonary function in patients with COPD. The improvement involves also small airways that have not been investigated thus far.

Topics: Aged; Bronchodilator Agents; Cholinergic Antagonists; Female; Humans; Lung; Male; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

A combination of bronchodilators may be effective in the treatment of chronic obstructive pulmonary disease (COPD). We examined the effect of adding a long-acting anti-cholinergic agent (tiotropium) to a transdermal-type beta(2)-agonist (tulobuterol) on dyspnea as well as pulmonary function.. In a multicentre, randomized, parallel design study, 60 COPD patients treated with the transdermal beta(2)-agonist tulobuterol were divided into a tiotropium added group (Tulo+Tio group, n=40) or transdermal beta(2)-agonist tulobuterol alone group (Tulo group, n=20), and then treated for 4 weeks after a 2 week run-in period. Pulmonary function and a dyspnea (Medical Research Council (MRC)) scale were assessed before and after the treatment. Daily peak expiratory flow (PEF) monitoring was also performed.. After 4 weeks, the Tulo+Tio group showed a significant increase in pulmonary function compared with the Tulo group; DeltaFVC (0.31+/-0.06 L vs. 0.06+/-0.05 L, p< 0.01), DeltaFEV(1) (0.15+/-0.03 L vs. -0.02+/-0.02 L, p<0.0001), and DeltaPEF (41.0+/-5.1 L/min vs. 0.5+/-3.5 L/min, p<0.0001). The MRC dyspnea scale was also significantly improved in Tulo+Tio, but not in Tulo group.. These results suggest that tiotropium caused a significant improvement in both pulmonary function and dyspnea in COPD patients already treated with the transdermal beta(2)-agonist tulobuterol.

Topics: Administration, Cutaneous; Administration, Inhalation; Adrenergic beta-Agonists; Aged; Bronchodilator Agents; Drug Synergism; Dyspnea; Female; Forced Expiratory Volume; Humans; Male; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Terbutaline; Tiotropium Bromide

We explored the additive effect of titrated oral theophylline in patients with stable chronic obstructive pulmonary disease (COPD) who received both tiotropium, 18mug od, and formoterol, 12mug bid. Thirty-six patients with moderate-to-severe COPD were enrolled in this two-period trial. They were initially treated with formoterol+tiotropium for 4 weeks. After this first period, they were divided in two groups of 18 patients. Both groups continued with the initial treatment for further 4 weeks, but the first group received also placebo whereas the second group received oral theophylline. The combination therapy with formoterol+tiotropium induced a significant improvement in mean predose FEV(1) and FVC at the end of the first period, and a significant reduction in dyspnea score as measure by a visual analogic scale and in use of rescue salbutamol. The second period of treatment elicited a significant further improvement in lung function and reduction in dyspnea score and salbutamol use in both groups. On the contrary, differences in improvements in FEV(1) and FVC and reduction in dyspnea score and salbutamol use between theophylline and placebo arms at the end of the second treatment period were not significant, although 5 patients reported an important relief in dyspnea during the theophylline administration period. These findings question the importance of adding theophylline in stable COPD patients already treated with two long-acting bronchodilators, but also indicate the possibility that some of them can benefit from theophylline because of a symptomatic improvement.

Topics: Aged; Albuterol; Bronchodilator Agents; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Dyspnea; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Single-Blind Method; Theophylline; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The ability to predict exacerbations in patients with COPD might permit more rational use of preventive interventions. Our objective was to develop risk indexes for exacerbations and hospitalizations due to exacerbations that might be applied to the individual patient.. Spirometry, demographics, and medical history were obtained at baseline in 1,829 patients with moderate-to-very severe COPD who entered a trial of inhaled tiotropium. Information about exacerbations and hospitalizations due to exacerbation was collected during the 6-month follow-up period. Analyses of first outcomes were modeled using univariable and multivariable Cox proportional hazards regressions.. During follow-up, 551 patients had at least one exacerbation and 151 patients had at least one hospitalization due to exacerbation. In the multivariable model for exacerbation, older age, percentage of predicted FEV(1), duration of COPD, a productive cough, antibiotic or systemic corticosteroid use for COPD in the prior year, hospitalization for COPD in the prior year, and theophylline use at baseline predicted a higher risk. In the multivariable model for hospitalization, older age, percentage of predicted FEV(1), unscheduled clinic/emergency department visits for COPD in the prior year, any cardiovascular comorbidity, and prednisone use at baseline were associated with greater risk. Both the exacerbation and the hospitalization models provided moderately good discrimination, the validated concordance indexes being 0.66 and 0.73, respectively. Methods for calculating risk in individual patients are provided.. Spirometry along with a few questions directed to the patient are strongly predictive of exacerbations and related hospitalizations over the ensuing 6 months.

Topics: Aged; Bronchodilator Agents; Female; Forced Expiratory Volume; Hospitalization; Hospitals, Veterans; Humans; Male; Medical History Taking; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Risk Factors; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; United States

Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied.. To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone.. Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006.. 27 academic and community medical centers in Canada.. 449 patients with moderate or severe COPD.. 1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol.. The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics.. The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo.. More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists.. Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cause of Death; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Hospitalization; Humans; Male; Middle Aged; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Our objective was to assess the 5-year cost effectiveness of bronchodilator therapy with tiotropium, salmeterol or ipratropium for chronic obstructive pulmonary disease (COPD) from the perspective of the Spanish National Health System (NHS). A probabilistic Markov model was designed wherein patients moved between moderate, severe or very severe COPD and had the risk of exacerbation and death. Probabilities were derived from clinical trials. Spanish healthcare utilisation, costs and utilities were estimated for each COPD and exacerbation state. Outcomes were exacerbations, exacerbation-free months, quality-adjusted life years (QALYs), and cost(-effectiveness). The mean (SE) 5-year number of exacerbations was 3.50 (0.14) for tiotropium, 4.16 (0.40) for salmeterol and 4.71 (0.54) for ipratropium. The mean (SE) number of QALYs was 3.15 (0.08), 3.02 (0.15) and 3.00 (0.20), respectively. Mean (SE) 5-year costs were 6,424 euro (305 euro) for tiotropium, 5,869 euro (505 euro) for salmeterol, and 5,181 euro (682 euro) for ipratropium (2005 values). Ipratropium and tiotropium formed the cost-effectiveness frontier, with tiotropium being preferred when willingness to pay (WTP) exceeded 639 euro per exacerbation-free month and 8,157 euro per QALY. In Spain, tiotropium demonstrated the highest expected net benefit for ratios of the willingness to pay per QALY, well within accepted limits.

Topics: Albuterol; Bronchodilator Agents; Cost-Benefit Analysis; Humans; Ipratropium; Markov Chains; National Health Programs; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Salmeterol Xinafoate; Scopolamine Derivatives; Spain; Tiotropium Bromide

In a three-way crossover pilot study, the acute effects of tiotropium 18 microg inhalation on the respiratory function and arterial blood gas tensions of 30 patients with stable chronic obstructive pulmonary disease (COPD) were compared with those of salmeterol 50 microg and formoterol 12 microg. In each study day, lung function and arterial blood gas analyses were performed before and up to 180 min after inhalation. All treatments significantly improved lung function, increased DLco, decreased PaO2, and increased P(A-a)O2, with no change in PaCO2. The effects of salmeterol and tiotropium on PaO2 were slower in onset and more prolonged than those of formoterol but PaO2AUC0-180 min was significantly greater for formoterol and salmeterol than for tiotropium. It is likely that the significant but small decreases in PaO2 and increases in P(A-a)O2 have been caused by pulmonary vasodilator effects. Since the three agents were similar in inducing bronchodilation, we believe that tiotropium is preferable in patients with hypoxemia caused by stable COPD because it seems to carry a smaller risk of worsening systemic hypoxemia.

Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Aged; Aged, 80 and over; Albuterol; Blood Gas Analysis; Bronchodilator Agents; Carbon Dioxide; Cross-Over Studies; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Oxygen; Oxygen Consumption; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Exercise limitation and exertional dyspnea are important symptoms of chronic obstructive pulmonary disease (COPD), which may be partially relieved by tiotropium. Although the mechanism of relief is multifactorial, improved dynamic ventilatory mechanics appear to be important. It is not however known whether tiotropium may also act by improving cardiovascular function during exercise.. We conducted a randomized, placebo-controlled crossover study in 18 COPD subjects with a FEV(1) 40+/-3% predicted (mean+/-SEM). Subjects inhaled either tiotropium 18 microg or placebo once daily for 7-10 days then the other intervention for a further 7-10 days after a 35-day washout period. Subjects performed constant work rate cycle exercise at 75% of maximum after each treatment period. Heart rate, blood pressure, oxygen uptake, operating lung volumes and breathing pattern were measured.. Heart rate was 7 beats/min lower at rest and throughout exercise with tiotropium compared to placebo (p=0.001). Oxygen uptake was unchanged throughout exercise. Oxygen pulse on exercise was greater by 7.4% (p<0.01) and systolic blood pressure was lower by 7 mmHg (p=0.03). The cardiac rate pressure product was reduced by 7.6% (p<0.01) with tiotropium. Exercise endurance tended to be greater with tiotropium. Reduction in heart rate on exercise correlated with an increase in inspiratory reserve volume (r=-0.50, p=0.04).. Tiotropium may improve cardiac as well as pulmonary function during exercise in COPD. We suggest that this effect may be due, in part, to improved cardiopulmonary interaction as a result of mechanical unloading of the ventilatory muscles however further study is required.

Topics: Blood Pressure; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Dyspnea; Exercise Test; Exercise Tolerance; Female; Heart Rate; Humans; Male; Middle Aged; Oxygen Consumption; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation. Tiotropium has been shown to reduce exacerbation frequency, but its effect on airway inflammation is unknown. The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency. Patients (n = 142) were randomised to receive tiotropium or placebo in addition to their usual medication for 1 yr. Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary. There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups, but sputum IL-8 level was increased in the tiotropium arm. There was no difference between start and end of study in serum IL-6 or C-reactive protein level. Tiotropium was associated with a 52% reduction in exacerbation frequency (1.17 versus 2.46 exacerbations.yr(-1)). Of patients on tiotropium, 43% experienced at least one exacerbation, compared with 64% on placebo. The total number of exacerbation days was reduced compared with placebo (17.3 versus 34.5 days). Tiotropium reduces exacerbation frequency in chronic obstructive pulmonary disease, but this effect does not appear to be due to a reduction in airway or systemic inflammation.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; C-Reactive Protein; Cytokines; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Peroxidase; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sputum; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Clinical trials of tiotropium have principally recruited patients from secondary care with more severe chronic obstructive pulmonary disease (COPD), and typically had included limitation of concomitant medication. In primary care, which is the most common setting for COPD management, many patients may have milder disease, and also may take a broad range of concomitant medication.. This randomised, placebo-controlled, parallel-group, 12-week, 44-centre study investigated the efficacy (trough forced expiratory volume in 1 second [FEV1] response) and safety of additional treatment with once-daily tiotropium 18 mug via the HandiHaler in a primary care COPD population (tiotropium: N = 191, FEV1 = 1.25 L [47.91% predicted]; placebo: N = 183, FEV1 = 1.32 L [49.86% predicted]). Secondary endpoints included: trough forced vital capacity (FVC) response, weekly use of rescue short-acting beta-agonist, and exacerbation of COPD (complex of respiratory symptoms/events of >3 days in duration requiring a change in treatment). Treatment effects were determined using non-parametric analysis.. At Week 12, median improvement in trough FEV1 response with tiotropium versus placebo was 0.06 L (p = 0.0102). The improvement was consistent across baseline treatment and COPD severity. Median improvement in FVC at 2, 6 and 12 weeks was 0.12 L (p < 0.001). The percentage of patients with > or =1 exacerbation was reduced (tiotropium 9.5%; placebo 17.9%; p = 0.0147), independent of disease severity. Rescue medication usage was significantly reduced in the tiotropium group compared with placebo. Adverse event profile was consistent with previous studies.. Tiotropium provides additional benefits to usual primary care management in a representative COPD population.. The identifier is: NCT00274079.

Topics: Aged; Bronchodilator Agents; Cohort Studies; Female; Humans; Male; Middle Aged; Placebo Effect; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; United Kingdom; Xerostomia

Lung deposition of 18 microg tiotropium administered via a dry-powder inhaler was investigated in 5 healthy subjects and patients with mild (n = 4), moderate (n = 6), and severe (n = 5) chronic obstructive pulmonary disease after 14 days of treatment with 18 microg tiotropium. On day 15, subjects inhaled 2 capsules of radiolabeled tiotropium, and lung deposition was assessed using gamma scintigraphy. Repeated plasma and urine collections were performed on days 14 and 15. Mean delivered dose from the dry-powder inhaler was 45.1%. Mean lung deposition relative to the delivered dose was 42% (19%, relative to nominal dose) with low intersubject variability (20%). Mean extrathoracic deposition was 57.5% (25.8%, relative to nominal dose). There were no significant differences in deposition among the subgroups. No significant correlation between individual tiotropium deposition and lung function was observed. These results suggest that all stages of chronic obstructive pulmonary disease may gain full therapeutic benefit from the drug.

Topics: Administration, Inhalation; Adult; Aged; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Radiopharmaceuticals; Scopolamine Derivatives; Sodium Pertechnetate Tc 99m; Tiotropium Bromide

Premature discontinuation from clinical trials may bias results against effective therapies. In the present study mortality rates were retrospectively reviewed in a 6-month, randomised, placebo-controlled trial in which tiotropium 18 mug daily was shown to decrease chronic obstructive pulmonary disease exacerbations. Patients participated for 6 months even if trial medication was prematurely discontinued. Exposure-adjusted incidence rates (IRs) were calculated for randomisation-end trial, randomisation-end trial drug (0-ED) and end trial drug-end trial (ED-ET). Of 1,829 patients (forced expiratory volume in one second 1.04 L (36% predicted), mean age 68 yrs, 99% male), 16% tiotropium and 27% placebo patients prematurely stopped trial medication. The number of fatal events for the entire cohort was: 62 all cause, including 16 cardiac and 16 lower respiratory. IRs for fatal events per 100 patient-yrs were higher in the discontinued period: 1.9 (0-ED) versus 23.0 (ED-ET) in the tiotropium group and 1.8 versus 19.0 in the placebo group. Respective IRs for fatal cardiac events were 0.7 versus 2.8 (tiotropium) and 0.5 versus 6.2 (placebo); for fatal lower respiratory events were 0.7 versus 2.8 (tiotropium) and 0.8 versus 5.4 (placebo). Rate ratios (tiotropium/placebo) for fatal events were lower in the discontinued period: 1.4 versus 0.5 for cardiac and 0.9 versus 0.5 for lower respiratory. Higher incidence rates of fatal events occurred following premature discontinuation of study medication. Incomplete information from rate ratios occurs as a result of failure to consider outcomes of patients who discontinue early from clinical trials.

Topics: Aged; Bronchodilator Agents; Double-Blind Method; Female; Humans; Male; Patient Dropouts; Pulmonary Disease, Chronic Obstructive; Research Design; Retrospective Studies; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Tiotropium is a new long-acting anticholinergic bronchodilator, which is recommended as first-line therapy in the management of chronic obstructive pulmonary disease (COPD). It is currently available in the form of a dry powder inhaler worldwide. Some COPD patients find it difficult to generate inspiratory flow rates of up to 40 l/min, which is required for the drug to reach the airways. To overcome this, a new pMDI form has been developed for administration of tiotropium in patients with COPD. The clinical efficacy of this mode of tiotropium delivery has, so far, not been compared with the currently available dry powder inhaler (DPI) devices.. To compare the bronchodilator effects of a single dose of 18 mcg of tiotropium administered via a pressurized meter dose inhaler (pMDI) and spacer with the currently available DPI form through Rotahaler.. A randomized, double-blind, double-dummy, three-period, placebo-controlled, crossover, single-center study was conducted in 19 patients with stable COPD. Single doses of tiotropium (18 mcg) or placebo were administered on three separate study days (4-7 days apart) through a Rotahaler and pMDI with a non-static spacer (Zerostat, Cipla Ltd.). During each study visit forced expiratory volume in 1s (FEV(1)) and forced vital capacity (FVC) were measured over a period of 24 h at 11 different time points (0, 15, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24h), using a bellows spirometer (Vitalograph) 2160, UK) while static parameters like inspiratory capacity (IC), residual volume (RV), intrathoracic gas volume (ITGV) and total lung capacity (TLC) were measured by bodyplethysmography (Jaeger Masterscreen, Germany) at 0 min, 3, 8 and 24 h.. Tiotropium administered through both pMDI (and spacer) and DPI showed significantly better mean FEV(1) and mean FVC differences from baseline, in terms of mean maximum change and area under curve over a period of 24 h (AUC(0-24 h)), as compared to placebo. The mean IC and trough FEV(1) values also improved significantly with tiotropium administered through both the devices as compared to placebo. For all these parameters, there was no difference in the efficacy between pMDI and DPI. There was also no significant difference between the time to onset, time to maximum response and duration of response between tiotropium administered through both the study devices. On the other hand, there was no significant difference in RV, ITGV and TLC by a single dose of tiotopium delivered through either of the devices when compared with placebo over a period of 24 h.. This is the first study to demonstrate that tiotropium administered by pMDI and spacer shows a superior time-dependent bronchodilator response when compared to placebo, and that this therapeutic efficacy is similar to tiotropium administered by DPI. We recommend the use of tiotropium administered through a pMDI and spacer to those COPD patients who prefer to use the pMDI device, and especially in those who cannot generate sufficient inspiratory flows required for dry powder inhaler devices.

Topics: Adult; Aged; Area Under Curve; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Inspiratory Capacity; Lung; Male; Metered Dose Inhalers; Middle Aged; Nebulizers and Vaporizers; Plethysmography; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

Hyperinflation is widely accepted as an abnormal state affecting clinical symptoms, activities of daily living and exercise tolerance in chronic obstructive pulmonary disease (COPD). Reducing hyperinflation is an essential theme in COPD treatment. In this study, we let patients with COPD hyperventilate to evoke hyperinflation, and evaluated the effects of tiotropium alone or in combination with salmeterol on hyperventilation-evoked hyperinflation.. Thirty-eight patients with COPD received pulmonary function tests including hyperventilation-evoked hyperinflation testing and the St. George's Respiratory Questionnaire (SGRQ) before treatment, after tiotropium administration for 8 weeks, and after combined therapy with salmeterol for 8 weeks.. Before treatment, inspiratory capacity (IC) after hyperventilation decreased significantly in a breathing frequency-dependent manner. After tiotropium administration, forced expiratory volume in one second (FEV1) increased significantly. IC after hyperventilation decreased significantly in a breathing frequency-dependent manner; however, IC was significantly greater than that before treatment (at rest, p=0.001; after hyperventilation at twice the resting respiratory rate, p=0.0009; and after hyperventilation at three times the resting respiratory rate, p<0.0001). The SGRQ score also improved significantly. After combined therapy with salmeterol, FEV1 increased significantly compared with after tiotropium alone. However, there was no significant difference between the IC after tiotropium alone and that after combined therapy, at each stage. However, after combined therapy the SGRQ score significantly improved compared with that after tiotropium alone.. Tiotropium improved airflow obstruction and hyperventilation-evoked hyperinflation. In combination with salmeterol, the improvement in airflow obstruction was greater, but hyperventilation-evoked hyperinflation was not further improved.

Topics: Aged; Albuterol; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Hyperventilation; Inspiratory Capacity; Lung; Lung Volume Measurements; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Combining bronchodilators has been shown to be beneficial in patients with COPD. The additive effects of short-acting bronchodilators added to maintenance tiotropium therapy, however, are unknown.. Following 3 weeks of tiotropium pretreatment, 60 patients with COPD (FEV1 40% of predicted) participated in a randomized, placebo-controlled study to assess add-on bronchodilator effects of ipratropium bromide (40 microg) or fenoterol (200 microg). Short-acting bronchodilators were added as a single dose 2 h and 8 h after tiotropium dosing. Serial lung function tests were performed over 9 h.. The peak FEV1 add-on response within 6 h with fenoterol was significantly greater than with placebo (137 mL) or ipratropium (84 mL); the response with ipratropium was slightly but significantly larger than with placebo (52 mL). One hour after the second dose of the test drugs, a similar order of treatment responses was found. The peak FVC add-on response was significant for fenoterol (249 mL) but not for ipratropium (42 mL).. In conclusion, both short-acting bronchodilator classes were effective when added to maintenance treatment with tiotropium. The addition of the beta2-adrenergic fenoterol provided greater additional bronchodilatation than the short-acting anticholinergic ipratropium. This is consistent with the expected effects of combining bronchodilators with different pharmacologic mechanisms. This randomized controlled trial was registered at www.clinicaltrials.gov (NCT00274066).

Topics: Bronchodilator Agents; Drug Therapy, Combination; Female; Fenoterol; Forced Expiratory Volume; Humans; Ipratropium; Male; Middle Aged; Plethysmography; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Because additive effects of inhaled corticosteroids and long-acting anticholinergics are unclear, we undertook this study to compare the efficacy of tiotropium alone and tiotropium plus budesonide in patients with chronic obstructive pulmonary disease. The study subjects were randomized to receive either tiotropium 18 microg once daily with or without budesonide 200 microg twice daily for 6 weeks. The efficacy variables were changes in trough forced expiratory volume in one second (FEV1), St. George's Respiratory Questionnaire (SGRQ), 6-minute walk distance (6MWD), and use of rescue medication. One hundred patients were randomized and 81 completed the study. The mean age was 64.0 yr, and the mean FEV1 was 39.7% predicted. Compared with tiotropium alone (N=40), the tiotropium/budesonide combination (N=41) was related to an improvement in the SGRQ total score (tiotropium -2.8 units and tiotropium/budesonide -5.6 units, p=0.003). 6MWD was improved by 13.5 m in the tiotropium group and by 22.5 m in the tiotropium/budesonide group (p=0.031). Changes in trough FEV1 and the use of rescue medication were similar between two groups. In conclusion, compared with tiotropium alone, the tiotropium/budesonide combination was related to an improved health-related quality of life. These data support that low-dose budesonide may enhance the efficacy of tiotropium.

Topics: Aged; Bronchodilator Agents; Budesonide; Exercise; Female; Humans; Male; Middle Aged; Models, Statistical; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Spirometry; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

This was a multicenter, randomized, double-blind within device, parallel-group, dose-ranging study. COPD patients (n = 202; 86% male; mean age: 61 years) were randomized to receive tiotropium 1.25 microg, 2.5 microg, 5 microg, 10 microg, or 20 microg Respimat SMI (a novel, propellant-free device); tiotropium 18 microg HandiHaler; placebo Respimat; or placebo HandiHaler for 3 weeks. The primary endpoint was trough FEV1 on Day 21. Other assessments included FVC, PEFR, rescue medication use, safety, and pharmacokinetics. In general, all active treatments improved the primary and secondary endpoints on Day 21 (steady state) compared with placebo. Tiotropium 5 microg Respimat, 20 microg Respimat, and tiotropium 18 microg HandiHaler were statistically significantly higher than placebo for the primary endpoint (mean change in trough FEV1 was 150 mL (both Respimat doses) versus 20 mL (placebo Respimat); p < 0.05; and 230 mL (HandiHaler) versus -90 mL (placebo HandiHaler); p < or = 0.001). The urinary excretion (up to 2 hours post-dose) of tiotropium 5-10 microg Respimat was comparable with tiotropium 18 microg HandiHaler; the overall incidence of adverse events was comparable across treatment groups. Tiotropium 5 and 10 microg Respimat improve lung function in COPD patients and appear to be comparable with tiotropium 18 microg HandiHaler.

Topics: Aged; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Female; Humans; Male; Metered Dose Inhalers; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

In 20 COPD patients (FEV(1) < or =65% predicted, IC<80% predicted), we evaluated changes in the degree of pulmonary hyperinflation after acute administration of tiotropium 18 microg or budesonide/formoterol 320/9 microg. The study consisted of a screening visit and two study days separated by at least one week. Functional parameters were measured before and 30, and 120 min after inhalation of single study drug. Both tiotropium and budesonide/formoterol induced significant changes in functional parameters after 30 and 120 min. However, the impact of tiotropium on the degree of pulmonary hyperinflation was larger than that of budesonide/formoterol, although only differences in IC and TGV between the two treatments were significant (P<0.05), at least after 120 min, whereas those in RV were not significant. The documentation that tiotropium is able to modify IC even after an acute administration indicates its capacity of influencing expiratory flow limitation in a very fast manner and this is an important finding. In fact, changes in IC after bronchodilators in patients with COPD with expiratory flow limitation at rest may represent an objective tool for prescribing these drugs to attain symptomatic improvement and better quality of life, even in the absence of a significant increase in FEV(1).

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Combinations; Ethanolamines; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Humans; Inspiratory Capacity; Male; Middle Aged; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, which results in the progressive development of dyspnea and exercise limitation.. To compare the effect of tiotropium with placebo on forced vital capacity (FVC) in patients with moderate-to-severe COPD and lung hyperinflation, using exercise endurance, dyspnea and health-related quality of life (HRQoL) as secondary endpoints. One hundred patients were randomized to receive either tiotropium 18 mug once daily or placebo for 12 weeks.. Trough (predose) FVC was significantly improved with tiotropium compared to placebo on day 42 (0.27 +/- 0.08 liters) and 84 (0.20 +/- 0.08 liters; p < 0.05 for both). Trough inspiratory capacity (IC) was also significantly improved with tiotropium compared to placebo on day 42 (0.16 +/- 0.07 liters) and 84 (0.15 +/- 0.07 liters; p < 0.05 for both). Tiotropium increased the mean distance walked during the shuttle walking test by 33 +/- 12 (day 42) and 36 +/- 14 m (day 84) compared to placebo (p < 0.05 for both). On day 84, 59% of the patients in the tiotropium group and 35% of the patients in the placebo group had significant and clinically meaningful improvements in the St. George's Respiratory Questionnaire total score (p < 0.05). Numerical decreases in the focal score in the Transition Dyspnea Index in patients receiving tiotropium versus placebo suggest that tiotropium also improved dyspnea during activities of daily living.. Tiotropium 18 mug once daily reduced hyperinflation with consequent improvements in walking distance and HRQoL in patients with COPD and lung hyperinflation.

Topics: Adult; Aged; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; France; Humans; Male; Middle Aged; Patient Selection; Placebos; Plethysmography; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

This randomised, double-blind, parallel-group, 1-yr study compared the effect of tiotropium 18 microg once daily (n=500) and placebo (n=510) on exacerbations, associated health resource use (HRU) and airflow limitation in chronic obstructive pulmonary disease (COPD) patients. The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40, the mean weekly morning peak expiratory flow (PEF) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second (FEV1) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days, reduced the proportion of patients experiencing more than one exacerbation by 17%, and decreased the number of exacerbations by 35% and exacerbation days by 37% versus placebo. Tiotropium also decreased HRU versus placebo, as indicated by the significant reductions in the use of concomitant respiratory medications, antibiotics and oral steroids, and the number of unscheduled physician contacts. Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study. At the end of the study, tiotropium significantly improved trough (pre-dose) FEV1, forced vital capacity, slow vital capacity and inspiratory capacity versus placebo. In conclusion, tiotropium reduced exacerbations and associated health resource use, and improved airflow over 1 yr in chronic obstructive pulmonary disease patients.

Topics: Aged; Bronchodilator Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) management guidelines recommend regular treatment with one or more long-acting bronchodilators for patients with moderate to severe COPD.. To compare the onset and duration of action of formoterol and tiotropium in patients with COPD.. This randomized, multicentre, open-label crossover study in 38 patients with COPD (mean age 64 years; mean FEV(1) 55% predicted) assessed the effect of 7 days of treatment with formoterol (12 microg b.i.d. via Foradil Aerolizer) vs. tiotropium (18 microg o.d. via Spiriva HandiHaler) on lung function measured over a period of 12 h after the first dose on day 1 and the last dose on day 8.. The primary efficacy variable, FEV(1)-AUC during the first 2 h post-dose (FEV(1)-AUC(10-120 min)), was significantly higher for formoterol compared with tiotropium, with between-treatment differences of 124 ml (p = 0.016) after the first dose and 80 ml (p = 0.036) after 7 days' treatment in favour of formoterol. FEV(1) measured 12 h after inhalation did not differ statistically significantly between treatments. Adverse events occurred in 2 (5%) patients after treatment with formoterol and in 5 (12%) patients after treatment with tiotropium.. This study demonstrates faster onset of action and greater bronchodilation of formoterol vs. tiotropium for bronchodilation within the first 2 h of inhalation (FEV(1)-AUC(10-120 min)) and comparable bronchodilation 12 h post-inhalation in patients with moderate to severe COPD.

Topics: Aged; Bronchodilator Agents; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Safety; Scopolamine Derivatives; Smoking; Tiotropium Bromide; Treatment Outcome

The combination of short-acting beta(2)-agonists and anticholinergics in the treatment of COPD has been well documented, but data on combination of long-acting agents are lacking.. A randomized, open-label, placebo-controlled, three-way crossover study was conducted comparing 2-week treatment periods of tiotropium alone to tiotropium plus formoterol once or twice daily following a 2-week pretreatment period with tiotropium. Lung function (FEV(1), FVC, and resting inspiratory capacity [IC]) serially over 24 h was measured in 95 patients with stable COPD at baseline and after 2 weeks of each treatment.. Mean baseline FEV(1) was 1.05 L (38% of predicted). There was a circadian variation in FEV(1), FVC, and IC at baseline that was maintained during all treatment periods. Average FEV(1) (0 to 24 h) improved by 0.08 L with tiotropium, by 0.16 L with tiotropium plus formoterol once daily, and by 0.20 L with tiotropium plus formoterol twice daily (p < 0.01 for all comparisons). Compared with tiotropium alone, add-on formoterol in the morning produced improvement in FEV(1), FVC, and IC for > 12 h. The second add-on dose of formoterol in the evening caused further improvement in FEV(1) for 12 h, but in FVC and IC for < 12 h. Peak increase in FEV(1) was 0.23 L (22% of baseline) with tiotropium and 0.39 L (37% of baseline) with tiotropium plus formoterol (p < 0.0001). Compared with tiotropium alone, add-on formoterol once and twice daily reduced the use of rescue salbutamol during the daytime (p < 0.01) and with add-on formoterol twice daily also during the nighttime (p < 0.05). The combination of tiotropium and formoterol was well tolerated.. In the treatment of COPD, there is benefit from adding formoterol once or twice daily to tiotropium once daily in terms of improvement in airflow obstruction, resting hyperinflation, and the use of rescue salbutamol.

Topics: Adrenergic beta-Agonists; Aged; Bronchodilator Agents; Cholinergic Antagonists; Circadian Rhythm; Cross-Over Studies; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The aim of our study was to evaluate the pharmacodynamic effects of 1-day treatment with formoterol, tiotropium and their combination in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Twenty-one (19 males, mean age 72+/-8 years, mean FEV1 38+/-14% of predicted values) patients with mild to moderate AECOPD were enrolled. Patients received formoterol (12 microg deliver via Modulite b.i.d.), tiotropium (18 microg dry powder capsules delivered via HandiHaler once daily), and their combination, in randomized sequence. Serial measurements of FEV1, FVC, IC, SpO2 and HR were performed over 24h. Formoterol, tiotropium, and their combination significantly improved the area under curves (AUCs) for FEV1, FVC and IC over 12 and 24h. The mean FEV1, FVC and IC AUC(0-12h) and AUC(0-24h) after formoterol and tiotropium combination were significantly higher than formoterol and tiotropium alone, whereas the differences between the two single drugs were not statistically significant. Formoterol, either alone or in combination with tiotropium, elicited a significantly faster onset of action, and combination elicited a greater maximum bronchodilation than both single drugs in terms of FEV1 and FVC. After 24h the bronchodilating effect of the three treatments disappeared, with the exception of the combination on FEV1. The results of this study have documented that, although the time course of the effects of evaluated drugs differs significantly from that in stable COPD, with a shorter bronchodilation both for tiotropium and formoterol, these two long-acting bronchodilators appear to also be complementary in mild to moderate AECOPD.

Topics: Acute Disease; Aged; Aged, 80 and over; Area Under Curve; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Female; Formoterol Fumarate; Heart Rate; Humans; Male; Middle Aged; Oxygen Consumption; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

During constant-work-rate exercise in chronic obstructive pulmonary disease, dyspnea increases steeply once inspiratory reserve volume (IRV) falls to a critical level that prevents further expansion of tidal volume (Vt). We studied the effects of this mechanical restriction on the quality and intensity of exertional dyspnea and examined the impact of an anticholinergic bronchodilator. In a randomized, double-blind, crossover study, 18 patients with chronic obstructive pulmonary disease (forced expiratory volume in 1 s = 40 +/- 3%predicted; mean +/- SE) inhaled tiotropium 18 mug or placebo once daily for 7-10 days each. Pulmonary function tests and symptom-limited cycle exercise at 75% of each patient's maximal work capacity were performed 2 h after dosing. Dyspnea intensity (Borg scale), operating lung volumes, breathing pattern, and esophageal pressure (n = 11) were measured during exercise. Dynamic hyperinflation reached its maximal value early in exercise and was associated with only mild increases in dyspnea intensity and the effort-displacement ratio, which is defined as the ratio between tidal swings of esophageal pressure (expressed relative to maximum inspiratory pressure) and Vt (expressed relative to predicted vital capacity). After a minimal IRV of 0.5 +/- 0.1 liter was reached, both dyspnea and the effort-displacement ratio rose steeply until an intolerable level was reached. Tiotropium did not alter dyspnea-IRV relationships, but the increase in resting and exercise inspiratory capacity was associated with an improved effort-displacement ratio throughout exercise. Once a critically low IRV was reached during exercise, dyspnea rose with the disparity between respiratory effort and the Vt response. Changes in dyspnea intensity after tiotropium were positively correlated with changes in this index of neuromechanical coupling.

Topics: Administration, Inhalation; Bronchodilator Agents; Double-Blind Method; Dyspnea; Exercise; Exercise Test; Female; Humans; Male; Middle Aged; Physical Exertion; Pulmonary Disease, Chronic Obstructive; Pulmonary Ventilation; Respiratory Mechanics; Scopolamine Derivatives; Tiotropium Bromide

Use of maintenance bronchodilator therapy is currently recommended in symptomatic patients with Chronic obstructive pulmonary disease (COPD) and in those with Stage II or greater COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Because no prospective data describe when rescue therapy alone is insufficient or the optimal time to start maintenance therapy, it is unclear whether maintenance therapy has benefits in milder disease. To explore potential benefits we asked: Does once-daily tiotropium improve lung function, health status, and/or symptoms in "undertreated" COPD patients (i.e., those who are not receiving maintenance bronchodilator therapy) or patients considered by their health care providers as having milder disease?. A post-hoc analysis of data from COPD patients participating in two, 1-year, placebo-controlled trials with tiotropium was performed. Patients were defined as "undertreated" if they received no respiratory medication or only as-needed short-acting beta-agonists prior to enrollment. Measures included serial spirometry, Transition Dyspnea Index (TDI), and St. George's Respiratory Questionnaire (SGRQ).. Of 921 patients enrolled, 218 (23.7%) were "undertreated": 130 received tiotropium; 88 received placebo. Demographics for the two treatment groups were comparable. Tiotropium-treated patients had significantly improved forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) compared with patients using placebo on all study days. Additionally, TDI and SGRQ scores significantly improved with tiotropium compared with placebo.. Once-daily tiotropium provides significant improvement in lung function, health status, and dyspnea when used as maintenance therapy in undertreated COPD patients who were not previously receiving maintenance bronchodilator therapy.

Topics: Aged; Bronchodilator Agents; Double-Blind Method; Dyspnea; Female; Forced Expiratory Volume; Health Status; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Aim of this study was to evaluate the efficacy of inhaled Tiotropium bromide in COPD patients of different severities in pneumological practices during a three months clinical trial.. A randomized, double blind, placebo controlled study including COPD-patients (FEV1/FVC < 70 %, FEV1 < or = 70 % predicted; age > or = 40 years; > or = 10 pack years) of different severities was performed. The efficacy of 18 microg Tiotropium bromide once daily on lung function and exacerbations over 12 weeks was evaluated by respective pulmonary function tests (spirometry) before (trough value) and 2 hours after inhalation of study medication.. 1639 patients (1236 Tiotropium bromide, 403 placebo; FEV1 reversibility after 200 microg Ipratropium bromide + 200 microg Fenoterol: 7.9 +/- 7.5 % predicted [mean +/- sd]) were randomized. After 12 weeks of treatment Tiotropium bromide led to significant increases of trough FEV1 (23 - 24 h after last inhalation; + 79 +/- 17 ml), and 2 h after Tiotropium bromide inhalation (+ 128 +/- 19 ml) (all values vs. placebo, adjusted mean +/- se, p < 0.0001). FVC and IVC were also improved significantly. In mild COPD (FEV1 > or = 50 - 70 %) improvements were most pronounced (trough FEV1 + 113 +/- 29 ml, 2 h post-inhalation + 181 +/- 33 ml; all values vs. placebo., p < 0.0001). 14.6 % of patients treated with Tiotropium bromide had a COPD exacerbation vs. 19.9 % of patients treated with placebo (p = 0.0151). The time to first exacerbation was prolonged (p = 0.0092 vs. placebo).. Tiotropium bromide 18 microg once daily led to a persistent improvement of lung function and a reduction of exacerbations in patients with COPD of different severities.

Topics: Adult; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Patient Selection; Placebos; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The addition of an alternative class of long-acting bronchodilator is recommended for COPD patients who do not respond satisfactorily to monotherapy. The aim of this study was to investigate the additive benefit of tiotropium in severe COPD and to establish whether the improvement in lung function in these patients can be predicted from their acute bronchodilator response to ipratropium or salbutamol.. Forty-six patients with severe COPD treated with inhaled long-acting beta(2) agonists and corticosteroids (LABA/CS) were enrolled. Their prebronchodilator FEV(1) was less than 50% of the predicted value. Tiotropium (18 microg, once daily) was added via a dry-powder inhaler device. After a month of treatment, tiotropium was stopped but their previous medication was continued. Patients were reassessed a month later. Acute bronchodilator response to ipratropium and salbutamol was assessed prior to tiotropium treatment. Pulmonary function and health status were evaluated.. Adding tiotropium significantly improved FVC, FEV(1) and inspiratory capacity (IC). The increase in FVC was significantly associated with an increase in IC (r = 0.36, P = 0.019) and a decrease in residual volume (r =-0.56, P < 0.001). Total scores of St. George Respiratory Questionnaire scores were significantly improved after adding tiotropium treatment (P < 0.001). After tiotropium withdrawal, FVC, FEV(1) and IC decreased markedly. Bronchodilator response to ipratropium did not predict the tiotropium-mediated improvement in FEV(1) or FVC.. Adding tiotropium to inhaled LABA/CS can yield clinical benefits in lung function and improved quality of life in COPD patients, as both drugs act through separate yet complementary pathways to maintain airway calibre.

Topics: Aged; Albuterol; Bronchodilator Agents; Drug Therapy, Combination; Female; Forced Expiratory Volume; Health Status; Humans; Inspiratory Capacity; Ipratropium; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

To compare the efficacy and safety of tiotropium and ipratropium in patients with chronic obstructive pulmonary disease (COPD) in Taiwan.. This double-blind, randomized, placebo-controlled, parallel group study was conducted at six hospitals in Taiwan. COPD patients aged > or = 40 years, with a forced expiratory volume in 1 second (FEV1) < or = 65% of predicted and FEV1/forced vital capacity (FVC) < or = 70% were enrolled. After a 2-week screening/baseline period, 132 patients were randomized to receive 4 weeks of treatment with either tiotropium 18 microg once daily from a dry powder inhaler (HandiHaler) or two puffs of ipratropium 20 microg four times daily from a metered dose inhaler. The primary outcome was the change in trough FEV1 from baseline to week 4. The secondary outcome measures were trough FVC response, FEV1 and FVC responses at 2 hours postinhalation.. After 4 weeks, trough FEV1 had increased by 61.7 +/- 25.3 mL for tiotropium but decreased by 16.4 +/- 27.9 mL for ipratropium. The difference between groups was significant (p < 0.05; 95% CI, 10-146.1). The trough FVC also increased by 137.2 +/- 49.3 mL for tiotropium but was decreased by 84.5 +/- 54.5 mL for ipratropium (p < 0.001; 95% CI, 89.0-354.3). No major drug-related adverse events associated with tiotropium and ipratropium were observed.. Tiotropium 18 microg once daily using HandiHaler was significantly more effective than ipratropium 40 microg four times daily in improving trough FEV1 and FVC over a 4-week period. The safety profiles of both drugs are comparable.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Female; Humans; Ipratropium; Lung Diseases; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Taiwan; Tiotropium Bromide; Treatment Outcome

To assess the discriminative properties of the EuroQol five-dimension questionnaire (EQ-5D) with respect to COPD severity according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria in a large multinational study.. Baseline EQ-5D visual analog scale (VAS) scores, EQ-5D utility scores, and St. George Respiratory Questionnaire scores were obtained from a subset of patients in the Understanding the Potential Long-term Impact on Function with Tiotropium trial, which was a 4-year placebo-controlled trial designed to assess the effect of tiotropium on the rate of decline in FEV(1) in COPD patients aged > or = 40 years, an FEV(1) of < 70% predicted, an FEV(1)/FVC ratio of < or = 70%, and a smoking history of >/= 10 pack-years.. A total of 1,235 patients (mean post bronchodilator FEV(1), 48.8% predicted) from 13 countries completed the EQ-5D. The EQ-5D VAS and utility scores differed significantly among patients in GOLD stages 2, 3, and 4, also after correction for age, sex, smoking, body mass index (BMI), and comorbidity (p < 0.001). The mean EQ-5D VAS scores for patients in GOLD stages 2, 3, and 4 were 68 (SD, 16), 62 (SD, 17), and 58 (SD, 16), respectively. The mean utility scores were 0.79 (SD, 0.20) for patients in GOLD stage 2, 0.75 (SD, 0.21) for patients in GOLD stage 3, and 0.65 (SD, 0.23) for patients in GOLD stage 4. Effect sizes for the difference in utility scores between patients in GOLD stages 3 and 4 were more than twice as high as those for the difference between patients in GOLD stages 2 and 3. Gender, postbronchodilator FEV(1) percent predicted, the number of hospital admissions and emergency department visits in the year prior to baseline measurements, measures of comorbidity, and BMI were independently associated with EQ-5D utility. EQ-5D utility scores also differed between patients from different countries. French patients especially had lower utility scores than US patients. Utility scores calculated with the US value set were on average 5% higher than those calculated with the UK value set.. Increasing severity of COPD was associated with a significant decline in EQ-5D VAS scores and utility scores. These results demonstrate that a generic instrument can assess COPD impact on quality of life and that the scores discriminate between patient groups of known severity. These utility scores will be useful in cost-effectiveness assessments.

Topics: Activities of Daily Living; Aged; Body Mass Index; Bronchodilator Agents; Comorbidity; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pain Measurement; Psychometrics; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Self Care; Sensitivity and Specificity; Severity of Illness Index; Sickness Impact Profile; Surveys and Questionnaires; Tiotropium Bromide; Vital Capacity

To compare the efficacy and safety between tiotropium capsule and ipratropium MDI in a 4 week treatment in patients with chronic obstructive pulmonary disease (COPD).. A multi-center, randomized, double blind, double dummy and parallel comparison clinical trial was conducted in 221 stable moderate to severe patients with COPD. They were randomized into tiotropium 18 microg once per day arm or ipratropium 2 puffs qid. arm for four weeks. The spirometry was conducted at 5 minutes pre-medication; and 30, 60, 120, and 180 minutes post-medication before; 2 weeks and 4 weeks after treatment.. The forced expiratory volume in one second (FEV(1)) trough response, the primary endpoint, was significantly higher in the tiotropium arm than that of the ipratropium with (0.063 +/- 0.024) L (95% CI 0.016 - 0.111 L, t = 2.63, P = 0.009) after 4 weeks of treatment. Meanwhile the clinical evidences indicated the continuous improvement of bronchodilation in the tiotropium arm. Forced vital capacity (FVC) trough response was also significantly higher in the tiotropium arm 4 weeks after treatment with (0.133 +/- 0.047) L (t = 2.83, P = 0.005). By comparison with baseline, no significant differences were found between these two arms in the average change of FEV(1) as well as FVC 0 - 3 hours after inhalation (all P > 0.05). There was no significant difference in rescue medication consumptions (t = 0.60, P = 0.548). Adverse events occurred in 12 (10.9%) patients in the tiotropium arm and 18 (16.2%) in the ipratropium arm, without statistical difference (chi(2) = 1.326, P = 0.249). The major adverse event in the tiotropium group was dry mouth (5, 4.5%). No cardiac disorder or abnormal electrocardiogram was reported.. The results indicated that tiotropium 18 microg once per day is more potent than ipratropium qid. in bronchodilation to COPD patients with the similar tolerance of ipratropium.

Topics: Aerosols; Aged; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Ipratropium; Male; Middle Aged; Powders; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Pulmonary rehabilitation (PR) improves exercise tolerance in COPD patients. Tiotropium is a once-daily, inhaled anticholinergic bronchodilator that provides sustained 24-h improvements in airflow and lung hyperinflation reduction. We hypothesized that ventilatory mechanics improvements from tiotropium would permit enhanced ability to train muscles of ambulation and therefore augment exercise tolerance benefits of PR.. In a randomized, double-blind, placebo-controlled trial (tiotropium, n = 47; placebo, n = 44), tiotropium (18 microg qd) was administered to COPD patients participating in 8 weeks of PR (treadmill training three times a week; >/= 30 min per session) at 17 sites. Study drug was administered 5 weeks prior to, 8 weeks during, and 12 weeks following PR. The primary end point was treadmill walking (0% incline) endurance time at 80% of maximum speed attained in an initial incremental test. The transition dyspnea index (TDI), St. George's respiratory questionnaire (SGRQ), and rescue albuterol use were secondary end points.. Mean age of the 93 participants was 67 years, 57% were men, and mean FEV(1) was 0.88 L (34% predicted).. Mean endurance time differences (tiotropium minus placebo) prior to PR, at the end of PR, and 12 weeks after PR were 1.65 min (p = 0.183), 5.35 min (p = 0.025), and 6.60 min (p = 0.018), respectively. Mean TDI focal scores at the end of PR were 1.75 for tiotropium and 0.91 for placebo (p > 0.05). At 12 weeks after PR, TDI focal scores were 1.75 for tiotropium and 0.08 for placebo (p < 0.05). Relative to placebo, tiotropium improved SGRQ total scores by 3.86 at the end of PR and 4.44 at 12 weeks after PR (p > 0.05). Mean albuterol use declined following PR plus tiotropium, compared to PR alone (p

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Dyspnea; Exercise Test; Exercise Therapy; Exercise Tolerance; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

Bronchodilators are still the most effective drugs for controlling the symptoms of chronic obstructive pulmonary disease (COPD). Tiotropium bromide, a long-acting anticholinergic drug, has recently been added to the therapeutic arsenal for the disease. To date, there have been no studies combining 2 long-acting bronchodilators. The aim of the present trial was to determine whether the combination of salmeterol and tiotropium improved lung function in COPD patients more than either of them alone.. Twenty-two patients (20 men) diagnosed with COPD, with a mean age of 64 years, were enrolled in this cross-over trial. Active smokers were excluded. Mean (SD) forced expiratory volume in 1 second (FEV1) was 43% (14%) of predicted. All patients were experienced in the use of inhalers. The following 3 therapeutic combinations were randomly assigned to be administered for a 1-week period: a) fluticasone (500 microg/12 h), salmeterol (50 microg/12 h) and placebo; b) fluticasone, tiotropium (18 microg/24 h), and placebo; and c) fluticasone, salmeterol, and tiotropium. At the end of each period, forced spirometry was performed before inhalation of the therapeutic combination (between 8:30 am and 9:30 am) and 2 hours after inhalation. Throughout the week, morning peak flow rates measured immediately before inhalation were recorded, and there was a 48-hour wash-out period between each therapeutic combination.. All the patients completed the protocol. There were no significant differences in preinhalation or postinhalation FEV1 with salmeterol compared to tiotropium (preinhalation FEV1, 1.17 [0.55] L compared to 1.19 [0.49] L; postinhalation FEV1, 1.32 [0.65] L compared to 1.29 [0.61] L). In all cases postinhalation FEV1 was significantly higher than preinhalation FEV1. The combination of fluticasone, salmeterol, and tiotropium proved superior to the other 2 combinations with respect to both preinhalation FEV1 and postinhalation FEV1 (preinhalation FEV1, 1.32 [0.56] L, [P<.03 in both comparisons]; postinhalation FEV1, 1.49 [0.68] L [P<.001 in both comparisons]). Peak flow rate was also significantly higher with the combination of the 2 bronchodilators (345 L/min compared to 291 L/min and 311 mL, respectively [P <.04 in both cases]). There were no notable side effects.. In terms of improvement in lung function, the combination of salmeterol and tiotropium together with fluticasone is more effective in patients with moderate-to-severe COPD than either of the 2 bronchodilators administered alone.

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Cross-Over Studies; Data Interpretation, Statistical; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome

We conducted a randomized, crossover trial with tiotropium 18 microg once daily (group A), and formoterol 12 microg twice daily (group B) over a 5-day period for each drug, with a 10-day washout, in 20 COPD patients. At the end of each period, patients inhaled both drugs separated by 180 min in alternate sequence (group A: tiotropium 18 microg+formoterol 12 microg; group B: formoterol 12 microg+tiotropium 18 microg). FEV1 and FVC were measured at baseline and after 30, 60, 120, 180, 210, 240, 300 and 360 min. FEV1 and FVC further improved after crossover with both sequences. The mean maximal change in FEV1 over baseline was 0.226 L (0.154-0.298) after tiotropium+formoterol and 0.228 L (0.165-0.291) after formoterol+tiotropium; the mean maximal change in FEV1 over pre-inhalation the second drug value was 0.081 L (0.029-0.133) after tiotropium+formoterol and 0.054 L (0.016-0.092) after formoterol+tiotropium. The mean maximal change in FVC over baseline was 0.519 L (0.361-0.676) after tiotropium+formoterol and 0.495 L (0.307-0.683) after formoterol+tiotropium; the mean maximal change in FVC over pre-inhalation of the second drug value was 0.159 L (0.048-0.270) after tiotropium+formoterol and 0.175 L (0.083-0.266) after formoterol+tiotropium. The FEV1 AUCs(0-360 min) were 62.70 (45.67-79.74) after tiotropium+formoterol and 69.20 (50.84-87.57) after formoterol+tiotropium, the FEV1 AUCs(0-180 min) were 24.70 (18.19-31.21) after tiotropium+formoterol and 29.74 (21.02-38.46) after formoterol+tiotropium, whereas the FEV1 AUCs(180-360 min) were 15.70 (10.88-20.52) after tiotropium+formoterol and 11.71 (7.21-16.21) after formoterol+tiotropium. Differences between the two treatments were not statistically significant (P>0.05). The addition of second different long-acting bronchodilator to a regularly administered long-acting bronchodilator seems to be to patient's advantage.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Analysis of Variance; Area Under Curve; Bronchodilator Agents; Cholinergic Antagonists; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

This study compared the bronchodilator effects of tiotropium, formoterol and both combined in chronic obstructive pulmonary disease (COPD). A total of 71 COPD patients (mean forced expiratory volume in one second (FEV1) 37% predicted) participated in a randomised, double-blind, three-way, crossover study and received tiotropium 18 microg q.d., formoterol 12 microg b.i.d. or both combined q.d. for three 6-week periods. The end-points were 24-h spirometry (FEV1, forced vital capacity (FVC)) at the end of each treatment, rescue salbutamol and safety. Compared with baseline (FEV1 prior to the first dose in the first period), tiotropium produced a significantly greater improvement in average daytime FEV1 (0-12 h) than formoterol (127 versus 86 mL), while average night-time FEV1 (12-24 h) was not different (tiotropium 43 mL, formoterol 38 mL). The most pronounced effects were provided by combination therapy (daytime 234 mL, night-time 86 mL); both differed significantly from single-agent therapies. Changes in FVC mirrored the FEV1 results. Compared with both single agents, daytime salbutamol use was significantly lower during combination therapy (tiotropium plus formoterol 1.81 puffs.day(-1), tiotropium 2.41 puffs x day(-1), formoterol 2.37 puffs x day(-1)). All treatments were well tolerated. In conclusion, in chronic obstructive pulmonary disease patients, tiotropium q.d. achieved a greater improvement in daytime and comparable improvement in night-time lung function compared with formoterol b.i.d. A combination of both drugs q.d. was most effective and provided an additive effect throughout the 24-h dosing interval.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

The efficacy of thiotropium bromide, 18 microg/day, versus ipratropium bromide, 160 microg/day, was studied in 20 patients with chronic obstructive lung disease (COLD) treated with a drug for 4 weeks. Clinical and spirographic parameters and arterial blood gas composition were determined. According to clinical and spirographic data, thiotropium bromide has some advantage over ipratropium. Both test drugs improved blood gas composition.

Topics: Administration, Inhalation; Blood Gas Analysis; Cholinergic Antagonists; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

Patients with chronic obstructive pulmonary disease (COPD) frequently develop exacerbations, leading to major clinical and health resource use ramifications.. To prospectively evaluate the effectiveness of a long-acting inhaled anticholinergic bronchodilator, tiotropium, in reducing COPD exacerbations and exacerbation-related health care utilization.. Randomized, double-blind study.. 26 Veterans Affairs medical centers.. 1829 patients with moderate to severe COPD (mean baseline FEV(1), 36% predicted).. Once-daily tiotropium (18 microg) or placebo for 6 months. Patients otherwise received usual care, except for other anticholinergic bronchodilators.. The coprimary end points were the percentage of patients with a COPD exacerbation and the percentage of patients with a COPD-related hospitalization.. Tiotropium significantly reduced the percentage of patients experiencing 1 or more exacerbations compared with placebo (27.9% vs. 32.3%, respectively; difference, -5.7 percentage points [95% CI, -10.4 to -1.0 percentage points]; P = 0.037). Fewer tiotropium patients were hospitalized because of COPD exacerbation (7.0% vs. 9.5%, respectively; difference, -3.0 percentage points [CI, -5.9 to -0.1 percentage points]; P = 0.056), although this difference was of borderline statistical significance. Analysis of secondary outcomes indicates that tiotropium may lengthen the time to first COPD exacerbation (P = 0.028) and reduce health care utilization for exacerbations, including the frequency of hospitalizations (P = 0.047), unscheduled clinic visits (P = 0.019), and days of antibiotic treatment (P = 0.015). Tiotropium did not statistically significantly reduce all-cause hospitalization rates.. Trial participants were enrolled from 1 health care system, and 99% were men. The follow-up period extended for only 6 months.. Tiotropium reduces COPD exacerbations and may reduce related health care utilization in patients with moderate to severe COPD.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Female; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Failure

We have previously shown that tiotropium at 18 mug reduces lung hyperinflation and dyspnea during exercise and improves exercise tolerance in patients with COPD. The present study was designed to gain further insight into the duration of improvements.. A randomized, double-blind, placebo-controlled, parallel-group study was conducted in 261 COPD patients (mean age, 62.5 +/- 7.4 years [+/- SD]; 189 men and 72 women; mean FEV1, 1.2 +/- 0.4 L [43 +/- 12.7% predicted]). On day 0 (first dose), day 21, and day 42 of treatment, pulmonary function tests were performed before and 1 h 20 min after dosing, followed by a constant work rate cycle ergometry test (75% maximum work capacity) to symptom limitation at 2.25 h after dosing. On day 42, an additional constant work rate cycle ergometry test was performed at 8 h after dosing.. Adjusted mean (+/- SE) endurance time (ET) on day 42 was 803 +/- 40 s (tiotropium), vs 568 +/- 42 s (placebo) at 2.25 h after dosing (primary end point; treatment difference, 236 +/- 58 s; p = 0.0001) and 665 +/- 40 s (tiotropium) vs 494 +/- 42 s (placebo) at 8 h after dosing (treatment difference, 171 +/- 58 s; p = 0.0035). Adjusted mean dyspnea intensity at isotime on day 42 was 4.60 +/- 0.16 Borg units (tiotropium), vs 5.65 +/- 0.16 Borg units (placebo) at 2.25 h after dosing (p < 0.001), and 5.54 +/- 0.17 Borg units (tiotropium) vs 6.51 +/- 0.18 Borg units (placebo) at 8 h after dosing (p < 0.001). Adjusted mean pre-exercise inspiratory capacity (IC) on day 42 was 2.41 +/- 0.03 L (tiotropium) vs 2.19 +/- 0.03 L (placebo) at 2.25 h after dosing (p < 0.001), and 2.31 +/- 0.03 L (tiotropium) vs 2.16 +/- 0.03 L (placebo) at 8 h after dosing (p < 0.001). The significant increase in IC with tiotropium compared with placebo was maintained throughout exercise.. The present study confirms that tiotropium reduces lung hyperinflation at rest and during exercise, reduces exertional dyspnea, and improves symptom-limited exercise tolerance in COPD patients. Furthermore, this study shows that this improvement is present at 2.25 h and at 8 h after dosing after 6 weeks of treatment.

Topics: Aged; Bronchodilator Agents; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends long-acting bronchodilators as first-line maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). A study was conducted comparing the long-acting anticholinergic tiotropium with the long-acting beta-agonist salmeterol to confirm the significant improvements in daytime bronchodilator efficacy seen with tiotropium in previous studies.. Randomized, double-blind, double-dummy, parallel-group study, comparing daytime bronchodilator efficacy of tiotropium 18 mcg once daily with salmeterol 50 mcg twice daily in patients with COPD. Serial spirometry was performed over 12 h after 12 weeks of treatment. Co-primary endpoints were average (over 12 h) and peak FEV1 at 12 weeks.. 653 patients were randomized (328 tiotropium, 325 salmeterol): mean age 64 years; 66% male; mean baseline FEV1 1.05 l (37.7% predicted). After 12 weeks, the average post-dose FEV1 over 12 h was significantly higher with tiotropium compared with salmeterol (167 vs. 130 mL, respectively, p=0.03), as was peak FEV1 (262 vs. 216 ml, respectively, p=0.01). The average FEV1 responses from 0-6 h and 6-12 h were higher in the tiotropium group compared with salmeterol (p<0.05). Peak and average FVC were significantly higher with tiotropium compared with salmeterol (p<0.01). Morning pre-dose FEV1 responses were not significantly different; however, tiotropium demonstrated a significantly higher pre-dose FVC than salmeterol (p<0.05).. Tiotropium demonstrated significantly greater post-dose improvements in spirometric parameters compared with salmeterol. These improvements were sustained over 12 h.

Topics: Aged; Albuterol; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease (COPD), and to establish previously reported symptomatic efficacy.. Randomized, double-blind, placebo-controlled, parallel-group study.. Twelve outpatient investigational centers in the United States.. One hundred ninety-six patients with COPD.. Patients received either tiotropium 18 mug once/day or placebo, delivered by the HandiHaler device.. Electrocardiography (predose and 5 min postdose) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo. Efficacy measures (spirometry, global COPD ratings, scores on the EuroQol Health Questionnaire [EQ-5D], albuterol inhaler as needed) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies. Mean baseline forced expiratory volume in 1 second (FEV1) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups. No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring. Frequency of premature beats and mean maximal changes in PR, QRS, QT, QTcB, and QTcF intervals were similar in both groups. No patients developed new-onset QT or QTc intervals greater than 500 msec, and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec, 30-60 msec, or greater than 60 msec. At 12 weeks, predose and postdose improvements in FEV1 were 184 and 265 ml, respectively, with tiotropium versus placebo (p<0.001). Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium (p<0.05); as-needed albuterol was reduced by 25% relative to placebo (p<0.05).. Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate, rhythm, QT intervals, or conduction.

Topics: Aged; Bronchodilator Agents; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

To evaluate whether multidisciplinary pulmonary rehabilitation programme (PRP) provides additional benefit over tiotropium therapy in managing chronic obstructive pulmonary disease (COPD) in primary care.. A randomized controlled trial to analyse the difference in outcomes of COPD patients receiving tiotropium plus PRP vs. tiotropium treatment alone.. Two primary care teaching clinics affiliated with a university which serves a population of 600,000.. Fifty primary care COPD patients.. Fifty subjects underwent spirometry and their status of COPD was confirmed by using the Vitalograph Gold Standard. They were then assessed by the 6-min walking distance (6MWD), Peak Visual Analogue Scale (Peak VAS) and Chronic Respiratory Disease Questionnaire (CRQ). All subjects were given tiotropium to optimize their treatment. After a 6-week period, half were randomized to the intervention group (i.e. receiving PRP), whereas the rest were randomized to control group which received only medication. Spirometry, 6MWD, Peak VAS and CRQ were performed in both groups at 6 weeks, 12 weeks and 3 months.. Spirometry, 6MWD, Peak VAS and CRQ.. Significant improvement (P < 0.05) was seen in 6MWD, symptoms of dyspnoea measured by Peak VAS and CRQ. The improvement was sustained at 3-month follow-up. However, no additional significant improvement was seen in the intervention group when compared with control.. Tiotropium therapy has improved health outcomes in COPD patients in primary care settings. A 6 weekly PRP did not give any additional benefits in patients already given tiotropium.

Topics: Aged; Bronchodilator Agents; Cholinergic Antagonists; Exercise Therapy; Female; Health Behavior; Hong Kong; Humans; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

The aim of this double-blind, double-dummy, cross-over, randomized, pilot study was to compare the acute bronchodilator efficacy of a single dose of formoterol with that of tiotropium in patients with stable chronic obstructive pulmonary disease (COPD). Because the potential of tiotropium for additive effects is yet unknown, the acute effects of adding this anticholinergic agent to formoterol were also explored. A total of 20 outpatients with stable COPD were enrolled. Single doses of 12 microg formoterol, 18 microg tiotropium, and 12 microg formoterol+18 microg tiotropium were given. Serial measurements of FEV1 were performed over 24 h. Formoterol, either alone or in combination with tiotropium, elicited a significantly faster onset of action and showed a trend for a greater maximum bronchodilation than tiotropium alone. At 24 h, mean FEV1 continued to be significantly higher than pre-dosing value following tiotropium and formoterol+tiotropium. These findings indicate that formoterol and tiotropium have different profiles that make both agents attractive alternatives in the treatment of stable COPD. Since tiotropium ensures prolonged bronchodilation, whereas formoterol adds fast onset and a greater peak effect, the two drugs appear complementary.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Area Under Curve; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Maximal Expiratory Flow Rate; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The aim of this paper is to assess the health economic consequences of substituting ipratropium with the new, once-daily bronchodilator tiotropium in patients with a diagnosis of chronic obstructive pulmonary disease (COPD). This prospective cost-effectiveness analysis was performed alongside two 1-yr randomised, double-blind clinical trials in the Netherlands and Belgium. Patients had a diagnosis of COPD and a forced expiratory volume in one second (FEV1) < or = 65% predicted normal. Patients were randomised to tiotropium (18 microg once daily) or ipratropium (2 puffs of 20 microg administered four times daily) in a ratio of 2:1. The mean number of exacerbations was reduced from 1.01 in the ipratropium group (n = 175) to 0.74 in the tiotropium group (n = 344). The percentages of patients with a relevant improvement on the St. George's Respiratory Questionnaire (SGRQ) were 34.6% and 51.2%, respectively. Compared to ipratropium, the number of hospital admissions, hospital days and unscheduled visits to healthcare providers was reduced by 46%, 42% and 36% respectively. Mean annual healthcare costs including the acquisition cost of the study drugs were 1721 Euro (SEM 160) in the tiotropium group and 1,541 Euro (SEM 163) in the ipratropium group (difference 180 Euro). Incremental cost-effectiveness ratios were 667 Euro per exacerbation avoided and 1084 Euro per patient with a relevant improvement on the SGRQ. Substituting tiotropium for ipratropium in chronic obstructive pulmonary disease patients offers improved health outcomes and is associated with increased costs of 180 Euro per patient per year.

Topics: Aged; Belgium; Bronchodilator Agents; Cost-Benefit Analysis; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Health Care Costs; Humans; Ipratropium; Male; Middle Aged; Netherlands; Patient Readmission; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Referral and Consultation; Scopolamine Derivatives; Tiotropium Bromide; Utilization Review

To assess the effects of tiotropium on lung mucociliary clearance in COPD.. Randomized, double-blind, placebo-controlled, parallel-group study.. Outpatients of an urban-area university teaching hospital.. Thirty-four patients with COPD aged 40 to 75 years classified equally into two groups.. Single (18 microg) daily dose of tiotropium inhalation capsules or of placebo for 21 days.. Six-hour tracheobronchial clearance of inhaled 99mTc-labeled polystyrene particles using a 48-h retention measurement to determine the "nontracheobronchial" deposition fraction.. Test radioaerosol penetration into the lungs increased significantly (p < 0.003) as did FEV1 (p < 0.006) in the tiotropium-treated patients, but measured mucociliary clearance was not significantly changed despite the increased pathway length for clearance (mean +/- SE area under the tracheobronchial retention curve changed from 442 +/- 22 to 453 +/- 20%/h). Smaller (nonsignificant) decreases of radioaerosol penetration and FEV1 occurred in the placebo group together with a small (nonsignificant) decrease in the area under the retention curve.. Twenty-one days of inhaled tiotropium, 18 microg/d, as a dry powder does not retard mucus clearance from the lungs.

Topics: Administration, Inhalation; Adult; Aged; Bronchodilator Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Mucociliary Clearance; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Oxygen desaturation occurs during sleep in severe chronic obstructive pulmonary disease (COPD), especially during rapid eye movement (REM) sleep, due to hypoventilation and ventilation-perfusion mismatching, but the possible contribution of airflow limitation is unclear. In a randomised, placebo-controlled, double-blind study of severe, stable COPD patients, the authors compared 4 weeks treatment with a long-acting inhaled anticholinergic agent (tiotropium), taken in the morning (tiotropium-AM), or in the evening (tiotropium-PM), on sleeping arterial oxygen saturation (Sa,O2) and sleep quality. Overnight polysomnography was performed at baseline and after 4 weeks treatment. A total of 95 patients with awake resting arterial oxygen tension < or = 9.98 kPa (75 mmHg) were randomised, with a mean age of 66.4 yrs and mean forced expiratory volume in one second (FEV1) of 32% predicted. A total of 80 patients completed the study, of which 56 fulfilled the polysomnographic criterion of at least 2 h sleep in both sleep study nights and represent the group analysed. Tiotropium significantly improved spirometry compared with placebo. Both tiotropium-AM and tiotropium-PM groups had higher Sa,O2 during REM than placebo (+2.41% and +2.42%, respectively, and both pooled and tiotropium-PM groups had higher Sa,O2 during total sleep time (+2.49% and +3.06%, respectively). End-of-treatment FEV1 correlated with Sa,O2 during REM sleep, however, tiotropium did not change sleep quality. Sustained anticholinergic blockade improves sleeping arterial oxygen saturation without affecting sleep quality.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Analysis of Variance; Cholinergic Antagonists; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Humans; Least-Squares Analysis; Male; Middle Aged; Oxygen; Polysomnography; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sleep Stages; Spirometry; Tiotropium Bromide; Treatment Outcome

The aim of this study was to test the hypothesis that use of tiotropium, a new long-acting anticholinergic bronchodilator, would be associated with sustained reduction in lung hyperinflation and, thereby, would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease. A randomised, double-blind, placebo-controlled, parallel-group study was conducted in 187 patients (forced expiratory volume in one second 44 +/- 13% pred): 96 patients received 18 microg tiotropium and 91 patients received placebo once daily for 42 days. Spirometry, plethysmographic lung volumes, cycle exercise endurance and exertional dyspnoea intensity at 75% of each patient's maximal work capacity were compared. On day 42, the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to placebo: vital capacity and inspiratory capacity (IC) increased, with inverse decreases in residual volume and functional residual capacity. Tiotropium increased post-dose exercise endurance time by 105 +/- 40 s (21%) as compared to placebo on day 42. At a standardised time near end-exercise (isotime), IC, tidal volume and minute ventilation all increased, whilst dyspnoea decreased by 0.9 +/- 0.3 Borg scale units. In conclusion, the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise. Resultant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance.

Topics: Aged; Analysis of Variance; Cholinergic Antagonists; Double-Blind Method; Dyspnea; Exercise Test; Exercise Tolerance; Female; Humans; Lung Volume Measurements; Male; Middle Aged; Physical Endurance; Plethysmography; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Healthcare costs for chronic obstructive pulmonary disease (COPD) have continued to increase with the increasing prevalence of the disease. New interventions that can reduce the medical costs of COPD are needed. Tiotropium bromide, a once-daily inhaled anticholinergic, has been evaluated in patients with COPD enrolled in two 1-year randomised, double-blind, placebo-controlled (usual care) trials which showed the drug reduced exacerbations and improved spirometry, dyspnoea, and health status.. To retrospectively assess the direct costs of medical care for COPD in a US healthcare setting for patients treated with tiotropium in addition to usual care compared with usual care alone over a 1-year timeframe. The study was based on resource utilisation in the two previously described trials.. Resource utilisation and clinical data were prospectively collected for the two 1-year, randomised, double-blind trials of tiotropium plus usual care versus usual care alone (placebo) in 921 patients with COPD. Usual care was defined as any medication for COPD used prior to the trial except anticholinergics and long-acting beta-adrenoceptor agonists. Medical care resource utilisation was recorded at every scheduled visit in each trial. Mean total costs were calculated retrospectively by combining the resources utilised with the appropriate unit costs (1999 US dollars), excluding study drug (tiotropium) costs.. Compared with usual care, patients receiving tiotropium in addition to usual care had significantly fewer COPD exacerbations (20% decrease), hospitalisations (44% reduction) and hospital days (50% reduction). Utilisation of resources other than hospitalisation did not differ between study groups. As a consequence, patients receiving tiotropium had significantly lower mean per- patient costs of hospitalisation compared with patients receiving usual care alone (tiotropium US 1,738 dollars +/- US 259 dollars; placebo US 2,793 dollars +/- US 453 dollars). The mean difference in the cost of hospitalisation (resulting from all causes, including COPD) between treatment groups was -US 1,056 dollars (95% CI -US 2,078 dollars, -US 34 dollars), and the difference in total healthcare costs (excluding study drug acquisition cost) was -US 1,043 dollars (95% CI -US 2,136 dollars, US 48 dollars) in favour of tiotropium. The cost of hospital admissions accounted for 48% of the total direct medical costs in this trial.. As hospitalisation is a large contributor to the cost of COPD, the addition of tiotropium to usual care therapy may have the potential to reduce the economic burden of COPD in a US healthcare setting. However, as our study did not consider the acquisition cost of tiotropium, further economic evaluation including this cost is needed to address whether tiotropium is cost saving compared with usual care (placebo).

Topics: Adult; Aged; Cholinergic Antagonists; Female; Health Care Costs; Hospitalization; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide

The aim of this double-blind, double-dummy, crossover, randomised, pilot study was to explore the acute effects of adding salmeterol and tiotropium in patients with stable COPD. A total of 20 outpatients with stable COPD were enrolled. Single doses of 18-microg tiotropium, 50-microg salmeterol, and 18-microg tiotropium+ 50-microg salmeterol were given. Serial measurements of forced expiratory volume in 1 s (FEV1) were performed over 24h. The mean maximum increases in FEV1 from pre-dosing value on each of the dosing days were 0.165l (95% CI: 0.098-0.232) for tiotropium, 0.241 l (95% CI: 0.151-0.332) for salmeterol, and 0.290 l (95% CI: 0.228-0.353) for the combination and occurred 4 h after inhalation of tiotropium or salmeterol and 3 h after the combination. At 12h, the mean increases in FEV1 from pre-dosing value were 0.071 l (95% CI: 0.001-0.141; P = 0.047) for tiotropium, 0.069 l (95% CI: 0.018-0.120; P = 0.010) for salmeterol, and 0.108 l (95% CI: 0.047-0.170; P = 0.001) for the tiotropium + salmeterol combination. Only the difference between salmeterol and tiotropium + salmeterol was statistically significant (P = 0.009). At 24h, the mean FEV1 value was still higher than the mean pre-dosing value for tiotropium (0.042 l; 95% CI: -0.012-0.097; P=0.119) and the tiotropium+salmeterol combination (0.051 l; 95% CI: 0.01 5-0.087; P = 0.007), but not for salmeterol alone (-0.013 l; 95% CI: -0.041-0.014; P = 0.324). The FEV1 area under the curve (AUCs0-12h) were 1.657 l (95% CI: 1.152-2.162) for tiotropium, 2.068 (95l CI: 1.385-2.752) for salmeterol, and 2.541 l (95% CI: 1.954-3.129) for tiotropium + salmeterol. Only the difference between tiotropium and the tiotropium +salmeterol combination was statistically significant (P = 0.01). The FEV1 AUCs0-24h were 2.854 l (95% CI: 1.928-3.780) for tiotropium, 2.786 l (95% CI: 1.913-3.660) for salmeterol, and 3.640 l (95% CI: 2.674-4.605) for tiotropium + salmeterol. ALL differences between treatments were not statistically significant (P> 0.05). These results seem to indicate that the use of the tiotropium + salmeterol combination is more efficacious than the single agents alone, but the once-daily administration of the two drugs is inadvisable due to the broncholytic profile of salmeterol.

Topics: Aged; Aged, 80 and over; Albuterol; Anthropometry; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Combinations; Female; Forced Expiratory Volume; Heart Rate; Humans; Male; Metered Dose Inhalers; Middle Aged; Oxygen; Partial Pressure; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

Tiotropium is a once-daily, inhaled anticholinergic for the treatment of chronic obstructive pulmonary disease that acts as a prolonged antagonist of the M3-receptor. To ascertain whether electrophysiologic effects can be detected following tiotropium treatment in patients with chronic obstructive pulmonary disease, serial electrocardiograms were incorporated into multiple placebo-controlled clinical trials including long-term (6 and 12-month) trials with tiotropium 18 mcg daily (n=2,128) and a 4-week dose-ranging study with tiotropium up to 36 mcg daily (n= 169). In addition, 24-hour electrocardiographic (Holter) monitoring was performed as part of a 6-week, placebo-controlled trial with tiotropium 18 mcg daily (n= 121). Electrocardiograms were performed before and up to 6 times during treatment in the 12-month trials, and before and at the end of treatment in the 6-month trials. For both the 12 and 6-month trials, electrocardiograms were recorded as adverse events if significant changes occurred, and were retrospectively sent for centralized analysis. During the 6-week trial, Holter monitoring was performed prior to the first dose and following 6 weeks of treatment. In all of these trials, no significant differences were observed in any of the electrocardiogram or Holter outcome parameters compared to placebo. Specifically, there was no clinically relevant difference in heart rate, atrio-ventricular conduction or the occurrence of ventricular or supraventricular arrhythmias. In conclusion, tiotropium was not associated with any signs of cardiac safety concerns as defined by electrocardiographic evaluations in placebo-controlled clinical trials.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography, Ambulatory; Follow-Up Studies; Humans; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

An accelerated loss of lung function is one of the defining characteristics of chronic obstructive pulmonary disease (COPD). To date, the only successful intervention shown to conclusively attenuate the loss of lung function over time is smoking cessation. Pharmacological interventions including inhaled corticosteroids and ipratropium bromide have not altered the rate of decline of lung function. Tiotropium is an inhaled anticholinergic that provides 24-hour bronchodilation with once-daily dosing due to prolonged muscarinic M3 receptor blockade. Controlled clinical trials have suggested sustained efficacy for periods of up to one year. We therefore initiated a four-year, controlled clinical trial (UPLIFT, Understanding the Potential Long-Term Impacts on Function with Tiotropium) in patients with COPD to evaluate the long-term effects of tiotropium on the rate of decline in lung function and health status as well as the frequency of exacerbations. The design of such large, long-term clinical trials presents unique methodological challenges including the definition of endpoints, the quality and variability of spirometric measurements and premature patient discontinuations from the trial. The present manuscript outlines the rationale for the UPLIFT study, and reviews the study design and the steps taken to address methodological challenges experienced in other long term studies. Careful design and implementation of the UPLIFT trial is anticipated to yield high quality results that will help in increasing our understanding of the long term natural history of COPD in a global population as well as to elucidate the role that tiotropium can play in affecting the course of this debilitating disease.

Topics: Administration, Inhalation; Adult; Bronchodilator Agents; Double-Blind Method; Follow-Up Studies; Forced Expiratory Volume; Health Status; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome

Inhaled anticholinergic drugs are considered one of the principal bronchodilator treatments for chronic obstructive pulmonary disease (COPD). Ipratropium bromide is an anticholinergic drug frequently administered for the treatment of COPD. Unfortunately, ipratropium has a short duration of action, requiring administration every 6 hours; this regimen affects adherence to drug therapy. Tiotropium bromide is structurally similar to ipratropium and is under development in the United States. The duration of action of tiotropium is approximately 24 hours, allowing for once-daily dosing. Other than xerostomia being more common with tiotropium than with ipratropium, the safety profiles of these drugs were similar in studied populations. On the basis of its improvements in trough spirometric measurements and improved pharmacokinetic profile compared with that of ipratropium, tiotropium is likely to become the first-line anticholinergic agent in the treatment of patients with COPD.

Topics: Administration, Inhalation; Cholinergic Antagonists; Drug Administration Schedule; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Ths object of this study was to examine validity, meaningful effect sizes, and patterns of response of the Transition Dyspnea Index (TDI) in a clinical trial cohort of chronic obstructive pulmonary disease (COPD) patients. The design was a retrospective analysis of data from a randomized, double-blind placebo-controlled clinical trial. We analyzed fifty clinical investigation sites in United States. There were 921 patients with stable COPD. Tiotropium 18 microg dry powder or matching placebo was used. Patients were allowed to remain on usual care less ipratropium bromide. Construct validity was demonstrated by significant correlations (P <.05) between Baseline Dyspnea Index (BDI) and other baseline measures, as well as between TDI and changes in other measures at the end of 1 year. Concurrent validity was observed by the significant correlation between TDI and dyspnea diary responses. Changes in TDI focal score were in the range of one unit when the group was stratified by a minimal change in the physician's global evaluation. Significantly less (P <.05) supplemental albuterol was observed in the group of responders defined by a one-unit improvement in TDI. Responders also had few exacerbations and better health status. The validity of the TDI is supported in a large clinical trial setting. A one-unit change in the TDI focal score represented the minimal important difference.

Topics: Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Double-Blind Method; Dyspnea; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

A study was undertaken to record exacerbations and health resource use in patients with COPD during 6 months of treatment with tiotropium, salmeterol, or matching placebos.. Patients with COPD were enrolled in two 6-month randomised, placebo controlled, double blind, double dummy studies of tiotropium 18 micro g once daily via HandiHaler or salmeterol 50 micro g twice daily via a metered dose inhaler. The two trials were combined for analysis of heath outcomes consisting of exacerbations, health resource use, dyspnoea (assessed by the transitional dyspnoea index, TDI), health related quality of life (assessed by St George's Respiratory Questionnaire, SGRQ), and spirometry.. 1207 patients participated in the study (tiotropium 402, salmeterol 405, placebo 400). Compared with placebo, tiotropium but not salmeterol was associated with a significant delay in the time to onset of the first exacerbation. Fewer COPD exacerbations/patient year occurred in the tiotropium group (1.07) than in the placebo group (1.49, p<0.05); the salmeterol group (1.23 events/year) did not differ from placebo. The tiotropium group had 0.10 hospital admissions per patient year for COPD exacerbations compared with 0.17 for salmeterol and 0.15 for placebo (not statistically different). For all causes (respiratory and non-respiratory) tiotropium, but not salmeterol, was associated with fewer hospital admissions while both groups had fewer days in hospital than the placebo group. The number of days during which patients were unable to perform their usual daily activities was lowest in the tiotropium group (tiotropium 8.3 (0.8), salmeterol 11.1 (0.8), placebo 10.9 (0.8), p<0.05). SGRQ total score improved by 4.2 (0.7), 2.8 (0.7) and 1.5 (0.7) units during the 6 month trial for the tiotropium, salmeterol and placebo groups, respectively (p<0.01 tiotropium v placebo). Compared with placebo, TDI focal score improved in both the tiotropium group (1.1 (0.3) units, p<0.001) and the salmeterol group (0.7 (0.3) units, p<0.05). Evaluation of morning pre-dose FEV(1), peak FEV(1) and mean FEV(1) (0-3 hours) showed that tiotropium was superior to salmeterol while both active drugs were more effective than placebo.. Exacerbations of COPD and health resource usage were positively affected by daily treatment with tiotropium. With the exception of the number of hospital days associated with all causes, salmeterol twice daily resulted in no significant changes compared with placebo. Tiotropium also improved health related quality of life, dyspnoea, and lung function in patients with COPD.

Topics: Administration, Inhalation; Albuterol; Bronchodilator Agents; Double-Blind Method; Dyspnea; Female; Forced Expiratory Volume; Hospitalization; Humans; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications. Initially, tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties. However, generally such observations have been reported in asthma. A 6-month randomized, double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD. Spirometry was measured over 12h at baseline and at days 15, 57, 116 and 169. Changes over time from baseline were compared relative to changes observed with placebo. A total of 623 patients participated (tiotropium = 209, salmeterol = 213, placebo = 201). The groups were similar in age (mean = 65 years), gender (75% men), and baseline FEV1 (mean = 1.08 +/- 0.37l [40 +/- 12% predicted]). Relative to placebo, both active drugs improved morning pre-drug, peak and average FEV1 and FVC throughout the trial. However, from day 1 to 169, salmeterol was associated with a higher decline in average FEV1 and FVC (0-12h) (difference from placebo: -36 and -115 ml, P < 0.05), which was most prominent over the 8-12 h period (difference from placebo: -45 and -138 ml, P < 0.01). Significant declines in peak FVC relative to placebo (-83 ml, P < 0.05) but not FEV1 (-12ml) were observed with salmeterol. Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial. In conclusion, tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics.

Topics: Aged; Albuterol; Analysis of Variance; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

In chronic obstructive pulmonary disease (COPD), the degree of circadian variation in forced expiratory volume in 1 second (FEV1) and the influence of anticholinergic blockade is not known. Tiotropium is a long acting inhaled anticholinergic bronchodilator that increases daytime FEV1 in COPD. We hypothesised that tiotropium would modify the overnight change in FEV1, and this would be unaffected by the timing of drug administration.. A double blind, randomised, placebo controlled trial was conducted with tiotropium 18 mg once daily in the morning (09.00 hours), evening (21.00 hours), or an identical placebo. Patients with stable COPD (n=121, FEV1=41% predicted) underwent spirometric tests every 3 hours for 24 hours at baseline and after 6 weeks of treatment.. There were no significant differences at baseline between the groups. Tiotropium improved mean (SE) FEV1 (over 24 hours) in the morning (1.11 (0.03) l) and evening (1.06 (0.03) l) groups compared with placebo (0.90 (0.03) l), and nocturnal FEV1 (mean of 03.00 and 06.00 hours) in the morning (1.03 (0.03) l) and evening (1.04 (0.03) l) groups compared with placebo (0.82 (0.03) l) at the 6 week visit (p<0.01). FEV1 before morning or evening dosing was similar, while the peak FEV1 moved later in the day with active treatment. The mean percentage change in FEV1 from 09.00 hours to 03.00 hours (the nocturnal decline in FEV1) was -2.8% in the morning group, -1.0% in the evening group, and -12.8% in the placebo group. The magnitude of the peak to trough change in FEV1 was not statistically different.. Tiotropium produced sustained bronchodilation throughout the 24 hour day without necessarily abolishing circadian variation in airway calibre.

Topics: Aged; Bronchodilator Agents; Cholinergic Antagonists; Circadian Rhythm; Cross-Over Studies; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

The HandiHaler is a novel breath-actuated dry powder system designed for the delivery of tiotropium 18microg daily in the treatment of COPD. We compared patient ability to use the HandiHaler or metered dose inhaler (MDI) device correctly 4 weeks after receiving brief instructions and device demonstration. A single-blind study was conducted in COPD patients in two centers in Denmark. ALL patients (n = 151) received one placebo capsule via the HandiHaler daily and ipratropium (20 microg) two actuations via the MDI q.i.d. Mean FEV1 for all patients was 1.25 + 0.54 (46% predicted). Twelve instructions establishing proper device use were evaluated for the MDI and Handihaler. Error scores were analyzed by number of patients with less, equal or more errors when using HandiHaler compared to MDI in the total efficacy population (n = 139) and according to those who had not previously used an MDI for at least 12 months (MDI beginners) (n = 74) and those who had used an MDI (MDI experienced) (n = 65). Four weeks after device instruction, a higher proportion of patients in the total population (P < 0.01) had fewer errors with the HandiHaler (35.3%) compared to the MDI (15.1%). The number of errors was equal in 50% of patients. Similar findings were observed in the subgroup of patients who were MDI beginners (42% vs. 11%, P < 0.01) with non-significant trends in favor of the HandiHaler in those patients who were MDI experienced (29.7% vs. 18.9%, P = 0.096). Similar results in favor of HandiHaler were noted across different age and sex strata. The proportion of patients correctly using the device on the first of three attempts was 59.7% and 54.7% for the HandiHaler and MDI, respectively (P = 0.399). In summary, use of the HandiHaler can be easily taught with fewer errors compared to the MDI. Furthermore, patient performance using the HandiHaler was superior to that with an MDI despite prior MDI experience and more frequent usage.

Topics: Administration, Inhalation; Adult; Age Factors; Aged; Aged, 80 and over; Bronchodilator Agents; Female; Humans; Male; Metered Dose Inhalers; Middle Aged; Nebulizers and Vaporizers; Patient Education as Topic; Patient Participation; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sex Factors; Single-Blind Method; Tiotropium Bromide; Treatment Outcome

Missing data resulting from premature study withdrawal are a common problem in the analysis of longitudinal data in clinical trials. To date, this subject has received little attention in the context of economic evaluations and with regard to the analysis of cost data.. To (i) demonstrate the impact of patients who drop out during the study on the outcomes of an economic evaluation, and (ii) to compare the mean and variation in costs after applying five different methods to deal with incomplete data: multiple imputation, complete cases analysis, linear extrapolation, predicted mean and hot decking.. The study was performed using cost data collected in two randomised clinical trials comparing patients with chronic obstructive pulmonary disease receiving either tiotropium bromide or ipratropium bromide. The overall dropout rate was 17%, with the daily costs of the dropouts approximately 4 times higher than the costs of the completers.. Multiple imputation is a principled method that deals with missing observations by replacing each missing observation with a set of multiple plausible values. The variance between the resulting multiple datasets is combined with the variance between the datasets to take account of the extra uncertainty that results from missing data. The outcomes after multiple imputation were compared with the results of four naive methods to deal with missing observations: complete cases analysis, linear extrapolation, predicted mean and hot decking. All costs were expressed in 2001 euros.. In the tiotropium bromide group, mean (standard error) costs varied from Euro 955 (137) after complete cases analysis to Euro 1298 (198) after linear extrapolation. The corresponding estimates in the ipratropium bromide group were Euro 970 (125) and Euro 1561 (244), respectively. The difference in costs between treatment groups varied from -Euro 15 (95% CI: -379 to 349) after complete cases analysis to -Euro 402 (95% CI: -883 to 79) after predicted mean, in favour of the tiotropium bromide group. The difference in costs according to the other methods varied from -Euro 263 (95% CI: -878 to 353) after linear extrapolation to -Euro 265 (95% CI: -709 to 180) after multiple imputation to -Euro 359 (95% CI: -771 to 54) after hot decking.. This study showed that the method of dealing with the data of the dropouts had a large impact on the outcomes of an economic evaluation. Information about the rate of patient withdrawal and the way data of dropouts are treated is of vital importance in assessing the results of economic evaluations and should always be reported. Multiple imputation is a principled method that can be used to deal with the data of these patients.

Topics: Bronchodilator Agents; Data Collection; Health Care Costs; Humans; Ipratropium; Patient Dropouts; Pulmonary Disease, Chronic Obstructive; Quality of Life; Research Design; Scopolamine Derivatives; Tiotropium Bromide

In patients with COPD, changes in inspiratory capacity (IC) have shown a higher correlation to patient-focused outcomes, such as dyspnea with exercise, than other standard spirometric measurements. Changes in IC reflect changes in hyperinflation. Tiotropium is a once-daily inhaled anticholinergic that has its effect through prolonged M3 muscarinic receptor antagonism and has demonstrated sustained improvements in spirometric and health outcomes. We sought to evaluate changes in resting IC and lung volumes after long-term administration of tiotropium.. To evaluate the effect of tiotropium, 18 micro g/d, on IC, a 4-week, randomized, double-blind, placebo-controlled study was conducted in 81 patients with stable COPD. At each of the visits (weeks 0, 2, and 4) FEV(1), FVC, IC, slow vital capacity (SVC), and thoracic gas volume (TGV) were measured prior to study drug (- 60 and - 15 min) and after study drug (30 min, 60 min, 120 min, and 180 min).. Mean age was 64 years; 62% were men. Mean baseline FEV(1) was 1.12 L (43% predicted). The mean differences (tiotropium - placebo) in FEV(1) trough (morning before drug), peak, and area under the curve over 3 h values (adjusted for baseline and center differences) at week 4 were 0.16 L, 0.22 L, and 0.22 L, respectively (p < 0.01 for all); differences in IC for these variables were 0.22 L, 0.35 L, and 0.30 L (p < 0.01 for all). Differences in TGV were - 0.54 L, - 0.60 L, and - 0.70 L, respectively (p < 0.01 for all). The percentage improvement in area under the curve above baseline with tiotropium was similar among FEV(1) and lung volumes (FEV(1), 18%; FVC, 20%; SVC, 16%; IC, 16%; TGV, 14%).. Observed improvements in IC and reductions in TGV with once-daily tiotropium reflect improvements in hyperinflation that are maintained over 24 h.

Topics: Airway Resistance; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Inspiratory Capacity; Lung Volume Measurements; Male; Middle Aged; Plethysmography, Whole Body; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Vital Capacity

Tiotropium, a once-daily anticholinergic, and salmeterol represent two inhaled, long-acting bronchodilators from different pharmacologic classes. A trial was designed to examine the efficacy and safety of both compounds with multiple outcome measures, including lung function, dyspnea, and health-related quality of life (HRQoL) in patients with COPD.. A 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group study of tiotropium, 18 microg once daily via dry-powder inhaler, compared with salmeterol, 50 microg bid via metered-dose inhaler, was conducted in patients with COPD. Efficacy was assessed by 12-h monitoring of spirometry, transition dyspnea index (TDI), and the St. George's Respiratory Questionnaire (SGRQ).. A total of 623 patients participated (tiotropium, n= 209; salmeterol, n = 213; and placebo, n = 201). The groups were similar in age (mean, 65 years), gender (75% men), and baseline FEV(1) (mean, 1.08 +/- 0.37 L; percent predicted, 40 +/- 12% [+/- SD]). Compared with placebo treatment, the mean predose morning FEV(1) following 6 months of therapy increased significantly more for the tiotropium group (0.14 L) than the salmeterol group (0.09 L; p < 0.01). The average FEV(1) (0 to 12 h) for tiotropium was statistically superior to salmeterol (difference, 0.08 L; p < 0.001). Tiotropium improved TDI focal score by 1.02 U compared with placebo (p = 0.01), whereas there was no significant change in TDI focal score with salmeterol (0.24 U). Tiotropium was superior to salmeterol in improving TDI focal score (p < 0.05). At 6 months, the mean improvement in SGRQ total score vs baseline was tiotropium, - 5.14 U (p < 0.05 vs placebo); salmeterol, - 3.54 U (p = 0.4 vs placebo); and placebo, - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo. Both active drugs reduced the need for rescue albuterol (p < 0.0001).. Tiotropium once daily produces superior bronchodilation, improvements in dyspnea, and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD.

Topics: Aged; Albuterol; Bronchodilator Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome

Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2+/-8.7 yrs (mean+/-SD), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 microg or placebo (mean screening forced expiratory volume in one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response (approximately 12% over baseline) (p<0.01) and mean response during the 3 h following dosing (approximately 22% over baseline) (p<0.001) over the 12-month period. Tiotropium recipients showed less dyspnoea (p<0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations (p<0.05). Adverse events were comparable with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p<0.05). Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Drug Administration Schedule; Female; Health Status; Humans; Male; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Tiotropium, a novel once-daily inhaled anticholinergic, has been shown to improve lung function over a 24-h period. In order to extend these findings, health-outcomes were evaluated over 1 yr in chronic obstructive pulmonary disease (COPD) patients. Spirometric results, peak expiratory flow rate (PEFR), salbutamol use and effects on dyspnoea, health-related quality of life and COPD exacerbations were assessed in two identical 1-yr randomized double-blind double-dummy studies of tiotropium 18 microg once daily (n=356) compared with ipratropium 40 microg q.i.d. (n=179). Screening forced expiratory volume in one second (FEV1) were 1.25+/-0.43 L (41.9+/-12.7% of the predicted value) (tiotropium) and 1.18+/-0.37 L (39.4+/-10.7% pred) (ipratropium). Trough FEV1 at 1 yr improved by 0.12+/-0.01 L with tiotropium and declined by 0.03+/-0.02 L with ipratropium (p<0.001). Significant improvement in PEFR, salbutamol use, Transition Dyspnea Index focal score, and the St George's Respiratory Questionnaire total and impact scores were seen with tiotropium (p<0.01). Tiotropium reduced the number of exacerbations (by 24%, p<0.01), and increased time to first exacerbation (p<0.01) and time to first hospitalization for a COPD exacerbation (p<0.05) compared with ipratropium. Apart from an increased incidence of dry mouth in the tiotropium group, adverse events were similar between treatments. Tiotropium was effective in improving dyspnoea, exacerbations, health-related quality of life and lung function in patients with chronic obstructive pulmonary disease, and exceeds the benefits seen with ipratropium. The data support the use of tiotropium once-daily as first-line maintenance treatment in patients with chronic obstructive pulmonary disease.

Topics: Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Ipratropium; Male; Middle Aged; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

Tiotropium (Spiriva) is a new once-daily inhaled anticholinergic that has its effect through prolonged muscarinic (M)3 receptor antagonism. It has a clinically documented, long duration of action with once-daily dosing in chronic obstructive pulmonary disease (COPD). A single-centre, double-blind, ipratropium-controlled study was conducted in order to characterize the onset of pharmacodynamic steady state of tiotropium in patients with COPD. Thirty-one patients (25 male, six female) with a mean age of 62 yrs and a mean forced expiratory volume in one second (FEV1) of 1.13 L (38% of predicted) were randomly assigned to receive either tiotropium 18 microg once-daily from a dry-powder inhaler (HandiHaler, 20 patients), or ipratropium 40 microg four-times daily from a pressurized metered-dose inhaler (11 patients) for a period of 1 week. FEV1 and forced vital capacity (FVC) were measured 1 h prior to, and just before inhalation (mean value of the two measurements on test-day 1 was the baseline value, while on all other test days it was the trough value), and 0.5, 1, 2, 3, 4, 5, and 6 h after inhalation of the morning dose of the study drug (one capsule and two puffs) on days 1, 2, 3, and 8. Trough FEV1 following 8 days of tiotropium was 0.19 L (18%) above baseline. Approximately 90% of this increase was achieved within 24 h of the first dose (0.17 L, 16%). Trough FVC increased 0.67 L (27%) on test-day 8. Approximately 70% of the improvement was observed after two tiotropium doses (0.47 L, 19%). Achievement of FVC steady state was delayed compared to FEV1. Ipratropium performed typically with an onset of action within 30 min, a peak response between 1-2 h postdosing and a duration of action of approximately 4 h. It was concluded that forced expiratory volume in one second steady state with tiotropium is reached within 48 h, while continued improvements in forced vital capacity can be expected over or beyond the first week of therapy. The continued increases in forced vital capacity beyond 48 h suggests that maintenance bronchodilator therapy is required to achieve maximal changes in hyperinflation.

Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Drug Administration Schedule; Female; Humans; Ipratropium; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Muscarine acetylcholine receptors (mAChRs) regulate a variety of central and peripheral physiological functions and emerge as important therapeutic targets for a number of diseases including chronic obstructive pulmonary disease (COPD). Inspired by two active natural products, we designed and synthesized a series of 2-(2,2-diarylethyl)-cyclamine derivatives for screening M3 mAChR antagonists. On this skeleton, the structural units including N heterocycle, aryl groups and its substituents on aryl were examined and resulted in a clear structure-activity relationships on the M3 mAChR. In general, these 2-(2,2-diarylethyl)-cyclamine derivatives exhibited good to excellent M3 antagonistic potency and receptor selectivity. The most active 5b-C1 had an IC

Topics: Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Scopolamine Derivatives; Tiotropium Bromide

There are limited studies on the use of bronchodilators for the treatment of bronchiectasis. This study investigated the efficacy of tiotropium in patients with bronchiectasis and airflow limitation.. This study was a prospective cohort study, including 169 patients with bronchiectasis and airflow limitation from 2015 to 2019. The clinical outcomes observed in our study were the effect of tiotropium on the frequency of moderate exacerbations, the time to the first severe exacerbation, and the annual decline in FEV. After 12 months, the annual decline in the FEV. In conclusion, prospective cohort study showed that tiotropium effectively ameliorated the annual decline in the FEV

Topics: Bronchiectasis; Bronchodilator Agents; Humans; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Bronchiectasis; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

ATS and GOLD guidelines recommend treating low-exacerbation risk COPD patients with dual (LAMA/LABA) agents and reserving triple therapy (TT; LAMA/LABA and inhaled corticosteroids [ICS]) for severe cases with higher-exacerbation risk. However, TT often is prescribed across the COPD spectrum. This study compared COPD exacerbations, pneumonia diagnosis, healthcare resource utilization, and costs for patients initiating tiotropium bromide/olodaterol (TIO/OLO) and a TT, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), stratified by exacerbation history.. COPD patients who initiated TIO/OLO or FF/UMEC/VI between 06/01/2015-11/30/2019 (index date=first pharmacy fill-date with ≥30 consecutive treatment days) were identified from the Optum Research Database. Patients were ≥40 years old and continuously enrolled for 12 months during the baseline period and ≥30 days during follow-up. Patients were stratified into GOLD A/B (0-1 baseline non-hospitalized exacerbation), No exacerbation (subset of GOLD A/B), and GOLD C/D (≥2 non-hospitalized and/or ≥1 hospitalized baseline exacerbation). Baseline characteristics were balanced with propensity score matching (1:1). Adjusted risks of exacerbation, pneumonia diagnosis, and COPD and/or pneumonia-related utilization and costs were evaluated.. Adjusted exacerbation risk was similar in GOLD A/B and No exacerbation subgroups, and lower in GOLD C/D for FF/UMEC/VI versus TIO/OLO initiators (hazard ratio: 0.87; 95% CI: 0.78, 0.98, p=0.020). Adjusted pneumonia risk was similar between cohorts across the GOLD subgroups. Adjusted COPD and/or pneumonia-related population annualized pharmacy costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators across subgroups, p<0.001. Adjusted COPD and/or pneumonia-related population annualized total healthcare costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators in the GOLD A/B and No exacerbation, subgroups, p<0.001 (cost ratio [95% CI]: 1.25 [1.13, 1.38] and 1.21 [1.09, 1.36], respectively), but similar in the GOLD C/D subgroup.. These real-world results support ATS and GOLD recommendations for treating low-exacerbation risk COPD patients with dual bronchodilators and TT for more severe, higher-exacerbation risk COPD patients.

Topics: Administration, Inhalation; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Patient Acceptance of Health Care; Pneumonia; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tiotropium Bromide

To investigate the clinical efficacy of combining budesonide formoterol with tiotropium bromide for treating asthma-chronic obstructive pulmonary disease overlap syndrome (AOCS).. The data of 104 patients with AOCS admitted to our hospital from December 2019 to December 2020 were assessed, randomly and divided into an experimental group (comprising 52 patients, receiving drug combination therapy) and a conventional group (comprising 52 patients, receiving drug therapy alone). Patients' clinical efficacy, pulmonary function, fractioned exhaled nitric oxide (FeNO), immune function, endothelial function, serum lipid peroxidation injury indexes, adverse reactions, and quality of life scores were compared.. Prior to treatment, no significant differences were observed in various pulmonary function indicators, FeNO, immune function, endothelial function, and lipid peroxidation injury indexes between the two groups (. The combination of budesonide formoterol to tiotropium bromide in treating asthma-COPD overlap syndrome may significantly improve pulmonary function, endothelial function, and immune status of patients and encourage the recovery of serum lipid peroxidation injury; therefore, this may deserve widespread adoption and application.

Topics: Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Tiotropium Bromide

This retrospective cohort study used primary care data from the Clinical Practice Research Datalink Aurum database linked with secondary care administrative data from Hospital Episode Statistics. Patients with a COPD diagnosis at age ≥35 years were included (indexed) following initiation of single-inhaler UMEC/VI or TIO/OLO between July 1, 2015, and September 30, 2019. Outcomes included the number of rescue medication prescriptions at 12-months (primary), and at 6-, 18- and 24-months (secondary), adherence at 6-, 12-, 18- and 24-months post-index, defined as proportion of days covered ≥80% (secondary), and time-to-initiation of triple therapy (exploratory). Inverse probability of treatment weighting (IPTW) was used to balance potential confounding baseline characteristics. Superiority of UMEC/VI versus TIO/OLO for the primary outcome of rescue medication prescriptions was assessed using an intention-to-treat analysis with a p-value < 0.05.. In total, 8603 patients were eligible (UMEC/VI: n = 6536; TIO/OLO: n = 2067). Following IPTW, covariates were well balanced across groups. Patients initiating UMEC/VI had statistically significantly fewer (mean [standard deviation]; p-value) rescue medication prescriptions versus TIO/OLO in both the unweighted (4.84 [4.78] vs 5.68 [5.00]; p < 0.001) and weighted comparison (4.91 [4.81] vs 5.48 [5.02]; p = 0.0032) at 12 months; consistent results were seen at all timepoints. Adherence was numerically higher for TIO/OLO versus UMEC/VI at all timepoints. Time-to-triple therapy was similar between treatment groups.. UMEC/VI was superior to TIO/OLO in reducing rescue medication prescriptions at 12 months after treatment initiation in a primary care cohort in England, potentially suggesting improvements in symptom control with UMEC/VI compared with TIO/OLO.

Topics: Administration, Inhalation; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Drug Prescriptions; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies; Tiotropium Bromide; Treatment Outcome

For patients with chronic obstructive pulmonary disease (COPD) who remain symptomatic despite maintenance treatment, clinical management guidelines recommend a stepwise escalation from monotherapy to dual therapy, and from dual therapy to triple therapy. However, in clinical practice, patients are often escalated directly from monotherapy to triple therapy based on disease severity. This study evaluated the cost-effectiveness of once-daily, single-inhaler fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) triple therapy compared with long-acting muscarinic antagonist monotherapy with once-daily tiotropium (TIO) in patients with symptomatic moderate-to-very severe COPD, from a UK National Health Service perspective.. The validated GALAXY-COPD disease progression model was populated with patient baseline characteristics and treatment effect data from the 12-week GSK Study 207626 comparing FF/UMEC/VI with TIO in patients with moderate-to-very severe COPD. UK unit costs and drug costs (British Pound, 2021) were applied to healthcare resource utilization and treatments. The base case analysis was conducted over a lifetime horizon, and costs and health outcomes (except for life years [LYs]) were discounted at 3.5% per year. Model outputs included exacerbation rates, healthcare costs, LYs, quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios.. Overall, treatment with FF/UMEC/VI resulted in increased clinical benefit (reduction in total exacerbations and increased overall survival and QALYs), coupled with cost savings (derived from lower maintenance and exacerbation healthcare costs) compared with TIO monotherapy. In the base case analysis, FF/UMEC/VI provided an additional 0.393 LYs (95% range: 0.176, 0.655) and 0.443 QALYs (0.246, 0.648), at a cost saving of £880 (£54, £1608) versus TIO. FF/UMEC/VI remained the cost-effective (dominant) treatment option across sensitivity and scenario analyses.. FF/UMEC/VI offers greater clinical benefits and is a cost-effective treatment option compared with TIO for the treatment of adult patients with COPD with persistent symptoms and/or who are at risk of exacerbation in the UK.

Topics: Adult; Cost-Benefit Analysis; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; State Medicine; Tiotropium Bromide; United Kingdom

Bronchiolitis obliterans syndrome (BOS) is the lung manifestation of chronic graft-versus-host disease after hematopoietic stem cell transplantation (HSCT). We assessed whether inhaled tiotropium add-on to the combination regimen including budesonide/formoterol improve pulmonary function and the chronic obstructive pulmonary disease assessment test (CAT) scores in patients with BOS.. Post-HSCT patients diagnosed as BOS in Seoul St. Mary's Hospital were reviewed retrospectively. Patients defined as BOS and treated with budesonide/formoterol/tiotropium combination therapy after budesonide/formoterol therapy from January 2011 to June 2019 were enrolled.. Total of 86 patients were evaluated. After tiotropium add-on, the absolute FEV1 increased significantly from 1.47 ± 0.49 to 1.53 ± 0.57 L (p = 0.023) and the % predicted FEV1 from 45.0 ± 12.8 to 46.8 ± 14.5% (p = 0.031). The % predicted DLCO increased significantly after tiotropium add-on (from 61.6 ± 16.7 to 64.3 ± 16.3%, p = 0.028). Among 56 patients with complete CAT scores, no significant change was present in total CAT scores. In all, 30 of the 72 patients (41.7%) evidenced FEV1 increases > 100 mL, and 20 of 56 patients (35.7%) had CAT score decreases of ≥ 2 points. When the FEV1 and CAT scores were combined, the overall response rate to tiotropium add-on was 56.2% (41/73). The response group evidenced a significantly greater FVC increase, and a significant decrease in the RV/TLC ratio compared to the no-response group.. Inhaled tiotropium add-on to combination budesonide/formoterol significantly improved lung function, but not respiratory symptoms, in patients with post-HSCT BOS.

Topics: Bronchiolitis Obliterans; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Hematopoietic Stem Cell Transplantation; Humans; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Tiotropium Bromide

Tiotropium/olodaterol (TIO/OLO) fixed-dose combination (FDC) can improve lung function and quality of life for patients with chronic obstructive pulmonary disease (COPD), and is not inferior to other LAMA/LABAs. The aim of this study was to assess the cost-effectiveness of TIO/OLO FDC in patients with moderate to very severe COPD in China.. A Markov model was developed to estimate the cost-effectiveness of TIO/OLO FDC versus TIO in the treatment of COPD from Chinese health system perspective. Four health states were based on 2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD 2021), which included moderate (GOLD II, 50% ≤ FEV1 ≤ 80% of predicted), severe (GOLD III, 30% ≤ FEV1 ≤ 50% of predicted) and very severe (GOLD IV, FEV1 > 30% of predicted) COPD and death. The model simulated in cycles yearly. The indicators of total costs, number of COPD exacerbations, life years (LYs) and quality-adjusted life-years (QALYs) were used as the model output. Costs and outcomes were discounted at a 5% annual rate. A cost-effectiveness analysis was conducted over a 10-year time horizon. The threshold of incremental total cost per unit effectiveness gained (ICER) was 1.5 times of GDP per capita. Uncertainty was assessed by one-way and probabilistic sensitivity analysis.. TIO/OLO was 0.007 QALYs more than TIO but 0.012 LYs lower, which increased the total cost by $2268.17 per patient, but the total exacerbations number was less. Incremental cost effectiveness analysis had shown that the ICER exceeded the willingness to pay threshold. Results were robust under most parameter variation, except the parameters of total drug cost of TIO/OLO FDC in univariate sensitivity analyses.. Although TIO/OLO FDC could reduce the exacerbation risk, it was not cost-effective, and needed to be repriced.

Topics: China; Cost-Effectiveness Analysis; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide

The aim: To evaluate the dynamics of the interferon and collagen-IV systems in bronchoalveolar lavage in the treatment of chronic obstructive pulmonary disease using the tiotropium bromide medication.. Materials and methods: The study involved 60 COPD patients with bronchial obstruction of the II degree before and on days 30 and 60 of therapy using conventional treatment regimens and inhalations of tiotropium bromide a the dose of 18 mcg once a day. The collagen-IV levels in bronchoalveolar fluid were determined by means of enzyme-linked immunoassay using "StatFax 303 Plus" analyzer and "Biotrin Collagen IV EIA" reagents. The level of IFN-γ was identified with the help of enzyme-linked immunoassay using "StatFax 303 Plus" analyzer and "ProKon" reagents (LLC "Protein Contour", Russia) in bronchoalveolar fluid obtained during fiber-optic bronchoscopy.. Results: When examining Group I patients on the 30th day we found out that the content of collagen-IV in the bronchoalveolar fluid had decreased by only 10.29% (p <0.05). Detection of collagen-IV indices in Group II patients on the 30th day of tiotropium bromide use showed the 29.43% (p <0.05) decrease in its content as compared to the initial indices. In Group III patients, the concentration of collagen-IV had a maximum tendency to normalize and made up (24.72 ± 1.15) ng/ml, and decreased by 2.44 times (p <0.05) as compared to the initial indices. Our examination of 12 patients from the comparison group I on the 60th day of treatment revealed even a slight increase in the content of collagen-IV in the bronchoalveolar fluid, as compared with the data obtained on the 30th day. The identified IFN-γ deficiency is indicative for the COPD of the II degree of bronchial obstruction, and its indices were 2.29 times lower than those observed in people from the control group. On day 30, we found out that the content of IFN-γ in Group I patients increased by only 10.29% (p>0.05). Detection of IFN-γ in Group II patients showed 42.27% (p<0,05) increase in its content as compared to the initial indices. The most favorable dynamics of IFN-γ levels in bronchoalveolar contents was observed in Group III patients, and at the time of observation it made up (1.16 ± 0.08) pg/ml, having 2 times (p<0.05) increased as compared to the initial indices. However, in contrast to those taking tiotropium bromide, we examined 12 patients from Group I on the 60th day of treatment and found no significant positive dynamics of IFN-γ content in bronchoalveolar fluid as compared to the indices obtained on day 30.. Conclusions: The obtained findings indicate the effect of tiotropium bromide on the reduction of interferon-γ and reduce of collagen-IV levels, which depend on the duration of its use.

Topics: Bronchoalveolar Lavage; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Long-acting beta-agonists (LABA) and long-acting muscarinic antagonists (LAMA) combination therapy improved lung function and health-related quality-of-life and reduced exacerbation rates and dyspnea in symptomatic chronic obstructive pulmonary disease (COPD) patients. We compared the real-world effects of three fixed-dose LABA/LAMA combinations for COPD in Taiwan.. This multicenter, retrospective study evaluated 1-year outcomes after LABA/LAMA combination therapy in patients with symptomatic COPD. Exacerbations and symptoms of COPD, lung functions, and therapy escalation were compared among patients using tiotropium/olodaterol, umeclidinium/vilanterol and indacaterol/glycopyrronium. Propensity score matching (PSM) was applied to balance the baseline characteristics.. Data of 1,617 patients were collected. After PSM, time to first moderate-to-severe COPD exacerbation was comparable among three groups, while the annualized rates of the exacerbation (episodes/patient/year) in patients receiving tiotropium/olodaterol (0.19) or umeclidinium/vilanterol (0.17) were significantly lower than those receiving indacaterol/glycopyrronium (0.38). COPD-related symptoms were stable over the treatment period, and there was no significant difference in the changes of symptom scores including CAT and mMRC among three groups at the end of the study period.. This study presented valuable real-world outcome in terms of exacerbation and treatment response of COPD patients treated with fixed-dose LABA/LAMA regimens in Taiwan. The annualized rates of moderate-to-severe exacerbation in patients receiving tiotropium/olodaterol or umeclidinium/vilanterol were significantly lower than those receiving indacaterol/glycopyrronium, though the time to first moderate-to-severe exacerbation was similar among different fixed-dose LABA/LAMA combinations.

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Retrospective Studies; Taiwan; Tiotropium Bromide; Treatment Outcome

Mucociliary clearance (MCC) is an essential defense mechanism in airway epithelia for removing pathogens from the respiratory tract. Impaired ciliary functions and MCC have been demonstrated in asthma and chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators, which are used for treating asthma and COPD; however, the effects of LAMAs on ciliary function remain unclear. This study aimed to identify the effects of LAMAs on airway ciliary functions.. Wild-type BALB/c mice were treated with daily intranasal administrations of glycopyrronium for 7 days, and tracheal samples were collected. Cilia-driven flow and ciliary activity, including ciliary beat frequency (CBF), ciliary beating amplitude, effective stroke velocity, recovery stroke velocity and the ratio of effective stroke velocity to recovery stroke velocity, were analyzed by imaging techniques. Using in vitro murine models, tracheal tissues were transiently cultured in media with/without LAMAs, glycopyrronium or tiotropium, for 60 min. Cilia-driven flow and ciliary activity were then analyzed. Well-differentiated normal human bronchial epithelial (NHBE) cells were treated with glycopyrronium, tiotropium, or vehicle for 60 min, and CBF was evaluated. Several mechanistic analyses were performed.. Intranasal glycopyrronium administration for 7 days significantly increased cilia-driven flow and ciliary activity in murine airway epithelium. In the murine tracheal organ culture models, treatment with glycopyrronium or tiotropium for 60 min significantly increased cilia-driven flow and ciliary activity in airway epithelium. Further, we confirmed that 60-min treatment with glycopyrronium or tiotropium directly increased CBF in well-differentiated NHBE cells. In the mechanistic analyses, neither treatment with glycopyrronium nor tiotropium affected intracellular calcium ion concentrations in well-differentiated NHBE cells. Glycopyrronium did not increase protein kinase A activity in well-differentiated NHBE cells. Moreover, glycopyrronium had no effect on extracellular adenosine triphosphate concentration.. LAMAs exert a direct effect on airway epithelium to enhance ciliary function, which may improve impaired MCC in asthma and COPD. Further investigations are warranted to elucidate the underlying mechanisms of the effects of LAMAs on the promotion of airway ciliary function.

Topics: Animals; Asthma; Epithelium; Glycopyrrolate; Humans; Mice; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Stroke; Tiotropium Bromide; Trachea

Long-acting muscarinic antagonists (LAMA) are used for long-term treatment of bronchial asthma in adults. Its use in the management of pediatric bronchial asthma, however, is currently not approved in Japan. Nonetheless, there have been a few reports of its use in children, particularly in cases of severe bronchial asthma or those without atopic disease that are refractory to existing treatment protocols. We report the progress of LAMA in infantile asthma patients.. Three out of four patients had LAMA introduced at 3 to 5 years of age after being diagnosed with asthma at 1 to 3 years old. Three patients had non-IgE-related asthma and an underlying disease, such as Apert and Noonan syndrome, while one patient had severe IgE-related asthma without a pre-existing disease. In all cases, conventional long-term medications such as medium to high-dose inhaled corticosteroids and long-acting beta-agonists, were given. However, severe bronchial asthma persisted, with some patients having uncontrolled secretions. Since uncontrolled severe-persistent bronchial asthma results in repeated hospitalization and intensive care unit admission, we introduced LAMA, specifically 2.5μg/day of tiotropium (Tio). After the introducing Tio, none of the patients had an acute exacerbation that required hospitalization and the frequency of wheezing was reduced. LAMA was administered for up to 19 months, with no adverse events.. The results of this series suggest that LAMA is an effective and safe option for uncontrolled infantile asthma.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Asthma; Bronchodilator Agents; Child; Child, Preschool; Humans; Infant; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Health‑related quality of life in patients with chronic obstructive pulmonary disease (COPD) can be measured by the Clinical COPD Questionnaire (CCQ). In this study, the CCQ was used to assess the therapeutic success of a fixed‑dose tiotropium / olodaterol combination treatment in Polish COPD patients.. We aimed to evaluate the changes in the CCQ score in Polish patients with COPD after 6 weeks of treatment with tiotropium / olodaterol and to assess the predictors of response to this treatment.. Data of the Polish subgroup of the NIS‑CCQ observational study (NCT03663569) were extracted. COPD patients who had received a new tiotropium / olodaterol prescription were included. The primary end point was therapeutic success predefined as a 0.4‑point reduction in the CCQ score after 6 weeks of tiotropium / olodaterol treatment. Post‑hoc logistic regression analysis was performed to identify the predictors of response to the treatment.. After 6 weeks of treatment, 72.4% of patients achieved therapeutic success. The therapy was successful in 83.4% of treatment‑naïve patients, as compared with 62.6% and 73.3% of those previously treated with long‑acting muscarinic antagonists or long‑acting β2 agonists in monotherapy and in combination with inhaled corticosteroids, respectively. Therapeutic success was achieved by at least 50% of patients regardless of the COPD severity and exacerbation history but it was more frequent in patients with more severe disease. The airflow limitation severity grades 2 to 4, modified Medical Research Council Dyspnea Scale classes 2 to 4, exacerbations within the last year before the study, and treatment‑naïve status predicted a better response to tiotropium / olodaterol.. Tiotropium / olodaterol treatment improved clinical control in Polish COPD patients. Therapeutic success was the most pronounced in individuals with more severe COPD and in the treatment‑naïve group but occurred also in those with moderate disease and in previously treated participants.

Topics: Benzoxazines; Bronchodilator Agents; Humans; Poland; Pulmonary Disease, Chronic Obstructive; Quality of Life; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

Objective To explore the effect of down-regulation of high mobility group box 1 (HMGB1) expression on inflammatory response and epithelial mesenchymal transition (EMT) in the lung tissue of mice with chronic obstructive pulmonary disease (COPD) and its related mechanism. Methods The COPD model was induced by cigarette smoking, and HMGB1 expression in lung tissue of mice was down-regulated by small interfering RNA (siRNA). The mice were divided into negative control group (NC group), COPD group, si-NC intervention COPD group, si-HMGB1 intervention COPD group, and tiotropium bromide intervention COPD group (positive control group). After 4 weeks of cigarette smoking induction, the general condition of mice were observed, and the body mass changes of each group were recorded every week. HE staining was used to observe the pathological changes of lung tissue in each group. The expression of HMGB1 mRNA and protein in lung tissues of mice weredetected by real time quantitative PCR and Western blot analysis. The BALF of mice in each group was collected, and the levels of IL-6, TNF-α, IL-1β and TGF-β1 in BALF were detected by ELISA. The expressions of E-cadherin and α-SMA in lung tissues of mice were observed by immunohistochemical staining. The expression of RAGE, TLR4, TGF-β1 and the phosphorylation of NF-κB p65 in lung tissues were detected by Western blot analysis. Results COPD mouse model induced by cigarette smoking was successfully established. Compared with COPD group, down-regulation of HMGB1 expression in lung tissue significantly improved the general vital signs of mice, promoted the increase of body mass, and improved the pathological damage of lung tissue in mice. Compared with the control group, HMGB1 mRNA and protein expression levels increased significantly in COPD group, COPD combined with si-NC group and COPD combined with tiotropium group, while no significant HMGB1 expression was detected in COPD combined with si-HMGB1 group. Compared with the control group, the secretion levels of IL-6, TNF-α, IL-1β, TGF-β1 in BALF, the expression levels of α-SMA, RAGE, TLR4, TGF-β1 and the phosphorylation level of NF-κB p65 in lung tissues were significantly increased in COPD model group, while the expression level of E-cadherin significantly decreased. Compared with the COPD group or the COPD combined with si-NC group, the changes of the above indexes in the lung tissue of mice in the COPD combined with si-HMGB1 group and the COPD combined with tiotropium g

Topics: Animals; Cadherins; Down-Regulation; Epithelial-Mesenchymal Transition; HMGB1 Protein; Interleukin-6; Mice; NF-kappa B; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; Tiotropium Bromide; Toll-Like Receptor 4; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

This study assessed the delivery of tiotropium via Respimat® in addition to standard care of treatment among chronic obstructive pulmonary disease (COPD) patients. We study the efficacy, clinical outcome of handling inhaler device, rate of exacerbation and frequency of hospital admission of tiotropium via Respimat® with and without the use of a spacer (AeroChamber®).. Randomised, open-label study of COPD patients which was randomised into two groups: spacer or nonspacer groups using tiotropium via Respimat®. Treatment with their pre-existing inhalers continued. Subjects were assessed at weeks 0, and 8 for forced expiratory volume in 1 second (FEV1), COPD assessment tool (CAT), St. George's Respiratory Questionnaire (SGRQ), and satisfaction questionnaire.. We enrolled 96 subjects: 49 in the spacer group and 47 in the non-spacer group. The mean predicted FEV1 in spacer group was 54.48% at baseline and 57.5l% at week 8: p=0.011. In the non-spacer groups, FEV1 was 54.48% at baseline and 59.20% with a mean increment of 4.72 in both groups: p=0.002. There were no difference of exacerbation rates and hospital admission between both groups. At baseline, mean CAT score in the spacer group was 14.01 which improved to 9.80 (p<0.001) and 14.01 to 8.80 (p<0.001) in the non-spacer group. SGRQ total score reduced in both groups with mean difference of 3.1 (p<0.001) and 3.7: (p<0.001) at weeks 0 to 8.. There was no difference between exacerbation and hospital admissions between both groups. There was no difference in FEV1, CAT and SQRQ score using Tiotropium via Respimat® with or without a spacer.

Topics: Bronchodilator Agents; Humans; Patient Satisfaction; Personal Satisfaction; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The long-acting muscarinic antagonist (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). A post-authorization safety study was initiated to assess potential cardiovascular risks associated with LAMAs versus long-acting beta2-agonists.. To estimate incidence rates and adjusted incidence rate ratios (IRRs) for acute myocardial infarction (AMI), stroke, and major adverse cardiac events (MACE) in new users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA compared with initiators of LABA.. This population-based cohort study included patients with COPD aged ≥40 years initiating COPD medications in the UK Clinical Practice Research Datalink (CPRD) Aurum database from 2012 to 2019. Poisson regression models were used to estimate the IRR for AMI, stroke, and MACE in users of COPD medications versus LABA, adjusting for clinically relevant covariables.. The study included 11,121 new users of aclidinium, 4804 of aclidinium/formoterol, 56,198 of tiotropium, 23,856 of other LAMA, 17,450 of LAMA/LABA, 70,289 of LABA/ICS, and 13,716 of LABA. During periods of continuous medication use after initiation (current use), crude incidence rates per 1000 person-years for AMI ranged from 8.7 (aclidinium/formoterol) to 12.4 (LAMA/LABA), for stroke ranged from 4.8 (aclidinium/formoterol) to 7.2 (LAMA/LABA), and for MACE ranged from 13.5 (aclidinium/formoterol) to 19.3 (LAMA/LABA). Using LABA as reference, adjusted IRRs [95% confidence intervals] were close to 1 for all study drugs for AMI (lowest for aclidinium/formoterol, 0.95 [0.60-1.52], and highest for LAMA/LABA, 1.23 [0.91-1.67]), stroke (lowest for aclidinium/formoterol, 0.64 [0.39-1.06], and highest for tiotropium, 1.02 [0.81-1.27] for tiotropium) and for MACE (lowest for aclidinium, 0.93 [0.75-1.16], and highest for LAMA/LABA, 1.24 [0.97-1.59]).. Risks of AMI, stroke, and MACE in current users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, LAMA/LABA, or LABA/ICS were similar to the risks among current users of LABA.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Bronchodilator Agents; Cohort Studies; Drug Therapy, Combination; Formoterol Fumarate; Humans; Muscarinic Antagonists; Myocardial Infarction; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Stroke; Tiotropium Bromide

Inhaled long-acting muscarinic antagonist (LAMA) is recommended for the treatment of chronic obstructive pulmonary disease (COPD). However, there is still concern that LAMA may cause cardiovascular adverse events in COPD patients. Therefore, this study aimed to determine whether the administration of tiotropium, the first commercially available LAMA, could increase the risk of coronary heart disease (CHD) in COPD patients through a nationwide cohort study. We used the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC) database between 2002 and 2014 for the analysis. We applied a washout period of COPD diagnosis during 2002-2003 and excluded the patients who used an inhaler before the diagnosis of COPD. We also excluded patients who were diagnosed with CHD before inhaler use. Among a total of 5787 COPD patients, 1074 patients were diagnosed with CHD. In the Cox regression models with time-dependent tiotropium usage, we found that tiotropium significantly increased the risk of CHD in a subgroup of age [Formula: see text]55 years compared to non-users of tiotropium (adjusted hazard ratio [aHR], 1.24; 95% confidence interval [CI], 1.003-1.54). When analyzed by dividing into tertiles (high/middle/low) according to the cumulative tiotropium exposure, the high tertile exposure group of tiotropium was associated with a higher risk of CHD compared with the low tertile exposure group of tiotropium. Additionally, the risk of CHD was higher in the high tertile exposure group of tiotropium in the age 55 and older group and in the never smoker group. When prescribing tiotropium for COPD patients, particularly those over 55 years of age and never-smokers, it is desirable to evaluate the risk of CHD in advance and closely follow-up for CHD occurrence.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Cohort Studies; Coronary Disease; Humans; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

The aim: Show the efficacy of the Tiotropium / olodaterol combination in real clinical practice.. Materials and methods: 100 patients with the diagnosis of COPD were included onto the study during the period of 2019-2020, an average age was 64.09±1.94 years, 66 were men (66 %) and 34 were women (34 %). There were 68 % of smokers with the average smoking experience of 24.44±4.84 pack-years. Average COPD duration was 9.35±2.42 years. There were 3 visits in the study - visit 1 (baseline), visit 2 (4-6 weeks) visit 3 (1 year). Source documentation was assessed at visit 1 and visit 3 for amount of exacerbations, antibiotic, glucocorticosteroid, methylxanthines use; mMRC and CAT were assessed at all visits.. Results: Combined therapy with tiotropium/olodaterol improves clinical course of COPD, which is characterized by the significant decreased of the amount of exacerbations (2.63±0.29 to 1.63±0.21) and hospital admissions (1.2±0.2 tо 0.37±0.11). Improvement of symptoms and amount of exacerbation leads to much less use of antibiotics and glucocorticosteroids. A part of patients that used antibiotics decreased from 86±6.9 % to 67±9.3 %, amount of antibiotic courses from 1.37±0.17 tо 0.88±0.15, duration of treatment with antibiotics from 10.85±1.53 to 6.12±1.17 days. Part of the patients that used glucocorticosteroids decreased from 50±9.9 % tо 30±9.1 %, duration of treatment with antibiotics reduced from 3.97±1.06 tо 1.86±0.91 days. There also was a tendency towards a lesser used of methylxanthines. Combined therapy with tiotropium/olodaterol significantly decreased symptoms of COPD according to the mMRC (2.3±0.14 to 1.87±0.15) and САТ (23.28±1.71 to 15.77±1.58).. Conclusions: Tiotropium/olodaterol combination showed its efficacy in real clinical practice. There was significant reduction in amount of exacerbation and antibiotic, gluco¬corticosteroid use during the study, which was also accompanied by the reduction is symptoms.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Drug Combinations; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Topics: Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

A variety of dual-combination maintenance inhalers are used to treat asthma and chronic obstructive pulmonary disease (COPD). Understanding patient preferences for treatment attributes may help select an optimal treatment from the patient perspective.. Patient preferences for maintenance inhaler device and medication attributes were elicited through a discrete choice experiment and used in benefit-risk assessments to calculate predicted choice probabilities (PrCPs) for 14 dual-combination maintenance inhalers in four treatment classes: lower- and higher-dose inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) inhalers for asthma, and ICS/LABA and long-acting muscarinic antagonist (LAMA)/LABA inhalers for COPD.. For all treatment classes, reduced exacerbations and faster onset of action were the most important attributes. For all classes, patients were willing to tolerate an extra yearly exacerbation to decrease the medication's onset of action from 30 to 5 min. For patients with asthma using lower-dose ICS/LABA (n = 497), budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pressurized metered-dose inhaler (pMDI) had the highest PrCP (28.4%), and for those using a higher-dose ICS/LABA (n = 285), PrCPs were highest for mometasone furoate/formoterol fumarate dihydrate (200 μg/5 μg) pMDI (27.0%) and budesonide/formoterol fumarate dihydrate (160 μg/4.5 μg) pMDI (26.9%). For patients with COPD using an ICS/LABA (n = 574), budesonide/formoterol fumarate dihydrate (160 μg/4.5 μg) pMDI had the highest PrCP (56.6%), and for those using a LAMA/LABA inhaler (n = 217), tiotropium/olodaterol (2.5 μg/2.5 μg) soft mist inhaler had the highest PrCP (42.3%).. Patient preference data for maintenance inhaler attributes can be used to identify a preference order of inhalers in different treatment classes.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Asthma; Benzoxazines; Budesonide; Delayed-Action Preparations; Disease Progression; Drug Combinations; Drug Therapy, Combination; Formoterol Fumarate; Maintenance Chemotherapy; Nebulizers and Vaporizers; Patient Preference; Patient-Centered Care; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Tiotropium Bromide

The total population consisted of 61,985 patients (tiotropium/olodaterol n = 2684; LABA/ICS n = 59,301); after reweighting, the total was 42,953 patients (tiotropium/olodaterol n = 2600; LABA/ICS n = 40,353; mean age 65 years; female 54.5%). Patients treated with tiotropium/olodaterol versus LABA/ICS experienced a reduction in the risk of COPD exacerbations (adjusted hazard ratio 0.76 [95% confidence interval 0.68, 0.85]), pneumonia (0.74 [0.57, 0.97]), escalation to triple therapy (0.22 [0.19, 0.26]), and any one of these events (0.45 [0.41, 0.49]); the combined risk was similar irrespective of baseline eosinophils and exacerbation history.. In patients with COPD, tiotropium/olodaterol was associated with a lower risk of COPD exacerbations, pneumonia, and escalation to triple therapy versus LABA/ICS, both individually and in combination; the combined risk was reduced irrespective of baseline eosinophils or exacerbation history.. ClinicalTrials.gov identifier, NCT04138758 (registered 23 October 2019).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Drug Therapy, Combination; Female; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

In this active-comparator cohort study, new users of tiotropium/olodaterol (n = 1436) and tiotropium monotherapy (n = 5352) were identified from a large Japanese hospital-based database (Medical Data Vision Co., Ltd., Tokyo; prespecified study period: 1 April 2015 to 31 March 2019); patients in each group were matched 1:1 using high-dimensional propensity scores (hdPS). The primary outcome was time-to-escalation to triple therapy.. For the prespecified study period in the hdPS-matched cohort, escalation to triple therapy was infrequent among new users of tiotropium/olodaterol (n = 1302, 7 escalation events) and tiotropium monotherapy (n = 1302, 8 escalation events). The difference in time-to-escalation to triple therapy between groups was not statistically significant (median [interquartile range]: 28 days [15.0-139.2] for tiotropium monotherapy vs 193 days [94.5-302.0] for tiotropium/olodaterol; hazard ratio: 0.89; 95% CI: 0.32-2.46). Similar findings (hazard ratio: 0.71; 95% Cl: 0.36-1.40) were observed in a post hoc analysis, which extended the study period by 1 year to 31 March 2020. Risks of first moderate and/or severe COPD exacerbation were lower for tiotropium/olodaterol than tiotropium monotherapy (between-group differences not significant). There were no significant between-group differences for the risks of all-cause inpatient mortality, major adverse cardiovascular events, and first use of home oxygen therapy.. ICS monotherapy or ICS/LABA added to tiotropium or tiotropium/olodaterol is limited in Japanese clinical settings. The number of escalations to triple therapy was very limited in the dataset and there was insufficient power to detect differences between the treatment groups in the primary hdPS-matched cohort.

Topics: Administration, Inhalation; Aged; Benzoxazines; Cholinergic Antagonists; Dose-Response Relationship, Drug; Drug Combinations; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Japan; Male; Propensity Score; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Time Factors; Time-to-Treatment; Tiotropium Bromide; Treatment Outcome

Adherence to chronic obstructive pulmonary disease (COPD) maintenance medication is important for managing symptoms and exacerbation risk, and is associated with reduced mortality, hospitalizations, and costs. This study compared on-treatment exacerbations, medical costs, and medication adherence in patients with COPD initiating treatment with umeclidinium/vilanterol (UMEC/VI) or tiotropium (TIO).. Each cohort included 3929 matched patients. Kaplan-Meier rates of on-treatment COPD-related exacerbations were similar between cohorts (hazard ratio at 12 months; overall: 0.93, moderate: 0.92, severe: 1.07; all p > 0.05). UMEC/VI versus TIO initiators had significantly higher adherence (mean PDC: 0.44 vs 0.37; p < 0.001; proportion with PDC ≥ 0.8: 22.0% vs 16.4%; p< 0.001) and significantly lower mean on-treatment COPD-related total medical costs ($867 vs $1095 PPPM; p = 0.028), driven by lower outpatient visit costs.. These findings provide valuable information for physicians considering UMEC/VI or TIO as initial maintenance therapy options for patients with COPD.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Databases, Factual; Drug Combinations; Female; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Medication Adherence; Middle Aged; Muscarinic Antagonists; Propensity Score; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies; Time-to-Treatment; Tiotropium Bromide; United States

Chronic obstructive pulmonary disease (COPD) guidelines advocate treatment with combinations of long-acting bronchodilators for patients with COPD who have persistent symptoms or continue to have exacerbations while using a single bronchodilator. This study assessed the cost-utility of the fixed dose combination of the bronchodilators tiotropium and olodaterol versus two comparators, tiotropium monotherapy and long-acting β2 agonist/inhaled corticosteroid (LABA/ICS) combinations, in three European countries: Finland, Sweden and the Netherlands.. A previously published COPD patient-level discrete event simulation model was updated with most recent evidence to estimate lifetime quality-adjusted life years (QALYs) and costs for COPD patients receiving either tiotropium/olodaterol, tiotropium monotherapy or LABA/ICS. Treatment efficacy covered impact on trough forced expiratory volume in 1 s (FEV. Treatment with tiotropium/olodaterol gained QALYs ranging from 0.09 (Finland and Sweden) to 0.11 (the Netherlands) versus tiotropium and 0.23 (Finland and Sweden) to 0.28 (the Netherlands) versus LABA/ICS. The Finnish payer's incremental cost-effectiveness ratio (ICER) of tiotropium/olodaterol was €11 000/QALY versus tiotropium and dominant versus LABA/ICS. The Swedish ICERs were €6200/QALY and dominant, respectively (societal perspective). The Dutch ICERs were €14 400 and €9200, respectively (societal perspective). The probability that tiotropium/olodaterol was cost-effective compared with tiotropium at the country-specific (unofficial) threshold values for the maximum willingness to pay for a QALY was 84% for Finland, 98% for Sweden and 99% for the Netherlands. Compared with LABA/ICS, this probability was 100% for all three countries.. Based on the simulations, tiotropium/olodaterol is a cost-effective treatment option versus tiotropium or LABA/ICS in all three countries. In both Finland and Sweden, tiotropium/olodaterol is more effective and cost saving (ie, dominant) in comparison with LABA/ICS.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Cost-Benefit Analysis; Finland; Humans; Netherlands; Pulmonary Disease, Chronic Obstructive; Sweden; Tiotropium Bromide; Treatment Outcome

Spirometry is a crucial test used in the diagnosis and monitoring of patients with chronic obstructive pulmonary disease (COPD). Severe acute respiratory syndrome coronavirus 2 pandemic has posed numerous challenges in performing spirometry. Dynamic-ventilatory digital radiography (DR) provides sequential chest radiography images during respiration with lower doses of radiation than conventional X-ray fluoroscopy and computed tomography. Recent studies revealed that parameters obtained from dynamic DR are promising for evaluating pulmonary function of COPD patients. We report two cases of COPD evaluated by dynamic-ventilatory DR for pulmonary function and treatment efficacy and discuss the potential of dynamic DR for evaluating COPD therapy.

Topics: Aged; Asthma; Bronchodilator Agents; Drug Combinations; Fluticasone; Formoterol Fumarate; Glycopyrrolate; Humans; Indans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Radiographic Image Enhancement; Radiography, Thoracic; Spirometry; Tiotropium Bromide; Treatment Outcome

Topics: Bronchodilator Agents; Glycopyrrolate; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quinolones; Tiotropium Bromide

To analyze the legal demands of tiotropium bromide to treat chronic obstructive pulmonary disease.. We included secondary data from the pharmaceutical care management systems made available by the Paraná State Drug Center.. Public interest civil action and ordinary procedures, among others, were the most common used by the patients to obtain the medicine. Two Health Centers in Paraná (Londrina and Umuarama) concentrated more than 50% of the actions. The most common specialty of physicians who prescribed (33.8%) was pulmonology. There is a small financial impact of tiotropium bromide on general costs with medicines of the Paraná State Drug Center. However, a significant individual financial impact was observed because one unit of the medicine represents 38% of the Brazilian minimum wage.. Our study highlights the need of incorporating this medicine in the class of long-acting anticholinergic bronchodilator in the Brazilian public health system.

Topics: Brazil; Bronchodilator Agents; Drugs, Essential; Health Services Accessibility; Health Services Needs and Demand; Humans; Judicial Role; National Health Programs; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Statistics, Nonparametric; Time Factors; Tiotropium Bromide

Topics: Administration, Inhalation; Bronchodilator Agents; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

A traditional principle of the randomized controlled trial is that the p-value comparing treatment groups should be computed from the simple crude data. This assumes that the size of the study is sufficiently large for an accurate and precise estimation of the difference between groups. There are situations where the accuracy and precision of the study can be improved by statistical adjustment for baseline covariates, including when the outcome is continuous and available at baseline. The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) recommend covariate adjustment in trials as a tool to improve the efficiency of the analysis and to avoid conditional bias from chance covariate imbalance. The recent DYNAGITO randomized controlled trial compared the effectiveness of the single inhaler tiotropium-olodaterol combination for the treatment of COPD with tiotropium alone in reducing the rate of exacerbations over 52 weeks. The pre-specified crude analysis produced a rate ratio of 0.93 (p-value > 0.01, not significant) comparing the tiotropium-olodaterol combination with tiotropium alone. However, a sensitivity analysis adjusted for the baseline rate of exacerbations and other factors produced a rate ratio of 0.89 (p-value 0.001, significant). The DYNAGITO trial is an example where statistical adjustment was justified but not used. Future trials of COPD therapy could be designed more efficiently, be made less costly, while improving the accuracy and precision of their data and the resulting conclusions.

Topics: Benzoxazines; Bronchodilator Agents; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide

Long-acting bronchodilators are the therapy with the best evidence for treating stable chronic obstructive pulmonary disease (COPD). Long-acting combinations of β2 agonists and anticholinergics (LABA-LAMA) are recommended in advanced stages when monotherapy has not generated the desired effects. Pulmonary Rehabilitation (PR) is an effective non-pharmacological strategy. The aim of this study was to compare the results obtained in patients with COPD who received monotherapy versus dual bronchodilator therapy in terms of functional aerobic capacity, symptoms and quality of life.. Prospective non randomized intervention study; the patients were divided into two groups: in one group patients were treated with LAMA (Tiotropium Bromide, 5 μg every 24 h) and in the other group patients were treated with LABA + LAMA (Indacaterol/Glycopyrronium, 110/50 μg once a day). After receiving the concept of pulmonology, patients were intervened with 8 weeks of PR. The study was approved by the committee of the Clinica Neumológica del Pacifico in Cali and the Institución Universitaria Escuela Nacional del Deporte, Colombia. To determine the differences, t pair test for intragroup, and t-test was performed for intergroup analysis. For all tests, a p-value <0.05 was considered as statistically significant.. 53 patients participated in this study, of which 20 were assigned to the LAMA group and 33 to the LAMA + LABA group. Patients in both groups presented changes in the distance of the 6MWT, in the VO2e, dyspnea and in all the SGRQ domains. Regarding the comparison between groups, there were found no differences in the variables at the beginning of the PR and significant differences (p < 0.05) at the end of the 8 week-period in favor of the LABA + LAMA group, in symptoms with the mMRC scale, functional aerobic capacity with the 6 min walking test and in health related quality of life specifically in the symptoms domain, where the dual therapy group obtained better results.. The addition of LABA to the treatment with LAMA showed better response results compared with the monotherapy in patients with COPD who attended PR.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Bronchodilator Agents; Drug Therapy, Combination; Female; Glycopyrrolate; Humans; Indans; Male; Middle Aged; Muscarinic Antagonists; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinolones; Tiotropium Bromide

The concept of chronic obstructive pulmonary disease (COPD) control has been proposed to guide treatment decisions in COPD. In this study, we aimed to validate the prospective value of this concept in the SPARK study population. Control was assessed based on COPD stability and impact. Patients with low impact and stability during weeks 1-12 were classified as controlled, and exacerbations were measured during a 52-week follow-up. Of the 2044 patients included a majority were non-controlled (80%), frequently due to high impact. During the follow-up, the rate of moderate/severe exacerbations was significantly lower in controlled patients (rate ratio, 0.56, 95% CI 0.48 to 0.65 p<0.0001) and time-to-first moderate/severe exacerbation was significantly delayed. This study demonstrated an association between control status and risk of exacerbations.

Topics: Aged; Bronchodilator Agents; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycopyrrolate; Humans; Indans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinolones; Reproducibility of Results; Respiratory Function Tests; Risk Assessment; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

Topics: Adult; Bronchodilator Agents; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Adult; Bronchodilator Agents; Formoterol Fumarate; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The 2018 Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends combination long-acting muscarinic antagonists/long-acting beta2-agonists (LAMA + LABA) as preferred maintenance therapy for patients with symptomatic chronic obstructive lung disease (COPD) after monotherapy and stepping up to triple therapy (TT; LAMA + LABA + inhaled corticosteroids [ICS]) in case of further exacerbations. Restrictions on TT recommendations have primarily been driven by higher pneumonia risk associated with regular ICS use. Evidence suggests that TT is overprescribed, which may affect economic and clinical outcomes.. To compare health plan-paid costs, COPD exacerbations, and pneumonia diagnoses among patients newly treated with a LAMA + LABA regimen composed of tiotropium (TIO) + olodaterol (OLO) in a fixed-dose combination inhaler (TIO + OLO) or TT in a U.S. Medicare Advantage Part D insured population.. This retrospective study identified COPD patients aged ≥ 40 years who were initiating TIO + OLO or TT (index regimen) between January 1, 2014, and March 31, 2018, from a national administrative claims database. Continuous insurance coverage for 12 months pretreatment (baseline) and ≥ 30 days posttreatment (follow-up) was required. Patients were followed until the earliest of study end (May 31, 2018), discontinuation of index regimen (≥ 60-day gap in index regimen coverage), switch to a different regimen, or health plan disenrollment. Before analysis of outcomes, TIO + OLO and TT patients were 1:1 propensity score-matched on baseline demographics, comorbidities, COPD medication use, medical resource use, and costs. Cohort differences in post-match outcomes were assessed by Wald Z-test (annualized costs) and Kaplan-Meier method (time to first COPD exacerbation and pneumonia diagnosis).. After matching, each cohort had 1,454 patients who were well balanced on baseline characteristics. Compared with TT, the TIO + OLO cohort incurred $7,041 (41.1%) lower mean COPD-related total costs ($10,094 vs. $17,135;. COPD patients initiating TIO + OLO incurred lower costs to health plans and experienced fewer COPD exacerbation and pneumonia events relative to TT. These findings provide important real-world economic and clinical insight into the GOLD recommendations for TIO + OLO and LAMA + LABA therapy. The study findings also indicate the continued inconsistency between the recommendations and real-world clinical practices pertaining to TT.. This study was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). Palli and Franchino-Elder are employees of BIPI. Frazer, DuCharme, Buikema, and Anderson are employees of Optum, which was contracted by BIPI to conduct this study. The authors received no direct compensation related to the development of the manuscript. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Aged, 80 and over; Benzoxazines; Bronchodilator Agents; Cohort Studies; Drug Combinations; Drug Therapy, Combination; Female; Follow-Up Studies; Glucocorticoids; Humans; Male; Medicare Part D; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Tiotropium Bromide; United States

Patients with chronic obstructive pulmonary disease (COPD) and cardiovascular comorbidities may have an increased risk of medication-related cardiac arrhythmias. We therefore performed an analysis of Holter electrocardiogram (ECG) data from two large, long-term, controlled clinical COPD trials to investigate whether tiotropium/olodaterol increased the risk of cardiac arrhythmia and mean heart rate.. After 12 weeks of treatment, there was no difference in the number of patients who had an increase or decrease from baseline in 24-hour supraventricular premature beats or ventricular premature beats between tiotropium/olodaterol 5/5 µg combination therapy and its monocomponents. Compared with baseline, a small but statistically significant increase in adjusted mean heart rate was observed for tiotropium 5 µg (+1.6 beats per minute [bpm]; P=0.0010), but no difference was observed for olodaterol 5 µg (+0.3 bpm; P=0.2778) or tiotropium/olodaterol 5/5 µg (-0.1 bpm; P=0.4607). MACE and fatal MACE were limited to 1 to 3 patients across treatment groups.. Compared with the compounds given as monotherapy, treatment with tiotropium/olodaterol fixed-dose combination therapy is not associated with medically relevant or statistically significant effects on arrhythmia as assessed by Holter ECG. Based on these findings, there is no evidence to assume a clinically relevant impact on cardiac function from dual tiotropium/olodaterol treatment.. TONADO 1 (ClinicalTrials.gov: NCT01431274); TONADO 2 (ClinicalTrials.gov: NCT01431287).

Topics: Administration, Inhalation; Arrhythmias, Cardiac; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Electrocardiography, Ambulatory; Forced Expiratory Volume; Heart Rate; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Tiotropium is a muscarinic antagonist that reduces the risk of acute exacerbations of chronic obstructive pulmonary disease, possibly through an as yet incompletely characterized anti-inflammatory activity. We hypothesized that muscarinic activation of bronchial epithelial cells and endothelial cells causes the release of proinflammatory microparticles and that tiotropium inhibits the phenomenon. Microparticle generation was assessed by a functional assay, by flow cytometry and by NanoSight technology. Immortalized bronchial epithelial cells (16HBE) and umbilical vein endothelial cells were treated with acetylcholine in the presence of varying concentrations of tiotropium. Intracellular calcium concentration, extracellular regulated kinase phosphorylation and chemokine content in the conditioned media were assessed by commercial kits. Acetylcholine causes microparticle generation that is completely inhibited by tiotropium (50 pM). Microparticles generated by acetylcholine-stimulated cells increase the synthesis of proinflammatory mediators in an autocrine fashion. Acetylcholine-induced upregulation of microparticle generation is inhibited by an inhibitor of extracellular regulated kinase phosphorylation and by a phospholipase C inhibitor. Tiotropium blocks both extracellular regulated kinase phosphorylation and calcium mobilization, consistent with the hypothesis that the drug prevents microparticle generation through inhibition of these critical pathways. These results might contribute to explain the effect of tiotropium in reducing acute exacerbations of chronic obstructive pulmonary disease.

Topics: Bronchi; Calcium; Cell Line; Cell-Derived Microparticles; Chemokines; Culture Media, Conditioned; Endothelial Cells; Epithelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Inflammation Mediators; Muscarinic Antagonists; Phosphorylation; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Tiotropium Bromide

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Aged, 80 and over; Benzoxazines; Bronchodilator Agents; Disease Progression; Drug Combinations; Drug Therapy, Combination; Female; Health Expenditures; Humans; Insurance Claim Review; Male; Medicare; Middle Aged; Models, Economic; Muscarinic Antagonists; Pneumonia; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome; United States

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Pulmonary Medicine; Tiotropium Bromide

In Japan, most asthma deaths occur among the elderly. We should improve the control of asthma in elderly patients to reduce the number of deaths due to asthma. This retrospective study aimed to evaluate the efficacy of tiotropium Respimat. Our retrospective study suggests that Tio-Res improves symptoms, pulmonary function, and respiratory impedance in symptomatic asthmatics aged 75 or over with irreversible airflow limitation despite the use of high-dose ICS plus LABA.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Aged, 80 and over; Asthma; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Japan; Lung; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Smoking; Tiotropium Bromide; Treatment Outcome

Inhaled anticholinergics, recommended as first-line maintenance treatment for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), has been demonstrated to be associated with an increased risk of cardiovascular diseases. Nevertheless, why COPD patients using inhaled anticholinergics have this higher risk remains unknown. One of mechanisms may be an autonomic imbalance because anticholinergics yield reduced vagal nervous activity. To test our hypothesis, we studied heart rate recovery (HRR) after exercise, recognized as a marker of cardiac autonomic function, in COPD patients using and not using inhaled anticholinergics.. Sixty patients with COPD were involved in this study (mean FEV. HRR was significantly lower in patients using tiotropium than in the controls (16 ± 6 vs 22 ± 8 beats/min, respectively, p < 0.05). Multivariate regression analysis revealed that tiotropium use and peak VCO. These findings suggest that anticholinergics bronchodilators reduce HRR after exercise in COPD patients. This has the potential to aggravate autonomic nervous imbalance. Therefore, we recommend that COPD patients taking anticholinergic bronchodilators should be considered for monitoring of cardiac function and prescribers should be alert for cardiovascular events that may arise from autonomic nervous imbalance.

Topics: Administration, Inhalation; Aged; Autonomic Nervous System; Bronchodilator Agents; Cardiovascular Diseases; Cholinergic Antagonists; Exercise Test; Female; Heart Rate; Humans; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Regression Analysis; Respiratory Function Tests; Tiotropium Bromide

Aclidinium bromide is an inhaled long-acting muscarinic antagonist (LAMA). Although the initial potential increased cardiovascular and mortality risk among users of tiotropium has been ruled out by several observational studies, and clinical trials, there are still concerns related to the use of newer LAMA medications. The current study aimed to evaluate the risk of death among users of aclidinium and other LAMAs.. We conducted a cohort and nested case-control study among patients with COPD aged 40 years or older to compare the risk of all-cause mortality among users of aclidinium and other COPD medications with the risk among users of long-acting β2 agonists (LABA), in the Clinical Practice Research Datalink (CPRD) in the United Kingdom (2012-2017).. Mortality rates per 1,000 person-years were 32.9 for aclidinium, 43.8 for tiotropium, 38.0 for other LAMA, 47.1 for LABA/ICS, and 38.1 for LABA. The RR of death compared with current use of LABA was 0.54 (confidence interval [95% CI], 0.40-0.72) for aclidinium, 0.96 (95% CI, 0.76-1.21) for tiotropium, 0.76 (95% CI, 0.58-0.99) for other LAMA, and 1.08 (95% CI, 0.90-1.31) for LABA/ICS. Decreased risk for death observed among users of aclidinium was driven by overall current single use (RR = 0.41; 95% CI, 0.22-0.79), which corresponded to 26% of the aclidinium users (<15 cases) and not by multiple use (RR = 1.02; 95% CI, 0.71-1.48).. Use of aclidinium, tiotropium, other LAMA, or LABA/ICS was not associated with an increased risk of all-cause mortality as compared with the use of LABAs.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Case-Control Studies; Cholinergic Antagonists; Female; Humans; Male; Middle Aged; Mortality; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Risk Factors; Tiotropium Bromide; Tropanes; United Kingdom

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antifungal Agents; Bronchodilator Agents; Bronchopneumonia; Candidiasis; Diagnosis, Differential; Disease Progression; Drug Therapy, Combination; Fluticasone; Humans; Itraconazole; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Tiotropium Bromide

Oral inhalation is the main drug delivery route for treating obstructive lung conditions. Thus, many inhaler devices with various design and pharmaceutical formulation have been introduced. The fine particle dose (FPD) and mass median aerodynamic diameter (MMAD ≤ 5 μm) of the aerosol delivered dose (DD) dictate the therapeutically effective peripheral lung deposition. This study evaluated the in vitro aerosol emission performance of tiotropium bromide emitted from Spiriva® Respimat® soft mist inhalers (R) after living under patients' real-world, post-dispensing handling environments.. This was a two-stage investigation. In the first clinical stage, research ethical approval was obtained to enrol patients already been using R for at least 3 months. Those who signed consent were given both new R to use and temperature and relative humidity (RH) handheld, portable data loggers to keep in the vicinity of the given R. The participants returned the given R and data loggers after 2 weeks. Patient recruitment took place in Amman, Jordan, during the summer (RS) and winter (RW). Subsequently, in the second laboratory stage, other R were strictly stored at an average of 21.0 °C and 46.9% RH as control (RC). The Next Generation Impactor (NGI) was used to evaluate the RS, RW and RC. The NGI was operated at a flow rate of 30 L/min.. The RS were exposed to an average (range) 23.6 °C (18.2-37.5 °C) and 43.8% RH (21.4-60.0% RH) that were statistically comparable (p > 0.05) to that of the RW; 17.3 °C (13.2-26.7 °C) and 52.8% RH (26.3-69.1% RH). The RW and RC retention environments were statistically different (p < 0.05), whilst the RS and RC had comparable (p > 0.05) conditions. No significant differences (p > 0.05) were found in the tiotropium bromide DD (2.39 vs 2.43 μg), FPD (0.88 vs 0.90 μg) and MMAD (5.1 vs 4.98 μm) between the RS and RW, respectively. Compared to the RC inhalers, both the RS and RW devices had significantly higher FPD and relatively smaller tiotropium bromide particles.. Using the R under the fluctuating summer and winter environments of our patients would not affect its overall tiotropium bromide emission performance. The significant increase in the respirable mass of the RS and RW might be offset by the increase in particles <1 μm particularly in patients with poor inhaler technique.

Topics: Administration, Inhalation; Adult; Aerosols; Bronchodilator Agents; Female; Humans; Male; Metered Dose Inhalers; Middle Aged; Particle Size; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Benzoxazines; Delayed-Action Preparations; Drug Combinations; Dry Powder Inhalers; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Tiotropium Bromide; Vital Capacity

No specific (only subgroup) recommendations for the use of long-acting muscarinic antagonists in chronic obstructive pulmonary disease (COPD) exist. The aim of this exploratory hypothesis generating study was to assess whether different phenotypic/endotypic characteristics could be determinants of the short-term ineffectiveness of the initial tiotropium bromide monotherapy in treatment naïve moderate to severe COPD patients.. A total of 51 consecutively recruited COPD patients were followed for 3 months after the initial evaluation and prescribed initial treatment (tiotropium). Short-term treatment ineffectiveness was assessed as a composite measure comprising COPD exacerbations, need for additional treatment, and no improvement in functional parameters, e.g. 6‑min walking test (6MWT), body-mass index, airflow obstruction, dyspnea, and exercise (BODE) index and forced expiratory volume in 1 s (FEV. Treatment ineffectiveness was significantly associated with baseline hemoglobin level, COPD assessment test (CAT) score, modified Medical Research Council (mMRC) scale and BODE index (p = 0.002). Incident exacerbation during the follow-up was associated with baseline bronchoalveolar lavage fluid (BALF) alpha-amylase level and CAT score (p < 0.001), and change in treatment with leukocyte count, 6MWT desaturation and fatigue (p < 0.001). No improvement in 6MWT was associated with baseline CAT score, body mass index, mMRC, fatigue, 6MWT and BODE index (p = 0.002). No improvement in BODE index was associated with leukocyte count, serum interleukin 8 (IL-8) and BALF albumin levels (p < 0.001); and no improvement in FEV. Our results suggest that there is a possibility to identify predictors of short-term tiotropium ineffectiveness in patients with moderate to severe COPD.

Topics: Aged; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide

Topics: Asthma; Bronchodilator Agents; Child; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

To examine the clinical and economic outcomes associated with the use of long-acting bronchodilators for initial maintenance treatment of chronic obstructive pulmonary disease (COPD) by analyzing health insurance claims data in the US.. A retrospective, observational, matched cohort study used health insurance claims data (January 2008 to June 2013) to assess COPD-related outcomes for subjects aged ≥40 years. Subjects were assigned to a study cohort according to the first observed prescription fill for a long-acting bronchodilator (fluticasone propionate 250 mcg/salmeterol 50 mcg [FSC] or tiotropium bromide 18 mcg [TIO]). The analysis period for each subject comprised a 1-year pre-index date and 1-year post-index date. Primary outcome measure was total COPD-related costs per-patient per-year (PPPY) during the follow-up period. Secondary outcome measures included COPD-related exacerbations and the components of COPD-related costs.. Overall, 24,040 subjects were identified; the analysis sample consisted of 19,090 subjects (9,545 per cohort) with no significant differences between cohorts. Mean COPD-related total costs PPPY were numerically lower among the FSC cohort; however, the difference was not statistically significant ($2,224 [±4,108] vs $2,352 [±3,721], p = .057). There was no difference between cohorts for COPD-related medical costs (p = .894). COPD-related pharmacy costs were significantly, yet modestly, lower in the FSC cohort compared with the TIO cohort ($1,160 [±1,106] vs 1,275 [±1,110], p < .001). There were no statistically significant differences in the rate or number of exacerbations between the matched cohorts.. While propensity scoring achieved balance in baseline characteristics, some residual confounding unobserved in the database may be present.. Few clinical and economic differences between subjects initiating maintenance therapy with FSC or TIO were observed.

Topics: Age Factors; Aged; Aged, 80 and over; Bronchodilator Agents; Drug Combinations; Female; Fluticasone-Salmeterol Drug Combination; Health Expenditures; Humans; Insurance Claim Review; Male; Managed Care Programs; Middle Aged; Models, Econometric; Pulmonary Disease, Chronic Obstructive; Residence Characteristics; Retrospective Studies; Severity of Illness Index; Sex Factors; Tiotropium Bromide

To characterize subjects with chronic obstructive pulmonary disease (COPD) newly initiated on long-acting muscarinic antagonists (LAMA) or dual LAMA/long-acting β2-adrenergic agonist (LABA) therapy.. This pilot/preliminary analysis was a retrospective crosssectional study of subjects with COPD from the Optum Impact National Managed Care Benchmark Database.. Subjects with at least one LAMA prescription in the index period (July 2008-June 2009) were included and stratified by treatment. Data were collected in the year before the index date and included comorbidities, medication use, COPD-related costs, health care resource use, and exacerbations.. Of 5,311 eligible subjects, 2,057 initiated LAMA therapy (LAMA cohort) and 191 initiated LAMA+LABA therapy (LAMA+LABA cohort). The Charlson comorbidity index was slightly lower in the LAMA+LABA cohort than the LAMA cohort (mean±SD: 0.63±1.13 vs. 0.66±1.28), but the number of prescriptions was higher (mean±SD: 42.9±23.2 vs. 30.5±27.2). The LAMA+LABA cohort had higher short-acting inhaled β2 agonist (56.0% vs. 35.7%), oral corticosteroid (37.7% vs. 32.6%), and home oxygen therapy use (14.1% vs. 3.2%) than the LAMA cohort. Total medical costs were greater in the LAMA+LABA cohort than the LAMA cohort (mean±SD: $3,320.40±4085.9 vs. $1,226.20±3602.9), although emergency department ($11.00±66.8 vs. $30.70±259.2) and outpatient visit ($39.60±163.1 vs. $41.70±424.3) costs were lower. Resource use and exacerbation incidence were similar between cohorts.. In this first look, subjects with COPD initiating LAMA or LAMA+LABA therapy exhibited different clinical and resource use characteristics in the year before treatment. Subjects receiving LAMA+LABA were older, with higher COPD co-medication use, more prescriptions, and associated higher pharmacy costs compared with subjects initiating LAMA. These differences may reflect a higher severity of COPD in those starting LABA+LAMA treatment.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Cross-Sectional Studies; Drug Therapy, Combination; Female; Formoterol Fumarate; Health Resources; Humans; Insurance Coverage; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome; United States

Topics: Anti-Inflammatory Agents; Benzoxazines; Double-Blind Method; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Glycopyrronium is a once-daily, inhaled long-acting muscarinic antagonist (LAMA) demonstrating similar efficacy to inhaled tiotropium in patients with moderate-to-severe COPD; however, the benefit of LAMAs on COPD symptoms has been variable. COPD is a progressive disease in which many patients develop an acute or sustained deterioration. Data on the prevention of clinically important deteriorations (CID) using LAMAs are limited. A pooled analysis was performed on four Phase III trials (n = 2936) that compared the efficacy of glycopyrronium (n = 1859) with tiotropium (n = 1077). The primary endpoint was significant delay and/or reduction in the occurrence of CID. CID was defined as any of the following: ≥100 mL decrease from baseline in pre-dose forced expiratory volume in 1 second (FEV

Topics: Administration, Inhalation; Aged; Cholinergic Antagonists; Delayed-Action Preparations; Female; Follow-Up Studies; Glycopyrrolate; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Vital Capacity

This study investigated the efficacy and safety of budesonide/formoterol (B/F) and tiotropium combination in the management of chronic obstructive pulmonary disease (COPD) in Chinese patients.Between January 2015 and November 2017, 113 eligible Chinese patients with COPD were included and divided into an intervention group and a control group. Sixty-three patients in the intervention group underwent B/F combined tiotropium, while 50 patients in the control group received tiotropium alone. The primary outcome was severity of dyspnea on exertion (DOE), measured by the 6-minute walk test (6MWT) scale. The secondary outcomes included lung function, measured by the forced expiratory volume in 1 second (FEV1), quality of life, measured by the St. George's Respiratory Questionnaire (SGRQ), and adverse events. All outcomes were measured at the end of 12-week treatment.B/F and tiotropium combination showed greater efficacy in DOE (P < .01), lung function (P < .01), and quality of life (P < .01), compared with tiotropium alone at the end of 12-week treatment. In addition, adverse events in both groups were similar and tolerable.The findings suggest that B/F and tiotropium combination can be used as an effective treatment in Chinese patients with COPD.

Topics: Aged; Anti-Asthmatic Agents; Asian People; Bronchodilator Agents; Budesonide, Formoterol Fumarate Drug Combination; Drug Therapy, Combination; Dyspnea; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Retrospective Studies; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Walk Test

Retrospective study of patients with COPD enrolled in a US health insurance plan during 2013-2015 and newly initiated on TIO or UMEC/VI. Patients were ≥40 years of age at index (date of therapy initiation) with continuous enrollment for 12 months pre-index and ≥30 days post-index. LAMA users were propensity score matched 1:1 to LAMA/LABA users, with TT initiation rates reported by cohort using pharmacy claims.. 35,357 patients initiating on TIO and 2407 patients initiating on UMEC/VI were identified. After propensity score matching, the rate of TT initiation was significantly higher in new TIO users (n = 1320) than in new UMEC/VI users (n = 1320) (0.92 vs 0.49 per 100 months of exposure, respectively; p < 0.001). Relative to the UMEC/VI cohort, the TIO cohort had an 87% higher risk of TT initiation (hazard ratio: 1.87; 95% confidence interval: 1.4-2.5; p = 0.001).. Patients receiving UMEC/VI progressed to TT more slowly, and were at lower risk of progressing to TT, than patients receiving TIO.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Benzyl Alcohols; Chlorobenzenes; Delayed-Action Preparations; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies; Tiotropium Bromide; Treatment Outcome

The aim of this study was to analyze the association between therapy adherence to inhaled corticosteroids (ICSs) and tiotropium on the one hand and morbidity and mortality in COPD on the other hand.. Therapy adherence to ICSs and tiotropium over a 3-year period of, respectively, 635 and 505 patients was collected from pharmacy records. It was expressed as percentage and deemed optimal at ≥75-≤125%, suboptimal at ≥50%-<75%, and poor at <50% (underuse) or >125% (overuse). The association between adherence and time to first hospital admission for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), community acquired pneumonia (CAP), and mortality was analyzed, with optimal use as the reference category.. Suboptimal use and underuse of ICSs and tiotropium were associated with a substantial increase in mortality risk: hazard ratio (HR) of ICSs was 2.9 (95% CI 1.7-5.1) and 5.3 (95% CI 3.3-8.5) and HR of tiotropium was 3.9 (95% CI 2.1-7.5) and 6.4 (95% CI 3.8-10.8) for suboptimal use and underuse, respectively. Suboptimal use and overuse of tiotropium were also associated with an increased risk of CAP, HR 2.2 (95% CI 1.2-4.0) and HR 2.3 (95% CI 1.2-4.7), respectively. Nonadherence to tiotropium was also associated with an increased risk of severe AECOPD: suboptimal use HR 3.0 (95% CI 2.01-4.5), underuse HR 1.9 (95% CI 1.2-3.1), and overuse HR 1.84 (95% CI 1.1-3.1). Nonadherence to ICSs was not related to time to first AECOPD or first CAP.. Poor adherence to ICSs and tiotropium was associated with a higher mortality risk. Furthermore, nonadherence to tiotropium was associated with a higher morbidity. The question remains whether improving adherence can reduce morbidity and mortality.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Community-Acquired Infections; Disease Progression; Female; Humans; Male; Medication Adherence; Netherlands; Pneumonia; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

The FDA issued 2 main drug safety communications (DSCs) on the cardiovascular safety of tiotropium in March 2008 (warning of a potential increased stroke risk) and January 2010 (informing of an absence of a significant increased stroke risk or cardiovascular events based on findings from a large trial).. To describe the effect of the FDA DSCs on medication dispensing of tiotropium in a large U.S. claims database.. Initiation of tiotropium products among patients with chronic obstructive pulmonary disease (COPD) aged 40 years and older was determined monthly from 2006-2012 using medication dispensing from the IMS Lifelink Health Plan Claims Database. Similarly, monthly initiation of products containing long-acting beta-agonists (LABAs) was calculated to explore product switching. The effect of the 2008 and 2010 FDA DSCs was measured using interrupted time-series analysis. Subgroups of patients with greater cardiovascular risk were also examined.. A decreasing trend in initiation of tiotropium-containing products was present before the initial 2008 DSC. The decline in tiotropium initiation continued until January 2010, accompanied by an increased initiation of LABA-containing products in patients with COPD. In the presence of the existing decreasing trend, the initial DSC was followed by an immediate 2.8% (P = 0.02) further reduction in tiotropium initiation. Tiotropium initiation increased 2.5% (P = 0.03) immediately after the 2010 DSC, reducing the overall decline in rate and stabilizing (flattening) the trend. No significant changes in dispensing level or trend were observed among COPD patients with cardiovascular comorbidity.. Cardiovascular safety concerns may have affected tiotropium initiation as indicated by the decrease in tiotropium dispensing shown immediately following the initial DSC. The effect was alleviated as concerns lessened following the most recent DSC.. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors are employed by the FDA and have no conflict of interest relevant to the content of this study. The views expressed herein do not necessarily represent the views of the FDA.

Topics: Administration, Inhalation; Administrative Claims, Healthcare; Adrenergic beta-2 Receptor Agonists; Adult; Aged; Bronchodilator Agents; Drug Prescriptions; Drug Substitution; Drug Therapy, Combination; Female; Health Communication; Humans; Interrupted Time Series Analysis; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Stroke; Tiotropium Bromide; United States; United States Food and Drug Administration

The long-acting muscarinic antagonist tiotropium received an indication for the treatment of asthma from the FDA in 2015.. This paper summarizes much of the published findings on tiotropium and asthma and explores the heterogeneity of the asthma population vis-à-vis recent changes in guidelines for management of COPD. The accompanying case study provides an illustration of how tiotropium might be added to a patient's regimen appropriately.. Tiotropium has been shown in many studies to be beneficial to patients with asthma as an add-on medication. It should be considered as an agent by the clinician managing patients with both allergic and non-allergic asthma.

Topics: Administration, Inhalation; Asthma; Cholinergic Agents; Dyspnea; Female; Guidelines as Topic; Humans; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide

To examine the risk of cardiovascular disease (CVD) from tiotropium added to inhaled long-acting β. This nested case-control study included 65,966 patients with COPD treated with LABAs and ICSs identified from the Taiwan nationwide health care claims database from January 1, 2007, through June 30, 2011. Cases were all patients with a first primary diagnosis of ischemic heart disease, heart failure, stroke, or arrhythmia from inpatient or emergency care settings during follow-up, and each was matched with 4 disease risk score-matched controls from risk sets. The use of tiotropium in the year before the index/event date was measured, stratified by duration since therapy initiation, concomitant COPD medications, and dosage form. Conditional logistic regression models were used to estimate odds ratios of the CVD risk from add-on tiotropium therapy.. From the study cohort, with a mean age of 70.3 years (interquartile range, 61.8-79.4 years), 3188 CVD cases (incidence rate, 6.2 [95% CI, 6.0-6.4] cases per 100 person-years) and 12,349 matched controls were identified. The new use of tiotropium was associated with a 1.88-fold (95% CI, 1.44-2.46) increased CVD risk within 30 days of therapy initiation, and the association was sustained up to 60 days after treatment initiation (adjusted odds ratio, 1.71; 95% CI, 1.08-2.70). The risk persisted across all tiotropium regimens, with a case-crossover analysis, and in comparison with new add-on theophylline therapy.. Tiotropium newly added to LABA/ICS combination therapy was associated with an increased cardiovascular risk in patients with COPD.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cardiovascular Diseases; Case-Control Studies; Correlation of Data; Delayed-Action Preparations; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Incidence; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Risk Factors; Taiwan; Time Factors; Tiotropium Bromide

An extensive clinical trial program supports the efficacy and safety of tiotropium/olodaterol in chronic obstructive pulmonary disease (COPD). We examined the safety of tiotropium/olodaterol compared with tiotropium in a large population of patients, focusing on cardiovascular and respiratory events.. Patients (n = 9942) who received once-daily tiotropium/olodaterol 5/5 μg or tiotropium 5 μg (via Respimat. Fewer patients discontinued due to AEs with tiotropium/olodaterol (5.9%) versus tiotropium (7.9%; rate ratio [RR] 0.72; 95% confidence interval [CI] 0.62-0.84). There was no significant difference in the incidence of AEs, SAEs, cardiovascular AEs or central nervous system vascular AEs between treatments. Incidences of major adverse cardiovascular events (MACE) were 2.11 per 100 patient-years with tiotropium/olodaterol and 2.22 with tiotropium (RR 0.95; 95% CI 0.72-1.25), and incidences of fatal MACE (including death with undetermined cause) were 0.91 and 1.00 per 100 patient-years with tiotropium/olodaterol and tiotropium, respectively (RR 0.91; 95% CI 0.60-1.37). Respiratory AEs were generally balanced between treatment groups.. These results provide robust evidence that the benefits of tiotropium/olodaterol versus tiotropium are not at the expense of an increased risk of safety events. The combination is a suitable option for patients with COPD, even in the presence of cardiovascular risk factors.. clinicaltrials. gov (TONADO 1 and 2: NCT01431274, NCT01431287; DYNAGITO: NCT02296138).

Topics: Benzoxazines; Cardiovascular Diseases; Central Nervous System Diseases; Drug Combinations; Female; Humans; Incidence; Male; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk; Risk Factors; Safety; Time Factors; Tiotropium Bromide

The objective of this study was to assess the cost-effectiveness of maintenance treatment with UMEC/VI compared with tiotropium (TIO) 18 μg, open dual LAMA + LABA treatment, or no long-acting bronchodilator treatment in patients with moderate to very severe COPD.. A Markov model was developed to estimate the costs and outcomes associated with UMEC/VI treatment in patients with moderate to very severe COPD (GSK study number: HO-13-13411). Clinical efficacy, costs, utilities, and mortality obtained from the published literature were used as the model inputs. Costs are presented in US dollars based on 2015 prices. The model outputs are total costs, drug costs, other medical costs, number of COPD exacerbations, and quality-adjusted life-years (QALYs). Costs and outcomes were discounted at a 3% annual rate. Incremental cost-effectiveness ratios were calculated. One-way and probabilistic sensitivity analyses were conducted to assess the effects of changing parameters on the uncertainty of the results.. UMEC/VI treatment for moderate to very severe COPD was associated with lower lifetime medical costs ($82,344) compared with TIO ($88,822), open dual LAMA + LABA treatment ($114,442), and no long-acting bronchodilator ($86,751). Fewer exacerbations were predicted to occur with UMEC/VI treatment compared with no long-acting bronchodilator treatment. UMEC/VI provided an 0.11 and 0.25 increase in QALYs compared with TIO and no long-acting bronchodilator treatment, and as such, dominated these cost-effectiveness analyses. Sensitivity analyses confirmed that the results were robust.. The results from this model suggest that UMEC/VI treatment would be dominant compared with TIO and no long-acting bronchodilator treatment, and less costly than open dual LAMA + LABA treatment in patients with moderate to very severe COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cost-Benefit Analysis; Drug Combinations; Drug Costs; Humans; Markov Chains; Models, Economic; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Quinuclidines; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

Topics: Adolescent; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

To describe and compare demographic and clinical profile of patients newly initiated on aclidinium (ACL) or tiotropium (TIO) and identify factors associated with newly initiated ACL in real-life clinical practice during 2013 in Catalonia.. We performed a population-based, retrospective, observational study with data obtained from the Information System for Research Development in Primary Care, a population database that contains information of 5.8 million inhabitants (more than 80% of the Catalan population). Patients over 40 years old, with a recorded diagnosis of COPD and newly initiated treatment with either ACL or TIO during the study period (January to December 2013), were selected. A descriptive analysis of demographic and clinical characteristics was performed, and treatment adherence was also assessed for both cohorts.. A total of 8,863 individuals were identified, 4,293 initiated with ACL and 4,570 with TIO. They had a mean age of 69.4 years (standard deviation: 11.3), a median COPD duration of 3 years (interquartile range: 0-8), and 71% were males. Patients treated with ACL were older, with more respiratory comorbidities, a longer time since COPD diagnosis, worse forced expiratory volume in 1 second (% predicted), and with a higher rate of exacerbations during the previous year compared with TIO. It was found that 41.3% of patients with ACL and 62.3% of patients with TIO had no previous COPD treatment. Inhaled corticosteroid and long-acting β2-agonist were the most frequent concomitant medications (32.9% and 32.6%, respectively). Approximately 75% of patients were persistent with ACL or TIO at 3 months from the beginning of treatment, and more than 50% of patients remained persistent at 9 months.. Patients initiated with ACL had more severe COPD and were taking more concomitant respiratory medications than patients initiated with TIO. ACL was more frequently initiated as part of triple therapy, while TIO was more frequently initiated as monotherapy.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchodilator Agents; Databases, Factual; Drug Therapy, Combination; Female; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Primary Health Care; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Severity of Illness Index; Spain; Time Factors; Tiotropium Bromide; Treatment Outcome; Tropanes

The cardiovascular risk of concurrently using long-acting β

Topics: Adrenergic beta-2 Receptor Agonists; Algorithms; Arrhythmias, Cardiac; Bronchodilator Agents; Cardiovascular Diseases; Cholinergic Antagonists; Cohort Studies; Heart Failure; Humans; Muscarinic Antagonists; Myocardial Infarction; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Research Design; Risk Factors; Tiotropium Bromide; Treatment Outcome; United Kingdom

The superiority of tiotropium/olodaterol is demonstrated in improvement of lung function, dyspnea, lung hyperinflation, and quality of life compared with either monotherapy in patients with chronic obstructive pulmonary disease (COPD). Japanese Respiratory Society Guidelines for COPD management include improvement of exercise tolerance and daily physical activity as the treatment goals; however, there is limited evidence in Japanese patients with COPD.. A total of 180 Japanese patients with COPD, aged ≥40 years will be enrolled into the double-blind, multicenter, active-controlled, crossover study (NCT02629965) and will be randomized to receive either tiotropium/olodaterol FDC or tiotropium for 6 weeks each [two puffs via RESPIMAT. The VESUTO. ClinicalTrials.gov: NCT02629965 (registered on December 1, 2015).. The VESUTO study was funded by Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Benzoxazines; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Tolerance; Female; Humans; Japan; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Tiotropium Bromide

Although the prevalence of chronic obstructive pulmonary disease (COPD) increases with age, no specific therapeutic approaches are available till date for the elderly population.. To assess the efficacy and safety of once-daily indacaterol 150 and 300 μg in elderly patients with moderate to severe COPD.. Data were pooled from 11 randomized, double-blind, placebo- and active-controlled studies (8445 patients with COPD). The patient population was stratified into age groups: young (≥40-<65 years; 52.3%), elderly (≥65-<75 years; 36.4%), and very elderly (≥75 years; 11.4%). The efficacy outcomes included improvements in trough forced expiratory volume in 1 s (FEV. At Week 12, the mean improvement in FEV. This pooled analysis suggests that the efficacy and safety of indacaterol treatment is similar between elderly and younger patients with COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Bronchodilator Agents; Clinical Trials, Phase III as Topic; Double-Blind Method; Dyspnea; Female; Forced Expiratory Volume; Formoterol Fumarate; Health Status; Humans; Indans; Male; Middle Aged; Netherlands; Prevalence; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Severity of Illness Index; Smoking; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Combining in vitro mouth-throat deposition measurements, cascade impactor data and computational fluid dynamics (CFD) simulations, four different inhalers were compared which are indicated for chronic obstructive pulmonary disease (COPD) treatment.. The Respimat inhaler, the Breezhaler, the Genuair, and the Ellipta were coupled to the idealized Alberta throat model. The modeled dose to the lung (mDTL) was collected downstream of the Alberta throat model using either a filter or a next generation impactor (NGI). Idealized breathing patterns from COPD patient groups - moderate and very severe COPD - were applied. Theoretical lung deposition patterns were assessed by an individual path model.. For the Respimat the mDTL was found to be 59% (SD 5%) for the moderate COPD breathing pattern and 67% (SD 5%) for very severe COPD breathing pattern. The percentages refer to nominal dose (ND) in vitro. This is in the range of 44%-63% in vivo in COPD patients who display large individual variability. Breezhaler showed a mDTL of 43% (SD 2%) for moderate disease simulation and 51% (SD 2%) for very severe simulation. The corresponding results for Genuair are mDTL of 32% (SD 2%) for moderate and 42% (SD 1%) for very severe disease. Ellipta vilanterol particles showed a mDTL of 49% (SD 3%) for moderate and 55% (SD 2%) for very severe disease simulation, and Ellipta fluticasone particles showed a mDTL of 33% (SD 3%) and 41% (SD 2%), respectively for the two breathing patterns. Based on the throat output and average flows of the different inhalers, CFD simulations were performed. Laminar and turbulent steady flow calculations indicated that deposition occurs mainly in the small airways. In summary, Respimat showed the lowest amount of particles depositing in the mouth-throat model and the highest amount reaching all regions of the simulation lung model.

Topics: Administration, Inhalation; Androstadienes; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Computer Simulation; Drug Combinations; Dry Powder Inhalers; Equipment Design; Glycopyrrolate; Humans; Hydrodynamics; Lung; Metered Dose Inhalers; Models, Anatomic; Muscarinic Antagonists; Pharynx; Pulmonary Disease, Chronic Obstructive; Respiration; Severity of Illness Index; Tiotropium Bromide; Tropanes

Topics: Administration, Inhalation; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Adrenergic beta-Agonists; Asian People; Bronchodilator Agents; Delayed-Action Preparations; Drug Therapy, Combination; Forced Expiratory Volume; Formoterol Fumarate; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Topics: Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Benzoxazines; Bronchodilator Agents; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Long-acting bronchodilators, including long-acting beta. We identified a cohort of new users of long-acting bronchodilators between 2002 and 2012, age 55 or older, from the United Kingdom's Clinical Practice Research Datalink. Patients initiating tiotropium were matched on high-dimensional propensity scores and prior inhaled corticosteroid use with patients initiating LABAs, and followed for 1 year for the occurrence of acute myocardial infarction, stroke, heart failure, arrhythmia, and pneumonia.. A total of 26,442 tiotropium initiators were matched to 26,442 LABA initiators, mainly single inhalers combined with inhaled corticosteroids. The hazard ratio of acute myocardial infarction associated with tiotropium initiation, relative to LABA initiation, was 1.10 (95% CI, 0.88-1.38), whereas for stroke it was 1.02 (95% CI, 0.78-1.34), for arrhythmia 0.81 (95% CI, 0.60-1.09), and heart failure 0.90 (95% CI, 0.79-1.02). The incidence of pneumonia was significantly less with tiotropium (hazard ratio, 0.81; 95% CI, 0.72-0.92).. COPD treatment initiation with tiotropium compared with LABA does not increase cardiovascular risk in the first year of treatment. The risk of pneumonia is higher with LABA, a likely effect of the inhaled corticosteroids present in many LABA inhalers used in real world clinical practice.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Canada; Cardiovascular Diseases; Delayed-Action Preparations; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Pneumonia; Propensity Score; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Tiotropium Bromide

Acute exacerbations of chronic obstructive pulmonary disease (COPD) can be prevented by inhaled treatment. Errors in inhaler handling, not taken into account in clinical trials, could impact drug delivery and minimise treatment benefit. We aimed to assess real-life inhaler device handling in COPD patients and its association with COPD exacerbations.To this end, 212 general practitioners and 50 pulmonologists assessed the handling of 3393 devices used for continuous treatment of COPD in 2935 patients. Handling errors were observed in over 50% of handlings, regardless of the device used. Critical errors compromising drug delivery were respectively made in 15.4%, 21.2%, 29.3%, 43.8%, 46.9% and 32.1% of inhalation assessment tests with Breezhaler® (n=876), Diskus® (n=452), Handihaler® (n=598), pressurised metered-dose inhaler (pMDI) (n=422), Respimat® (n=625) and Turbuhaler® (n=420).The proportion of patients requiring hospitalisation or emergency room visits in the past 3 months for severe COPD exacerbation was 3.3% (95% CI 2.0-4.5) in the absence of error and 6.9% (95% CI 5.3-8.5) in the presence of critical error (OR 1.86, 95% CI 1.14-3.04, p<0.05).Handling errors of inhaler devices are underestimated in real life and are associated with an increased rate of severe COPD exacerbation. Training in inhaler use is an integral part of COPD management.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Disease Progression; Equipment Design; Female; France; Humans; Logistic Models; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Surveys and Questionnaires; Tiotropium Bromide

Comparisons of the use of aclidinium bromide and tiotropium bromide for the treatment of chronic obstructive pulmonary disease often concentrate on key end points (exacerbations) at the expense of other benefits and risks. Multicriteria decision analysis (MCDA) can help overcome this by using stakeholder preferences to combine multiple end points into an overall value estimate.. To evaluate the use of aclidinium bromide twice daily via Pressair™ (AstraZeneca Pharmaceuticals LP, Wilmington, DE) and of tiotropium once daily via HandiHaler. Literature reviews and clinician engagement were used to identify value criteria. Performance of criteria was estimated from a clinical trial and clinician opinion. Scores and swing weights came from six clinicians who, during a 2-day workshop, reflected their patients' preferences. Scenario and sensitivity analyses were used to explore uncertainty in model designs and inputs.. Fourteen criteria, covering clinical effectiveness, safety, and convenience of the treatments of chronic obstructive pulmonary disease, were identified. Exacerbations and device preloading were identified as the most important to patients; the least important was rescue medication use. Tiotropium's higher overall clinical effectiveness score was offset by aclidinium's better performance on safety and convenience outcomes. The MCDA generated a -42 (worst performance) to 100 (best performance) scale. The net impact of benefits over risks of aclidinium (38.5) exceeded that of tiotropium (13.2), and patients preferred aclidinium 79.7% of the time.. When considering clinical benefits and risks, aclidinium and tiotropium generate similar value to patients, but when convenience criteria are considered, aclidinium may be preferred. Further work is required to replicate these results, including eliciting preferences directly from patients.

Topics: Administration, Inhalation; Bronchodilator Agents; Forced Expiratory Volume; Humans; Nebulizers and Vaporizers; Patient Preference; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide; Tropanes; United States

Unlike many other COPD studies, the 4-year UPLIFT trial permitted inhaled corticosteroid (ICS) use during run-in and treatment phases. This provided the opportunity to prospectively observe the continuing effects of ICS on respiratory events in closely observed COPD population.. We aimed to determine rate and number of episodes of pneumonia and exacerbations of COPD in patients entering the study on no ICS, fluticasone proprionate (FP), and other ICS.. The UPLIFT dataset was examined retrospectively, and patients were divided into three groups based on their medications at entry: no ICS, FP and other ICS. Poisson regression was used to compare the frequency of respiratory adverse events.. At entry, the groups were well matched apart from a higher FEV1% predicted (38 vs. 41%; ICS vs. no ICS, respectively) and prevalence of current smoking (26 vs. 36%; ICS vs. no ICS, respectively). Incidence rates of pneumonia were significantly higher in patients taking ICS compared to no ICS (0.068 vs. 0.056 respectively; p = 0.012). When the FP group was compared to the other ICS, the event rate was even higher (0.077 vs. 0.058, respectively; p < 0.001). COPD exacerbations were more frequent in patients taking ICS, with significantly greater rate in the FP group compared to that seen with other ICS (0.93 vs. 0.84 respectively; p = 0.013).. ICS use was associated an increase in respiratory adverse event rates, but whether this was due to more severe illness at entry is unknown. In subgroup analysis, the excess of morbidity in the ICS group appeared to be mainly associated with those receiving FP at randomisation.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Cholinergic Antagonists; Disease Progression; Female; Fluticasone; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Pneumonia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Time Factors; Tiotropium Bromide; Treatment Outcome

To validate outcomes of presently available chronic obstructive pulmonary disease (COPD) cost-effectiveness models against results of two large COPD trials-the 3-year TOwards a Revolution in COPD Health (TORCH) trial and the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial.. Participating COPD modeling groups simulated the outcomes for the placebo-treated groups of the TORCH and UPLIFT trials using baseline characteristics of the trial populations as input. Groups then simulated treatment effectiveness by using relative reductions in annual decline in lung function and exacerbation frequency observed in the most intensively treated group compared with placebo as input for the models. Main outcomes were (change in) total/severe exacerbations and mortality. Furthermore, the absolute differences in total exacerbations and quality-adjusted life-years (QALYs) were used to approximate the cost per exacerbation avoided and the cost per QALY gained.. Of the six participating models, three models reported higher total exacerbation rates than observed in the TORCH trial (1.13/patient-year) (models: 1.22-1.48). Four models reported higher rates than observed in the UPLIFT trial (0.85/patient-year) (models: 1.13-1.52). Two models reported higher mortality rates than in the TORCH trial (15.2%) (models: 20.0% and 30.6%) and the UPLIFT trial (16.3%) (models: 24.8% and 36.0%), whereas one model reported lower rates (9.8% and 12.1%, respectively). Simulation of treatment effectiveness showed that the absolute reduction in total exacerbations, the gain in QALYs, and the cost-effectiveness ratios did not differ from the trials, except for one model.. Although most of the participating COPD cost-effectiveness models reported higher total exacerbation rates than observed in the trials, estimates of the absolute treatment effect and cost-effectiveness ratios do not seem different from the trials in most models.

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Computer Simulation; Cost-Benefit Analysis; Decision Making; Economics, Medical; Female; Fluticasone; Humans; Male; Middle Aged; Models, Econometric; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome

Two inhaler devices (Respimat® and HandiHaler®) are available for tiotropium, a long acting anticholinergic agent. We aimed to analyze drug utilization, off-label usage and generalizability of the TIOSPIR trial results for both devices.. Patients aged ≥18 years exhibiting at least one documented prescription of tiotropium in the database of the Association of Statutory Health Insurance Physicians, Bavaria, Germany, were included (years 2004-2008). Annual period prevalence rates (PPRs) were calculated stratified by age, gender and inhaler devices. Off-label usage (patients lacking a chronic obstructive pulmonary disease (COPD) diagnosis) and the proportion of patients meeting the inclusion and exclusion criteria of the TIOSPIR trial were analyzed.. Between 2004 and 2008, PPRs increased and varied between 49.2 and 74.5 per 10 000 persons for HandiHaler® and between 1.5 and 9.3 per 10 000 persons for Respimat®. Small differences regarding patient characteristics existed between the two inhaler devices. Only about 30% (HandiHaler® 32.1%, Respimat® 30.0%) of the database patients receiving tiotropium could be theoretically included in the TIOSPIR trial.. Comparing the two tiotropium devices, no clinically relevant differences regarding patient and prescribing characteristics were revealed. Results of the TIOSPIR trial were generalizable only to a minority of our study patients, underlining the need for real-life data.

Topics: Administration, Inhalation; Aged; Cholinergic Antagonists; Clinical Trials as Topic; Databases, Factual; Drug Utilization; Dry Powder Inhalers; Female; Humans; Male; Metered Dose Inhalers; Off-Label Use; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Chronic therapy with long-acting bronchodilators (LB) is recommended to treat moderate-to-severe COPD. Although the benefits of adding inhaled corticosteroid (ICS) to LB are still unclear, patients who experience repeated exacerbations are suggested to add ICS to their LB treatment. The objective of this study is to analyze whether adding ICS to LB therapy reduces mortality.. We identified a cohort of patients discharged from hospital with COPD diagnosis between 2006 and 2009. The first prescription for LB or ICS following discharge was defined as the index prescription. Only new users were included (no use of any study drug in the 6 months before treatment). A 4-day time window was used to classify patients into "LB alone" or "LB plus ICS" initiators. We used propensity score to balance the study groups. Sensitivity analyses were performed in patients with recent out-of-hospital exacerbations.. Among the 18615 adults enrolled, 12207 initiated "LB plus ICS" therapy and 6408 "LB alone." Crude mortality rates were 110 and 143 cases per 1000 person-years in the "LB plus ICS" and "LB alone" groups, respectively. The adjusted hazard ratio (HR) was 0.83 (95% CI: 0.72-0.97; p-value: 0.024). When analyzing patients with recent out-of-hospital exacerbations, the benefit of the combination therapy was more pronounced, HR = 0.63 (95% CI: 0.44-0.90; p-value: 0.012).. Our findings showed a beneficial effect on mortality of adding inhaled corticosteroids to long-acting bronchodilators. The advantage was much more pronounced in patients with frequent exacerbations.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Aged, 80 and over; Bronchodilator Agents; Cohort Studies; Delayed-Action Preparations; Disease Progression; Drug Combinations; Drug Prescriptions; Drug Therapy, Combination; Female; Humans; Italy; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Anticholinergic drug products are not part of the current treatment paradigm for asthma, despite their widespread availability for chronic obstructive pulmonary disease (COPD) and interest in their use for asthma. Published study results, mostly of short duration and primarily with ipratropium and tiotropium, have revealed inconsistent efficacy results. Consequently, the role of inhaled anticholinergic drugs in the treatment of asthma has been unclear. This commentary discusses and comments on data from five clinical trials in adults that were submitted by Boehringer Ingelheim to the U.S. Food and Drug Administration to support approval of tiotropium delivered by the Respimat device (Spiriva Respimat) for the treatment of asthma. These trials provided substantial evidence that supported the approval of Spiriva Respimat at a recommended dose of 2.5 μg once daily for asthma. Notably, in trials that evaluated two doses of tiotropium, 2.5 μg and 5 μg (the dose approved for COPD), pulmonary function measures for Spiriva Respimat 2.5 μg once daily were better overall than those obtained for the 5-μg once-daily dose, thus justifying selection of the lower dose for asthma. Spiriva Respimat represents the first new class of drug approved by the U.S. Food and Drug Administration for the treatment of asthma in more than a decade. The availability of Spiriva Respimat for asthma along with other novel therapies currently under development has the potential to impact asthma treatment guidelines.

Topics: Adult; Asthma; Bronchodilator Agents; Disease Progression; Drug Approval; Forced Expiratory Volume; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; United States; United States Food and Drug Administration; Vital Capacity

Topics: Bronchodilator Agents; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Long-acting bronchodilators, i.e. beta-2-agonists (LABA) and tiotropium are commonly used in COPD treatment. Choice of a specific agent is based on effectiveness and safety. Evidence yields controversial results with respect to mortality. The present study compared one-year mortality associated to treatment with tiotropium versus LABA.. A population-based cohort study using data from Italian health information systems was performed. Patients aged 45+ years, discharged with COPD diagnosis in 2006-2009 were identified. Through record linkage with drug claims, patients who received a first prescription of LABA or tiotropium within 6 months after discharge were enrolled. The main analysis was restricted to naïve users (no prior use of either LABA or tiotropium). We used 'intention to treat' (ITT) and 'as treated' (AT) approaches. We followed patients for a maximum of 12 months. Hazard ratios (HRs) were calculated by Cox regression including quintiles of propensity score. In sensitivity analysis patients receiving tiotropium + LABA combination were included in the tiotropium group.. Among the 33 891 enrolees, 28% were exposed to Tio, 56% to LABA, 16% to both. Overall mean age was 74 years and the mortality rate was 122/1000 person-years (py) at the ITT analysis and 108/1000 py at the AT analysis. The adjusted HR for tiotropium only compared with LABA only was 1.06 (95%CI: 0.94-1.20) at the ITT analysis and 1.00 (95%CI: 0.93-1.08) at the AT analysis. Results were robust in sensitivity analysis.. In this real-world study use of tiotropium was not associated with an increased risk of one-year mortality compared with LABA. © 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Bronchodilator Agents; Cohort Studies; Female; Humans; Italy; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Umeclidinium/vilanterol (UMEC/VI) is a novel fixed dose combination of a long-acting muscarinic receptor antagonist (LAMA) and a long-acting beta 2 receptor antagonist (LABA) agent. This analysis evaluated the incremental cost-effectiveness ratio (ICER) of UMEC/VI compared with tiotropium (TIO), from the Spanish National Health System (NHS) perspective.. A previously published linked equations cohort model based on the epidemiological longitudinal study ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points) was used. Patients included were COPD patients with a post-bronchodilator forced expiratory volume in 1 second (FEV1) ≤70% and the presence of respiratory symptoms measured with the modified Medical Research Council dyspnea scale (modified Medical Research Council ≥2). Treatment effect, expressed as change in FEV1 from baseline, was estimated from a 24-week head-to-head phase III clinical trial comparing once-daily UMEC/VI with once-daily TIO and was assumed to last 52 weeks following treatment initiation (maximum duration of UMEC/VI clinical trials). Spanish utility values were derived from a published local observational study. Unitary health care costs (€2015) were obtained from local sources. A 3-year time horizon was selected, and 3% discount was applied to effects and costs. Results were expressed as cost/quality-adjusted life years (QALYs). Univariate and probabilistic sensitivity analysis (PSA) was performed.. UMEC/VI produced additional 0.03 QALY and €590 vs TIO, leading to an ICER of €21,475/QALY. According to PSA, the probability of UMEC/VI being cost-effective was 80.3% at a willingness-to-pay of €30,000/QALY.. UMEC/VI could be considered as a cost-effective treatment alternative compared with TIO in symptomatic COPD patients from the Spanish NHS perspective.

Topics: Administration, Inhalation; Aged; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Cost-Benefit Analysis; Drug Combinations; Female; Forced Expiratory Volume; Humans; Longitudinal Studies; Male; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Quinuclidines; Severity of Illness Index; Spain; Symptom Assessment; Tiotropium Bromide; Treatment Outcome

Despite inhaled medications that decrease exacerbation risk, some COPD patients experience frequent exacerbations. We determined prospective risk factors for exacerbations among subjects in the COPDGene Study taking inhaled medications.. 2113 COPD subjects were categorized into four medication use patterns: triple therapy with tiotropium (TIO) plus long-acting beta-agonist/inhaled-corticosteroid (ICS ± LABA), tiotropium alone, ICS ± LABA, and short-acting bronchodilators. Self-reported exacerbations were recorded in telephone and web-based longitudinal follow-up surveys. Associations with exacerbations were determined within each medication group using four separate logistic regression models. A head-to-head analysis compared exacerbation risk among subjects using tiotropium vs. ICS ± LABA.. In separate logistic regression models, the presence of gastroesophageal reflux, female gender, and higher scores on the St. George's Respiratory Questionnaire were significant predictors of exacerbator status within multiple medication groups (reflux: OR 1.62-2.75; female gender: OR 1.53 - OR 1.90; SGRQ: OR 1.02-1.03). Subjects taking either ICS ± LABA or tiotropium had similar baseline characteristics, allowing comparison between these two groups. In the head-to-head comparison, tiotropium users showed a trend towards lower rates of exacerbations (OR = 0.69 [95 % CI 0.45, 1.06], p = 0.09) compared with ICS ± LABA users, especially in subjects without comorbid asthma (OR = 0.56 [95% CI 0.31, 1.00], p = 0.05).. Each common COPD medication usage group showed unique risk factor patterns associated with increased risk of exacerbations, which may help clinicians identify subjects at risk. Compared to similar subjects using ICS ± LABA, those taking tiotropium showed a trend towards reduced exacerbation risk, especially in subjects without asthma.. ClinicalTrials.gov NCT00608764, first received 1/28/2008.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Aged; Asthma; Bronchodilator Agents; Cohort Studies; Comorbidity; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Gastroesophageal Reflux; Humans; Logistic Models; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Risk Factors; Sex Factors; Tiotropium Bromide

Delivery of inhaled medications via an inhaler device underpins the effectiveness of treatment for patients with chronic obstructive pulmonary disease (COPD). Correct inhaler technique among patients is also a predictor of achieving treatment compliance and adherence. Reporting of patient satisfaction with inhalers is therefore gaining increasing attention and is now recognized as an important patient-reported outcome in clinical trials involving patients with COPD or asthma. In this cross-sectional study, we use the validated Patient Satisfaction and Preference Questionnaire (PASAPQ) to assess the handling and satisfaction for Respimat(®) Soft Mist™ Inhaler (SMI) compared with the Breezhaler(®) dry powder inhaler (DPI) among patients with COPD in Spain. Patients were already assigned to therapy with either SPIRIVA(®) (tiotropium) Respimat(®) or with Hirobriz(®)/Onbrez(®)/Oslif(®) (indacaterol) Breezhaler(®) for at least 3 but not more than 6 months before completing the PASAPQ at a single visit to the study site. The primary endpoint of the trial was the mean total PASAPQ score. Secondary endpoints were the performance score domain of the PASAPQ, the convenience score domain of the PASAPQ, and the overall satisfaction score of the PASAPQ. For the primary endpoint, the mean PASAPQ total score in the Respimat(®) and Breezhaler(®) groups was 80.7 and 79.9, respectively (difference of 0.8, 95% confidence interval [CI] -2.9 to 4.5; P=0.67). The mean total performance scores were 82.5 and 78.2 (difference of 4.3, 95% CI -0.3 to 8.9; P=0.06), and the mean total convenience scores were 78.6 and 81.9 (difference of -3.3, 95% CI -7.0 to 0.4; P=0.08) for the Respimat(®) and Breezhaler(®) groups, respectively. Patients gave the Respimat(®) SMI and the Breezhaler(®) DPI overall satisfaction PASAPQ scores of 6.0 and 5.9, respectively, which shows that patients were satisfied with these inhalers.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cross-Sectional Studies; Equipment Design; Female; Humans; Indans; Male; Middle Aged; Nebulizers and Vaporizers; Patient Preference; Pulmonary Disease, Chronic Obstructive; Quinolones; Spain; Surveys and Questionnaires; Tiotropium Bromide

IL-17A plays a key role in the persistence of airway inflammation, oxidative stress, and reduction of steroid-sensitivity in COPD. We studied the effect of IL-17A on chromatin remodeling and IL-8 production.. We measured the levels of IL-8 and IL-17A in induced sputum supernatants (ISS) from healthy controls (HCs), healthy smokers (HSs), and COPD patients by enzyme-linked immunosorbent assay (ELISA). A human bronchial epithelial cell line (16HBE) was stimulated with ISS from HCs, HSs, or COPD subjects. IL-8 was evaluated in 16HBE by Western blot and real-time polymerase chain reaction (PCR). Histone deacetylase 2 (HDAC2), acetyl histone H3 (Ac-His H3) (k9) and inhibitor kappa kinase alpha (IKKα) levels were evaluated in the nuclear extract by Western blot. Finally, we evaluated the effect of IL-17A depletion in ISS, the silencing of IKKα, and the anti-inflammatory effects of Tiotropium Spiriva® (100nM) on 16HBE.. IL-8 and IL-17A levels were higher in ISS from COPD patients and HSs than from HCs. IL-8 protein and messenger RNA (mRNA) levels were increased in 16HBE stimulated with ISS from COPD patients compared with untreated cells. Furthermore, ISS from COPD patients reduced the nuclear levels of HDAC2 while increasing the activity of both Ac-His H3 (k9) and IKKα in stimulated 16HBE. IL-17A depletion in ISS and the IKKα silencing in 16HBE significantly increased the nuclear levels of HDAC2, reduced Ac-His H3 (k9), and promoted IL-8 synthesis in stimulated 16HBE. Tiotropium controls the proinflammatory activity generated by ISS from COPD patients in 16HBE.. IL-17A present in the airway of COPD patients, which induces chromatin remodeling, promotes the release of IL-8 in the bronchial epithelium. Tiotropium is able to control this proinflammatory activity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Bronchi; Cells, Cultured; Chromatin Assembly and Disassembly; Epithelial Cells; Histone Deacetylase 2; Histones; Humans; Interleukin-17; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Smoking; Sputum; Tiotropium Bromide

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Bronchodilator Agents; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Italy; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) clinical trials evaluating hard endpoints (mortality, hospitalized exacerbations) require a large number of subjects and prolonged observational periods. We hypothesized that a composite endpoint of respiratory outcomes (CERO) can help evaluate safety and benefit in COPD trials.. Retrospective analysis of 5992 patients enrolled in the 4-year UPLIFT® trial, a randomized trial of tiotropium versus placebo in patients with moderate-to-severe COPD. Patients were permitted to continue using their usual COPD medications except for other anticholinergics. The CERO included deaths, respiratory failure, hospitalized exacerbations, and trial dropout due to COPD worsening. The incidence rates (IRs) per 100 patient-years and risk ratios (RRs and 95 % CI) were determined at years 1 to 4. The effect of treatments on CERO was similarly assessed. A power analysis helped calculate the sample size needed to achieve outcome differences between treatments.. The CERO IRs at years 1 to 4 for tiotropium versus placebo were 16, 13, 11, and 11, and 21, 16, 14, and 13, respectively. The RRs of CERO between tiotropium and placebo at the same time points were: RR-year 0.76 (0.67, 0.86), 0.80 (0.72, 0.88), 0.81 (0.74, 0.89), and 0.84 (0.77, 0.92). Using the IRs and RRs, the sample size (alpha = 0.05 two-sided, 90 % power) for studies of 1, 2, 3, and 4 years would be 1546, 1392, 1216, and 1504 per treatment group, respectively, with 575, 810, 930, 1383 required events, respectively, for hypothetical, event-driven studies.. A composite endpoint incorporating relatively infrequent serious or significant COPD-related safety outcomes could be useful in clinical trials. In UPLIFT®, CERO events were significantly reduced in patients receiving tiotropium compared with placebo.. NCT00144339 .

Topics: Aged; Bronchodilator Agents; Cholinergic Antagonists; Disease Progression; Endpoint Determination; Female; Humans; Kaplan-Meier Estimate; Lung; Male; Middle Aged; Multicenter Studies as Topic; Odds Ratio; Patient Dropouts; Patient Safety; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Sample Size; Time Factors; Tiotropium Bromide; Treatment Outcome

Topics: Bronchodilator Agents; Dry Powder Inhalers; Germany; Humans; Lung; Particle Size; Phenotype; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Topics: Albuterol, Ipratropium Drug Combination; Benzoxazines; Drug Approval; Drug Combinations; Germany; Humans; Long-Term Care; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Bronchodilator Agents; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Topics: Bronchodilator Agents; Humans; Pharmacology, Clinical; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Maintaining and improving physical functioning is key to mitigating the cycle of deconditioning associated with chronic obstructive pulmonary disease (COPD). We evaluated the impact of free combination of the long-acting anticholinergic tiotropium plus the long-acting β2-agonist olodaterol on physical functioning in a real-world clinical setting.. In this open-label noninterventional study, Global initiative for chronic Obstructive Lung Disease (GOLD) B-D patients with COPD aged ≥40 years were treated for 4-6 weeks with either tiotropium 5 μg + olodaterol 5 μg (both via Respimat(®) inhaler) or tiotropium 18 μg (HandiHaler(®)) + olodaterol 5 μg (Respimat(®)) once daily. Physical functioning was assessed by the self-reported 10-item Physical Functioning Questionnaire (PF-10). The primary end point was the percentage of patients achieving therapeutic success, defined as a 10-point increase in the PF-10 between baseline (visit 1) and weeks 4-6 (visit 2). Secondary end points included absolute PF-10 scores, Physicians' Global Evaluation, satisfaction with Respimat(®) and adverse events.. A total of 1,858 patients were treated: 1,298 (69.9%) with tiotropium 5 μg + olodaterol 5 μg and 560 (30.1%) with tiotropium 18 μg + olodaterol 5 μg. At study end, 1,683 (92.6%) and 1,556 patients (85.6%) continued using tiotropium and olodaterol, respectively; 48.9% (95% confidence interval: 46.5, 51.3) achieved the primary end point. Therapeutic success rates were significantly higher for maintenance-naïve patients compared to those who had received prior therapy (59.1% vs 44.5%; P<0.0001), largely driven by maintenance-treatment-naïve GOLD B (59.8%) and C (63.0%) patients. Absolute physical functioning scores increased from an average baseline of 44.0 (standard deviation: 25.2) to 54.2 (standard deviation: 26.9) at visit 2. Patients' general condition improved from baseline to visit 2, and patients were largely satisfied with the Respimat(®) inhaler. Adverse events were reported by 7.5% of patients; the most common were respiratory in nature.. Tiotropium + olodaterol improved physical functioning within 4-6 weeks in patients with moderate-to-very severe COPD. GOLD B and C patients with no prior maintenance treatment demonstrated the greatest benefit.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Cholinergic Antagonists; Drug Combinations; Female; Health Status; Humans; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome

As lung function declines rapidly in the early stages of chronic obstructive pulmonary disease (COPD), the effects of bronchodilators in patients with moderate disease and those who have not previously received maintenance therapy are of interest. OTEMTO® 1 and 2 were two replicate, 12-week, Phase III studies investigating the benefit of tiotropium + olodaterol on lung function and quality of life in patients with moderate to severe disease. Post hoc analyses were performed to assess the benefits for patients according to disease severity and treatment history.. Four subgroup analyses were performed: Global initiative for chronic Obstructive Lung Disease (GOLD) 2/3, GOLD A/B/C/D, treatment naive/not treatment naive and receiving inhaled corticosteroids (ICS) at baseline/not receiving ICS at baseline. Primary end points were change in forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h response, change in trough FEV1 and St George's Respiratory Questionnaire (SGRQ) total score. Transition Dyspnoea Index (TDI) focal score was a secondary end point, and SGRQ and TDI responder analyses were further end points; all were assessed at 12 weeks.. In all subgroups, patients receiving tiotropium + olodaterol responded better overall than those receiving tiotropium monotherapy. Improvements with tiotropium + olodaterol over placebo or tiotropium monotherapy were noted across GOLD 2/3 and GOLD A/B/C/D; however, improvements in SGRQ total score were most evident in the GOLD B subgroup. Moreover, lung-function outcomes were generally greater in those patients who had been receiving previous long-acting bronchodilator and/or ICS maintenance treatment.. These data suggest that tiotropium + olodaterol should be considered as a treatment option in patients with moderate COPD who are initiating maintenance therapy, as well as those with more severe disease.. ClinicalTrials.gov: NCT01964352 and NCT02006732 .

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials, Phase III as Topic; Drug Combinations; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Recovery of Function; Severity of Illness Index; Spirometry; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome

The objective of this study was to compare the cost-effectiveness of the fixed-dose combination (FDC) of tiotropium + olodaterol Respimat(®) FDC with tiotropium alone for patients with chronic obstructive pulmonary disease (COPD) in the Italian health care setting using a newly developed patient-level Markov model that reflects the current understanding of the disease.. While previously published models have largely been based around a cohort approach using a Markov structure and GOLD stage stratification, an individual-level Markov approach was selected for the new model. Using patient-level data from the twin TOnado trials assessing Tiotropium + olodaterol Respimat(®) FDC versus tiotropium, outcomes were modelled based on the trough forced expiratory volume (tFEV1) of over 1000 patients in each treatment arm, tracked individually at trial visits through the 52-week trial period, and after the trial period it was assumed to decline at a constant rate based on disease stage. Exacerbation risk was estimated based on a random-effects logistic regression analysis of exacerbations in UPLIFT. Mortality by age and disease stage was estimated from an analysis of TIOSPIR trial data. Cost of bronchodilators and other medications, routine management, and costs of treatment for moderate and severe exacerbations for the Italian setting were included. A cost-effectiveness analysis was conducted over a 15-year time horizon from the perspective of the Italian National Health Service.. Aggregating total costs and quality-adjusted life years (QALYs) for each treatment cohort over 15 years and comparing tiotropium + olodaterol Respimat(®) FDC with tiotropium alone, resulted in mean incremental costs per patient of €1167 and an incremental cost-effectiveness ratio (ICER) of €7518 per additional QALY with tiotropium + olodaterol Respimat(®) FDC. The lung function outcomes observed for tiotropium + olodaterol Respimat(®) FDC in TOnado drove the results in terms of slightly higher mean life-years (12.24 versus 12.07) exacerbation-free months (11.36 versus 11.32) per patient and slightly fewer moderate and severe exacerbations per patient-year (0.411 versus 0.415; 0.21 versus 0.24) versus tiotropium. Probabilistic sensitivity analyses showed tiotropium + olodaterol Respimat(®) FDC to be the more cost-effective treatment in 95.2% and 98.4% of 500 simulations at thresholds of €20,000 and €30,000 per QALY respectively.. Tiotropium + olodaterol Respimat(®) FDC is a cost-effective bronchodilator in the maintenance treatment of COPD for the Italian health care system.

Topics: Aged; Benzoxazines; Bronchodilator Agents; Cost-Benefit Analysis; Drug Combinations; Female; Forced Expiratory Volume; Humans; Italy; Male; Markov Chains; Middle Aged; Models, Economic; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Respiratory Function Tests; Tiotropium Bromide; Treatment Outcome

Poor adherence to inhaled medications in COPD patients seems to be associated with an increased risk of death and hospitalization. Knowing the determinants of nonadherence to inhaled medications is important for creating interventions to improve adherence.. To identify disease-specific and health-related quality of life (HRQoL) factors, associated with adherence to inhaled corticosteroids (ICS) and tiotropium in COPD patients.. Adherence of 795 patients was recorded over 3 years and was deemed optimal at >75%-≤125%, suboptimal at ≥50%-<75%, and poor at <50% (underuse) or >125% (overuse). Health-related quality of life was measured with the Clinical COPD Questionnaire and the EuroQol-5D questionnaire.. Patients with a higher forced expiratory volume in 1 second (FEV1)/vital capacity (VC) (odds ratio [OR] =1.03) and ≥1 hospitalizations in the year prior to inclusion in this study (OR =2.67) had an increased risk of suboptimal adherence to ICS instead of optimal adherence. An increased risk of underuse was predicted by a higher FEV1/VC (OR =1.05). Predictors for the risk of overuse were a lower FEV1 (OR =0.49), higher scores on Clinical COPD Questionnaire-question 3 (anxiety for dyspnea) (OR =1.26), and current smoking (OR =1.73). Regarding tiotropium, predictors for suboptimal use were a higher FEV1/VC (OR =1.03) and the inability to perform usual activities as asked by the EuroQol-5D questionnaire (OR =3.09). A higher FEV1/VC also was a predictor for the risk of underuse compared to optimal adherence (OR =1.03). The risk of overuse increased again with higher scores on Clinical COPD Questionnaire-question 3 (OR =1.46).. Several disease-specific and quality of life factors are related to ICS and tiotropium adherence, but a clear profile of a nonadherent patient cannot yet be outlined. Overusers of ICS and tiotropium experience more anxiety.

Topics: Activities of Daily Living; Administration, Inhalation; Adrenal Cortex Hormones; Aged; Anxiety; Bronchodilator Agents; Chi-Square Distribution; Cholinergic Antagonists; Dyspnea; Female; Forced Expiratory Volume; Humans; Lung; Male; Medication Adherence; Middle Aged; Multivariate Analysis; Netherlands; Odds Ratio; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quality of Life; Risk Factors; Smoking; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The fixed-dose dual bronchodilator combination (FDC) of tiotropium and olodaterol showed increased effectiveness regarding lung function and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD) compared with the use of its mono-components. Yet, while effectiveness and safety have been shown, the health economic implication of this treatment is still unknown. The aim of this study was to assess the cost-utility and budget impact of tiotropium-olodaterol FDC in patients with moderate to very severe COPD in the Netherlands.. A cost-utility study was performed, using an individual-level Markov model. To populate the model, individual patient-level data (age, height, sex, COPD duration, baseline forced expiratory volume in 1 second) were obtained from the tiotropium-olodaterol TOnado trial. In the model, forced expiratory volume in 1 second and patient-level data were extrapolated to utility and survival, and treatment with tiotropium-olodaterol FDC was compared with tiotropium. Cost-utility analysis was performed from the Dutch health care payer's perspective using a 15-year time horizon in the base-case analysis. The standard Dutch discount rates were applied (costs: 4.0%; effects: 1.5%). Both univariate and probabilistic sensitivity analyses were performed. Budget impact was annually assessed over a 5-year time horizon, taking into account different levels of medication adherence.. As a result of cost increases, combined with quality-adjusted life-year (QALY) gains, results showed that tiotropium-olodaterol FDC had an incremental cost-effectiveness ratio of €7,004/QALY. Without discounting, the incremental cost-effectiveness ratio was €5,981/QALY. Results were robust in univariate and probabilistic sensitivity analyses. Budget impact was estimated at €4.3 million over 5 years assuming 100% medication adherence. Scenarios with 40%, 60%, and 80% adherence resulted in lower 5-year incremental cost increases of €1.7, €2.6, and €3.4 million, respectively.. Tiotropium-olodaterol FDC can be considered a cost-effective treatment under current Dutch cost-effectiveness thresholds.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Budgets; Cholinergic Antagonists; Cost-Benefit Analysis; Disease Progression; Drug Combinations; Drug Costs; Female; Forced Expiratory Volume; Humans; Lung; Male; Markov Chains; Medication Adherence; Middle Aged; Models, Economic; Netherlands; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

Increasing age is associated with poor prognosis in patients with COPD.. This analysis from the replicate Phase III OTEMTO. In these double-blind, parallel-group, active-controlled, multicenter, randomized studies, patients received tiotropium + olodaterol 2.5/5 μg or 5/5 μg, tiotropium 5 μg or 2.5 μg (TONADO only), olodaterol 5 μg (TONADO only), or placebo (OTEMTO only). This analysis used the approved doses of tiotropium + olodaterol 5/5 μg, tiotropium 5 μg, and olodaterol 5 μg. Primary end points at 12 weeks (OTEMTO) or 24 weeks (TONADO) included St George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in 1 second (FEV. No differences were noted in relative responses to treatment or safety when using tiotropium + olodaterol 5/5 μg compared to monotherapies or placebo across all age groups.

Topics: Adrenergic beta-2 Receptor Agonists; Adult; Age Factors; Aged; Aged, 80 and over; Benzoxazines; Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials, Phase III as Topic; Drug Combinations; Forced Expiratory Volume; Health Status; Humans; Lung; Male; Middle Aged; Multicenter Studies as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Recovery of Function; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Allergens; Anti-Asthmatic Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Asthma; Bronchial Thermoplasty; Bronchodilator Agents; Environmental Exposure; Eosinophilia; Humans; Practice Guidelines as Topic; Prenatal Care; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide; Vitamin D; Vitamins

Topics: Fluticasone; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA) bronchodilators and their combination are recommended for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Although the efficacy of LAMAs and LABAs has been well established through randomized controlled trials (RCTs), questions remain regarding their cardiovascular (CV) safety. Furthermore, while the safety of LAMA and LABA monotherapy has been extensively studied, data are lacking for LAMA/LABA combination therapy, and the majority of the studies that have reported on the CV safety of LAMA/LABA combination therapy were not specifically designed to assess this. Evaluation of CV safety for COPD treatments is important because many patients with COPD have underlying CV comorbidities. However, severe CV and other comorbidities are often exclusion criteria for RCTs, contributing to a lack in external validity and generalizability. Real-world observational studies are another important tool to evaluate the effectiveness and safety of COPD therapies in a broader population of patients and can improve upon the external validity limitations of RCTs. We examine what is already known regarding the CV and cerebrovascular safety of LAMA/LABA combination therapy from RCTs and real-world observational studies, and explore the advantages and limitations of data derived from each study type. We also describe an ongoing prospective, observational, comparative post-authorization safety study of a LAMA/LABA combination therapy (umeclidinium/vilanterol) and LAMA monotherapy (umeclidinium) versus tiotropium, with a focus on the relative merits of the study design.

Topics: Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Cardiovascular Diseases; Chlorobenzenes; Comorbidity; Drug Combinations; Evidence-Based Medicine; Humans; Lung; Muscarinic Antagonists; Patient Safety; Patient Selection; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Factors; Time Factors; Tiotropium Bromide; Treatment Outcome

The chronic use of the long-acting anticholinergic agent, tiotropium, in chronic obstructive pulmonary disease (COPD) has been linked in some reports to an increase in adverse cardiovascular effects. Decreased heart rate variability (HRV) is a condition seen in COPD patients that has also been linked to poor cardiovascular outcome. We aimed in this study to investigate changes in HRV caused by tiotropium administration to COPD patients in order to determine whether changes occurred that might contribute to an increase in adverse cardiovascular events.. Seventy patients with moderate-to-severe stable COPD were treated with once-daily dosing of tiotropium (two puffs of Spiriva Respimat, 2.5 μg solution) for 3 months. HRV, pulmonary function, and quality of life were measured before and after 1 and 3 months of therapy.. Pulmonary function and quality of life improved significantly, after both 1 and 3 months of therapy. No significant change in HRV parameters occurred, except for a significant decrease in the high-frequency and increase in the low-frequency component of HRV at the 1-month assessment.. Changes in HRV caused by tiotropium use are not sufficient to explain a possible increase in adverse cardiovascular events.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchodilator Agents; Cholinergic Antagonists; Drug Administration Schedule; Female; Heart Rate; Humans; Lung; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recovery of Function; Risk Factors; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

To understand the factors influencing persistence with tiotropium in patients with chronic obstructive pulmonary disease (COPD).. Patients classified as 'persistent' or 'non-persistent' with tiotropium were identified from pharmacy dispensing records. Patients were compared for health status, beliefs and behaviours using data from questionnaires and interviews.. Perceptions of the risks and benefits of medication, fear of worsening illness, and the GP's emphasis on the importance of the medication were key determinants of tiotropium persistence.. Perceptions, attitudes and beliefs of patients and doctors influence persistence with tiotropium. These complex interactions need to be targeted to improve persistence with medicines in COPD.

Topics: Bronchodilator Agents; Data Mining; Health Knowledge, Attitudes, Practice; Health Status; Humans; Medication Adherence; Patients; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Tiotropium bromide, a long-acting anticholinergic agent, improves pulmonary function and quality of life of patients suffering from chronic obstructive pulmonary disease (COPD). We retrospectively examined the factors that determine the long-term persistence with tiotropium bromide. Among 6,301 patients who underwent pulmonary function tests in our pulmonary clinic between 2006 and 2009, 644 met the following criteria: 1) age > 40 years, 2) ≥ 20 pack-years smoking history, and 3) forced expiratory volume in 1 sec / forced vital capacity ratio < 0.7. The clinical information, including the prescription of tiotropium, was obtained from the patients' records. Tiotropium was administered to 255 patients (40%), of whom 48 (19%) discontinued treatment within 1 year, and 65 (25%) discontinued treatment within the median observation period of 32 months. The drug was discontinued because of ineffectiveness in 35 patients (73%), and because of adverse drug effects in 13 patients (27%). Young age, current smoking, absence of respiratory symptoms alleviation, and less severe disease characterized by a) mild airflow limitation, b) mild to moderate emphysema, or c) no exacerbation of COPD during the 1(st) year of treatment were predictors of drug discontinuation.

Topics: Age Factors; Aged; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Male; Medication Adherence; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Severity of Illness Index; Smoking; Tiotropium Bromide; Vital Capacity

Recent studies show that several Siglec receptors, such as Siglec-8 and Siglec-14, may be important therapeutic targets in asthma and COPD. Siglecs are a family of lectins belonging to the immunoglobulin superfamily and recognize sialic acid residues of glycoproteins. Most of Siglecs have intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIM), implicating them in the suppression of immunoreceptor signaling. Siglec-5/14 may be involved in the negative regulation of innate immune responses. The aim of this study was to analyze Siglec-5/14 expression in induced sputum cells of COPD patients in the following treatment combinations: (1) a long-acting beta2-agonist, formoterol; (2) formoterol combined with a long-acting antimuscarinic agent, tiotropium; and (3) formoterol combined with an inhaled corticosteroid or formoterol combined with tiotropium and with an inhaled corticosteroid. Siglec expression was assessed in sputum cells by flow cytometry using a specific monoclonal antibody. Double staining of cells indicated that Siglec-5/14 is expressed in monocyte/macrophages and neutrophils, but not in lymphocytes. Siglec-5/14 expression was significantly higher in patients receiving combined therapy including inhaled corticosteroids compared with patients taking only formoterol or formoterol + tiotropium. Our results suggest that inhaled corticosteroids may exert beneficial or negative effects, depending on the patients' phenotype, through increased immunosuppressive Siglec-5 or immunoactivatory Siglec-14 receptors, respectively.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Androstadienes; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Bronchodilator Agents; Budesonide; Cell Separation; Cholinergic Antagonists; Drug Therapy, Combination; Ethanolamines; Fluticasone; Formoterol Fumarate; Gene Expression; Humans; Immunophenotyping; Lectins; Macrophages; Neutrophils; Pulmonary Disease, Chronic Obstructive; Receptors, Cell Surface; Scopolamine Derivatives; Sputum; T-Lymphocytes; Tiotropium Bromide

Immune cells expressing the activation markers HLA-DR and regulatory T cells (Tregs) may be involved in the regulation of chronic inflammation in chronic obstructive pulmonary disease (COPD). In this study we analyzed native and activated cell profiles in sputum of 22 stable COPD patients receiving formoterol (F) or formoterol + tiotropium (F + T) for 3 months. Cells were isolated from induced sputum and were examined on Coulter flow cytometer using fluorescent antibodies specific for CD3, CD4, CD8, CD14, CD19, CD25, CD127, and HLA-DR antigens. Cell profiles and cell activation were assessed by analysis of HLA-DR, CD25, and CD127 co-expression in double-stained samples. Tregs were defined as CD4⁺CD25(high) CD127(low) cells. We found that the combined therapy significantly decreased the CD8⁺ cell number (p < 0.01). At baseline, HLA-DR was expressed in about 10 % of sputum T or B cells and a higher expression was found on monocytes. The HLA-DR expression on lymphocytes, but not monocytes, was significantly lower (p < 0.01) in patients treated with F + T. Fractions of activated [CD4⁺ CD25⁺] cells were also significantly lower in the combined therapy group, except for the subpopulation of CD4⁺CD25(high) CD127(low) cells which was not altered. We conclude that tiotropium in add-on therapy to formoterol affects Treg cell profiles and decreases HLA-DR expression in airway lymphocytes.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Antigens, CD; Bronchodilator Agents; Cell Separation; Cholinergic Antagonists; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Gene Expression; HLA-DR Antigens; Humans; Immunophenotyping; Male; Middle Aged; Monocytes; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sputum; T-Lymphocytes, Regulatory; Tiotropium Bromide

The need for a rapid onset of action and a long duration of the broncholytic effect is the likely reason for the development of new long-acting β2-agonists (LABAs) that are fast acting and have true 24 h duration of action. Indacaterol is the archetype of once-daily LABAs and already marketed as a maintenance therapy in patients with moderate to severe chronic obstructive pulmonary disease (COPD).. Meta-analyses of published data or pooled analyses of primary data provide good insight into the clinical role of indacaterol in COPD.. The choice of the once-daily bronchodilator to start treatment in a patient with COPD mainly depends on the outcome of interest. Indacaterol is more effective than tiotropium if we consider symptoms or health-related quality of life as the primary outcome. Moreover, in symptomatic patient indacaterol should be preferred to tiotropium because of its rapid onset of action. By contrast, tiotropium appears to be more effective than indacaterol if exacerbations are the expected primary outcome. However, as indacaterol/glycopyrronium fixed-dose combination (QVA149) shows superior efficacy compared to glycopyrronium and tiotropium in patients with moderate to severe COPD, a fundamental question regarding the use of indacaterol that requires clarification is whether it is preferable to start immediately with QVA149 rather than using indacaterol alone.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Administration Schedule; Drug Combinations; Glycopyrrolate; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Quinolones; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Evidence-based medicine promotes the current best evidence from clinical trials to guide decisions for individual patients. We assessed whether chronic obstructive pulmonary disease (COPD) patients included in exercise training studies and pharmacologic trials match those from a non-selected COPD target population sample.. Exercise training studies were identified in a literature search. Towards a Revolution in COPD Health (TORCH) and Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) were chosen to represent pharmacologic trials. Burden of Obstructive Lung Disease (BOLD) data were used to characterize target COPD population (BOLD target), defined as the presence of dyspnea (modified Medical Research Council ≥2) and non-reversible airway obstruction (post-bronchodilator FEV1/FVC ≤0.7 and FEV1% predicted ≤70 %).. Overall 240 exercise training studies with 13,901, TORCH and UPLIFT with 12,105, and BOLD with 16,218 participants were evaluated. Males were overrepresented in exercise training studies (67.5%) and pharmacologic trials (TORCH 75.8%; UPLIFT 74.6%), whereas in BOLD target 55.8% were males (p < 0.001). In exercise training studies, 7.2% were never-smokers, 0.0% in TORCH and UPLIFT, but 36.0% in BOLD target (p < 0.001). Subjects with cardiac comorbidity were excluded from 75.4% of exercise training studies, entirely from TORCH and UPLIFT, but comprised 24.5% of BOLD target.. COPD patients recruited in exercise training studies and in pharmacologic trials differ from target population of symptomatic COPD. Females, never-smokers, and patients with cardiac comorbidities are more likely excluded from the clinical trials.

Topics: Aged; Case-Control Studies; Clinical Trials as Topic; Comorbidity; Data Accuracy; Evidence-Based Medicine; Exercise Therapy; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Reproducibility of Results; Sex Factors; Tiotropium Bromide

Tiotropium is generally well tolerated; however, there has been debate whether antimuscarinics, particularly tiotropium administered via Respimat(®) Soft Mist(™) Inhaler, may induce cardiac arrhythmias in a vulnerable subpopulation with cardiovascular comorbidity. The aim of this study was to provide evidence of the cardiac safety of tiotropium maintenance therapy.. Combined analysis of Holter electrocardiogram (ECG) data from clinical trials of tiotropium in chronic obstructive pulmonary disease (COPD). Trials in the Boehringer Ingelheim clinical trials database conducted between 2003 and 2012, involving tiotropium HandiHaler(®) 18 μg and/or tiotropium Respimat(®) (1.25-, 2.5-, 5.0- and 10-μg doses) were reviewed. All trials involving Holter-ECG monitoring during this period were included in the analysis. Men and women aged ≥ 40 years with a smoking history of ≥ 10 pack-years, and a clinical diagnosis of COPD were included. Holter ECGs were evaluated for heart rate (HR), supraventricular premature beats (SVPBs), ventricular premature beats (VPBs) and pauses. Quantitative and categorical end-points were derived for each of the Holter monitoring days.. Four trials (n = 727) were included in the analysis. Respimat(®) (1.25-10 μg) or HandiHaler(®) (18 μg) was not associated with changes in HR, SVPBs, VPBs and pauses compared with placebo or the pretreatment baseline period. In terms of cardiac arrhythmia end-points, there was no evidence for an exposure-effect relationship.. In this analysis, tiotropium maintenance therapy administered using Respimat(®) (1.25-10 μg) or HandiHaler(®) (18 μg) once daily for periods of up to 48 weeks was well tolerated with no increased risk of cardiac arrhythmia in patients with COPD.

Topics: Adult; Aged; Electrocardiography; Female; Heart; Humans; Male; Middle Aged; Muscarinic Antagonists; Patient Safety; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide

Previous studies had demonstrated association between Tiotropium therapy (once-daily inhaled anticholinergic) and reductions of exacerbations, improvements in dyspnoea and quality of life in chronic obstructive pulmonary disease (COPD) patients. Little is known about the influence of adherence to Tiotropium on health-care utilization. Our objective was to examine whether adherence to Tiotropium is associated with decreased health-care utilization.. A computerized medical database was used to identify patients with COPD registered in an academic pulmonology institute who began therapy of Tiotropium 18 mg between 2008 and 2011 (n = 193). Adherence was assessed by calculating the proportion of days covered and defined as coverage of at least 80% of the follow-up period. Adherence to long-acting beta-agonists and/or inhaled corticosteroids (LABA and/or ICS) and health-care utilization were analysed 1 year before and 2 years after initiation of Tiotropium. A multivariate regression model was applied to examine determinants of change in health-care utilization.. The median age of study population was 67 (80% male). Forty-one percent of study population (n = 79) adhered to Tiotropium. Hospitalization costs decreased 1 year following treatment initiation only among adherent patient when their adherence to LABA and/or ICS improved (β = -463.6, P = 0.033). This cost did not change significantly in the consecutive second year (β = 206.3, P = 0.583).. Adherence to Tiotropium was associated with decreased hospitalizations only among patients who improved their adherence to LABA and/or ICS as well. Exploring reasons for high non-adherence and ways to improve adherence may optimize utilization of the scarce hospital resources.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Aged; Cholinergic Antagonists; Delayed-Action Preparations; Female; Health Services; Hospitalization; Humans; Male; Medication Adherence; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Tiotropium Bromide

Inhaled bronchodilators, including long-acting muscarinic receptor antagonists (LAMA) and long-acting β2-adrenoreceptor agonists (LABA), are the mainstay of pharmacological treatment of stable chronic obstructive pulmonary disease (COPD). Among approved LAMA, tiotropium bromide, glycopyrronium bromide, and umeclidinium bromide are administered once daily, whereas aclidinium bromide is administered every 12 h. New LAMA are under development for COPD. Among the approved LABA, indacaterol has a 24 h duration of action, whereas salmeterol and formoterol require twice-daily administration. New once-daily LABA, including vilanterol, olodaterol, milveterol, carmoterol, and abediterol, are in development. LAMA/LABA fixed dose combinations (FDCs) provide the convenience of two bronchodilators with different mechanism of action in a single inhaler. Indacaterol/glycopyrronium, umeclidinium/vilanterol, and olodaterol/tiotropium FDCs have been approved or are under approval and are likely to become a standard pharmacological strategy for COPD. Inhaled dual-pharmacology compounds, combining muscarinic antagonism and β2-agonism (MABA) in a single molecule, potentially provide additive or synergistic bronchodilation over either inhaled antimuscarinic or β2-agonist monotherapy.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Structure-Activity Relationship; Tiotropium Bromide

Tiotropium (Spiriva) is an inhaled muscarinic antagonist for patients with chronic obstructive pulmonary disease (COPD), and is available in two forms: the HandiHaler and the Respimat inhaler. The aim of this study was to investigate the handling of and preference for each device immediately after switching from the HandiHaler to the Respimat and 2-3 years after the switch.. The study comprised two surveys. A questionnaire was first administered to 57 patients with COPD (male:female 52:5, mean age 73.6±7.1 years) 8 weeks after switching from the HandiHaler (18 μg) to the Respimat (5 μg). A second similar but simplified questionnaire was administered to 39 of these patients who continued to use the Respimat and were available for follow-up after more than 2 years. Pulmonary function was also measured during each period.. In the first survey, 17.5% of patients preferred the HandiHaler, and 45.6% preferred the Respimat. There were no significant changes in pulmonary function or in the incidence of adverse events after the switch. In the second survey, performed 2-3 years later, the self-assessed handling of the Respimat had significantly improved, and the number of patients who preferred the Respimat had increased to 79.5%.. The efficacy of the Respimat was similar to that of the HandiHaler. This was clear immediately after the switch, even in elderly patients with COPD who were long-term users of the HandiHaler. The preference for the Respimat increased with continued use.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchodilator Agents; Equipment Design; Female; Forced Expiratory Volume; Health Care Surveys; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Patient Preference; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Topics: Bronchodilator Agents; Chemistry, Pharmaceutical; Humans; India; Patents as Topic; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Topics: Benzoxazines; Bronchodilator Agents; Female; Humans; Male; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Topics: Administration, Inhalation; Advisory Committees; Disease Progression; Drug Therapy, Combination; Female; Fluticasone; Humans; Incidence; Male; Primary Prevention; Prognosis; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome

Long-acting inhaled bronchodilators, including anticholinergic tiotropium, are recommended for the maintenance therapy of chronic obstructive pulmonary disease (COPD). It has been shown in a number of studies that treatment with tiotropium alleviates symptoms, improves exercise tolerance, health status, and reduces exacerbations in patients with moderate to very severe stage COPD.. The aim of this noninterventional study was to observe the early effects of the maintenance treatment with tiotropium in patients with COPD of different severities, who had been previously treated on a regular basis, or as required, with at least one short-acting bronchodilator, in a real-life setting in Poland. The effect of the treatment was assessed through the collection of COPD Assessment Test (CAT) data.. The MATHS clinical study was an observational, noninterventional, open-label, prospective, uncontrolled, single-arm, postmarketing, surveillance, real-life study conducted with the involvement of 236 pulmonology clinics based in Poland. The tiotropium observational period was 3 months. The health and COPD status was measured with the CAT questionnaire. The primary efficacy endpoint was the mean change from the baseline in the total CAT score at the end of the 3-month observational period.. Patients treated with 18 μg of tiotropium once daily for 3 months showed a statistically significant result, with a clinically meaningful mean reduction (improvement) of 7.0 points in the total CAT score. The improvement was slightly greater in patients with more severe COPD; the mean change in the total CAT score was 7.6 in the subgroup of patients with more severe COPD and 6.7 points in the subgroup of patients with moderate COPD.. Results of this real-life study provide further support for the use of tiotropium as a first-line maintenance treatment for patients with COPD of different severities in Poland.

Topics: Aged; Bronchodilator Agents; Cholinergic Antagonists; Female; Health Status; Humans; Lung; Male; Middle Aged; Poland; Product Surveillance, Postmarketing; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Severity of Illness Index; Time Factors; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Administration, Oral; Cholinergic Antagonists; Double-Blind Method; Humans; Oral Sprays; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide

Topics: Humans; Pneumoconiosis; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Bronchial asthma is becoming increasingly prevalent worldwide. Although first-line therapy with inhaled corticosteroids (ICS) with or without long-acting β2 agonists (LABA) has significantly improved the clinical outcomes of asthma, they cannot provide all asthmatics with good control and thus alternatives or add-on drugs are required. Tiotropium is a long-acting muscarinic antagonist that has been used to treat chronic obstructive pulmonary disease and it has been approved for treating asthma in some countries. This agent has similar bronchodilatory effects to those of LABA and might also have anti-inflammatory and anti-remodeling effects.. Some pivotal clinical trials have found tiotropium effective as an add-on medication for low-to-medium doses of ICS for treating symptomatic asthma and asthma that remains uncontrolled despite ICS plus LABA therapy.. Whether or not tiotropium has anti-inflammatory and anti-remodeling effects in humans with asthma is an important issue. Predictors that would identify patients who would derive the maximal potential benefit from treatment with tiotropium in addition to their current therapy are also needed. Although the cardiovascular toxicity of tiotropium is less remarkable in asthma than in chronic obstructive pulmonary disease, longer and larger studies are still needed to confirm the safety of tiotropium for treating asthma.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The study aims at investigating the influence of several factors on the probability of receiving one of the two tiotropium formulations (Respimat or Handihaler).. Drug utilisation study.. All residents in the Region Umbria, Italy, aged ≥45 years, who received prescriptions of tiotropium during 2011-2012.. Two groups of patients were studied: (1) incident users of the two tiotropium formulations (ie, without tiotropium prescriptions in the previous 6 months); (2) switchers from Handihaler to Respimat. Users of the two formulations were compared with regard to baseline characteristics and medical history. The adjusted OR of receiving Respimat was estimated for several factors.. Incident users of the two formulations (4390 participants) had similar characteristics. They were older and with more comorbidities than patients included in randomised control trials (RCTs). Among prevalent users of Handihaler, the probability of switching to Respimat was greater in patients with severe respiratory disease (users of ≥4 respiratory drugs: adjusted OR=4.62; 95% CI 2.46 to 8.69) and among β-blocker users (adjusted OR=1.76; 95% CI 1.13 to 2.75). Age above 75 years and lipid-lowering drug use reduced the probability of switching. A positive association was also found between neurological conditions and the use of Respimat.. When starting tiotropium treatment, the choice between the two formulations is weakly affected by comorbidities and chronic obstructive pulmonary disease severity. Instead, these characteristics influence the likelihood of switching from Handihaler to Respimat. Since tiotropium users in clinical practice are more severe than those included in RCTs, further aetiological studies are needed to compare the safety profile of the two formulations in routine care.

Topics: Administration, Inhalation; Adult; Aged; Bronchodilator Agents; Case-Control Studies; Comorbidity; Drug Administration Schedule; Drug Delivery Systems; Dry Powder Inhalers; Female; Humans; Italy; Male; Middle Aged; Prevalence; Pulmonary Disease, Chronic Obstructive; Risk Factors; Tiotropium Bromide; Treatment Outcome

A new approach to the treatment of COPD includes controlling inflammation because of its important role in exacerbation of the disease. Recently, roflumilast has been added as a therapeutic option for COPD. Roflumilast is an oral phosphodiesterase-4 inhibitor that targets inflammatory cells involved in triggering exacerbations of COPD. The objective of the current study was to evaluate roflumilast for its contribution to phagocytic activity in COPD patients.. Twenty-one patients diagnosed with COPD received roflumilast once daily for 6 months in combination with fluticasone (an inhaled corticosteroid), salmeterol (a long-acting β2-agonist), and tiotropium (a long-acting muscarinic antagonist) or combinations of these agents. The main inclusion criterion was stable disease for at least the previous 30 days. Neutrophils and spirometric changes, ie, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), were measured in the COPD patients at indicated time points. The first sample was taken before receiving roflumilast, the second 3 months later, and the third after 6 months. Examination of defective phagocytosis was done by flow cytometry using a FagoFlowEx(®) kit. The statistical analysis was performed using Statistica software.. Our results indicate that phagocytic activity was increased after 3 and 6 months of treatment when compared with baseline (P<0.001). Similarly, FVC and FEV1 were also increased during the 6-month period, but only FVC differed significantly from baseline (P<0.001).. Although the number of patients in this study was limited, our results indicate that roflumilast induces phagocytic activity, which improves lung function.

Topics: Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aminopyridines; Anti-Inflammatory Agents; Benzamides; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Flow Cytometry; Fluticasone; Forced Expiratory Volume; Greece; Humans; Lung; Muscarinic Antagonists; Phagocytosis; Phosphodiesterase 4 Inhibitors; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Salmeterol Xinafoate; Spirometry; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The anticholinergic properties of the mequitazine enantiomer V0162 make it a drug candidate for the treatment of chronic obstructive airway diseases. Here, we compared V0162's in vitro pharmacological activity at recombinant human M3 muscarinic acetylcholine receptors (hM3Rs) with that of other anticholinergics, using (i) a radioligand binding assay, (ii) a functional reporter gene assay and (iii) a bronchoconstriction inhibition assay on human bronchial preparations. V0162 had high affinity for hM3Rs, with a pKi varying from 9.01 after a 2 h incubation to 9.21 after 23 h. The other mequitazine enantiomer (V0114) was less potent. V0162 displayed rapid off-kinetics and a biphasic time course of binding. V0162 was found to be an antagonist behaving as an inverse agonist for hM3R-mediated reporter gene activation, with much the same efficacy as atropine, ipratropium and tiotropium. However, in contrast to ipratropium and atropine, V0162's inhibitory potency was only slightly affected by compound washout. V0162 antagonized acetylcholine-mediated contractions in a human bronchial preparation; the pA2 values increased with the incubation time (up to 2 h). Moreover, there was a progressive increase in V0162's ability to inhibit electrically-induced contractions, which persisted after compound washout. In conclusion, V0162 is the most active mequitazine enantiomer at hM3Rs and shows a complex pattern of binding to the membrane compartment. These particular features may be of therapeutic value when persistent antagonism at hM3Rs is required.

Topics: Acetylcholine; Aged; Animals; Atropine; Bronchi; Bronchoconstriction; Bronchodilator Agents; CHO Cells; Cricetulus; Female; Genes, Reporter; Humans; Ipratropium; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Tiotropium Bromide

Topics: Benzoxazines; Delayed-Action Preparations; Drug Combinations; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

The objective of this study was to compare the cost effectiveness of once-daily Seebri Breezhaler(®) (glycopyrronium bromide) 50 µg with Spiriva(®) (tiotropium bromide) 18 µg in the maintenance treatment of chronic obstructive pulmonary disease (COPD) in the Swedish setting.. A previously published COPD Markov model accounting for disease progression and treatment discontinuation was used. Disease progression included the annual decline in forced expiratory volume in the first second (FEV1) and occurrence of any exacerbations. Efficacy in the model consisted of FEV1 improvement between baseline and 12 weeks and the annual risk ratio of having an exacerbation compared to placebo. These clinical efficacy inputs were derived from a 1-year head-to-head trial comparing glycopyrronium 50 µg to tiotropium 18 µg. Utility values and cost estimates were obtained from the literature. The base-case analysis was performed for a 3-year time horizon. Cost and effects were discounted with 3% in accordance to Swedish guidelines. Uncertainty was assessed by one-way and probabilistic sensitivity analyses.. Glycopyrronium was found to be less costly and more effective than tiotropium in moderate to severe COPD patients with cost savings of 5197 Swedish kronor (€570, US$725) per patient over a 3-year time horizon. The probabilistic sensitivity analysis indicated that over 99% of the iterations produced dominant results for glycopyrronium.. Glycopyrronium bromide 50 µg once daily can be considered a cost effective alternative to tiotropium bromide 18 µg once daily in the maintenance treatment of COPD patients in Sweden.

Topics: Bronchodilator Agents; Cost-Benefit Analysis; Female; Forced Expiratory Volume; Glycopyrrolate; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Sweden; Tiotropium Bromide

To assess, using a standard observational tool, the ability of patients to demonstrate and maintain proper inhaled medication administration techniques following pharmacist education.. Six-month observational study.. Patients' homes or adult day health center.. Patients in a Program for All-inclusive Care for the Elderly (PACE) prescribed one or more inhaled medications used at least once daily.. Instruction by on-site clinical pharmacist.. Hickey's Pharmacies Inhaler Technique assessment (score range: 0-20, higher better).. Forty-two patients were evaluated at baseline, taught proper techniques for using inhaled medications, assessed immediately following the education, and re-assessed 4-6 weeks later. The mean pre-assessment score was 14 (SD 4.5, range 0-20), the initial post-assessment score increased to 18 (SD 3, range 10-20). The second post-assessment (4-6 weeks later) score mean was 17.7 (SD 3, range 10-20). Both follow-up scores were significantly improved from baseline (p < 0.05). Multivariable analysis indicated the strongest predictors of second post-training score were: score after initial pharmacist training and being subscribed to auto-refill. These characteristics predicted ∼70% of the variance in the second score (p < 0.001).. These results indicate that education by a pharmacist combined with an auto-refill program can improve and sustain appropriate inhaler use by community-dwelling elders in a PACE program. The improved score was maintained 4-6 weeks later indicating a sustained benefit of medication administration education. Optimal inhaler use ensures optimal dosing and supports appropriate inhaler treatment in lieu of oral agents.

Topics: Administration, Inhalation; Adult Day Care Centers; Age Factors; Aged; Aged, 80 and over; Asthma; Bronchodilator Agents; Drug Delivery Systems; Female; Fluticasone-Salmeterol Drug Combination; Humans; Independent Living; Male; Middle Aged; Nebulizers and Vaporizers; Outcome Assessment, Health Care; Patient Education as Topic; Pharmacists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Inhaled corticosteroid/long-acting β2-agonist combinations and/or long-acting muscarinic antagonists are recommended first-line therapies for preventing chronic obstructive pulmonary disease (COPD) exacerbation. Comparative effectiveness of budesonide/formoterol combination (BFC, an inhaled corticosteroid/long-acting β2-agonist combination) vs tiotropium (long-acting muscarinic antagonist) in the US has not yet been studied.. Using US claims data from the HealthCore Integrated Research Environment, COPD patients (with or without comorbid asthma) ≥40 years old initiating BFC or tiotropium between March 1, 2009 and February 28, 2012 and at risk for exacerbation were identified and followed for 12 months. Patients were propensity score matched on demographics and COPD disease severity indicators. The primary outcome was time to first COPD exacerbation. Secondary outcomes included COPD exacerbation rate, health care resource utilization, and costs.. The Cox proportional hazards model for time to first exacerbation yielded a hazard ratio (HR) of 0.78 (95% CI =[0.70, 0.87], P<0.001), indicating a 22% reduction in risk of COPD exacerbation associated with initiation of BFC versus tiotropium. A post hoc sensitivity analysis found similar effects in those who had a prior asthma diagnosis (HR =0.72 [0.61, 0.86]) and those who did not (HR =0.83 [0.72, 0.96]). BFC initiation was associated with lower COPD-related health care resource utilization and costs ($4,084 per patient-year compared with $5,656 for tiotropium patients, P<0.001).. In COPD patients new to controller therapies, initiating treatment with BFC was associated with improvements in health and economic outcomes compared with tiotropium.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Asthma; Bronchodilator Agents; Budesonide; Comorbidity; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Health Care Costs; Hospitalization; Humans; Insurance Claim Reporting; Male; Middle Aged; Muscarinic Antagonists; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a β2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.

Topics: Adrenergic beta-2 Receptor Agonists; Animals; Biological Availability; Bronchoconstriction; Bronchodilator Agents; CHO Cells; Cricetulus; Dogs; Humans; Ipratropium; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Rats; Receptor, Muscarinic M3; Salmeterol Xinafoate; Tiotropium Bromide; Triazoles

INFLOW (INdacaterol eFfectiveness and utiLizatiOn in COPD: real World evaluation) was a prospective, noninterventional study assessing the effectiveness and safety of long-acting bronchodilators in patients with chronic obstructive pulmonary disease (COPD) from the Middle East, Asia, and South Africa.. Patients newly prescribed or switched to indacaterol or other long-acting β2-agonist (LABA), or tiotropium (monotherapy or in combination) were evaluated over 6 months. The primary endpoint was the clinical COPD questionnaire overall score at the end of the study.. Data were analyzed from 1,710 patients (mean postbronchodilator forced expiratory volume in 1 second, 59% predicted) who received indacaterol (n=1,179), other LABA (n=68), tiotropium (n=271), indacaterol plus tiotropium (n=167), or other LABA plus tiotropium (n=25). Across treatments, clinical COPD questionnaire overall score improved from baseline by 0.81-1.26 points (all P<0.0001), 63%-84% of patients were satisfied/very satisfied, and physicians rated effectiveness as good/very good in 63%-80% of cases. The indacaterol inhaler was rated easy/very easy to use by the majority of patients, and physicians considered its use clearly understood by most patients. All treatments had acceptable tolerability.. In real life clinical practice across a diverse region, indacaterol and other long-acting bronchodilators improved health status and were well regarded by patients and physicians.

Topics: Administration, Inhalation; Adult; Africa; Aged; Asia; Bronchodilator Agents; Delayed-Action Preparations; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Quinolones; Tiotropium Bromide; Treatment Outcome

Tiotropium failed to slow the annual rate of forced expiratory volume in 1 second (FEV1) decline in chronic obstructive pulmonary disease (COPD) patients with <70% predicted FEV1. However, the rate of FEV1 decline is known to be faster at early stages, which suggests that the effects of tiotropium may be more prominent in early-stage of COPD patients. The aim of this study was to test the hypothesis that tiotropium modifies the rate of FEV1 decline in COPD patients with an FEV1≥70%.. We retrospectively reviewed the records of COPD patients diagnosed between January 1, 2004, and July 31, 2012, at Seoul National University Hospital, Seoul National University Bundang Hospital, and Seoul Metropolitan Government-Seoul National University Boramae Medical Center. The inclusion criteria were as follows: age ≥40 years, postbron-chodilator (BD) FEV1≥70% of predicted and FEV1/FVC (forced vital capacity) <0.70, and spirometry more than two times at certain times of the year. Conversely, the exclusion criteria were as follows: asthma, lung cancer, pulmonary tuberculosis, pulmonary resection, or long-term use of a short-acting muscarinic antagonist. The annual lung function decline in patients using tiotropium was compared with that in patients not using the drug.. Of the 587 patients enrolled in the study, 257 took tiotropium. Following propensity score matching, 404 patients were included in the analysis. The mean annual rate of post-BD FEV1 decline was 23.9 (tiotropium) and 22.5 (control) mL/yr (P=0.86); corresponding pre-BD values were 30.4 and 21.9 mL/yr (P=0.31), respectively. Mean annual rate of post-BD FVC decline was 55.1 (tiotropium) and 43.5 (control) mL/yr (P=0.33); corresponding pre-BD values were 37.1 and 33.3 mL/yr (P=0.13).. Therefore, tiotropium does not reduce the rate of lung function decline in COPD patients with FEV1≥70%.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Female; Humans; Male; Middle Aged; Patient Acuity; Prognosis; Propensity Score; Pulmonary Disease, Chronic Obstructive; Republic of Korea; Respiratory Function Tests; Retrospective Studies; Tiotropium Bromide; Treatment Outcome

A combination of long-acting anticholinergic agents (LAACs) and long-acting β2-adrenergic receptor agonist (LABA) is effective in improving lung function in chronic obstructive pulmonary disease (COPD) compared with monotherapy. However, evidence on whether this combination increases the incidence of stroke or other cardiac events remains sparse. The objective of the present study was to investigate the incidence of stroke and other cardiovascular diseases in COPD patients treated with LAAC, LABA, or a combination of the 2.We conducted this population-based study using the Taiwan National Health Insurance Research Database (1997-2008), identifying COPD patients and their prescribed medication from the International Classification of Disease, Ninth Revision codes 490-492 or 496. A multivariate Cox proportional-hazards model was used to compare the risk of stroke and other cardiovascular diseases over the 11-year period after treatment with LAAC or LABA only or in combination.Of the 596 COPD patients (mean age 70 y), 196 were treated with LAAC, 318 with LABA, and 82 were treated with a combination. The overall incidence of stroke (8.53%) significantly increased in the combination group compared with LAAC (2.04%) or LABA (1.26%) only. In the Cox regression analysis, the adjusted hazard ratio over the 11-year survey period for stroke in patients treated with the combination compared with LABA only was 1.04 (95% confidence interval, 1.06-2.99) and for LAAC, it was 0.31 (95% confidence interval, 0.02-2.32).This cohort study using a large health insurance database showed that treating patients with COPD, with a combination of LAAC and LABA, may be associated with an increased hazard of stroke compared with treatment with either agent alone. We should be particularly cautious about comedication of LAAC and LABA in patients with COPD.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide, Formoterol Fumarate Drug Combination; Cardiovascular Diseases; Cholinergic Antagonists; Cohort Studies; Delayed-Action Preparations; Drug Combinations; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Stroke; Taiwan; Tiotropium Bromide

COPD is the fourth leading cause of death in the world. In the case of exacerbations or persistent symptoms, regular treatment with long-acting bronchodilators is recommended to control the symptoms, reduce exacerbations and improve health status. Objectives. To describe patterns of drug utilization among patients diagnosed with COPD, to measure continuity with long-acting bronchodilators, to identify determinants of not receiving long-acting therapy continuously.. We identified a cohort of patients discharged from hospital with diagnosis of COPD between 2006 and 2008. Patients were observed for a two-year follow-up period, starting from the day of discharge. Follow-up was segmented in six-month periods, in order to dynamically evaluate prescription patterns of Long-Acting Beta-Agonists (LABA), tiotropium, and inhaled corticosteroids. Patients with prescriptions for LABA and/or tiotropium in each of the six-month periods were defined as "continuously treated with long-acting bronchodilators." The degree of drug treatment coverage was measured through the Medication Possession Ratio (MPR). Logistic regression was performed to identify determinants of not receiving long-acting bronchodilators continuously.. A total of 11,452 patients diagnosed with COPD were enrolled. Only 34.8% received long-acting bronchodilators continuously. The MPR was greater than 75% in 19.6% of cases. Among the determinants of not receiving long-acting bronchodilators continuously, older age and co-morbidities played an important role.. In clinical practice, the COPD pharmacotherapy is not consistent with clinical guidelines. Medical education is needed to disseminate evidence-based prescribing patterns for COPD, and to raise awareness among physicians and patients on the health benefits of an appropriate pharmacological treatment.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Age Factors; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Bronchodilator Agents; Comorbidity; Delayed-Action Preparations; Drug Combinations; Drug Prescriptions; Drug Therapy, Combination; Female; Humans; Male; Medication Adherence; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Albuterol; Bronchodilator Agents; Female; Humans; Male; Polymorphism, Genetic; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Diffusion of Innovation; Drug Discovery; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

T-lymphocytes, including Th17-cells and T-cells expressing acetylcholine (ACh), are key components of systemic inflammation in chronic obstructive pulmonary disease (COPD). We investigated whether ACh promotes Th17 cells in COPD. ACh, IL-17A, IL-22, RORγt, FOXP3 expression and AChIL-17A, AChIL-22, AChRORγt coexpression was evaluated in peripheral blood mononuclear cells (PBMC) from COPD patients (n=16), healthy smokers (HS) (n=12) and healthy control subjects (HC) (n=13) (cultured for 48 h with PMA) by flow cytometry. Furthermore, we studied the effect of Tiotropium (Spiriva®) (100 nM) and Olodaterol (1nM) alone or in combination, and of hemicholinium-3 (50 μM) on AChIL-17A, AChIL-22, AChRORγt, and FOXP3 expression in CD3+PBT-cells of PBMC from COPD patients (n=6) cultured for 48 h with PMA. CD3+PBT-cells expressing ACh, IL-17A, IL-22 and RORγt together with CD3+PBT-cells co-expressing AChIL-17A, AChIL-22 and AChRORγt were significantly increased in COPD patients compared to HC and HS subjects with higher levels in HS than in HC without a significant difference. CD3+FOXP3+PBT-cells were increased in HS than in HC and COPD. Tiotropium and Olodaterol reduced the percentage of CD3+PBT-cells co-expressing AChIL-17A, AChIL-22, and AChRORγt while increased the CD3+FOXP3+PBT-cells in PBMC from COPD patients, cultured in vitro for 48 h, with an additive effect when used in combination. Hemicholnium-3 reduced the percentage of ACh+IL-17A+, ACh+IL-22+, and ACh+RORγt+ while it did not affect FOXP3+ expression in CD3+PBT-cells from cultured PBMC from COPD patients. We concluded that ACh might promote the increased levels of Th17-cells in systemic inflammation of COPD. Long-acting β2-agonists and anticholinergic drugs might contribute to control this event.

Topics: Acetylcholine; Aged; Aged, 80 and over; Benzoxazines; Cholinergic Antagonists; Female; Forkhead Transcription Factors; Humans; Interleukin-17; Interleukin-22; Interleukins; Intracellular Space; Leukocytes, Mononuclear; Male; Middle Aged; Nuclear Receptor Subfamily 1, Group F, Member 3; Pulmonary Disease, Chronic Obstructive; Risk Factors; Scopolamine Derivatives; Th17 Cells; Tiotropium Bromide

Topics: Bronchodilator Agents; Humans; Meta-Analysis as Topic; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Review Literature as Topic; Scopolamine Derivatives; Tiotropium Bromide

Recent trends in prescriptions for medicines used to treat chronic obstructive pulmonary disease (COPD) in the United States have received little attention. Our objective was to examine trends in prescribing practices for medications used to treat COPD. We examined data from surveys of national samples of office visits to non-federal employed office-based physicians in the United States by patients aged ≥40 years with COPD recorded by the National Ambulatory Medical Care Survey from 1999 to 2010. From three diagnostic codes, office visits by patients with COPD were identified. Prescribed medications were identified from up to 8 recorded medications. The percentage of these visits during which a prescription for any medication used to treat COPD was issued increased from 27.0% in 1999 to 49.1% in 2010 (p trend < 0.001). Strong increases were noted for short-acting beta-2 agonists (17.6% in 1999 to 24.7% in 2010; p trend < 0.001), long-acting beta-2 agonists as single agents or combination products (6.2% in 1999 to 28.3% in 2010; p trend < 0.001), inhaled corticosteroids as single agents or combination products (10.9% in 1999 to 30.9% in 2010; p trend < 0.001), and tiotropium (3.8% in 2004 to 17.2% in 2010; p trend < 0.001). Since 1999, prescription patterns for medicines used to treat COPD have changed profoundly in the United States.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Delayed-Action Preparations; Drug Combinations; Drug Prescriptions; Drug Utilization; Female; Health Care Surveys; Humans; Ipratropium; Male; Middle Aged; Office Visits; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; United States; Xanthines

The majority of deaths in COPD are from cardiovascular causes. Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events, including cardiovascular mortality. Tiotropium Respimat is associated with a statistically significant increased risk of mortality (RR 1.52; 95% CI 1.06 to 2.16) and cardiovascular death (RR 2.05; 95% CI 1.06 to 3.99) compared with placebo in a meta-analysis of clinical trials. In the largest study, the subgroup of patients with COPD in the Respimat group with known rhythm and cardiac disorders at baseline had an especially high risk for cardiac death (RR 8.6; 95% CI 1.1 to 67.2). Although there was no significantly increased risk of mortality (HR 0.89; 95% CI 0.79 to 1.02) or myocardial infarction (MI) (RR 0.73; 95% CI 0.53 to 1.00) with tiotropium handihaler in the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, the reported excess of angina (RR 1.44; 95% CI 0.91 to 2.26), imbalance in strokes related to ischaemia and rates of supraventricular tachyarrhythmias are consistent with the pro-ischemic and pro-arrhythmic effects. The subjects at greatest risk of cardiovascular death, such as those with a recent history of MI, unstable or life-threatening cardiac arrhythmias or hospitalisation with heart failure, were excluded from the UPLIFT trial. The Prevention of Exacerbations with Tiotropium in COPD trial showed an excess of serious coronary ischaemic events of angina, myocardial ischaemia and MI with the tiotropium Handihaler compared with salmeterol. The authors urge caution in prescribing inhaled anticholinergics for patients with pre-existing arrhythmias or cardiac disorders.

Topics: Administration, Inhalation; Cholinergic Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Ipratropium; Male; Myocardial Infarction; Myocardial Ischemia; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Scopolamine Derivatives; Stroke; Tiotropium Bromide

Poor adherence to treatment may contribute to the treatment gap in chronic obstructive pulmonary diseases (COPD). The aim of the current study was to describe the association between adherence to treatment and the risk of COPD moderate (ME) and severe (SE) exacerbations, and health care utilization.. Observational single cohort study utilizing the Quebec Provincial Health Insurance databases. All patients older than 40 years with a diagnosis of COPD between 2001 and 2010 were entered in the study cohort at the time of their first prescription for tiotropium (TIO) alone or co-administered with fluticasone propionate/salmeterol (TIO + FSC). Follow-up continued to the last known claim or death. Adherence was measured by the medication possession ratio (MPR) ≥80% and persistence defined as no treatment gap ≥30 days.. ME was defined as use of an oral corticosteroid or antibiotic, SE as COPD related hospitalization or an emergency room (ER) visit. COPD related health care resource utilization ascertained was prescription of rescue medications, ER visits, hospitalizations, intensive care unit (ICU) admissions, intubations, and general practitioner (GP) and respirologist visits.. There were 23,707 patients included in this study. Compliance and persistence with TIO for monotherapy patients were 61.1% and 47.6% respectively. For patients treated with TIO + FSC, compliance and persistence for TIO were 62.9% and 45.3% respectively, and for FSC they were 35.4% and 33.0%. Multivariate analyses showed a significant (P < 0.001) adjusted odds ratios for ME (OR(ME)) and SE (OR(SE)) for TIO compliant vs. non-compliant patients (TIO: OR(ME) = 0.543, OR(SE) = 0.712; TIO + FSC: OR(ME) = 0.436, OR(SE) = 0.570). Similarly for FSC compliance: OR(ME) = 0.546; OR(SE) = 0.749. Similar results were observed for persistence. Compliance and persistence with TIO and FSC were associated with significantly reduced rates of health care utilization.. Despite the typical limitations of an administrative database study, the results of this large population-based study have shown that reduced adherence to treatment with TIO and FSC is associated with increased risk for exacerbations and higher health care utilization in COPD patients.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; Disease Progression; Drug Combinations; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Follow-Up Studies; Glucocorticoids; Health Services; Humans; Male; Medication Adherence; Middle Aged; Multivariate Analysis; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Quebec; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Aminopyridines; Benzamides; Bronchodilator Agents; Cyclopropanes; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Multicenter Studies as Topic; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

Topics: Benzyl Alcohols; Chlorobenzenes; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Drug Chronotherapy; Germany; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide; Tropanes

To compare clinical and demographic characteristics, resource utilization and costs of chronic obstructive pulmonary disease (COPD) patients prior to initiating budesonide-formoterol combination (BFC) or tiotropium-maintenance therapy.. This cross-sectional study used claims-based diagnosis to identify COPD patients in the HealthCore Integrated Research Database who initiated BFC or tiotropium therapy between March 1, 2009 and January 31, 2012 (intake period); the index date was defined as the initial prescription fill for either agent. Patients diagnosed with respiratory tract cancer or receiving inhaled corticosteroids/long-acting β2-adrenergic agonists or tiotropium in 12 months prior to index date were excluded. Categorical variables were evaluated with χ(2) tests; mean cost differences were evaluated using γ-regression.. Overall, 6,940 BFC and 10,831 tiotropium patients were identified. The BFC group was younger (mean age 64 versus 67 years), with a greater proportion of females (54% versus 51%). BFC-treated patients had more comorbid respiratory conditions, including asthma (25% versus 13%), but fewer comorbid cardiovascular conditions, including atherosclerosis (7% versus 10%) and myocardial infarction (4% versus 6%). A greater proportion of BFC patients received prior respiratory medication, including oral corticosteroids (46% versus 35%) and short-acting β2-agonists (44% versus 35%). Tiotropium-treated patients had a greater mean number of COPD-related outpatient visits (4.6 versus 4.1). BFC-treated patients had lower total all-cause ($17,259 versus $17,926) and COPD-related ($1,718 versus $1,930) health care costs, driven by lower all-cause and COPD-related inpatient expenditures.. Initiators of BFC or tiotropium showed differences in clinical and demographic characteristics and health care utilization and costs prior to starting COPD maintenance therapy.

Topics: Adrenergic beta-2 Receptor Agonists; Adult; Age Factors; Aged; Bronchodilator Agents; Budesonide; Chi-Square Distribution; Cholinergic Antagonists; Comorbidity; Cross-Sectional Studies; Data Mining; Databases, Factual; Drug Combinations; Drug Costs; Ethanolamines; Female; Formoterol Fumarate; Glucocorticoids; Health Expenditures; Humans; Male; Middle Aged; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sex Factors; Time Factors; Tiotropium Bromide; Treatment Outcome; United States

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Female; Fluticasone; Glucocorticoids; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lung associated with progressive airflow limitation. The aim of this study is to assess the influence of tiotropium treatment on airway inflammation and symptoms in stable COPD patients.. Inflammatory markers were measured in the expired breath condensate fluid (EBC) before starting tiotropium treatment and at the end of the first month.. Twenty-two patients (81% men) with a mean age of 65.4 ± 10.1 years completed the study. The mean nitrotyrosine and 8-isoprostane levels for oxidative stress markers in EBC before and after treatment were 4.5 ± 2.3, 3.5 ± 1.9 pg/mL (P = 0.06) and 7.3 ± 10.8, 8.1 ± 11.7 pg/mL (P = 0.28), respectively. The mean interleukin-6 and tumor necrosis factor-alpha levels for inflammation markers in EBC before and after treatment were 1.03 ± 1.1, 0.77 ± 0.8 pg/mL (P = 0.41) and 27.8 ± 2.6, 29.2 ± 5.7 pg/mL (P = 0.36) respectively. The mean symptom scores decreased significantly with tiotropium and a mean increase of 124.6 ± 0.86 mL was observed in a lung function test (FEV1).. Although a 4-week treatment with tiotropium did not modify any of the inflammatory or oxidative stress markers in EBC fluid, tiotropium treatment helps to control symptoms in COPD.

Topics: Aged; Bronchodilator Agents; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

In the model of chronic obstructive pulmonary disease, produced in rats by 60-day exposure to nitrogen dioxide, the effect of different options of combination therapy (corticosteroids, anticholinergics, adrenergic agonists) on the functional state of the bronchi was studied. The contractile activity of strips of the bronchi caused by nerve or smooth muscle stimulation was evaluated. Corticosteroid monotherapy resulted in deterioration of the functional state of the bronchial wall neuromuscular apparatus due to corticosteroid resistance, evolving under the influence of long-term exposure to nitrogen dioxide. Application of M-anticholinergic tiotropium had a beneficial effect on the functional state of the bronchi smooth muscles, leading to the full restoration of the bronchial wall contractile activity and removal the morphological manifestations of inflammatory lung tissue remodeling. Most effective in terms of impact on the functional state of the bronchial wall neuromuscular apparatus was corticosteroid therapy combined with M-cholinolytik or beta2-adrenoagonist.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Animals; Bronchoconstriction; Cholinergic Antagonists; Disease Models, Animal; Male; Pulmonary Disease, Chronic Obstructive; Rats; Scopolamine Derivatives; Tiotropium Bromide

A new diagnosis of chronic obstructive pulmonary disease is often made during the evaluation of patients requiring lung cancer surgery. The objective of the present study was to evaluate the clinical effects of inhaled tiotropium on the postoperative cardiopulmonary complications in patients with untreated chronic obstructive pulmonary disease requiring lung cancer surgery.. A retrospective study involving 104 consecutive patients with moderate to severe chronic obstructive pulmonary disease who underwent a lobectomy for lung cancer at two specialized thoracic centers between April 2008 and October 2011 was performed. The results were compared between patients who did and did not receive inhaled tiotropium during the perioperative period. The primary endpoint was the incidence of postoperative cardiopulmonary complications. The postoperative white blood cell counts and C-reactive protein levels as biomarkers of inflammation were also examined.. The incidence of postoperative cardiopulmonary complications was significantly lower in the tiotropium group than in the control group (18 vs. 48 %, P = 0.001). Patients in the tiotropium group also showed significantly lower white blood cell counts and C-reactive protein levels postoperatively.. Inhaled tiotropium treatment during the perioperative period had a prophylactic effect on postoperative cardiopulmonary complications in patients with newly diagnosed chronic obstructive pulmonary disease requiring lung cancer surgery.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cardiovascular Diseases; Female; Humans; Lung Neoplasms; Male; Middle Aged; Perioperative Care; Pneumonectomy; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Respiration Disorders; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide

A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.

Topics: Administration, Inhalation; Animals; Bronchoconstriction; Cycloheptanes; Disease Models, Animal; Guinea Pigs; Humans; Molecular Structure; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Albuterol; Asthma; Ethanolamines; Forecasting; Formoterol Fumarate; Glucocorticoids; Humans; Mometasone Furoate; Muscarinic Antagonists; Pregnadienediols; Pregnenediones; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Guidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms.. A post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 μg) and open-label tiotropium (18 μg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = 'less dyspnoea'; scores ≥2 = 'more dyspnoea'). Outcomes were assessed after 26 weeks.. The analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose ('trough') forced expiratory volume in 1 s (FEV1), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV1 and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV1, TDI and SGRQ total scores at week 26; indacaterol 300 μg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV1, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated.. In patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 μg may be a useful treatment option for patients with COPD who experience more severe breathlessness.

Topics: Bronchodilator Agents; Delayed-Action Preparations; Dose-Response Relationship, Drug; Dyspnea; Forced Expiratory Volume; Humans; Indans; Patient Acuity; Pulmonary Disease, Chronic Obstructive; Quinolones; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

In the treatment of chronic obstructive pulmonary disease (COPD), tiotropium bromide has a longer duration of action than ipratropium bromide; however, tiotropium bromide is a more expensive alternative treatment. At issue is whether tiotropium reduces the risk for hospital readmissions for COPD compared with ipratropium.. A population-based cohort study was conducted to assess whether tiotropium reduces the risk for hospital readmissions for COPD compared with ipratropium.. British Columbia (BC) linked provincial administrative health databases were used to identify new patients with COPD (aged ≥45 years) with a first hospital admission for COPD from 2003 to 2011. The study period was defined as the 30-day tiotropium or ipratropium treatment-initiation period after hospital discharge. Patients were followed up for ≤6 months from drug initiation to hospital readmission for COPD. In a subanalysis, the 2 treatment groups were matched on age, sex, and high-dimensional propensity scores derived from 200 empirically identified and predefined covariates. The risk for hospital readmission was estimated using multivariate Cox proportional hazards and logistic regression analyses.. In total, 3723 patients with COPD were dispensed tiotropium (n = 992) or ipratropium (n = 2731) within 30 days from the index hospital admission for COPD. The mean age of these patients was 72.8 years, and 50.8% were women. Tiotropium-treated patients were more likely to be in a higher income category and were more likely to use a greater number of medications compared with ipratropium-treated patients. Among the subset of 1500 matched patients, 215 (14.3%) were readmitted to hospital within 6 months. There was no statistically significant group difference in hospital readmissions using either analytical approach (hazard ratio = 0.98 [95% CI, 0.72-1.34]; odds ratio = 0.97 [95% CI, 0.70-1.36]).. In this select group of patients, neither tiotropium nor ipratropium was effective in significantly decreasing the risk for rehospitalization for COPD within 6 months.

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Cohort Studies; Female; Humans; Ipratropium; Male; Middle Aged; Patient Readmission; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium, a long-acting anticholinergic, is delivered via HandiHaler or via Respimat. Randomised controlled trials suggest that use of tiotropium Respimat increases the risk of dying. We compared the risk of mortality between tiotropium Respimat versus HandiHaler. Within the Integrated Primary Care Information database, we defined a source population of patients, aged ≥ 40 years, with ≥ 1 year of follow-up. Based on prescription data, we defined episodes of tiotropium use (Respimat or HandiHaler). The risk of mortality, within these episodes, was calculated using a Cox proportional hazard regression analysis. From the source population, 11 287 patients provided 24 522 episodes of tiotropium use. 496 patients died while being exposed to HandiHaler or Respimat. Use of Respimat was associated with almost 30% increased risk of dying (adjusted HR 1.27, 95% CI 1.03-1.57) with the highest risk for cardiovascular/cerebrovascular death (adjusted HR 1.56, 95% CI 1.08-2.25). The risk was higher in patients with co-existing cardiovascular disease (adjusted HR 1.36, 95% CI 1.07-1.73) than in patients without (adjusted HR 1.02, 95% CI 0.61-1.71). Use of tiotropium Respimat was associated with an almost 30% increase of mortality compared with HandiHaler and the association was the strongest for cardiovascular/cerebrovascular death. It is unclear whether this association is causal or due to residual confounding by chronic obstructive pulmonary disease severity.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cohort Studies; Databases, Factual; Drug Delivery Systems; Dry Powder Inhalers; Female; Humans; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Chronic Obstructive Pulmonary Disease (COPD) is a chronic, progressive disease that is not curable. However, there are effective treatments available. In the UK, long-acting bronchodilators are first-line treatments for COPD patients requiring maintenance therapy, and there are several options available. The aim of this study is to establish, from the UK National Health Service (NHS) perspective, the cost-effectiveness profile of indacaterol, the first once-daily long-acting beta2-agonist (LABA), compared with tiotropium and salmeterol, in patients with moderate to severe COPD. In assessing the cost-effectiveness of COPD therapies, this study has the advantage of using real world evidence on the resource use associated with COPD management across the spectrum of the disease.. A Markov model was developed with four health states following the GOLD classification for severity of airflow limitation. The model time horizon was 3 years, and the cycle length was 3 months. From each state, patients could experience a severe or non-severe exacerbation, move to a different COPD state, remain in the current state or die. Transition probabilities were based on data from the indacaterol clinical trials. The majority of the resource use data was taken from the Optimum Patient Care Research Database (OPCRD), which contains data from over 20,000 COPD patients in England and Scotland. Cost data were taken from UK-based sources and published literature and presented for the cost year 2011. Health-related quality of life was the main outcome of interest and utility data for the COPD states were based on data from the indacaterol clinical trials and disutility due to exacerbations were taken from the literature. Both one way and probabilistic sensitivity analyses were performed to test the robustness of the results.. Indacaterol dominated in the comparison with salmeterol producing an incremental QALY gain of 0.008 and cost savings of £110 per patient over a 3-year time horizon. In the comparison with tiotropium over the same time horizon, indacaterol remained the dominant strategy, producing an incremental QALY gain of 0.008 and cost savings of £248 per patient. The one-way sensitivity analysis indicates that the proportion of patients in each of the COPD stages and the mortality rate associated with Very Severe COPD are the variables with the largest impact on the results. The probabilistic sensitivity analyses showed that over 72 % and 89 % of the iterations when compared with salmeterol and tiotropium, respectively, produced dominant results for indacaterol.. The analyses demonstrate that indacaterol dominates both tiotropium and salmeterol in the base case and is likely to remain cost-effective under a range of assumptions.

Topics: Aged; Albuterol; Bronchodilator Agents; Cost-Benefit Analysis; Drug Administration Schedule; Drug Costs; Female; Humans; Indans; Male; Markov Chains; Middle Aged; Models, Economic; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; United Kingdom

Topics: Bronchodilator Agents; Cholinergic Antagonists; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is a common and deadly disease. Long-acting inhaled β-agonists and anticholinergics, first-line medications for COPD, have been associated with increased risk of cardiovascular outcomes. When choosing between the medications, patients and physicians would benefit from knowing which has the least risk.. To assess the association of these classes of medications with the risk of hospitalizations and emergency department visits for cardiovascular events.. We conducted a nested case-control analysis of a retrospective cohort study. We compared the risk of events between patients newly prescribed inhaled long-acting β-agonists and anticholinergics, after matching and adjusting for prognostic factors.. Health care databases from Ontario, the largest province of Canada, with a multicultural population of approximately 13 million.. All individuals 66 years or older meeting a validated case definition of COPD, based on health administrative data, and treated for COPD from September 1, 2003, through March 31, 2009.. New use of an inhaled long-acting β-agonist or long-acting anticholinergic.. An emergency department visit or a hospitalization for a cardiovascular event.. Of 191 005 eligible patients, 53 532 (28.0%) had a hospitalization or an emergency department visit for a cardiovascular event. Newly prescribed long-acting inhaled β-agonists and anticholinergics were associated with a higher risk of an event compared with nonuse of those medications (respective adjusted odds ratios, 1.31 [95% CI, 1.12-1.52; P < .001] and 1.14 [1.01-1.28; P = .03]). We found no significant difference in events between the 2 medications (adjusted odds ratio of long-acting inhaled β-agonists compared with anticholinergics, 1.15 [95% CI, 0.95-1.38; P = .16]).. Among older individuals with COPD, new use of long-acting β-agonists and anticholinergics is associated with similar increased risks of cardiovascular events. Close monitoring of COPD patients requiring long-acting bronchodilators is needed regardless of drug class.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Case-Control Studies; Cholinergic Antagonists; Cohort Studies; Female; Heart Failure; Humans; Male; Monitoring, Physiologic; Ontario; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Risk Assessment; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The findings of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) study may be poorly generalisable to tiotropium use in clinical practice.. An audit of 226 patients admitted to Wellington Hospital with a chronic obstructive pulmonary disease exacerbation determined the proportion of patients prescribed tiotropium on discharge that would have been ineligible for inclusion in the UPLIFT study.. Among 100 patients prescribed tiotropium, 38/100; 38% (95% CI 28.5% to 48.3%) would have been ineligible for UPLIFT at the time of the hospital discharge due to recent cardiovascular comorbidity or moderate to severe renal impairment.. The UPLIFT findings have limited generalisability to over a third of patients prescribed tiotropium following a hospital admission with a chronic obstructive pulmonary disease exacerbation in New Zealand.

Topics: Administration, Inhalation; Bronchodilator Agents; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is the only major disease with increasing death rate. In COPD, progressive reduction in quality of life is closely related to the increasing limitation of airflow due to chronic bronchitis, cell hyperplasia, fibrosis, and irreversible lung damage. Signaling pathways involved in inflammatory processes in COPD and inflammatory response to therapy are unknown. Our aim was to isolate cells from induced sputum of COPD patients treated with formoterol or formoterol + tiotropium and assess enzymatic activity of histone deacetylases (HDACs) acetylated histone 4 (AcH4) and expression of inducible nitric oxide synthase (iNOS). HDACs are important in signal transduction and inflammation. iNOS is generating nitric oxide (NO) relevant to blood pressure regulation, inflammation and infections. Thirty stable COPD patients (21 males and 9 females, mean age 67 years) receiving 12 μg b.i.d. formoterol were assayed before and after 3 months add-on therapy consisting of 18 μg q.i.d. tiotropium. In all patients, spirometry, lung volumes, and DLCO were performed before and after tiotropium therapy and all patients were subjected to sputum induction. Sputum cells were isolated and processed to obtain cytosolic and nuclear fractions. HDAC activity was measured in nuclear fraction using colorimetric assay. Expression AcH4 and iNOS was quantified using Western blot. In patients receiving both drugs, FEV1 and lung volumes significantly improved compared with formoterol-only treated patients. Mean HDAC activity was slightly decreased (P < 0.05), while AcH4 levels and iNOS expression were significantly elevated in tiotropium-treated patients (increase by about 65 %; P < 0.01 and 77 %; P < 0.01 respectively). Our data show that beneficial effects of tiotropium in add-on therapy to formoterol may be related to altered histone signaling and increased iNOS expression.

Topics: Aged; Bronchodilator Agents; Cell Nucleus; Cytosol; Ethanolamines; Female; Formoterol Fumarate; Gene Expression Regulation, Enzymologic; Histone Deacetylases; Histones; Humans; Lung; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Signal Transduction; Sputum; Time Factors; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is related to infiltration and activation of inflammatory cells in airways and pulmonary tissue. In COPD, neutrophils are prominent, while eosinophilic influx is typical to asthma. Inflammatory cells express sialic acid-binding immunoglobulin like lectins called Siglecs, a family of innate immune receptors that are transmembrane I-type lectins binding sialic acid. One member of the Siglec family, Siglec-8, is expressed mostly in eosinophils and may be an important therapeutic target in asthma or COPD. The aim of our project was to quantify Siglec-8 expression in induced sputum cells of COPD patients treated with long-acting beta2-agonists (LABA) or combined with long-acting antimuscarinic agents (LAMA) - tiotropium bromide. Thirty stable COPD patients (21 males and 9 females, mean age 67 years) receiving 12 μg BID formoterol therapy were assessed before and after 3 months' add-on therapy consisting of 18 μg QID tiotropium. In all patients, spirometry, lung volumes, and DLCO were performed before and after therapy. The patients were subjected to sputum induction before and after therapy. Sputum cells were isolated and processed to obtain cell membranes. Siglec-8 protein expression was assessed using Western blot. In patients receiving tiotropium and formoterol, improved FEV1 and lung volumes were observed compared with formoterol-only treated patients. The mean Siglec-8 level was significantly higher in eosinophilic subgroup of COPD patients compared with non-eosinophilic patients before therapy 40,000 vs. 15,000 Adj. Vol. INT/mm(2). Our data show that Siglec-8 may be involved in COPD pathogenesis and may influence COPD phenotyping.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Drug Combinations; Eosinophils; Ethanolamines; Female; Formoterol Fumarate; Gene Expression Regulation; Humans; Inflammation; Lectins; Male; Phenotype; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sputum; Tiotropium Bromide

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Female; Fluticasone; Humans; Male; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The long-acting inhaled anticholinergic agent, tiotropium, is recommended as first-line maintenance therapy for moderate to very severe Chronic Obstructive Pulmonary Disease (COPD) to improve symptoms, exercise tolerance, health status, and to reduce exacerbations. Few studies have evaluated the therapeutic efficacy of tiotropium in patients in routine clinical conditions. The current study was designed to investigate the therapeutic efficacy of tiotropium delivered via the HandiHaler® device on the health status of patients with COPD with Global initiative for chronic Obstructive Lung Disease (GOLD) disease classification 2-4 in six central and eastern European countries in a real-life clinical setting.. The study was an open-label, prospective, uncontrolled, and single-arm surveillance study with three clinic visits during a 6-month observation period (baseline, and months 3 and 6). Health status was measured using the disease-specific St George's Respiratory Questionnaire (SGRQ). The primary efficacy endpoint was the mean change from baseline in SGRQ total score at the end of the 6-month observational period.. Patients treated with tiotropium 18 μg once daily showed statistically significant and clinically meaningful reduction (improvement) of 21.7 units in the SGRQ total score, regardless of smoking status or cardiac comorbidities at enrollment (P < 0.0001). The analysis also showed that age, treatment compliance, and GOLD disease classification were significant factors that impact the health status of patients with COPD differently.. These results provide further support for the use of the tiotropium HandiHaler® as first-line maintenance treatment of patients with COPD with a clinician-assessed disease.

Topics: Administration, Inhalation; Age Factors; Aged; Bronchodilator Agents; Cholinergic Antagonists; Drug Administration Schedule; Europe, Eastern; Female; Health Status; Humans; Lung; Male; Medication Adherence; Middle Aged; Multivariate Analysis; Nebulizers and Vaporizers; Predictive Value of Tests; Product Surveillance, Postmarketing; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Risk Factors; Scopolamine Derivatives; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome

During the last decade, significant technological improvements in mass spectrometry have had a great impact on drug discovery. The development of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) has set a new frontier for the study of the distribution of endogenous and exogenous molecules present within a tissue. MALDI-IMS is a surface sampling technique that allows not only the detection of multiple analytes but also gives the spatial distribution of those analytes. Active compounds for pulmonary disease need an optimal and well-studied delivery into the lungs, in order to assure distribution with greater penetration into the peripheral or the alveolar region of the lung to maximize the therapeutic effects. IMS is very useful in the field of drug discovery, showing drug delivery and distribution in the body and organs. In this study, we present a comparison between two different ways of carrying out pulmonary drug administration: inhalation of a nebulized aerosol of aqueous drug solutions and intratracheal administration, which is much simpler, not expensive and commonly used during in vivo screening. Tiotropium bromide is a long-acting anticholinergic medicine used for maintenance treatment of chronic obstructive pulmonary disease. In the present work, tiotropium was administered by nebulization and by intratracheal instillation to guinea pigs at doses able to induce significant anti-bronchoconstrictive activity. Lung samples were dissected, frozen, cryosectioned and coated with matrix (α-hydroxy-cinnamic acid). IMS analyses were performed using a MALDI-LTQ-Orbitrap XL. Using this technique we were able to compare different distributions of the drug depending on the method of administration.

Topics: Administration, Inhalation; Aerosols; Animals; Cholinergic Antagonists; Drug Administration Routes; Drug Delivery Systems; Drug Discovery; Guinea Pigs; Lung; Male; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tiotropium Bromide; Tissue Distribution

Topics: Drug Combinations; Female; Glycopyrrolate; Humans; Indans; Male; Pulmonary Disease, Chronic Obstructive; Quinolones; Respiratory System; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Female; Humans; Indans; Male; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Female; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The study included 38 men with moderately severe chronic obstructive pulmonary disease (COPD) (mean age 60.6 ± 10.2 yr) and 42 ones with severe COPD (mean age 61.2 ± 7.2 yr). They were treated with tiotropium bromide, formoterol and beclomethasone dipropionate for 24 weeks (stage 1), TB alone for 12 weeks (stage 2) and TB+formoterol (long-acting bronchodilators, LABD) for another 12 weeks. Each stage was followed by evaluation of COPD symptoms using the St-George's Hospital questionnaire, daily requirements for short-acting beta-2 agonists (SABA), heart rate (HR), forced expiratory volume in the 1st second (FEV-1) before and after SABA test, hemoglobin saturation with oxygen in arterial blood during pulse oxymetry before and after 6 min walking test, blood surfactant protein D level (SP-D). The control group was comprised of 34 healthy men (mean age 62.3 ± 5.8 yr). Patients with moderately severe COPD experienced worsening of clinical symptoms (p < 0.001), required more SABA (p < 0.001), had increased HR (p = 0.01) and SP-D levels (p = 0.01) whereas FEV-1 (p = 0.05) decreased during stage 2 as compared with stage 1. Positive dynamics of all these variables except COPD symptoms and HR was observed at stage 3. Alteration in the extent of basal therapy in patients with stage III COPD did not result in dynamics of clinical and laboratory characteristics. The data obtained suggest the necessity of combined therapy with LABD or triple basal therapy of moderately severe COPD and the possibility of therapy with one or two LABD having different sites of action in the patients with clinically stable stage II COPD.

Topics: Aged; Anti-Asthmatic Agents; Beclomethasone; Bronchodilator Agents; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Aged; Albuterol; Antipsychotic Agents; Bronchodilator Agents; Depressive Disorder; Female; Fluorescein Angiography; Humans; Macular Edema; Pulmonary Disease, Chronic Obstructive; Risperidone; Scopolamine Derivatives; Serotonin Antagonists; Tiotropium Bromide; Tomography, Optical Coherence

Recently, tiotropium Respimat® Soft Mist™ Inhaler has been developed. Respimat is a multidose and propellant-free kit. The aerosol generated from Respimat improved lung drug deposition and required a lower dose of drug than HandiHaler®. The aim of this study is to assess the effect of switching from tiotropium HandiHaler to Respimat in patients with chronic obstructive pulmonary disease (COPD).. Thirty-four patients with COPD who received 18 μg of tiotropium delivered by the HandiHaler once daily were enrolled in this study between May and September 2010. Symptoms, adverse events, pulmonary functions, and usability of inhaler devices were assessed before and 12 weeks after switching from HandiHaler to 5 μg of tiotropium delivered by the Respimat. Symptoms and adverse events were also assessed 4 and 12 weeks after switching. Dyspnea was evaluated using the British Medical Research Council dyspnea scale. The usability of inhaler devices was scored using a 12-step checklist.. Twenty-nine patients were followed until 12 weeks after switching. The median FEV1 (forced expiratory volume in 1 sec) values before and 12 weeks after switching to Respimat were 1.41 L and 1.60 L, respectively. Dry mouth appeared to improve after switching to Respimat. Cough just after inhalation was observed in seven patients until 4 weeks after switching. However, six patients overcame cough as they got used to Respimat. Regarding the handling of inhaler devices, patients were not good at breathing out before inhalation and holding their breath just after inhalation both with HandiHaler and with Respimat. However, in general, both inhalers were considered to be easy to use. Twenty-one patients replied that handling of Respimat was easier than that of HandiHaler.. There was no major problem in switching from tiotropium HandiHaler to Respimat. Respimat and HandiHaler showed similar effects and usability. However, we should be aware of cough just after inhalation with Respimat.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchodilator Agents; Cohort Studies; Cough; Dyspnea; Equipment Design; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Xerostomia

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and chronic inflammation of airways and lung parenchyma. Our aim was to assess two important elements of intracellular signaling involved in regulation of inflammation in COPD in patients subjected to long-acting beta2-agonist or long-acting beta2-agonist plus long-acting antimuscarinic: peroxisome proliferator-activated receptor gamma (PPARγ) protein, which has antiinflammatory and immunomodulatory properties and cAMP response element binding protein (CREB) and activated (CREB-P) protein which has histone acetyltransferase activity and increases histone acetylation and transcriptional activation of chromatin. Twenty one stable COPD patients (18 males and 3 females, mean age 65 years) receiving 12 μg B.I.D formoterol were assayed before and after 3 month add-on therapy, consisting of 18 μg Q.D. tiotropium. In all patients, sputum induction, spirometry, lung volumes, and DLCO were performed before and after therapy. Sputum cells were isolated and processed to isolate cytosolic and nuclear fractions. PPARγ, CREB, or CREB-P proteins were quantified in subcellular fractions using Western blot. Tiotropium add-on therapy improved respiratory parameters: FEV1 and lung volumes. After therapy mean expression of PPARγ in cell nuclei was significantly increased by about 180%, while CREB and phosphorylated CREB levels in cytosol and nuclei were decreased by about 30%. Our data show that the mechanism whereby tiotropium reduces exacerbations may be associated not only with persistent increase in airway functions and reduced hyperinflation mediated by muscarinic receptors, but also with possible anti-inflammatory effects of the drug, involving increased PPARγ and decreased CREB signaling.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Anti-Inflammatory Agents, Non-Steroidal; Bronchodilator Agents; Cell Nucleus; Cyclic AMP Response Element-Binding Protein; Cytoplasm; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Lung Volume Measurements; Male; Muscarinic Antagonists; PPAR gamma; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Signal Transduction; Sputum; Tiotropium Bromide

Topics: Adenylyl Cyclases; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Calcium Signaling; Cyclic AMP; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Humans; Muscarinic Antagonists; Muscle, Smooth; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Receptors, Adrenergic, beta-2; Scopolamine Derivatives; Second Messenger Systems; Tiotropium Bromide

Tiotropium is an innovative intervention in chronic obstructive pulmonary disease (COPD). Early adherence to tiotropium remains inadequately explored, notably time from initiation to discontinuation (persistence). In patients with COPD, the factors associated with the risk of discontinuing the treatment with tiotropium within 12 months following initiation were identified (12-month persistence). Claim databases from the French Social Security were used. A random sample of patients (aged 50-80 years) who initiated tiotropium soon after launch was selected. Factors associated with the persistence were investigated (Log-rank test and multivariate Cox model). Of the 1147 newly treated patients (mean age 68 years, 33% women), 64% remained in the treatment of tiotropium for over a period of 12 months following initiation. More than 10% of the patients interrupted therapy after a single dispensing, most often those with mild COPD. Lower risks of discontinuing tiotropium within 12 months following initiation were observed when it was initiated by a private sector specialist (hazard ratio (HR) = 0.65, 95% confidence interval (CI) = (0.52-0.82)), by hospital-based physician (HR = 0.58, 95% CI = (0.42-0.78)), when ≥ 2 other respiratory drugs were associated (HR = 0.74, 95% CI = (0.58-0.95)) and in case of long-term disease status (HR = 0.78, 95% CI = (0.63-0.97)). Conversely, no clear effect appeared according to age or gender. In this population of patients with COPD, fewer early discontinuations of tiotropium were observed in patients having a severe condition.

Topics: Age Factors; Aged; Aged, 80 and over; Bronchodilator Agents; Databases, Factual; Delivery of Health Care; Female; France; Humans; Male; Medication Adherence; Middle Aged; Patient Dropouts; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Random Allocation; Risk Factors; Scopolamine Derivatives; Severity of Illness Index; Sex Factors; Tiotropium Bromide

Topics: Administration, Inhalation; Bronchodilator Agents; Cause of Death; Evidence-Based Medicine; Female; Humans; Male; Myocardial Infarction; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Assessment; Scopolamine Derivatives; Stroke; Survival Analysis; Tiotropium Bromide; United States; United States Food and Drug Administration

In patients with chronic obstructive pulmonary disease (COPD), multidetector-row computed tomography (MDCT) showed that tiotropium dilated the inner diameters in airways from the third to the sixth generation of the bronchi. Here we aimed to evaluate the morphological effect by adding a budesonide/formoterol combination to tiotropium in COPD patients using three-dimensional MDCT.. Pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ) and MDCT imaging studies were performed at the beginning and after budesonide/formoterol combination treatment for 12 weeks in 14 patients with COPD.. The median age was 73.5 years and the mean forced expiratory volume in 1 s (FEV1) as a percentage of the predicted value was 57.2 ± 18.3%. The luminal area in the fifth generation bronchi and the emphysema volume/CT-derived total lung volume were significantly correlated with FEV1 at baseline (r = 0.682, p < 0.02 and r = -0.868, p < 0.001, respectively). The average luminal area and wall area percentage in the third, fourth and fifth generations were correlated with the SGRQ total score. Budesonide/formoterol induced insignificant pulmonary function changes and significant symptoms improvement. CT images showed an increased inner luminal area and decreased wall area after budesonide/formoterol treatment. Average luminal area was significantly increased from 24.3 ± 9.7 to 26.0 ± 9.9 mm(2) in the third generation, 13.0 ± 6.5 to 14.7 ± 7.3 mm(2) in the fourth generation, 8.0 ± 4.8 to 9.4 ± 4.9 mm(2) in the fifth generation and 5.6 ± 2.7 to 6.7 ± 3.6 mm(2) in the sixth generation (p < 0.01). The average increase of the third generation luminal area was correlated with the FEV1 increase (r = 0.632, p < 0.03). The wall area percentage significantly decreased from 51.5 ± 9.2 to 49.1 ± 9.7 in the third generation, 56.1 ± 9.7 to 53.0 ± 11.1 in the fourth generation, and 62.3 ± 9.9 to 57.6 ± 9.8 in the fifth generation (p < 0.05). Emphysema volume/CT-derived total lung volume was unchanged with treatment.. MDCT demonstrated budesonide/formoterol induced bronchodilation in the non-small airway. CT imaging can evaluate drug therapeutic effect and may provide additional insights into pharmacotherapy for COPD.

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Female; Formoterol Fumarate; Humans; Lung; Male; Middle Aged; Multidetector Computed Tomography; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

The randomized, double-blind trial UPLIFT(®) demonstrated in 5,993 patients with moderate to very severe COPD that 4 years of tiotropium bromide therapy were associated with improvements in lung function, exacerbations, quality of life, and mortality compared with placebo. The pharmacoeconomic evaluation was performed through a probabilistic, patient-level simulation Markov model. Routine COPD care (RC) was compared with the inclusion of tiotropium bromide on it. The analysis was conducted over a lifetime horizon, with 1 year cycles and a 3.5% annual discount rate. Patients were characterized by gender, age, height, smoking status, and forced expiratory volume in 1 s (FEV1). FEV1 time trend was modeled according to the annual decline recorded in UPLIFT®. Mortality derived from that of the general Italian population was adjusted by smoking status and FEV1. Health utilities derived from published Italian observational studies and were varied in time according to UPLIFT® data. Exacerbation rates were derived from a published Italian observational prospective study. The cost perspective was that of the Italian National Health Service. Healthcare resource consumption for RC and exacerbations derived from Italian observational studies were valued according to current price and tariffs. Simulated patients in the tiotropium arm gained an average (95% CI) 0.50 (-1.63 to 6.27) Life Years (LYs) and 0.42 (-0.25 to 3.05) Quality-Adjusted Life Years (QALYs). The incremental lifetime cost resulted €3,357 (-€10,669 to €29,820). The incremental cost-effectiveness ratio (ICER) was €6,698/LY and €7,916/QALY. In the cost-effectiveness acceptability curve (CEAC), tiotropium had a 90% probability of being cost-effective for a willingness to pay (WTP) threshold of € 10,000/QALY.

Topics: Aged; Bronchodilator Agents; Economics, Pharmaceutical; Female; Humans; Italy; Male; Markov Chains; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Novel pharmacological strategies are aimed at the resolution of systemic inflammation in COPD potentiating peripheral blood T-cell (PBT-cell) apoptosis. Although muscarinic acetylcholine receptors (mAChRs) M(3) and choline-acetyltransferase (ChAT) participate in the airway inflammation of COPD, their role in PBT-cell apoptosis remains unexplained. We evaluated in PBT-cells from COPD patients, smoker (S) and control (C) subjects: (1) apoptosis (by annexin V binding), (2) mAChR M(3) and ChAT expression, acetylcholine (ACh)-binding; (3) choline levels in serum and PBT-cells extracts. We tested the effects of Tiotropium (Spiriva(®)) and hemicholinium-3 (HCh-3) on apoptosis, NFκB pathway, caspases 3 and 8 activity and choline levels, in PBT-cells from COPD patients. We showed that: (1) apoptosis, mAChR M(3) and ChAT expression and the CD3+ and CD8+ ACh-binding are increased in PBT-cells from COPD patients when compared to C subjects, while CD4+/CD8+ ratio of ACh-binding to PBT cells was reduced in COPD; (2) choline levels are higher in serum and PBT-cells extracts from COPD patients than in S and C; (3) Tiotropium and HCh-3 reduced CD4+ and increased CD8+ apoptosis via caspases 3 and 8 activities and via IκB mediated mechanisms in COPD patients. This study suggests the involvement of non-neuronal components of cholinergic system in the regulation of PBT-cell apoptosis in COPD and demonstrates that Tiotropium regulates CD4+ and CD8+ PBT-cell apoptosis. It provides novel putative pharmacological targets for the resolution of systemic inflammation in COPD.

Topics: Aged; Apoptosis; Caspase 3; Caspase 8; CD8-Positive T-Lymphocytes; Choline; Choline O-Acetyltransferase; Cholinergic Antagonists; Enzyme Activation; Female; Humans; Lymphocyte Count; Male; Middle Aged; NF-kappa B; Protein Binding; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Scopolamine Derivatives; Signal Transduction; Tiotropium Bromide

Tiotropium has been associated with an increased risk of mortality and/or cardiovascular events. Recent data from RCTs suggests tiotropium Handihaler to be safe, but its safety has not yet been fully investigated under real-life circumstances.. We conducted 2 nested case-control studies in a COPD cohort from the Dutch IPCI database. In the first case-control study, cases had a cardiovascular or cerebrovascular endpoint (CCVE): stroke and transient ischemic attack (TIA), myocardial infarction, heart failure and/or ventricular arrhythmia. In the second, cases were all patients who died. Cases were matched to controls on age, sex and index date. Conditional logistic regression analysis was used to calculate adjusted odds ratios (OR(adj)) with 95% confidence intervals (CI) for tiotropium vs. long-acting beta-agonists (LABA).. Within a cohort of 6788 COPD patients, 784 CCVE's and 1032 deaths were reported. Compared to current LABA use, use of tiotropium Handihaler was neither associated with an increased risk of a CCVE (OR(adj) 0.89, 95% 0.55-1.44) nor with an increased risk of death (OR(adj) 0.79, 95% CI 0.49-1.28).. In real life, use of tiotropium Handihaler in COPD patients is not associated with an increased risk of a CCVE or mortality compared to LABA.

Topics: Adrenergic beta-Agonists; Adult; Age Factors; Aged; Arrhythmias, Cardiac; Bronchodilator Agents; Cardiovascular Diseases; Case-Control Studies; Cerebrovascular Disorders; Cohort Studies; Confidence Intervals; Databases, Factual; Endpoint Determination; Female; Heart Failure; Humans; Ischemic Attack, Transient; Logistic Models; Male; Middle Aged; Myocardial Infarction; Nebulizers and Vaporizers; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Sex Factors; Stroke; Tiotropium Bromide

Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist currently in registration phase for the treatment of chronic obstructive pulmonary disease. Since urinary difficulty and retention have been reported for anticholinergic agents such as tiotropium and ipratropium, it is important to examine the preclinical urinary and renal safety profile of aclidinium.. The effect of aclidinium on urine and electrolyte excretion, renal function and voiding cystometry was analysed in conscious water-loaded Wistar rats (10-1000 μg/kg, s.c.), anaesthetised Beagle dogs (1000 μg/kg, i.v.) and anaesthetised guinea pigs (3-100μg/kg, intratracheally), respectively. Aclidinium plasma levels were determined in an independent study. Active comparators were tiotropium (all studies) and ipratropium (cystometry only).. Aclidinium 1000 μg/kg had no effect on urine excretion in rats, in contrast to tiotropium 100 μg/kg which significantly decreased this parameter (p<0.05). Aclidinium 1000 μg/kg also had no effect on renal function in Beagle dogs. In guinea pigs, aclidinium 3-100 μg/kg had no effect on urinary bladder function, whereas tiotropium and ipratropium 100 μg/kg decreased the peak micturition pressure (p<0.05), increased the volume of urine retained in the bladder (p<0.01) and showed a trend to decrease the volume of urine excreted.. Aclidinium had no significant effect on urinary and renal function in the animal models studied. These results, together with the rapid plasma clearance of aclidinium reported previously, suggest a lower propensity to induce urinary retention in humans than tiotropium and ipratropium.

Topics: Animals; Dogs; Female; Guinea Pigs; Kidney; Kidney Function Tests; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Tropanes

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive bronchial obstruction, and bronchodilators represent the maintenance therapeutic choice. Tiotropium is an anticholinergic drug that is proved to be safe, efficient and simple to handle; Respimat® technology was recently introduced as a new device for tiotropium administration.. This paper reviews clinical trials and meta-analyses, with tiotropium efficacy as a primary end point, found in MedLine, the Cochrane trials database and Embase. Only the literature published after the UPLIFT study has been considered.. Data published after the UPLIFT study confirms the efficacy of tiotropium as maintenance COPD therapy and its capacity to reduce airflow obstruction, as well as lung hyperinflation. Nevertheless, there is a certain inhomogeneity in the definition and evaluation of COPD exacerbations, in lung functional parameters and quality-of-life assessment, and there has not always been a proper comparison between tiotropium and other long-acting bronchodilators. Respimat is comparable in efficacy to the HandiHaler®, using bioequivalent doses of tiotropium.

Topics: Bronchodilator Agents; Clinical Trials, Phase II as Topic; Humans; Meta-Analysis as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Long-term therapy with systemic corticosteroids is not recommended in the treatment of chronic obstructive pulmonary disease (COPD). However, experience demonstrates that some patients receive low dose therapy. Our objective was to describe the demographic, physiologic and radiologic characteristics of COPD patients treated with chronic systemic corticosteroids. We analyzed COPD subjects with GOLD I-IV disease in the COPDGene® study. Subjects were divided into 2 groups based on whether they reported using chronic oral steroids or not; 1264 subjects were included. Fifty-eight (4.5%) reported chronic systemic corticosteroid use. There were no differences in age, race, co-morbid conditions (other than asthma), or body mass index between the groups. There was a greater proportion of GOLD III (41% vs. 26%) and IV (41% vs. 13%) subjects in the group using chronic systemic corticosteroids. This group used more respiratory medications, required more oxygen (2.31 ± 0.21 vs. 0.59 ± 0.05 L/min; p < 0.0001), and walked less distance (245.4 ± 17.4 vs. 367.2 ± 3.9 meters; p < 0.0001). They reported more total (1.7 ± 0.16 vs. 0.62 ± 0.03; p < 0.0001) and severe exacerbations per year (0.41 ± 0.05 vs. 0.18 ± 0.01; p < 0.0001). BODE (5.0 ± 0.3 vs. 2.6 ± 0.1; p < 0.0001), MMRC (3.31 ± 0.19 vs. 1.90 ± 0.04; p < 0.0001) and SGRQ scores (54.9 ± 2.9 vs 53.3 ± 0.6; p < 0.0001) were higher. They also had a higher percentage of emphysema (22.4 ± 1.9 vs. 14.0 ± 0.4;%, p = <0.0001) on CT scan. COPD patients that report using chronic systemic corticosteroids have more severe clinical, physiologic, and radiographic disease.

Topics: Administration, Oral; Adrenergic beta-Agonists; Asthma; Bronchodilator Agents; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Hypersensitivity; Male; Middle Aged; Multidetector Computed Tomography; Nebulizers and Vaporizers; Oxygen; Oxygen Inhalation Therapy; Prednisone; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Quality of Life; Scopolamine Derivatives; Severity of Illness Index; Smoking; Spirometry; Theophylline; Tiotropium Bromide; United States; Walking

Tiotropium outperformed salmeterol in reducing the frequency of exacerbations in patients with moderate-to-severe COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Bronchodilator Agents; Drug Administration Schedule; Family Practice; Humans; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; United States

This retrospective cohort study compared the risks of exacerbations and COPD-related healthcare costs between patients with chronic obstructive pulmonary disease (COPD) initiating tiotropium (TIO) alone and patients initiating triple therapy with fluticasone-salmeterol combination (FSC) added to TIO.. Managed-care enrollees who had an index event of ≥ 1 pharmacy claim for TIO during the study period (January 1, 2003-April 30, 2008) and met other eligibility criteria were categorized into one of two cohorts depending on their medication use. Patients in the TIO+FSC cohort had combination therapy with TIO and FSC, defined as having an FSC claim on the same date as the TIO claim. Patients in the TIO cohort had no such FSC use. The risks of COPD exacerbations and healthcare costs were compared between cohorts during 1 year of follow-up.. The sample comprised 3333 patients (n = 852 TIO+FSC cohort, n = 2481 TIO cohort). Triple therapy with FSC added to TIO compared with TIO monotherapy was associated with significant reductions in the adjusted risks of moderate exacerbation (hazard ratio 0.772; 95% confidence interval [CI] 0.641, 0.930) and any exacerbation (hazard ratio 0.763; 95% CI 0.646, 0.949) and a nonsignificant reduction in COPD-related adjusted monthly medical costs.. Triple therapy with FSC added to TIO compared with TIO monotherapy was associated with significant reductions in the adjusted risks of moderate exacerbation and any exacerbation over a follow-up period of up to 1 year. These improvements were gained with triple therapy at roughly equal cost of that of TIO alone.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Disease Progression; Drug Combinations; Drug Therapy, Combination; Female; Fluticasone-Salmeterol Drug Combination; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Risk; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

To determine clinical and economic outcomes following COPD-related hospitalization/emergency department (ED) care in patients receiving COPD maintenance therapy.. In this retrospective, observational study using administrative claims data, we identified COPD patients age ≥40 years who received maintenance therapy within 30 days of an initial COPD-related hospitalization or ED visit with: (1) fluticasone propionate/salmeterol combination (FSC 250 mcg/50 mcg) as new therapy, or (2) an anticholinergic (AC; tiotropium or ipratropium with or without albuterol). The FSC and AC patients were matched (1:3 ratio) on various baseline characteristics using propensity scores to mitigate selection bias at baseline. The proportion of patients with COPD-related healthcare events, the mean event rates, and the mean costs in the subsequent 12 months were calculated.. The FSC cohort (N = 484) had a significantly lower proportion of rehospitalized patients during follow-up than did the AC cohort (N = 1452), 3.1% versus 4.6% (P = 0.047). The mean number of rehospitalizations was 0.03 in the FSC cohort and 0.07 in the AC cohort (P = 0.001). The proportion of patients with an exacerbation resulting in an ED or physician-outpatient visit and the mean number of such visits did not differ between cohorts. Total annual COPD-related medical costs were lower for FSC than for AC ($2080 versus $2636, P = 0.006), with lower medical and higher pharmacy costs.. Patients receiving FSC as maintenance therapy following an initial COPD-related hospitalization or ED visit experienced better clinical and economic outcomes than patients receiving AC.

Topics: Adult; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cholinergic Antagonists; Drug Combinations; Drug Costs; Female; Fluticasone-Salmeterol Drug Combination; Glucocorticoids; Health Care Costs; Humans; Ipratropium; Male; Middle Aged; Patient Readmission; Patient Selection; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; United States

We quantified TGF-β1 and acetylcholine (ACh) concentrations in induced sputum supernatants (ISSs) from 18 healthy controls (HC), 22 healthy smokers (HS) and 21 COPDs. ISSs from HC, HS and COPD as well as rhTGF-β1 were also tested in neutrophil adhesion and in mAChR2, mAChR3 and ChAT expression experiments in human bronchial epithelial cells (16-HBE). Finally, we evaluated the effects of Olodaterol (a novel inhaled β(2)-adrenoceptor agonist) and Tiotropium Spiriva®, alone or in combination, on neutrophil adhesion and mAChRs and ChAT expression in stimulated 16-HBE. The results showed that 1) TGF-β1 and ACh concentrations are increased in ISSs from COPD in comparison to HC and HS, and TGF-β1 in HS is higher than in HC; 2) ISSs from COPD and HS caused increased neutrophil adhesion to 16-HBE when compared to ISSs from HC. The effect of ISSs from COPD was significantly reduced by TGF-β1 depletion or by the pretreatment with Olodaterol or Tiotropium alone or in combination, while the effect of ISSs from HS was significantly reduced by the pretreatment with Olodaterol alone; 3) mAChR2, mAChR3 and ChAT expression was increased in 16-HBE stimulated with ISSs from COPD and TGF-β1 depletion significantly reduced this effect on mAChR3 and ChAT expression; 4) rhTGF-β1 increased mAChR2, mAChR3 and ChAT expression in 16-HBE; 5) Olodaterol did not affect the expression of mAChRs and ChAT in 16-HBE. Our findings support the use of β₂ long-acting and anticholinergic drugs to control the bronchoconstriction and TGF-β1-mediated neutrophilic inflammation in COPD.

Topics: Acetylcholine; Adrenergic beta-2 Receptor Agonists; Aged; Analysis of Variance; Benzoxazines; Bronchoconstriction; Bronchodilator Agents; Case-Control Studies; Cell Adhesion; Cell Line, Transformed; Choline O-Acetyltransferase; Cholinergic Antagonists; Drug Therapy, Combination; Epithelial Cells; Female; Flow Cytometry; Humans; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Scopolamine Derivatives; Smoking; Sputum; Tiotropium Bromide; Transforming Growth Factor beta1

To investigate equivalency of results from multivariable regression (MR) and propensity score matching (PSM) models, observational research methods used to mitigate bias stemming from non-randomization (and consequently unbalanced groups at baseline), using, as an example, a large study of chronic obstructive pulmonary disease (COPD) initial maintenance therapy.. Patients were 32,338 health plan members, age ≥40 years, with COPD initially treated with fluticasone propionate/salmeterol combination (FSC), tiotropium (TIO), or ipratropium (IPR) alone or in combination with albuterol. Using MR and PSM methods, the proportion of patients with COPD-related health care utilization, mean costs, odds ratios (ORs), and incidence rate ratios (IRRs) for utilization events were calculated for the 12 months following therapy initiation.. Of 12,595 FSC, 9126 TIO, and 10,617 IPR patients meeting MR inclusion criteria, 89.1% (8135) of TIO and 80.2% (8514) of IPR patients were matched to FSC patients for the PSM analysis. Methods produced substantially similar findings for mean cost comparisons, ORs, and IRRs for most utilization events. In contrast to MR, for TIO compared to FSC, PSM did not produce statistically significant ORs for hospitalization or outpatient visit with antibiotic or significant IRRs for hospitalization or outpatient visit with oral corticosteroid. As in the MR analysis, compared to FSC, ORs and IRRs for all other utilization events, as well as mean costs, were less favorable for IPR and TIO.. In this example of an observational study of maintenance therapy for COPD, more than 80% of the original treatment groups used in the MR analysis were matched to comparison treatment groups for the PSM analysis. While some sample size was lost in the PSM analysis, results from both methods were similar in direction and statistical significance, suggesting that MR and PSM were equivalent methods for mitigating bias.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Ambulatory Care; Androstadienes; Anti-Bacterial Agents; Bronchodilator Agents; Cost-Benefit Analysis; Drug Combinations; Drug Costs; Drug Therapy, Combination; Emergency Service, Hospital; Female; Fluticasone-Salmeterol Drug Combination; Hospitalization; Humans; Ipratropium; Linear Models; Logistic Models; Male; Middle Aged; Models, Economic; Models, Statistical; Multivariate Analysis; Muscarinic Antagonists; Odds Ratio; Propensity Score; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; United States

Pharmacological lung volume reduction in COPD is an important goal in treatment with long-acting bronchodilators because in addition to airflow limitation, lung hyperinflation considerably affects COPD symptoms. Quantitative computed tomography (CT) simultaneously provides structural information about airway dimensions, emphysematous changes, and lung volumes, some of which are difficult to be evaluated by pulmonary function. Here, we evaluated changes in CT parameters and pulmonary function in 30 patients with COPD who underwent CT scans before and one year after starting tiotropium treatment and in 12 patients with COPD who were not treated with long-acting bronchodilators. Baseline pulmonary function and CT parameters did not differ between the two groups. One-year tiotropium therapy improved physiological-indices including residual volume (RV) and ratio of RV to total lung capacity (RV/TLC) (-235 mL, p = 0.005, and -2.9%, p = 0.0001, respectively), and CT-indices including wall area percent (WA%) and inner luminal area in right upper lobe apical and lower lobe basal segmental bronchi (-1.59%, p = 0.01, 2.27 mm(2), p = 0.0005; and -1.33%, p = 0.0008, 3.42 mm(2), p < 0.0001, respectively), low attenuation volume (LAV) and total lung volume (CT-TLV) (-92 mL, p = 0.0003, and -211 mL, p = 0.002, respectively). Changes in LAV, CT-TLV, RV, and RV/TLC were significantly greater in the tiotropium, than the non-bronchodilator group. The tiotropium-induced reduction in LAV correlated with the decrease in RV (ρ = 0.45, p = 0.01). Our findings not only indicate the value of the comprehensive CT measurements in assessing the effects of bronchodilators, including pharmacological lung volume reduction, but also further understanding of the structural changes underlying physiological improvements induced by bronchodilators.

Topics: Aged; Bronchodilator Agents; Cohort Studies; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Lung; Lung Volume Measurements; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Tomography, X-Ray Computed; Total Lung Capacity; Treatment Outcome

Non-inferiority (NI) trials are becoming increasingly popular. The main purpose of NI trials is to assert the efficacy of a new treatment compared with an active control by demonstrating that the new treatment maintains a substantial fraction of the treatment effect of the control. Most of the statistical testing procedures in this area have been developed for three-arm NI trials in which a new treatment is compared with an active control in the presence of a placebo. However, NI trials frequently involve comparisons of several new treatments with a control, such as in studies involving different doses of a new drug or different combinations of several new drugs. In seeking an adequate testing procedure for such cases, we use a new approach that modifies existing testing procedures to cover circumstances in which several new treatments are present. We also give methods and algorithms to produce the optimal sample size configuration. In addition, we also discuss the advantages of using different margins for the assay sensitivity test between the active control and the placebo and the NI test between the new treatments and the active control. We illustrate the new approach by using data from a clinical trial.

Topics: Algorithms; Bronchodilator Agents; Clinical Trials as Topic; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quinolones; Sample Size; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

The objective of the present study was to evaluate the effects of inhaled tiotropium on pulmonary function and left ventricular diastolic function in chronic obstructive pulmonary disease patients ≥ 1 year after pulmonary resection for lung cancer.. This prospective single-arm analysis involved 21 chronic obstructive pulmonary disease patients who underwent pulmonary resection for lung cancer at least one year earlier. Blood pressures, heart rate, spirometry, transthoracic echocardiography including tissue Doppler imaging, and quality of life were evaluated prior to and after 3 months of inhaled tiotropium treatment. B-type natriuretic peptide, white blood cell counts, and C-reactive protein levels before and after inhaled tiotropium treatment were also examined.. There were no significant differences between before and after treatment in forced vital capacity and left ventricular ejection fraction. Forced expiratory volume in 1 second and early transmitral velocity/tissue Doppler mitral annular early diastolic velocity values improved from 1.60 ± 0.5 L and 8.97 ± 1.6, respectively, before treatment, to 1.84 ± 0.5 L and 7.59 ± 1.4, respectively, 3 months after treatment (P <0.001).. Treatment with inhaled tiotropium may be effective in improving not only pulmonary function but also left ventricular diastolic function of patients with chronic obstructive pulmonary disease in the chronic phase after pulmonary resection.

Topics: Administration, Inhalation; Aged; Biomarkers; Bronchodilator Agents; Diastole; Echocardiography, Doppler; Female; Forced Expiratory Volume; Humans; Japan; Lung; Lung Neoplasms; Male; Middle Aged; Pilot Projects; Pneumonectomy; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Scopolamine Derivatives; Spirometry; Stroke Volume; Time Factors; Tiotropium Bromide; Treatment Outcome; Ventricular Function, Left; Vital Capacity

Topics: Asthma; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking; Tiotropium Bromide

Exacerbations affect morbidity in chronic obstructive pulmonary disease (COPD). We sought to evaluate the association between exacerbation frequency and spirometric and health status changes over time using data from a large, long-term trial.. This retrospective analysis of data from the 4-year UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) trial compared tiotropium with placebo. Annualized rates of decline and estimated mean differences at each time point were analyzed using a mixed-effects model according to subgroups based on exacerbation frequency (events per patient-year: 0, >0-1, >1-2, and >2). Spirometry and the St George's Respiratory Questionnaire (SGRQ) were performed at baseline and every 6 months (also at one month for spirometry).. In total, 5992 patients (mean age 65 years, 75% male) were randomized. Higher exacerbation frequency was associated with lower baseline postbronchodilator forced expiratory volume in one second (FEV(1)) (1.40, 1.36, 1.26, and 1.14 L) and worsening SGRQ scores (43.7, 44.1, 47.8, and 52.4 units). Corresponding rates of decline in postbronchodilator FEV(1) (mL/year) were 40, 41, 43, and 48 (control), and 34, 38, 48, and 49 (tiotropium). Values for postbronchodilator forced vital capacity decline (mL/year) were 45, 56, 74, and 83 (control), and 43, 57, 83, and 95 (tiotropium). The rates of worsening in total SGRQ score (units/year) were 0.72, 1.16, 1.44, and 1.99 (control), and 0.38, 1.29, 1.68, and 2.86 (tiotropium). The proportion of patients who died (intention-to-treat analysis until four years [1440 days]) for the entire cohort increased with increasing frequency of hospitalized exacerbations.. Increasing frequency of exacerbations worsens the rate of decline in lung function and health-related quality of life in patients with COPD. Increasing rates of hospitalized exacerbations are associated with increasing risk of death.

Topics: Aged; Cholinergic Antagonists; Disease Progression; Female; Forced Expiratory Volume; Hospitalization; Humans; Lung; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Risk Factors; Scopolamine Derivatives; Spirometry; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Topics: Adrenergic beta-Agonists; Bronchodilator Agents; Humans; Indans; Pulmonary Disease, Chronic Obstructive; Quinolones; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) management was investigated in two sub-studies of the BEACH (Bettering the Evaluation and Care of Health) program at 5711 general practitioner-patient encounters in February to March 2010 and April to May 2011.

Topics: Aged; Albuterol; Asthma; Australia; Bronchodilator Agents; Comorbidity; Female; General Practice; Humans; Male; Middle Aged; Prevalence; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is one of the most important diseases because of high and constantly increasing prevalence, morbidity and mortality. An update of the Global strategy for the diagnosis, management, and prevention of COPD - GOLD report was published in the last days of 2011. In the paper the most important information concerning diagnosis, treatment and prevention of COPD based on GOLD statement 2011 were presented. The most interesting new information concerning diagnosis of COPD are following: post-bronchodilator ratio of FEV1/FVC < 0.7 still confirms the presence of airflow limitation in COPD; assessment of COPD symptoms is based on CAT and mMRC tests; acute bronchodilator reversibility test is no longer recommended for making COPD diagnosis; introduction of a new division of COPD patients into 4 groups (A, B, C or D) based on the level of airflow limitation, risk of exacerbations and severity of symptoms. The last change has fundamental impact on treatment guidelines, as in the past it was based only on spirometric classification, whereas currently it is guided by A-D groups selection.

Topics: Albuterol; Bronchodilator Agents; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Salmeterol Xinafoate; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

This study investigated the effects of tiotropium bromide on chronic asthma patients with persistent obstructive ventilatory impairment (FEV1/FVC%<70%) like COPD.. Twenty-four patients (14 males, 10 females, mean age 64.3±10.7 years old) were enrolled. They were all treated with a high dose inhaled steroids and a long-acting β2-agonist. All patients had bronchial reversibility, normal diffusing capacity (DLCO) and no low attenuation areas in HRCT. This study examined the FEV1 at baseline and after inhalation of short-acting bronchodilators (400 μg salbutamol and 40 μg ipratropium, 15 minutes and 30 minutes after, respectively). Eleven patients agreed to take an additional treatment with tiotropium, and received 18 μg of tiotropium per daily for one year. The usual treatments were continued for 7 patients that did not agree to take tiotropium and for 6 patients who were ineligible for tiotropium due to co-morbidities. The FVC, FEV1, FEV1/FVC%, V50, and IC were compared between the two groups after one year.. FEV1 and V50 were significantly elevated after one year in the tiotropium-treated patients in comparison to those in the 13 subjects that did not receive tiotropium bromide, after adjusting for age, smoking and the values determined on enrollment. There was a positive correlation between the change of FEV1 30 min after ipratropium inhalation (short-term effect) and FEV1 one year after tiotropium inhalation (long-term effect).. Combination treatment with tiotropium, high dose steroids and long-acting β2 agonist inhalation provides improvement in the expiratory flow limitations of asthma patients with persistent obstructive ventilatory impairment.

Topics: Administration, Inhalation; Asthma; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Female; Humans; Ipratropium; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiration Disorders; Scopolamine Derivatives; Steroids; Tiotropium Bromide

The optimization of a new series of muscarinic M(3) antagonists is described, leading to the identification of AZD9164 which was progressed into the clinic for evaluation of its potential as a treatment for COPD.

Topics: Blood Proteins; Drug Evaluation, Preclinical; Humans; Muscarinic Antagonists; Piperidines; Protein Binding; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Receptor, Muscarinic M3; Structure-Activity Relationship

Topics: Asthma; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Study Type--Harm (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Inhaled anticholinergic drugs have been associated with the risk of acute urinary retention (AUR), but this association was never studied under real life circumstances nor was this risk ever quantified. Use of inhaled anticholinergic drugs increases the risk of AUR by 40%. The risk of AUR is highest in recent starters, in patients with benign prostatic hyperplasia (BPH), and in patients receiving their anticholinergic drugs via nebulizer. It might be advisable to consider alternatives for inhaled anticholinergic drugs in COPD patients with BPH.. • To investigate the association between the use of inhaled anticholinergic drugs and the risk of acute urinary retention (AUR) under real-life circumstances.. • We conducted a nested case-control study within a cohort of patients with chronic obstructive pulmonary disease (COPD; as AUR has been associated with the use of inhaled anticholinergic drugs, which are used as first-line treatment for COPD) from the Integrated Primary Care Information (IPCI) database. • The cohort consisted of all patients with COPD aged ≥45 years, registered between 1996 and 2006, with ≥12 months of valid history. Cases were patients with a first diagnosis of AUR. • To each case, controls were selected matched for age, gender and index date. • Multivariate conditional logistic regression analysis was used to calculate adjusted odds ratios (OR(adj)) with 95% confidence intervals (95% CI).. • Within the cohort of 22,579 patients with COPD, 209 cases were identified. • Current use of inhaled anticholinergic drugs was associated with a 40% increase in risk for AUR (OR(adj) 1.40; 95% CI 0.99-1.98) compared with non-users. • Among current users, the risk was highest for the recent starters (OR(adj) 3.11; 95% CI 1.21-7.98). The risk of long-acting anticholinergic drug tiotropium was not substantially different from that of the short-acting anticholinergic ipratropium. • The association was not dose-dependent, but changed by mode of administration, with nebulizers having the highest risk (OR(adj) 2.92; 95% CI 1.17-7.31). • In men with COPD and benign prostatic hyperplasia (BPH) the association was strongest (OR(adj) 4.67; 95% CI 1.56-14.0).. • Current use of inhaled anticholinergic drugs increases the risk of AUR, especially in patients with BPH or if administered via a nebulizer.

Topics: Acute Disease; Administration, Inhalation; Aged; Cholinergic Antagonists; Female; Follow-Up Studies; Humans; Ipratropium; Male; Middle Aged; Nebulizers and Vaporizers; Netherlands; Prevalence; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Risk Factors; Scopolamine Derivatives; Sex Factors; Tiotropium Bromide; Urinary Retention; Urination

As COPD patients commonly suffer cardio- and cerebrovascular (CCV) co-morbidities, our purpose was to establish the CCV safety profile of indacaterol, a novel, inhaled, long-acting β(2)-agonist for COPD.. The indacaterol clinical trial database comprised 4635 patients with moderate-to-severe COPD enrolled into studies of ≥6 months' duration treated with indacaterol, placebo or other bronchodilators (formoterol, salmeterol, tiotropium). Adverse events (AEs) were analysed overall and according to Anti-Platelet Trialists' Collaboration (APTC) criteria and baseline cardiovascular risk factors. A subset of patients had Holter monitoring.. Compared with placebo, indacaterol did not increase the risk of CCV AEs; relative risks were not significantly different for indacaterol versus other treatments. In all treatment groups, including placebo, most CCV AEs occurred in patients with pre-existing cardiovascular risk factors. The risk of APTC events (e.g. myocardial infarction, stroke, cardiovascular-related death) was not significantly increased for indacaterol versus placebo. The incidence of notable QTc interval increases >60 ms was low with all active treatments (0-0.5%, versus 0.3% with placebo). Holter monitoring in the subset of patients receiving indacaterol, tiotropium or placebo showed no clinically relevant effect of indacaterol or tiotropium relative to placebo on the development of arrhythmias. The number of deaths adjusted for exposure was lower with all active treatments than with placebo, with a trend to reduced risk with indacaterol (relative risk 0.30, p = 0.054).. The overall CCV safety profile of indacaterol was similar to placebo and comparable with other long-acting bronchodilators, providing reassurance for regular long-term use of indacaterol in COPD. Data for this analysis were pooled from three studies, registered at ClinicalTrials.gov as: NCT00393458, NCT00463567 and NCT00567996.

Topics: Adult; Albuterol; Bronchodilator Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Indans; Male; Middle Aged; Placebos; Pulmonary Disease, Chronic Obstructive; Quinolones; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Smoking; Tiotropium Bromide

To evaluate chronic obstructive pulmonary disease (COPD)-related expenditure and hospitalisation in COPD patients treated with tiotropium versus alternative long-acting bronchodilators (LABDs).. Data were from the Thomson Reuters MarketScan Research Databases. COPD patients ≥ 35 years with at least one LABD claim between July 1, 2004 and June 30, 2006 were classified into five cohorts based on index LABD: monotherapy with tiotropium, salmeterol/fluticasone propionate, formoterol fumarate, or salmeterol or combination therapy. Demographic and clinical characteristics were evaluated for a 6-month pre-period and COPD-related utilisation and total costs were evaluated for a 12-month follow-up period. LABD relationship to COPD-related costs and hospitalisations were estimated by multivariate generalised linear modelling (GLM) and multivariate logistic regression, respectively.. Of 52,274 patients, 53% (n = 27,457) were male, 71% (n = 37,271) were ≥ 65 years, and three LABD cohorts accounted for over 90% of the sample [53% (n = 27,654) salmeterol/fluticasone propionate, 23% (n = 11,762) tiotropium, and 15% (n = 7755) combination therapy]. Patients treated with salmeterol/fluticasone propionate (p < 0.001), formoterol fumarate (p = 0.032), salmeterol (p = 0.004), or with combination therapy (p < 0.001) had higher COPD-related costs and a greater risk of inpatient admission (p < 0.01 for all) versus tiotropium.. These data are based on administrative claims and as such do not include clinical information or information on risk factors, like smoking status, that are relevant to this population.. Patients treated with tiotropim had lower COPD-related expenditures and risk of hospitalisation than patients treated with other LABDs.

Topics: Adult; Aged; Bronchodilator Agents; Drug Therapy, Combination; Female; Health Resources; Hospital Costs; Humans; Inpatients; Linear Models; Logistic Models; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; United States

Airway remodelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular remodelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway remodelling. This study aimed to investigate the role of acetylcholine in pulmonary inflammation and remodelling using an animal model of COPD. To this aim, guinea pigs were instilled intranasally with lipopolysaccharide (LPS) twice weekly for 12 weeks and were treated, by inhalation, with the long-acting muscarinic receptor antagonist tiotropium. Repeated LPS exposure induced airway and parenchymal neutrophilia, and increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size. Furthermore, LPS increased the number of muscularised microvessels in the adventitia of cartilaginous airways. Tiotropium abrogated the LPS-induced increase in neutrophils, goblet cells, collagen deposition and muscularised microvessels, but had no effect on emphysema. In conclusion, tiotropium inhibits remodelling of the airways as well as pulmonary inflammation in a guinea pig model of COPD, suggesting that endogenous acetylcholine plays a major role in the pathogenesis of this disease.

Topics: Acetylcholine; Airway Remodeling; Animals; Animals, Outbred Strains; Cholinergic Antagonists; Disease Models, Animal; Emphysema; Goblet Cells; Guinea Pigs; Lipopolysaccharides; Lung; Male; Mucin 5AC; Muscarinic Antagonists; Neutrophils; Pneumonia; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Scopolamine Derivatives; Tiotropium Bromide

Neutrophil influx into the airways is an important mechanism in the pathophysiology of the inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD). Previously it was shown that anticholinergic drugs reduce the release of non-neuronal paracrine mediators, which modulate inflammation in the airways. On this basis, we investigated the ability of the long-acting anticholinergic tiotropium bromide to inhibit a) alveolar macrophage (AM)-mediated chemotaxis of neutrophils, and b) cellular release of reactive oxygen species (ROS).. AM and neutrophils were collected from 71 COPD patients. Nanomolar concentrations of tiotropium bromide were tested in AM cultured up to 20 h with LPS (1 μg/ml). AM supernatant was tested for TNFα, IL8, IL6, LTB4, GM-CSF, MIPα/β and ROS. It was further used in a 96-well chemotaxis chamber to stimulate the migration of fluorescence labelled neutrophils. Control stimulants consisted of acetylcholine (ACh), carbachol, muscarine or oxotremorine and in part PMA (phorbol myristate acetate, 0.1 μg/ml). Potential contribution of M1-3-receptors was ascertained by a) analysis of mRNA transcription by RT-PCR, and b) co-incubation with selective M-receptor inhibitors.. Supernatant from AM stimulated with LPS induced neutrophilic migration which could be reduced by tiotropium in a dose dependent manner: 22.1 ± 10.2 (3 nM), 26.5 ± 18,4 (30 nM), and 37.8 ± 24.0 (300 nM, p < 0.001 compared to non-LPS activated AM). Concomitantly TNFα release of stimulated AM dropped by 19.2 ± 7.2% of control (p = 0.001). Tiotropium bromide did not affect cellular IL8, IL6, LTB4, GM-CSF and MIPα/β release in this setting. Tiotropium (30 nM) reduced ROS release of LPS stimulated AM by 36.1 ± 15.2% (p = 0.002) and in carbachol stimulated AM by 46.2 ± 30.2 (p < 0.001). M3R gene expression dominated over M2R and M1R. Chemotaxis inhibitory effect of tiotropium bromide was mainly driven by M3R inhibition.. Our data confirm that inhibiting muscarinic cholinergic receptors with tiotropium bromide reduces TNFα mediated chemotactic properties and ROS release of human AM, and thus may contribute to lessen cellular inflammation.

Topics: Anti-Inflammatory Agents; Cells, Cultured; Chemotaxis, Leukocyte; Cholinergic Agonists; Cholinergic Antagonists; Culture Media, Conditioned; Dose-Response Relationship, Drug; Female; Humans; Inflammation Mediators; Macrophage Activation; Macrophages, Alveolar; Male; Neutrophils; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide; Tumor Necrosis Factor-alpha

The aim of the current study was to characterize comparatively the binding of muscarinic receptor in the lung of rats intratracheally administered anticholinergic agents (tiotropium, ipratropium, glycopyrrolate) used clinically to treat chronic obstructive pulmonary disease (COPD) and asthma. Binding parameters of [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) were determined in tissues (lung, bladder, submaxillary gland) of rats intratracheally administered tiotropium, ipratropium, and glycopyrrolate. The in vitro binding affinity of tiotropium for the receptors was 10-11-fold higher than those of ipratropium and glycopyrrolate. Intratracheal administration of tiotropium (0.6-6.4 nmol/kg) caused sustained (lasting at least 24 h) increase in the apparent dissociation constant (K(d)) for [(3)H]NMS binding in rat lung compared with the control value. Concomitantly, there was a long-lasting decrease in the maximal number of binding sites (B(max)) for [(3)H]NMS. Similary, ipratropium and glycopyrrolate at 7.3 and 7.5 nmol/kg, respectively, brought about a significant increase in K(d) for [(3)H]NMS binding. The effect by ipratropium was observed at 2 h but not 12 h, and that by glycopyrrolate lasted for 24 h. Both agents had little influence on the muscarinic receptors in the bladder and submaxillary gland. The present study provides the first evidence that tiotropium, ipratropium, and glycopyrrolate administered intratracheally in rats selectively bound muscarinic receptors of the lung, and tiotropium and glycopyrrolate had a much longer-lasting effect than ipratropium.

Topics: Animals; Binding Sites; Bronchodilator Agents; Glycopyrrolate; Heart; Ipratropium; Lung; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Scopolamine Derivatives; Submandibular Gland; Tiotropium Bromide; Trachea; Urinary Bladder

Topics: Airway Remodeling; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is a complex and progressive respiratory disease characterized by incompletely reversible bronchial obstruction. The effects of current therapeutic options in early stages of COPD have been poorly investigated in the past, being this specific topic revamped by the results of recent secondary analyses from large international trials.. To measure and monitor in real life the changes in main clinical outcomes and health care resources in patients suffering from mild-to-moderate and severe COPD treated with only tiotropium br. for twenty-four months.. The population sample of the present observational retrospective study consists of 319 COPD subjects (214 males; average age 71.7 years ± 06 se) automatically extracted from the DataBase of the Health Care Institution. Inclusion criteria were: age ≥ 40 y; basal FEV1 < 80% predicted and FEV1/FVC < 70%; regular treatment with only 18 mcg tiotropium br. for the following two years. All subjects were divided into two subsets according to their FEV1 basal value: (Group A ≤ 50%, and Group B >50% predicted). Lung function; n. exacerbations; n. hospitalizations; absenteeism; n. GP's visits, and use of systemic steroids or antibiotics were checked during the observational period and mean values compared in both subsets with those of the twelve months preceding tiotropium br. (such as during other therapeutic strategies). T test was used for checking the comparability of groups, while ANOVA--Duncan test was used to compare the trends of all variables over time; p < 0.05 was accepted.. Group A, 154 individuals (104 males; mean age 72.1 years ± 0.51 se) had a mean FEV1 value of 45.4% pred. ± 0.61 se, while the remaining 165, Group B (111 males; mean age 71.4 years ± 0.60 se) had a mean FEV1 value of 65.5% pred. ± 5.7 se (p < 0,01). The two subsets were well matched for gender, age, and previous use of systemic steroids, but significantly different in terms of basal lung function, COPD morbidity, and antibiotic use. Basically, the impact of COPD confirmed higher in severe patients even if it was unexpectedly remarkable in mild-to-moderate individuals in terms of consumption of health care resources. The overall reduction in COPD morbidity was significant in both groups, but the improvement in FEV1 and in other main long-term outcomes observed in subjects with mild-to-moderate COPD was particularly significant and substantial (p < 0.001), these subjects confirming to be worth of earlier therapeutic attention.. 18 mcg tiotropium br. monotherapy for twenty-four months on a regular daily basis enables a significant minimization of COPD impact, and consents the progressive lung function recovery also in mild-to-moderate individuals, thus suggesting a possible role of tiotropium br. in affecting the natural history of COPD.

Topics: Aged; Female; Forced Expiratory Volume; Health Resources; Humans; Male; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium, a Long-acting anticholinergic bronchodilator, has many beneficial effects in chronic obstructive pulmonary disease (COPD). Among them are: a bronchodilator effect which is additive to that of beta-adrenergic agonists, that persists long-term without tolerance; reduction of dyspnea; improved exercise tolerance; enhanced response to rehabilitation; improved quality of life; and reduced frequency of exacerbations and hospital admissions. Therefore, tiotropium is widely used, and has been added to the Health Basket by the Israel Ministry of Health. In March 2008, the manufacturer informed the US Food and Drug Administration (FDAI that ongoing safety monitoring had identified a possible increased risk of stroke in patients who take this medicine. In September 2008, Singh and colleagues published a meta-analysis suggesting an increased risk of cardiovascular events in COPD patients treated with tiotropium, although there was no difference in overall mortality. A month later, the UPLIFT investigators published a 4 year placebo-controlled trial of tiotropium involving 5993 patients, in which there were slightly less cardiovascular events in the treatment group, and a trend to reduced overall mortality. The authors review the benefits and safety data, and conclude that while the benefits of tiotropium in COPD are clear, the evidence of an adverse effect on cardiovascular mortality is not sufficiently convincing. Hence, the balance of evidence supports continued use of tiotropium, especially in severe COPD.

Topics: Adverse Drug Reaction Reporting Systems; Bronchodilator Agents; Cardiovascular Diseases; Humans; Israel; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease associated with increasing morbidity and mortality and an economic burden that stretches beyond the patient to healthcare systems. Avoiding exacerbations and subsequent hospitalizations is an important clinical aim and can avoid significant costs associated with the disease. International guidelines recommend the addition of an inhaled corticosteroid (ICS) to a long-acting β₂-adrenoceptor agonist (LABA) for patients with severe to very severe COPD and a history of exacerbations.. To evaluate retrospectively over a 3-month period, the cost effectiveness of budesonide/formoterol added to tiotropium bromide (tiotropium) compared with placebo added to tiotropium in COPD patients eligible for ICS/LABA combination therapy, based on the CLIMB study (NCT00496470).. A cost-effectiveness analysis of data from the 12-week, randomized, double-blind CLIMB study of COPD patients (n = 659; eligible for ICS/LABA; aged ≥ 40 years) comparing budesonide/formoterol (Symbicort® Turbuhaler® 320/9 μg twice daily) added to tiotropium (18 μg daily) or placebo added to tiotropium was conducted. A severe exacerbation was defined as a requirement for systemic glucocorticosteroids and/or ED visit and/or hospitalization. The effectiveness variable used for this analysis was the number of severe exacerbations avoided. Direct costs (medications, hospitalizations, ED and GP visits) were calculated by applying year 2009 unit costs from Australia ($A), Canada ($Can) and Sweden (Swedish krona [SEK]) to the study's pooled resource use. One-way sensitivity analyses for each country's mean incremental cost-effectiveness ratio and sensitivity to overall exacerbations were conducted. Bootstrapping was performed to estimate the variation around resource use, exacerbations and each country's mean incremental cost-effectiveness ratio.. The mean number of severe exacerbations per patient 3-month period was 0.11 in the budesonide/formoterol added to tiotropium arm and 0.29 in the placebo added to tiotropium arm--a 62% reduction in the rate of severe exacerbations. Treatment with budesonide/formoterol added to tiotropium costs less in Australia and Canada (-$A90 [-€58] and -$Can4.51 [-€3]) and only slightly more in Sweden (SEK444 [€43]), i.e. the savings associated with fewer exacerbations more than offset the additional budesonide/formoterol drug cost in Australia and Canada, and partially offset it in Sweden. In the Australian and Canadian perspectives, budesonide/formoterol added to tiotropium was a dominant treatment (fewer exacerbations at a lower cost) compared with placebo added to tiotropium. In Sweden, the estimated incremental cost per avoided exacerbation was SEK2502 (€244.40).. Budesonide/formoterol added to tiotropium was the dominant strategy compared with placebo added to tiotropium based on a 12-week study in COPD patients eligible for ICS/LABA combination therapy in Australia and Canada, and appears to be a cost-effective strategy in Sweden.

Topics: Australia; Budesonide; Canada; Cost-Benefit Analysis; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Health Care Costs; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Scopolamine Derivatives; Sweden; Tiotropium Bromide

Inhaled anticholinergic medications (IACs) are widely used treatments for chronic obstructive pulmonary disease (COPD). The systemic anticholinergic effects of IAC therapy have not been extensively studied. This study sought to determine the risk of acute urinary retention (AUR) in seniors with COPD using IACs.. A nested case-control study of individuals with COPD aged 66 years or older was conducted from April 1, 2003, to March 31, 2009, using population-based linked databases from Ontario, Canada. A hospitalization, same-day surgery, or emergency department visit for AUR identified cases, which were matched with up to 5 controls. Exposure to IACs was determined using a comprehensive drug benefits database. Conditional logistic regression analysis was conducted to determine the association between IAC use and AUR.. Of 565,073 individuals with COPD, 9432 men and 1806 women developed AUR. Men who just initiated a regimen of IACs were at increased risk for AUR compared with nonusers (adjusted odds ratio [OR], 1.42; 95% confidence interval [CI], 1.20-1.68). In men with evidence of benign prostatic hyperplasia, the risk was increased further (OR, 1.81; 95% CI, 1.46-2.24). Men using both short- and long-acting IACs had a significantly higher risk of AUR compared with monotherapy users (OR, 1.84; 95% CI, 1.25-2.71) or nonusers (2.69; 1.93-3.76).. Use of short- and long-acting IACs is associated with an increased risk of AUR in men with COPD. Men receiving concurrent treatment with both short- and long-acting IACs and those with evidence of benign prostatic hyperplasia are at highest risk.

Topics: Acute Disease; Administration, Inhalation; Aged; Canada; Case-Control Studies; Cholinergic Antagonists; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Safety Management; Scopolamine Derivatives; Tiotropium Bromide; Urinary Retention

Topics: Acute Disease; Administration, Inhalation; Aged; Case-Control Studies; Cholinergic Antagonists; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Reference Values; Risk Assessment; Safety Management; Scopolamine Derivatives; Tiotropium Bromide; Urinary Retention

The purpose of this study was to clarify the association between morphological phenotypes according to the predominance of emphysema and efficacy of long-acting muscarinic antagonist and β(2) agonist bronchodilators in patients with chronic obstructive pulmonary disease (COPD).. Seventy-two patients with stable COPD treated with tiotropium (n = 41) or salmeterol (n = 31) were evaluated for pulmonary function, dynamic hyperinflation following metronome-paced incremental hyperventilation, six-minute walking distance, and St George's Respiratory Questionnaire (SGRQ) before and 2-3 months following treatment with tiotropium or salmeterol. They were then visually divided into an emphysema dominant phenotype (n = 25 in the tiotropium-treated group and n = 22 in the salmeterol-treated group) and an emphysema nondominant phenotype on high-resolution computed tomography, and the efficacy of the two drugs in each phenotype was retrospectively analyzed.. Tiotropium significantly improved airflow limitation, oxygenation, and respiratory impedance in both the emphysema dominant and emphysema nondominant phenotypes, and improved dynamic hyperinflation, exercise capacity, and SGRQ in the emphysema dominant phenotype but not in the emphysema nondominant phenotype. Salmeterol significantly improved total score for SGRQ in the emphysema phenotype, but no significant effects on other parameters were found for either of the phenotypes.. These findings suggest that tiotropium is more effective than salmeterol for airflow limitation regardless of emphysema dominance, and also can improve dynamic hyperinflation in the emphysema dominant phenotype, which results in further improvement of exercise capacity and health-related quality of life.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Albuterol; Bronchodilator Agents; Exercise Test; Exercise Tolerance; Female; Humans; Japan; Lung; Male; Muscarinic Antagonists; Phenotype; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Quality of Life; Recovery of Function; Respiratory Function Tests; Retrospective Studies; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Time Factors; Tiotropium Bromide; Tomography, X-Ray Computed; Treatment Outcome

Topics: Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) exacerbations are associated with systemic consequences. Data from a 4-year trial (Understanding Potential Long-term Impacts on Function with Tiotropium [UPLIFT(®)], n = 5,992) were used to determine risk for nonlower respiratory serious adverse events (NRSAEs) following an exacerbation.. Patients with ≥ 1 exacerbation were analyzed. NRSAE incidence rates (incidence rate [IR], per 100 patient-years) were calculated for the 30 and 180 days before and after the first exacerbation. NRSAEs were classified by diagnostic terms and organ classes. Maentel-Haenszel rate ratios (RR) (pre- and postexacerbation onset) along with 95% confidence intervals (CI) were computed.. A total of 3,960 patients had an exacerbation. The mean age was 65 years, forced expiratory volume in 1 s (FEV(1)) was 38% predicted, and 74% were men. For all NRSAEs, the IRs 30 days before and after an exacerbation were 20.2 and 65.2 with RR (95% CI) = 3.22 (2.40-4.33). The IRs for the 180-day periods were 13.2 and 31.0 with RR (95% CI) = 2.36 (1.93-2.87). The most common NRSAEs by organ class for both time periods were cardiac, respiratory system (other), and gastrointestinal. All NRSAEs as well as cardiac events were more common after the first exacerbation, irrespective of whether the patient had cardiac disease at baseline.. The findings confirm that, after exacerbations, serious adverse events in other organ systems are more frequent, particularly those that are cardiac in nature.

Topics: Aged; Bronchodilator Agents; Disease Progression; Female; Forced Expiratory Volume; Gastrointestinal Diseases; Heart Diseases; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Respiratory Tract Diseases; Risk; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

To assess the misclassification of chronic obstructive pulmonary disease (COPD) in Australian primary care.. A cross-sectional study was performed in 31 (19%) practices in one Australian state. 341 patients with COPD (database diagnosis or current use of tiotropium plus GP confirmation) completed spirometry and questionnaires. Predictors of misclassification were investigated with multi-level mixed-effects logistic regression allowing for clustering by practice.. Spirometric confirmation of COPD (forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio <0.7) was not present in 107 (31%) patients; 60 (56%) had normal lung function, seven (7%) had scalloped flow-volume curves and FEV1 <80% predicted, 40 (37%) had restriction (FVC <80% predicted). Among 107 misclassified patients the bronchodilators used were tiotropium in 26% and long-acting β2-agonists in 22%. The likelihood of misclassification increased with overweight/obesity (odds ratio (OR) 2.66; 95% CI 1.50 to 4.70) and self-reported allergic rhinitis/hay fever (OR 1.72; 95% CI 1.13 to 2.64) after adjustment for age, gender, and smoking.. Symptom-based diagnosis of COPD in primary care is unreliable, especially if patients are overweight, so diagnostic spirometry is essential to avoid inappropriate management.

Topics: Bronchodilator Agents; Cross-Sectional Studies; Diagnostic Errors; Forced Expiratory Volume; Humans; Logistic Models; Primary Health Care; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Spirometry; Surveys and Questionnaires; Tasmania; Tiotropium Bromide

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Drug Therapy, Combination; Ethanolamines; Evidence-Based Medicine; Formoterol Fumarate; Humans; Muscarinic Antagonists; Nebulizers and Vaporizers; Pregnenediones; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Albuterol; Bronchodilator Agents; Cardiovascular Diseases; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Albuterol; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide

Indacaterol is a novel inhaled once-daily long-acting beta(2)-agonist (LABA) for the maintenance treatment of COPD that has been compared to existing inhaled monotherapies on a number of symptomatic endpoints in clinical studies. With constrained healthcare budgets, the objective of this analysis was to evaluate the cost-effectiveness of indacaterol 150 μg, the approved starting dose for maintenance therapy, from a German heath service perspective against the most widely used bronchodilator tiotropium, and the twice-daily LABA, salmeterol.. A Markov model was developed with the following main health states: Mild, Moderate, Severe, and Very Severe COPD, based on pre-bronchodilator FEV(1) measures reported in the indacaterol clinical trials, and death. Each disease severity health state had two associated health states for severe or non-severe exacerbation. The model considered patients with moderate to severe COPD, with a mean age of 64 years. The base case time horizon was three years, with discounting set at 3% for costs and benefits. Selected clinical inputs and health state utilities were derived from indacaterol clinical trials, while costs were based on publicly available drug prices and tariffs or published sources. Inputs describing disease progression were based on published data on the rate of FEV(1) decline.. Point-estimates show that indacaterol 150 μg is dominant (lower total costs and better outcomes) against tiotropium and salmeterol. An alternative analysis comparing indacaterol 300 μg (maximum dose) against tiotropium, showed an incremental cost-effectiveness ratio (ICER) of approximately €28,300 per QALY.. Indacaterol is cost-effective compared to tiotropium and salmeterol.

Topics: Albuterol; Bronchodilator Agents; Cost-Benefit Analysis; Female; Forced Expiratory Volume; Germany; Humans; Indans; Male; Markov Chains; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quinolones; Salmeterol Xinafoate; Scopolamine Derivatives; Survival Analysis; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Asthma; Bronchodilator Agents; Excipients; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Bronchoconstriction has been reported in asthma and chronic obstructive pulmonary disease (COPD) patients after administration of some aqueous inhalation solutions. We investigated the incidence of this event during long-term clinical trials of tiotropium delivered via Respimat(®) Soft Mist™ Inhaler (SMI). We retrospectively analyzed pooled data from two identical Phase III clinical trials, in which 1990 patients with COPD received 48 weeks' treatment with once-daily tiotropium (5 or 10 μg) or placebo inhaled via Respimat(®) SMI. We recorded the incidence of bronchospasm and of a range of respiratory events that could suggest bronchoconstriction during the first 30 minutes after inhalation of study treatment on each of the eight test days. No patients reported bronchospasm. Six patients (0.3%) reported a combination of at least two events suggestive of bronchoconstriction, and 21 (1.1%) reported either rescue medication use or a respiratory adverse event. Asymptomatic falls in forced expiratory volume in one second (FEV(1)) of ≥15% were recorded on all test days, with no change in incidence over time, and affected 8.2% of those in the tiotropium groups and 14.5% of those on placebo. In COPD patients receiving long-term treatment with tiotropium 5 or 10 μg via Respimat(®) SMI, no bronchospasm was recorded, and the number of events possibly indicative of paradoxical bronchoconstriction was very low.

Topics: Administration, Inhalation; Aged; Bronchial Spasm; Bronchoconstriction; Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials, Phase III as Topic; Female; Forced Expiratory Volume; Humans; Logistic Models; Lung; Male; Middle Aged; Multicenter Studies as Topic; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The expression of CD(8) (+)CD(25) (+)FoxP(3) (+) regulatory T cells (CD(8) (+)Tregs) in the peripheral blood of patients with stable chronic obstructive pulmonary disease (COPD), and the effect of muscarinic cholinergic receptor antagonist tiotropium bromide on the expression of CD(8) (+)Tregs were investigated. Twenty-three patients with moderate to severe stable COPD were enrolled in this study. All patients inhaled tiotropium bromide (18 μg daily) for 3 months. Before and after inhalation of tiotropium bromide, peripheral blood samples were collected from the patients, and T cells were labeled by three-color labeled monoclonal antibodies. Flow cytometry was used to detect the quantity and percentage of CD(8) (+)T cells, CD(8) (+)CD(25) (+)T cells, CD(8) (+)Tregs, CD(4) (+)T cells, CD(4) (+)CD(25) (+)T cells and CD(4) (+)CD(25) (+)FoxP(3) (+) regulatory T cells (CD(4) (+)Tregs) respectively. The percentage of CD(4) (+)T cells was increased from (27.82±2.18)% to (35.53±1.3)% (t=3.20, P=0.004) in the peripheral blood of patients with stable COPD after inhalation of tiotropium bromide for 3 months, that of CD(4) (+)CD(25) (+)T cells was decreased from (10.03 ±1.42)% to (4.21 ±0.65)% (t=3.78, P=0.001), and that of CD(8) (+)Tregs was increased from (8.41 ±1.68)% to (21.34 ±4.20)% (t=2.72, P=0.013). At baseline, CD(8) (+)T cells, CD(8) (+)CD(25) (+)T cells and CD(4) (+)Tregs were detectable in the peripheral blood, but no significant changes were observed after treatment. Linear correlation analysis revealed that the difference before and after treatment in CD(4) (+)T cells and CD(4) (+)CD(25) (+)T cells was negatively correlated with the ratio of change in CD(8) (+)Tregs before and after treatment (r=-0.61, P=0.013; r=-0.72, P=0.001 respectively). In the peripheral blood of patients with stable COPD, there was the expression of CD(8) (+)Tregs and CD(4) (+)Tregs. Muscarinic receptor antagonist, tiotropium bromide, can promote the amplification of CD(4) (+)T cells, inhibit the expression of CD(25) (+)T cells, and enhance the expression of CD(8) (+)Tregs. CD(8) (+)Tregs and CD(4) (+)Tregs can be used as new indicators to understand the immune status of patients. They are helpful in judging the treatment efficacy and disease immunophenotype.

Topics: Aged; CD8 Antigens; Female; Forkhead Transcription Factors; Gene Expression; Humans; Interleukin-2 Receptor alpha Subunit; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; T-Lymphocytes, Regulatory; Tiotropium Bromide

To compare, in commercially-insured individuals 240 years old, the risk of chronic obstructive pulmonary disease (COPD) exacerbations and COPD-related health care utilization and costs in patients initiating maintenance treatment with fluticasone propionate/salmeterol xinafoate 250 microg/50 microg (FSC) with those in patients initiating treatment with tiotropium bromide (TIO).. Retrospective observational cohort study.. The risk of COPD exacerbation (moderate, severe, and any), COPD-related health care utilization, and COPD-related costs (overall and by service setting) were assessed over 12 months after the initiation of treatment with FSC or TIO in commercially-insured patients > or =40 years old diagnosed with COPD.. After adjusting for covariates, treatment with FSC compared with treatment with TIO was associated with a 14% reduction in risk of severe exacerbation (p = 0.0406), defined as the occurrence of a COPD-related hospitalization; with less health care utilization across several categories of care; with 25% lower COPD-related medical costs ($1814 versus $2258 per patient, p < 0.0001); and with 10% lower COPD-related total costs ($2991 versus $3304 per patient, p < 0.0001) over a 12-month follow-up period. Pharmacy costs were equivalent between FSC and TIO.. Initiation of maintenance therapy with FSC compared with TIO was associated with significant reductions in the risk of severe exacerbations, health care utilization, and COPD-related medical and total costs. Considered in the context of other findings, these data suggest that earlier maintenance treatment with FSC offers clinical and economic benefits over maintenance treatment with TIO.

Topics: Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Cohort Studies; Drug Combinations; Drug Costs; Drug Therapy, Combination; Economics, Pharmaceutical; Female; Fluticasone-Salmeterol Drug Combination; Glucocorticoids; Humans; Insurance Coverage; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Cholinergic Antagonists; Humans; Meta-Analysis as Topic; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

To conduct a cost-effectiveness analysis comparing roflumilast/tiotropium therapy vs tiotropium monotherapy in patients with severe-to-very severe COPD.. The economic evaluation applied a disease-based Markov cohort model with five health states: (1) severe COPD, (2) severe COPD with a history of severe exacerbation, (3) very severe COPD, (4) very severe COPD with a history of severe exacerbation, and (5) death. Within a given health state, a patient may have a mild/moderate or severe exacerbation or die. Data from roflumilast clinical trials and published literature were used to populate model parameters. The model calculated health outcomes and costs for roflumilast/tiotropium therapy vs tiotropium monotherapy over a 5-year horizon. Incremental cost and benefits were then calculated as cost-effectiveness ratios, including cost per exacerbation avoided and cost per quality adjusted life year ($/QALY).. Over a 5-year horizon, the estimated incremental costs per exacerbation and per severe exacerbation avoided were $589 and $5869, respectively, and the incremental cost per QALY was $15,815. One-way sensitivity analyses varying key parameters produced an incremental cost per QALY ranging from $1963-$32,773.. A number of key parameters used in the model were obtained from studies in the literature that were conducted under different contexts. Specifically, the relative risk estimate for severe COPD patients originates from a small trial not designed to demonstrate the impact of roflumilast on frequency of exacerbations. In addition, the model extrapolates the relative risk estimates over periods of 5-30 years, even though the estimates were only observed in trials that spanned less than a year.. The addition of roflumilast to tiotropium is cost-effective for the treatment of severe to very severe COPD patients.

Topics: Aminopyridines; Benzamides; Bronchodilator Agents; Cost-Benefit Analysis; Cyclopropanes; Drug Combinations; Health Services; Health Status; Humans; Markov Chains; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Reproducibility of Results; Scopolamine Derivatives; Severity of Illness Index; Time Factors; Tiotropium Bromide

The clinical trial safety database for tiotropium has been augmented with a 4-year trial in patients with COPD, which provides an opportunity to better evaluate the cardiovascular (CV) profile of tiotropium.. Trials with the following criteria were considered: > or = 4 weeks, randomized, double-blind, parallel-group, placebo-controlled. Inclusion/exclusion criteria were similar, including spirometry-confirmed COPD, > or = 10 pack-year smoking, and age > or = 40 years. Adverse events were collected throughout each trial using standardized case report forms. Incidence rates (IRs) were determined from the total number of patients with an event divided by total time at risk. Rate ratios (RRs) and 95% CI for tiotropium/placebo were calculated. IRs were determined for all-cause mortality and selected CV events, including a composite CV end point encompassing CV deaths, nonfatal myocardial infarction (MI), nonfatal stroke, and the terms sudden death, sudden cardiac death, and cardiac death.. There were 19,545 patients randomized: 10,846 (tiotropium) and 8,699 (placebo) from 30 trials. Mean FEV(1) = 1.15 +/- 0.46 L (41 +/- 14% predicted), 76% men, mean age = 65 +/- 9 years. Cumulative exposure to study drug was 13,146 (tiotropium) and 11,095 (placebo) patient-years. For all-cause mortality, the IR was 3.44 (tiotropium) and 4.10 (placebo) per 100 patient-years (RR [95% CI] = 0.88 [0.77-0.999]). IR for the CV end point was 2.15 (tiotropium) and 2.67 (placebo) per 100 patient-years (RR [95% CI] = 0.83 (0.71-0.98]). The IR for the CV mortality excluding nonfatal MI and stroke was 0.91 (tiotropium) and 1.24 (placebo) per 100 patient-years (RR [95% CI] = 0.77 [0.60-0.98]). For total MI, cardiac failure, and stroke the RRs (95% CI) were 0.78 (0.59-1.02), 0.82 (0.69-0.98), and 1.03 (0.79-1.35), respectively.. Tiotropium was associated with a reduction in the risk of all-cause mortality, CV mortality, and CV events.

Topics: Administration, Inhalation; Aged; Cardiovascular Diseases; Cause of Death; Cholinergic Antagonists; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Incidence; Male; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Spirometry; Survival Rate; Tiotropium Bromide; Treatment Outcome; United States

Ipratropium bromide, an anticholinergic drug used for the treatment of asthma and chronic obstructive pulmonary disease, has low oral bioavailability, but systemic exposure, superior to oral administration, can be achieved by inhalation. Therefore, we investigated the pulmonary absorption mechanism of ipratropium using human bronchial epithelial BEAS-2B cells. [3H]Ipratropium uptake by BEAS-2B cells was temperature-dependent and saturable, with a K(m) value of 78.0 microM, suggesting involvement of carrier-mediated uptake. An RT-PCR study showed that organic cation/carnitine transporters OCTN1 and OCTN2 are expressed in BEAS-2B cells, but organic cation transporters (OCTs) are not. Uptake of [3H]ipratropium by HEK293 cells expressing OCTN1 (HEK293/OCTN1) and OCTN2 (HEK293/OCTN2) was significantly increased, compared with mock-transfected cells, and the estimated K(m) values were 444 microM and 53.0 microM, respectively. Finally, the contributions of OCTN1 and OCTN2 to ipratropium uptake were evaluated by measuring [3H]ipratropium uptake by BEAS-2B cells in which OCTN1 or OCTN2 gene expression had been silenced. Knock-down of OCTN1 or OCTN2 suppressed the uptake of [3H]ipratropium to 78.2% and 14.8% of that by control BEAS-2B cells, respectively. In addition, another anticholinergic, tiotropium, was also taken up by both HEK293/OCTN1 and HEK293/OCTN2 cells. Therefore, ipratropium and tiotropium are taken up primarily by OCTN2, and to a lesser extent by OCTN1, in bronchial epithelial cells. These findings are consistent with the pharmacological activity of the drugs after administration via inhalation.

Topics: Absorption; Administration, Inhalation; Base Sequence; Biological Transport, Active; Bronchi; Cell Line; Cholinergic Antagonists; DNA Primers; Epithelial Cells; Humans; Ipratropium; Kinetics; Lung; Organic Cation Transport Proteins; Pulmonary Disease, Chronic Obstructive; RNA Interference; RNA, Small Interfering; Scopolamine Derivatives; Solute Carrier Family 22 Member 5; Symporters; Tiotropium Bromide

This study presents a cost-effectiveness and budget impact analysis comparing cost and outcomes for UK patients with COPD treated with either tiotropium, ipratropium or salmeterol.. A previously-published COPD cost-effectiveness model was adapted for the UK, then used to estimate the cost-effectiveness of tiotropium compared to salmeterol and ipratropium. Additional epidemiological data were used to estimate the budget impact of switching patients from ipratropium or salmeterol to tiotropium.. In England, the estimated annual cost per patient on tiotropium was pound1350, on salmeterol was pound1404, and on ipratropium was pound1427; in Scotland/Wales/Northern Ireland (S/W/NI) these costs were pound1439, pound1565, and pound1631, respectively. Tiotropium patients experienced better quality-adjusted life-years (QALYs) across all comparisons, and this option was therefore dominant compared to salmeterol and ipratropium. The probability of tiotropium being dominant ranged from 72% to 87% across comparisons. At a willingness to pay threshold of pound20,000 per QALY, tiotropium had at least a 97% chance of being cost-effective. The estimated annual saving per primary care trust (PCT) of switching patients from salmeterol and ipratropium to tiotropium in England was pound230,000 and in S/W/NI was pound160,000.. Tiotropium is a cost-effective alternative to ipratropium and salmeterol, and switching COPD patients from ipratropium and salmeterol to tiotropium could result in considerable cost savings for PCTs along with improvements in quality-of-life.

Topics: Albuterol; Bronchodilator Agents; Cost-Benefit Analysis; Humans; Ipratropium; Models, Econometric; Multivariate Analysis; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; United Kingdom

Topics: Bronchodilator Agents; Cholinergic Antagonists; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide

To report a case of refractory tachycardia after an excessive dose of inhaled tiotropium.. A 74-year-old male with atrial fibrillation was admitted for increased heart rate and shortness of breath. The patient's heart rate was initially stabilized between 80 and 90 beats/min with metoprolol succinate 50 mg daily. During hospitalization, he accidentally received 5 capsules of tiotropium 18 microg inhaled as a single dose (total 90 microg) and, approximately 15 minutes later, his heart rate increased from 80 to 160 beats/min. Over 5 days of hospitalization, the patient's tachycardia was difficult to control and he required multiple atrioventricular (AV) nodal blocking agents (physostigmine, metoprolol tartrate, diltiazem) for effective stabilization prior to discharge. On outpatient follow-up 11 days after the ingestion the patient's heart rate was in the 40s and the AV nodal blocking agents were proportionately decreased.. Tiotropium is a long-acting anticholinergic medication used to treat chronic obstructive pulmonary disease. Little has been reported as to the potential systemic toxicities of tiotropium. Tachycardia is listed as a potential adverse effect, but based on a MEDLINE search (1966-July 2009) using tiotropium, tachycardia, and overdose as search terms, there have been no case reports published. Renal impairment may increase plasma concentrations of tiotropium; our patient's creatinine clearance was estimated to be below 50 mL/min. According to the Naranjo probability scale, our patient's development of tachycardia was probably associated with tiotropium inhalation.. Tiotropium can be temporally implicated in a rapid heart rate following excessive ingestion. Health care professionals should be aware of tachycardic effects of tiotropium, particularly in patients with underlying structural heart disease, atrial fibrillation, and renal impairment.

Topics: Administration, Inhalation; Aged; Atrial Fibrillation; Bronchodilator Agents; Drug Overdose; Follow-Up Studies; Heart Rate; Humans; Male; Medication Errors; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tachycardia; Tiotropium Bromide

Topics: Cardiovascular Diseases; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Albuterol; Androstadienes; Anti-Inflammatory Agents; Breathing Exercises; Bronchodilator Agents; Combined Modality Therapy; Drug Therapy, Combination; Fluticasone; Humans; Oxygen Inhalation Therapy; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide

Topics: Adrenergic beta-Agonists; Albuterol; Aminopyridines; Benzamides; Breast Neoplasms; Bronchodilator Agents; Cyclopropanes; Disease Progression; Early Detection of Cancer; Evidence-Based Medicine; Female; Humans; Papillomavirus Vaccines; Preventive Medicine; Primary Prevention; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Secondary Prevention; Tiotropium Bromide; Uterine Cervical Neoplasms

Tiotropium bromide is a long acting muscarinic antagonist (LAMA), marketed under the brand name Spiriva, for the treatment of chronic obstructive pulmonary disease (COPD). Besides its proven direct bronchodilatory activity, recent clinical studies demonstrated that tiotropium is able to reduce the exacerbation rate and impact the clinical course of COPD. One significant pathological feature believed to be causative for the progressive nature of COPD is chronic pulmonary inflammation. The aim of the present study was to investigate the anti-inflammatory activity of tiotropium on cigarette smoke-induced pulmonary inflammation in mice. C57Bl/6 mice were exposed to cigarette smoke (CS) for four days with increasing exposure time for up to 6h per day to elicit pulmonary inflammation and mediator release. One hour before smoke exposure, animals were treated with tiotropium by inhalation (0.01-0.3mg/mL) for 5 min; 18h after the last CS exposure a bronchoalveolar lavage was performed. Tiotropium concentration-dependently inhibited pulmonary neutrophilic inflammation with an IC(50) of 0.058 mg/mL and a maximum inhibition of 60% at 0.3mg/mL. Furthermore, the CS-induced pulmonary release of leukotriene B(4), interleukin-6, keratinocyte-derived chemokine, monocyte chemotactic protein-1, macrophage inflammatory protein-1 alpha and -2, and tumor necrosis factor alpha was dose-dependently reduced. The bronchodilatory activity of tiotropium against acetycholine-induced bronchoconstriction was found to be in the same dose range as the anti-inflammatory activity with an IC(50) of 0.045 mg/mL and a maximum bronchodilation of 90% at 0.3mg/mL. Our data suggest that the beneficial effects of tiotropium on the course of COPD shown in patients may be associated with an anti-inflammatory activity.

Topics: Acetylcholine; Administration, Inhalation; Animals; Bronchoconstriction; Bronchodilator Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Inflammation; Inhibitory Concentration 50; Mice; Mice, Inbred C57BL; Neutrophils; Nicotiana; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoke; Time Factors; Tiotropium Bromide

to investigate the levels of peripheral CD(8)(+)CD(25)(+)Foxp(3)(+) regulatory T cells (CD(8)(+)CD(25)(+)Treg) in stable chronic obstructive pulmonary disease (COPD) patients, and the effect of muscarinic cholinergic receptor antagonist, tiotropium bromide, on the expression of CD(8)(+)CD(25)(+)Treg.. from Oct. 2007 to Mar. 2008, 23 patients with stable moderate to severe COPD received tiotropium bromide inhalation (18 microg daily) for 3 months. Before and after the use of tiotropium bromide, lung function was performed and peripheral vein blood samples were collected from the patient. Lymphocytes were isolated by three-color labeled monoclonal antibodies flow cytometry to detect the quantity and percentage of CD(8)(+)T cell, CD(8)(+)CD(25)(+) T cell, CD(8)(+)CD(25)(+)Treg, CD(4)(+)T cell, CD(4)(+)CD(25)(+) T cell and CD(4)(+)CD(25)(+)Treg, respectively. Paired t test was used for comparison between data before and after treatment.. in patients with stable COPD, after tiotropium bromide treatment, the percentage of CD(4)(+) T cells was increased from (28 +/- 10)% to (36 +/- 6)%, and the difference was significant (t = 3.20, P < 0.01). CD(4)(+)CD(25)(+) was decreased from (10 +/- 7)% to (4 +/- 3)% (t = 3.78, P < 0.01), and CD(8)(+)CD(25)(+)Treg was increased from (8 +/- 8)% to (21 +/- 21)% (t = 2.72, P < 0.05). At baseline, CD(8)(+) cells, CD(8)(+)CD(25)(+) cells and CD(4)(+)CD(25)(+)Treg were detectable in the peripheral blood, but no significant changes were observed after treatment. After treatment with tiotropium bromide, the lung function was markedly improved; FEV(1), FEV(1)/Pre%, and FEV(1)/FVC were increased from (1.0 +/- 0.3) L, (35 +/- 10)% and (41 +/- 8)% to (1.1 +/- 0.3) L, (40 +/- 11)% and (45 +/- 11)%, respectively (t = 2.65, 2.56 and 2.37, respectively, all P < 0.05). By linear correlation analysis, the quantity of changes of CD(4)(+) T cells and CD(4)(+)CD(25)(+) T cells were negatively correlated with the rate of change in CD(8)(+)CD(25)(+)Treg (r = -0.61, P < 0.05 and r = -0.72, P < 0.01, respectively).. in the peripheral blood of patients with stable COPD, there was expression of CD(8)(+)CD(25)(+)Treg and CD(4)(+)CD(25)(+)Treg. The muscarinic receptor antagonist tiotropium bromide, promoted the amplification of CD(4)(+), inhibited the expression of CD(25)(+), and enhanced the expression of CD(8)(+)Treg, suggesting that muscarinic receptor antagonist tiotropium bromide may possess immunomodulation function.

Topics: Aged; Bronchodilator Agents; CD8-Positive T-Lymphocytes; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; T-Lymphocytes, Regulatory; Tiotropium Bromide

Topics: Bronchodilator Agents; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Tiotropium bromidum is an inhaled long acting anticholinergic used as first line monotherapy in stable COPD due to its beneficial effects on the lung function, respiratory symptoms, quality of life or disease morbidity. However there is limited data on its effects on mortality.. The results of the UPLIFT (Understanding Potential Long-Term Impacts on Function with Tiotropium) study evaluating the effects of 4 year therapy with tiotropium on above mentioned outcomes including mortality.. Tiotropium demonstrated an uniform beneficial effect on mortality risk reduction but subset analyses yielded relevant results as well.. On long-term basis tiotropium therapy can reduce mortality rate overall and can exert such protective effects in various subsets such as patients with very severe COPD.

Topics: Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Scopolamine Derivatives; Survival Rate; Tiotropium Bromide

28 Consecutive COPD patients performed four 6-minute walking tests (6-MWTs) in 2 different days before and 2, 4 and 6h after the inhalation of formoterol 12microg or tiotropium 18microg, respectively. Physical activity during each 6-MWT was assessed by the SenseWear Armband. At each time also spirometry was performed. Both formoterol and tiotropium induced a significantly sustained bronchodilation and influenced hyperinflation. Formoterol significantly increased distance walked in 6min at 2h and at 4h, whereas tiotropium significantly increased it at all time points. There was a trend to an increase in calories and metabolic equivalents of task (METs) after formoterol and a decrease after tiotropium, but changes were not statistically significant. Total energy expenditure for each 6-MWT was not changed by formoterol, but decreased in significant manner 6h after the inhalation of tiotropium. Active energy expenditure at physical activity level of more than 3 METs decreased significantly after tiotropium at each 6-MWT, but not after formoterol. We did not find any significant correlation between the changes in lung function and those of parameters recorded with SenseWear Armband. Our study seems to indicate that tiotropium, but not formoterol, is able to reduce energy expenditure in COPD patients, although both drugs elicit significant bronchodilation and are able to increase the distance walked in 6min.

Topics: Bronchodilator Agents; Drug Therapy, Combination; Energy Metabolism; Ethanolamines; Exercise Test; Exercise Tolerance; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide; Treatment Outcome; Walking

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Bronchodilator Agents; Clinical Trials as Topic; Female; Forced Expiratory Volume; Humans; Lung; Male; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide

Topics: Aged; Bronchodilator Agents; Forced Expiratory Volume; Humans; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide

Topics: Bronchodilator Agents; Dyspnea; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Withholding Treatment

Topics: Administration, Inhalation; Albuterol; Bronchodilator Agents; Drug Therapy, Combination; Humans; Myocardial Infarction; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Cardiovascular Diseases; Clinical Trials as Topic; Drug Approval; Humans; Meta-Analysis as Topic; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; United States; United States Food and Drug Administration

Chronic obstructive pulmonary disease (COPD) represents a significant burden for healthcare systems that is expected to grow further in the future. Inhaled long-acting bronchodilators, including tiotropium, represent the cornerstone of management of COPD patients. Economic studies evaluating the cost-effectiveness ratio of inhaled bronchodilators have to take into account several parameters, including the reduction of COPD exacerbations and related hospitalizations, as well as disease modification and improvement in quality of life and mortality. At an era when the healthcare resources are unlikely to grow as quickly as demand, economic analyses remain the cornerstone for the justification of the broad use of medication with an acceptable cost-effectiveness ratio. The greatest importance of such studies in COPD is the identification of subgroups of patients that will have the most benefit with an acceptable cost-effectiveness ratio for the healthcare providers. The development of models that will incorporate a global evaluation of the different aspects of this multi-component disease, in order to provide the best available care to each individual patient is urgently needed.

Topics: Bronchodilator Agents; Cost of Illness; Cost-Benefit Analysis; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium is reimbursed since March 2004 in Belgium for the treatment of Chronic Obstructive Pulmonary Disease (COPD). Questions however remain on this product's value for money. The purpose of this study is to calculate tiotropium's cost-effectiveness under real-world conditions.. Strengths of both observational and RCT data were combined in a model. A large longitudinal (2002-2006) observational dataset of regular tiotropium users (56,321 patients) was analysed to retrieve the baseline risk for exacerbations and exacerbation-related hospitalisations the year before the first delivery of tiotropium. The relative treatment effect from the UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) trial was then applied to this baseline risk to reflect the effect of tiotropium treatment and calculate the intervention's incremental cost-effectiveness ratio (ICER).. After 1000 Latin Hypercube simulations, the incremental benefit expressed as quality-adjusted life years (QALY) gained is on average 0.00048 (95% confidence interval (CI) 0.00009-0.00092). In combination with a substantial mean incremental cost of €373 per patient (95% CI 279-475), this results in an unfavourable average ICER of €1,244,023 (95% CI 328,571-4,712,704) per QALY gained. Results were most sensitive to the treatment effect on hospitalisations. Based on our large observational database, up to 89% of the patients were not hospitalised for COPD in the year before the first tiotropium delivery.. The main cause for tiotropium's unfavourable cost-effectiveness ratio is a combination of a relative high price for tiotropium, a low number of hospitalisations without tiotropium treatment (on average 0.14/year) and a non-significant treatment effect (on average 0.94) with respect to avoiding exacerbation-related hospitalisations. From an economic point of view, a revision of reimbursement modalities (e.g. with a lower price) would be justified and would entail a more efficient use of resources.

Topics: Aged; Belgium; Bronchodilator Agents; Confidence Intervals; Cost-Benefit Analysis; Female; Hospitalization; Humans; Insurance, Health, Reimbursement; Male; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Scopolamine Derivatives; Tiotropium Bromide

chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and structural alterations (ie, tissue remodeling) throughout the conducting airways, parenchyma, and pulmonary vasculature. Matrix metalloproteinases (MMPs) are extracellular degrading enzymes that play a critical role in inflammatory cell infiltration and tissue remodeling, but the influence of the agents that are used for the treatment of COPD on the production of MMPs is not well understood.. the present study aimed to examine the influence of tiotropium bromide hydrate (TBH) on the production of MMPs from lung fibroblasts (LFs) induced by transforming growth factor (TGF)-β in vitro.. LFs, at a concentration of 5 × 10(5) cells·mL(-1), were stimulated with TGF-β in the presence of various concentrations of TBH. MMP-1 and MMP-2 levels in culture supernatants were examined by enzyme-linked immunosorbent assay (ELISA), and MMP messenger ribonucleic acid (mRNA) expression was examined by real-time polymerase chain reaction (RT-PCR). The influence of TBH on TGF-β signaling pathways was also analyzed by examining Smad activation and signaling protein phosphorylation by ELISA.. TBH at more than 15 pg·mL(-1) inhibited the production of MMP-1 and MMP-2, but not tissue inhibitor of matrix metalloproteinase (TIMP)-1 and TIMP-2, from LFs, after TGF-β stimulation. TBH also suppressed MMP mRNA expression through the inhibition of Smad activation and signaling protein, extracellular-signal-regulated kinase (ERK) 1 and 2, and c-Jun N-terminal kinase (JNK), phosphorylation.. These results may suggest that TBH suppresses MMP production from LFs, through interference of TGF-β-mediated signaling pathways and results in favorable modification of the clinical status of COPD.

Topics: Adult; Aged; Base Sequence; Bronchodilator Agents; Cell Culture Techniques; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Humans; Lung; Male; Matrix Metalloproteinases; Middle Aged; Polymerase Chain Reaction; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smad2 Protein; Tiotropium Bromide; Transforming Growth Factor beta

We report the efficacy and safety of experimentally nebulized tiotropium use. We identified 19 elderly very severe COPD (GOLD stage IV) inpatients unable to use tiotropium in the Handihaler by themselves from January 2008 through May 2009. The contents of an 18 microg capsule of tiotropium were dissolved in 5 ml saline and nebulized via a nebulizer.. Nebulized tiotropium improved the symptoms of all COPD patients, and the ADL scores of 12 COPD patients. All COPD patients tolerated nebulized tiotropium well, although mild dry mouth was reported by a single COPD patient.. Tiotropium therapy for COPD patients is recommended in all GOLD stages. Our report showed that COPD patients (GOLD stage IV) who had difficulties using a tiotropium Handihaler benefitted from nebulized tiotropium. This helped them to continue their COPD therapy and was demonstrated to be an effective and well tolerated treatment option.

Topics: Aged, 80 and over; Cholinergic Antagonists; Female; Humans; Male; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

This observational study with tiotropium Respimat® was performed in a real-life setting to investigate its effectiveness with regard to physical functioning and tolerability.. Patients with chronic obstructive pulmonary disease (COPD; n = 1,230; mean age, 65.5 years) received tiotropium 5 μg once daily via Respimat® Soft Inhaler for 6 weeks in an open-label observational study. At baseline and week 6, patients completed the Physical Function subdomain [PF-10] of the Short Form (SF) 36 questionnaire.. Improvement in standardized PF-10 score of ≥10 points was achieved by 61.5% of patients. Mean (SD) standardized PF-10 scores improved by 13.4 (15.9) points, from 49.0 (24.5) to 62.3 points (23.5; P < 0.001). Results in smokers (n = 435) were not significantly different to those in nonsmokers. The general condition of patients improved during treatment. Adverse events were reported by 4.0% of patients and were chiefly respiratory symptoms and dry mouth.. In COPD patients receiving tiotropium Respimat® in daily practice, physical function improved rapidly within 6 weeks of treatment, irrespective of smoking status.

Topics: Activities of Daily Living; Administration, Inhalation; Aged; Bronchodilator Agents; Cholinergic Antagonists; Female; Germany; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Patient Satisfaction; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Scopolamine Derivatives; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible progressive airflow limitation related to tobacco smoking. This limitation is caused by chronic inflammation of the airways and lung parenchyma and is associated with increased activity of parasympathetic system. The most effective bronchodilators in COPD are muscarinic receptor antagonists (MRA), which reverse, at least in part, compromised respiratory function. MRA also contribute to control inflammatory processes via interactions with inflammatory signaling molecules. The use of the long-acting cholinolytic bronchodilatator - tiotropium, with high affinity to M3 receptors, is suggested as a first line maintenance treatment in COPD patients.. In this study we assessed M3 receptor protein expression in induced sputum of 27 stable COPD patients before and after therapy consisting of 18 μg once daily tiotropium for 12 weeks. Lung function tests including spirometry, lung volumes, and DLCO were performed before and after therapy in all COPD patients. The patients were subjected to the sputum induction procedures before and after therapy. Sputum cells were isolated, sample-specific cell profiles were characterized, and the cells were processed to isolate pure cytosolic fractions. Cytosolic M3 protein and HDAC2 levels and nuclear acetylated histone H3 (AcH3) expression was quantified using specific antibodies against human proteins and Western blot with enhanced luminescence detection.. Therapy significantly increased the mean forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) volume (P<0.05). The mean expression of M3 protein was higher by 37% after therapy (P<0.05), HDAC2 expression was not altered, while AcH3 level was increased by about 90% (P<0.01), compared with the corresponding data before therapy. HDAC2 expression before therapy was positively correlated with AcH3 expression (r = 0.74), while after therapy no correlation was detected. FEV1, FCV, and cytosolic M3 protein expression did not correlate with other biochemical parameters tested.. Twelve weeks of tiotropium therapy in COPD patients improves clinical indices of lung function and involves alterations in sputum cell chromatin acetylation and also increased cholinergic M3 receptor internalization.

Topics: Acetylation; Cytosol; Forced Expiratory Volume; Histones; Humans; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Scopolamine Derivatives; Sputum; Tiotropium Bromide; Vital Capacity

Relative costs and utilization-related outcomes of a fluticasone propionate 250 μg + salmeterol 50 μg combination (FSC), tiotropium bromide, and ipratropium as initial maintenance therapy in COPD have not been compared in a commercially-insured population.. This retrospective, observational cohort study used health care claims data from January 2004 to June 2009 from a large administrative database for patients aged ≥40 years with COPD. Time-to-first COPD-related health care event beginning 30 days following therapy initiation with FSC (n = 16,684), ipratropium alone or in fixed dose combination with albuterol (n = 14,449), or tiotropium (n = 12,659) was estimated using Cox proportional hazard models that controlled for differences in patient demographic characteristics, health care utilization, and comorbidities at baseline. Mean adjusted costs and numbers of COPD-related health care encounters and prescription medication fills were compared among patients with 12 months of follow-up (FSC, n = 12,595; ipratropium, n = 10,617; tiotropium, n = 9126).. With FSC as the reference, risk for a COPD-related hospitalization and/or emergency department visit was significantly higher for ipratropium (hazard ratio [HR] 1.64, 95% confidence interval [CI] 1.50-1.79) and tiotropium (HR 1.29, CI 1.17-1.41). Mean adjusted 12-month COPD-related total health care costs were lower for FSC ($2068, standard deviation [SD] $1190) than for ipratropium ($2841, SD $1858) and tiotropium ($2408, SD $1511, both P <0.05). Mean number of COPD-related hospitalizations, emergency department visits, and outpatient visits associated with an oral corticosteroid or antibiotic were also lower for FSC than for ipratropium and tiotropium (all P <0.05).. In this retrospective "real-world" observational sample of COPD patients, initiating treatment with FSC was associated with significantly better clinical and economic outcomes compared with short- and long-acting anticholinergic therapy. Consistent with the goal of preventing and reducing exacerbations advocated by global guidelines, the findings suggest that initiation of maintenance treatment with FSC may afford clinical benefits at a lower cost than anticholinergic treatment.

Topics: Aged; Albuterol; Ambulatory Care; Androstadienes; Cholinergic Antagonists; Cost-Benefit Analysis; Drug Combinations; Drug Costs; Drug Prescriptions; Emergency Medical Services; Female; Fluticasone-Salmeterol Drug Combination; Glucocorticoids; Hospital Costs; Hospitalization; Humans; Insurance, Pharmaceutical Services; Ipratropium; Kaplan-Meier Estimate; Male; Middle Aged; Models, Economic; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Risk Assessment; Risk Factors; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome; United States

To evaluate the efficacy and safety of Spiriva (thiotropium bromide 18 microg for inhalation via a HandiHaler device) in patients with chronic obstructive pulmonary disease (COPD) of all severities in routine clinical practice in Russia.. The study enrolled 407 patients (68 women and 339 men) with COPD who used thiotropium bromide (Spiriva) for 8 weeks. Most (72.3%) of the patients were aged 50-70 years; active smokers were 64.9%; ex-smokers were 27%; smoking duration averaged 38.6 pack-years; Severe, moderate, very severe, and mild COPD was observed in 38.6, 37.3, 18.4, and 5.7%, respectively. By the start of the trial, 305 (74.5%) had received concomitant therapy.. After 8-week thiotropium bromide therapy, there was a significant increase in bronchial patency, as suggested by considerable increments in the postbronchial indices: forced expiratory volume in one second (FEV1) by an average of 290 ml (20.4%) of the baseline level during treatment and forced vital capacity (FVC) by 310 ml (12.1%). By the end of the trial, the mean increase in inspiratory capacity (IC) by 180 ml (8.07%) of the baseline value was indicative of decreased lung hyperinflation in the treated patients. The significant increment in mean FEV1, FVC, and IC was observed in patients with any severity of COPD.. The RUSSE study has indicated that there may be very good results in patients with COPD of any severity and a steady-state positive effect just after 8-week thiotropium bromide treatment. This treatment improves bronchial patency and diminishes lung hyperinflation, thus improving the patients' health status and exercise endurance.

Topics: Administration, Inhalation; Bronchodilator Agents; Female; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Respiration; Respiratory Function Tests; Russia; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.

Topics: Administration, Inhalation; Animals; Bronchial Spasm; CHO Cells; Cricetinae; Cricetulus; Drug Stability; Esters; Guinea Pigs; Humans; Male; Mice; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quaternary Ammonium Compounds; Quinuclidines; Radioligand Assay; Receptor, Muscarinic M3; Stereoisomerism; Structure-Activity Relationship; Tropanes

Knowledge on the effects of the additive bronchodilatory effects of short-acting agents on the top of the effect of long-acting bronchodilators is limited. In this trial, we examined the influence of higher than conventional doses of the short-acting inhaled beta(2)-adrenergic agent salbutamol and the short-acting anticholinergic drug ipratropium bromide on bronchodilation induced by a regular treatment with the long-acting anticholinergic drug tiotropium 18 microg/day in 30 patients with stable COPD. On 3 separate days, a dose-response curve to inhaled salbutamol (100 microg puff-1), ipratropium bromide (20 microg puff-1) or placebo was constructed 3h after inhalation of the last dose of tiotropium, using one puff, one puff, two puffs and two puffs, for a total cumulative dose of 600 microg salbutamol or 120 microg ipratropium bromide. Doses were given at 30-min intervals and measurements made 15 min after each dose. At the highest cumulative dose, salbutamol showed a trend to be more effective than ipratropium bromide in improving FEV(1) (0.157 L vs 0.125 L), and reducing sRaw (-4.52 kPa/s vs 3.57 kPa/s), although the differences between the two treatments were always not significant (p>0.05), whereas there was no substantial difference between the two drugs in changing FVC (0.179 L vs 0.168 L), IC (0.254 L vs 0.240 L), TGV (-0.444 L vs -0.441 L), TLC (-0.334 L vs -0.318 L) and RV (-0.467 L vs -0.498 L). Both drugs did not affect heart rate and SpO2. Our results indicate that there is not much difference in bronchodilation between adding higher than conventional doses of salbutamol or ipratropium bromide to tiotropium in patients with stable COPD. Effective improvement of the pulmonary function may be achieved in such a type of patients by adding salbutamol 600 microg or ipratropium bromide 120 microg to regular tiotropium. These is an interesting finding mainly for those COPD patients suffering from cardiovascular co-morbidities that are at highest risk of myocardial infarction, congestive heart failure, cardiac arrest and sudden cardiac death when treated with elevated doses of a beta(2)-agonist (EudraCT number: 2007-001597-82).

Topics: Aged; Albuterol; Bronchi; Bronchodilator Agents; Dose-Response Relationship, Drug; Female; Forced Expiratory Flow Rates; Forced Expiratory Volume; Heart Rate; Humans; Ipratropium; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking; Tiotropium Bromide

Although airflow limitation improved by inhaled anticholinergic drugs varies among individuals with chronic obstructive pulmonary disease (COPD), the relationship between actual bronchodilation and improved pulmonary function and where in the lung such bronchodilation occurs remains unknown. A study was undertaken to determine the relationship between improved pulmonary function and changes in airway calibre at various sites in the airways in response to inhaled anticholinergic agents in patients with COPD using three-dimensional computed tomography (CT).. CT scans were performed at deep inspiration and detailed pulmonary function tests before and 1 week after daily inhalations of tiotropium bromide in 15 patients with clinically stable COPD. The airway luminal area was examined at the third (segmental) to the sixth generations of eight bronchi in the right lung.. Bronchodilation was demonstrated by an overall average increase of 39% in the inner luminal area, and the mean (SE) forced expiratory volume in 1 s (FEV(1)) increased from 1.23 (0.11) l to 1.47 (0.13) l. The magnitude of bronchodilation was closely correlated with improved pulmonary function, particularly with that of FEV(1) (r = 0.843, p<0.001). Such correlations were significant at the fourth to the sixth generation but not at the third generation of bronchi, and the slope of the regression lines became steeper from the third to the sixth generation.. Inhaled anticholinergic agents induce overall bronchodilation which is in proportion to improvements in FEV(1) in patients with COPD. Bronchodilation at the distal rather than the proximal airways is the determinant of functional improvement.

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Bronchi; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Tomography, X-Ray Computed; Vital Capacity

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Drug Combinations; Fluticasone-Salmeterol Drug Combination; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Bronchodilator Agents; Cholinergic Antagonists; Confounding Factors, Epidemiologic; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Renal Insufficiency; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Research Design; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Research Design; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Cardiovascular Diseases; Cholinergic Antagonists; Drug Therapy, Combination; Humans; Meta-Analysis as Topic; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Selection Bias; Tiotropium Bromide

Topics: Bronchodilator Agents; Cardiovascular Diseases; Cause of Death; Cholinergic Antagonists; Drug Therapy, Combination; Humans; Lung Neoplasms; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Urinary Retention

The magnitude of tiotropium (1) induced bronchodilation and (2) protection against dynamic hyperinflation in COPD phenotypes has not been studied.. We studied moderate to severe COPD patients with varying extent of emphysema as evaluated by high-resolution thin-section lung CT. Spirometry including inspiratory capacity (IC) was measured before and immediately after metronome paced hyperventilation (MPH) at 2 times resting respiratory rate for 20s to induce dynamic hyperinflation. Spirometry was obtained at baseline and pre- and 1.5h post-18 microg tiotropium via HandiHaler after 30 day tiotropium treatment period in a single blind, open label intervention.. In 29 COPD patients (15M), age 70+/-9 years (mean+/-SD) with smoking history of 53+/-37 pack years, baseline forced expiratory volume in 1s (FEV(1)) post-180 microg albuterol MDI was 1.6+/-0.4 L (61+/-8% predicted) and FEV(1)/FVC 59+/-6%. Lung CT emphysema score (LCTES) was 23+/-20 (mean+/-SD) on a scale of 0-100 (none to most severe emphysema). After 30-day tiotropium, FEV(1) increased 101+/-124 mL (mean+/-SD) (p<0.001) and Spearman correlation (r)=-0.04, p=0.8 with LCTES; IC increased 163+/-232 mL (p<0.001), and r=-0.2, p=0.3 with LCTES. Results following MPH induced DH before and after 30-day tiotropium were significant (p<0.001) and similar: IC decreased 340+/-280 mL before and 337+/-270 mL after tiotropium, and r=-0.3, p=0.9 with LCTES.. Tiotropium significantly increased FEV(1) (L) and inspiratory capacity in moderate-severe COPD, independent of extent of lung CT emphysema score. Despite bronchodilation and lower resting lung volume, tiotropium did not abbreviate induced dynamic hyperinflation, which was also independent of underlying emphysema.

Topics: Aged; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Hyperventilation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Respiratory Function Tests; Scopolamine Derivatives; Smoking; Tiotropium Bromide; Tomography, X-Ray Computed; Vital Capacity

Topics: Bronchodilator Agents; Forced Expiratory Volume; Humans; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Smoking Cessation; Smoking Prevention; Tiotropium Bromide

TORCH and UPLIFT are amongst the largest and most ambitious COPD trials ever undertaken. In terms of the primary outcomes, both trials were negative. Compared with placebo, combined salmeterol and fluticasone therapy did not significantly reduce all cause mortality over 3 years in TORCH, and tiotropium did not slow the decline in lung function over 4 years in UPLIFT. Secondary outcomes from these studies strongly confirmed findings from previous trials. Monotherapy with all three drugs provided small improvements in respiratory health status and reductions in exacerbation rates with some additive effect from the salmeterol/fluticasone combination. Both salmeterol/fluticasone and tiotropium also reduced COPD hospitalization rates. The trials provide very strong evidence that the long-acting bronchodilators, salmeterol and tiotropium, are not associated with increased risk of death or major cardiovascular adverse events.

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Drug Combinations; Fluticasone-Salmeterol Drug Combination; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Desmosine and Isodesmosine (D/I) are cross-linking amino acids which are present only in mature elastin. Changes in their concentration in body fluids indicate changes in elastin degradation and can be a reflection of tissue elastase activity. This study was undertaken to determine whether continuous therapy with the long-acting bronchodilator Tiotropium bromide (TTP) could result in reductions in D/I as measured by mass spectrometry in plasma, urine and sputum.. Twelve not currently smoking patients with chronic obstructive pulmonary disease (COPD), never on TTP, were selected for study. Levels of D/I, along with measurements of FVC, FEV1 and FEV1/FVC. were determined before starting TTP daily, and then one and two months after.. D/I decreased in plasma (10 of 12 patients), in sputum all (12 of 12), and in the percentage of free D/I in urine (10 of 12). Most patients showed slight increases in FVC and FEV1 percent predicted over two months.. The results are consistent with an effect of prolonged bronchodilitation by anti-cholinergic blockade to also result in reduced lung elastin degradation.

Topics: Bronchodilator Agents; Desmosine; Elastin; Forced Expiratory Volume; Humans; Isodesmosine; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking Cessation; Tiotropium Bromide; Vital Capacity

Topics: Cardiovascular Diseases; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Risk; Scopolamine Derivatives; Tiotropium Bromide

Topics: Cardiovascular Diseases; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Risk; Scopolamine Derivatives; Tiotropium Bromide

Topics: Cardiovascular Diseases; Cholinergic Antagonists; Heart Failure; Humans; Pulmonary Disease, Chronic Obstructive; Renal Insufficiency; Risk Factors; Scopolamine Derivatives; Tiotropium Bromide

Topics: Cardiovascular Diseases; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Risk; Scopolamine Derivatives; Tiotropium Bromide

Guidance for clinicians on how to interpret conflicting evidence from recent studies.

Topics: Cardiovascular Diseases; Cholinergic Antagonists; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Research Design; Scopolamine Derivatives; Tiotropium Bromide

The Visual Simplified Respiratory Questionnaire (VSRQ) was designed to assess health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD). It contains eight items: dyspnea, anxiety, depressed mood, sleep, energy, daily activities, social activities and sexual life. Psychometric properties were assessed during a clinical trial that evaluated the impact of tiotropium on HRQoL of COPD patients. These included the determination of structure, internal consistency reliability, concurrent validity with the St George's Respiratory Questionnaire (SGRQ), test - retest reliability, clinical validity and responsiveness to change over two weeks. Minimal important difference (MID) was calculated; cumulative response curves (CRC) were based on the dyspnea item. Psychometric analyses showed that VSRQ structure was unidimensional. The questionnaire demonstrated good internal consistency reliability (Cronbach's alpha = 0.84), good concurrent validity with SGRQ (Spearman = -0.70) and clinical validity, good test-retest reproducibility (ICC = 0.77), and satisfactory responsiveness (standardized response mean = 0.57; Guyatt's statistic = 0.63). MID was 3.4; CRC median value of the 'minimally improved' patients was 3.5. In conclusion, VSRQ brevity and satisfactory psychometric properties make it a good candidate for large studies to assess HRQoL in COPD patients. Further validation is needed to extend its use in clinical practice.

Topics: Activities of Daily Living; Aged; Anxiety; Cholinergic Antagonists; Depression; Dyspnea; Female; Humans; Lung; Male; Middle Aged; Psychometrics; Pulmonary Disease, Chronic Obstructive; Quality of Life; Reproducibility of Results; Respiration; Scopolamine Derivatives; Severity of Illness Index; Sexual Behavior; Sleep; Social Behavior; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome

Topics: Arrhythmias, Cardiac; Bronchodilator Agents; Dyspnea; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Smoking; Smoking Cessation; Tiotropium Bromide

Lung cancer patients with COPD are at high risk during surgery. Tiotropium, a long-acting bronchodilator, is a preferred maintenance therapy for COPD, but its efficacy in the perioperative period has not been clarified.. A retrospective review was performed of the medical records of 102 patients with primary lung cancer and COPD, who underwent scheduled surgery. Twenty-one lung cancer patients with untreated mild-to-severe COPD received tiotropium preoperatively. Spirometry was performed prior to and after 2 weeks of treatment with tiotropium, and at 3 months after surgery.. Two-week preoperative treatment with tiotropium significantly improved respiratory symptoms and pulmonary function as reflected by FVC (median 3.43 L pretreatment vs 3.52 L post-treatment), FEV(1) (median 2.06 L vs 2.32 L) and FEV(1)% (73.2% vs 81.0%) (all P < 0.001). Postoperative FEV(1)% was significantly increased from a median of 56.0% (interquartile range 51.6-60.3) to 63.4% (60.8-66.0) (P < 0.001). The increase in FEV(1) was inversely associated with severity of COPD (r = -0.59, P < 0.005). Lung resections were successfully accomplished without complications. The postoperative FEV(1) predicted prior to tiotropium treatment was underestimated (median predicted postoperative FEV(1) 1.65 L vs median measured postoperative FEV(1) 1.96 L, P < 0.001).. Preoperative treatment with tiotropium may facilitate surgical treatment for lung cancer patients with COPD. This is encouraging for COPD patients who may require curative lung resections.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Dose-Response Relationship, Drug; Forced Expiratory Volume; Humans; Lung; Lung Neoplasms; Male; Middle Aged; Preoperative Care; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation caused by persistent inflammatory processes in the airways. An increased cholinergic tone mediates different pathophysiological features of COPD, such as bronchoconstriction and mucus hypersecretion, mostly through activation of the human muscarinic M(3) receptor (hM(3)) subtype. Tiotropium bromide (Spiriva) is a well established muscarinic antagonist in the pharmacological management of COPD with a once-daily posology. The rationale behind the sustained bronchodilation obtained with tiotropium consists in its slow dissociation from hM(3) receptors. In this study, we performed a comprehensive preclinical comparison of tiotropium with other long-acting muscarinic antagonists (LAMAs) currently in clinical development, namely aclidinium bromide and glycopyrrolate. The different muscarinic antagonists were characterized for their 1) affinity toward the different human muscarinic receptor subtypes expressed in Chinese hamster ovary cells and kinetics of receptor dissociation, 2) potency in inhibiting the agonist-induced activation of muscarinic receptors through measurement of second messengers, and 3) efficacy and duration of bronchoprotection, as tested in a model of acetylcholine-induced bronchoconstriction in anesthetized dogs over a period of 24 h. All of the tested LAMAs showed high affinity and potency toward the hM(3) receptor (tiotropium, pA(2) = 10.4; aclidinium, pA(2) = 9.6; and glycopyrrolate, pA(2) = 9.7). However, dissociation half-lives of the LAMAs from the hM(3) receptor differed significantly (tiotropium, t((1/2)) = 27 h; aclidinium, t((1/2)) = 10.7 h; and glycopyrrolate, t((1/2)) = 6.1 h). In line with their kinetic properties at the hM(3), the tested LAMAs provided different levels of bronchoprotection in the in vivo setting 24 h after administration (tiotropium = 35%, aclidinium = 21%, and glycopyrrolate = 0% at 24 h) when applied at equieffective doses.

Topics: Animals; Binding Sites; Bronchoconstriction; CHO Cells; Cricetinae; Cricetulus; Delayed-Action Preparations; Dogs; Drug Evaluation, Preclinical; Drugs, Investigational; Humans; Male; Muscarinic Antagonists; Protein Binding; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

Currently, two methods for measuring TLC, RV, and FRC are used in clinical pulmonary function laboratories: body plethysmography and helium dilution. However, these methods are not interchangeable. In moderate-to-severe airflow obstruction, dilution method tends to underestimate and body plethysmography tends to overestimate RV.. In 21 patients suffering from COPD (basal FEV(1): 56.69+/-13.64), we investigated whether the two methods of measuring FRC and RV could respond differently to a 2-week treatment with tiotropium 18 microg/day.. Tiotropium induced a significant increase in FEV(1) and FVC but not in IC. At baseline, FRC(pleth), RV(pleth) and TLC(pleth) were higher than FRC(He), RV(He) and TLC(He). At the end of the study FRC(pleth), RV(pleth) and TLC(pleth) decreased and FRC(He), RV(He) and TLC(He) increased but only changes in FRC(pleth) and RV(pleth) were statistically significant.. The use of body plethysmography seems to be more appropriate in clinical trials aimed at assessing the impact of a therapeutic procedure in patients with COPD and lung hyperinflation.

Topics: Aged; Bronchodilator Agents; Female; Forced Expiratory Volume; Functional Residual Capacity; Helium; Humans; Lung Volume Measurements; Male; Pilot Projects; Plethysmography; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Total Lung Capacity

COPD exacerbations are responsible for the morbidity and mortality of this disease. The relationship between exacerbations and patient-related clinical outcomes is not clearly understood.. A retrospective analysis of two 1-year, placebo-controlled clinical trials with tiotropium 18 microg daily was conducted to examine relationships between exacerbations and other clinical outcomes. The relationship between FEV(1), St. George's Respiratory Questionnaire (SGRQ), and the transition dyspnea index (TDI) were examined based on the frequency of exacerbations (0, 1, 2, >2).. 921 patients participated in the trials (mean age 65 years, mean FEV(1) = 1.02 L (39% predicted). The percent change from baseline in FEV(1) in the tiotropium group was +12.6%, +12.0%, +2.1% and +8.9%; and in the placebo group was -3.4%, -3.4%, -5.7% and -6.7% for exacerbation frequencies of 0, 1, 2, >2, respectively. Compared with baseline, the largest improvement in SGRQ occurred in patients with no exacerbations. In the placebo group, there was a significant association between an increased frequency of exacerbations and worsening SGRQ scores. A reduction in exacerbation rates of 4.4% to 42.0% such as that shown in this study cohort was associated with meaningful changes in questionnaire based instruments.. In the placebo-treated patients increased frequency of exacerbations was associated with larger decrements in FEV(1), TDI, and SGRQ. A reduction in the frequency of exacerbations is associated with changes that are considered meaningful in these clinical outcomes.

Topics: Aged; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Health Status; Humans; Lung; Male; Multicenter Studies as Topic; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Recovery of Function; Retrospective Studies; Scopolamine Derivatives; Severity of Illness Index; Spirometry; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; United States

Topics: Bronchodilator Agents; China; Dose-Response Relationship, Drug; Forced Expiratory Volume; Humans; Lung; Lung Neoplasms; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

To date, there is mixed evidence on the safety and effectiveness of tiotropium. Our objective was to evaluate the comparative effectiveness of regimens containing tiotropium bromide vs other medication regimens for chronic obstructive pulmonary disease (COPD) in real-world clinical settings.. We conducted a cohort study on 2 separate cohorts with a diagnosis of COPD in the Veterans Affairs health care system. Patients with a diagnosis of COPD prescribed tiotropium and patients in a historic cohort prior to the introduction of tiotropium were selected for comparison using propensity scores, with the base case including scores from 0.1 to 0.4. Outcomes identified during follow-up were all-cause mortality, COPD exacerbations, and COPD hospitalizations. Exposure to COPD medication regimens was defined in a time-varying manner and Cox proportional hazards regression were used to evaluate outcomes.. For 42 090 patients in the base case, the regimen of tiotropium + inhaled corticosteroids (ICS) + long-acting beta-agonists (LABA) was associated with 40% reduced risk of death (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.45-0.79) compared with ICS + LABA. This combination was associated with reduced rates of COPD exacerbations (HR, 0.84; 95% CI, 0.73-0.97) and COPD hospitalizations (HR, 0.78; 95% CI, 0.62-0.98). Tiotropium in combination with 2 other medications was associated with increased risk of mortality, exacerbations, and hospitalizations.. When used with ICS and LABA, tiotropium use was associated with a decreased risk of mortality compared with treatment with ICS and LABA. However, this result was not consistent in other medication regimens that included tiotropium [corrected].

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Aged; Aged, 80 and over; Bronchodilator Agents; Cause of Death; Cohort Studies; Disease Progression; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Humans; Male; Middle Aged; Product Surveillance, Postmarketing; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Survival Analysis; Tiotropium Bromide; Veterans

Topics: Administration, Inhalation; Bronchodilator Agents; Drug Administration Schedule; Humans; Metered Dose Inhalers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Disease Progression; Forced Expiratory Volume; Global Health; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome

There has been recent uncertainty about whether the inhaled anticholinergic agents ipratropium bromide and tiotropium bromide increase or decrease cardiovascular risk in the treatment of patients with chronic obstructive pulmonary disease (COPD). This article synthesizes the available data in order to understand the controversy. COPD is a common cause of hospitalizations and is a rapidly increasing cause of mortality worldwide. Despite the heavy burden of COPD-related illness, the leading cause of hospitalization in COPD patients is cardiovascular disease. This link between COPD and cardiovascular disease is in part due to the fact that both diseases share common risk factors, such as tobacco smoking and advanced age. It is also hypothesized that systemic inflammation in COPD increases the risk for cardiac events such as myocardial infarction. Inhaled anticholinergics reduce COPD-related hospitalizations and respiratory deaths compared with placebo, and tiotropium bromide is more effective than ipratropium bromide. In randomized trials, patients receiving tiotropium bromide have lower discontinuation rates than those receiving placebo and, therefore, contribute more person-years to the analyses. In a recent large 4-year tiotropium bromide trial, the proportion of patients who died was similar in the tiotropium bromide and placebo groups, whereas the death rate per person-years was lower with tiotropium bromide, indicating longer overall survival. There has been conflicting evidence concerning cardiovascular risk associated with inhaled anticholinergics. One meta-analysis found that the risk for major cardiovascular events was higher with anticholinergics compared with placebo or active comparator controls, whereas two subsequent meta-analyses that included new trial data found no difference in risk. In a recent pooled safety analysis, when incidence rates of events over time were evaluated, tiotropium bromide was associated with a lower rate of major cardiovascular events and cardiovascular deaths compared with placebo. This risk reduction was mainly because of a reduction in serious cardiac events such as myocardial infarction and congestive heart failure. In conclusion, inhaled anticholinergics, especially tiotropium bromide, reduce COPD-related hospitalizations and deaths, and may improve total survival over time. Many COPD patients have concomitant cardiovascular disease processes. Thus, trials may observe more cardiovascular events associated with an

Topics: Administration, Inhalation; Bronchodilator Agents; Cardiovascular Diseases; Cholinergic Antagonists; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Risk; Scopolamine Derivatives; Tiotropium Bromide

To compare, in elderly Medicare beneficiaries, chronic obstructive pulmonary disease (COPD)-related healthcare costs for patients initiating treatment with fluticasone propionate/salmeterol 250 μg/50 μg (FSC) with those for patients initiating treatment with ipratropium bromide/albuterol (IPA), ipratropium bromide (IPR), and tiotropium bromide (TIO).. In this retrospective, observational, cohort study, COPD-related medical costs (inpatient/emergency department, outpatient) and pharmacy costs were assessed in Medicare beneficiaries ≥ 65 years old who were enrolled in a commercial Medicare health maintenance organization plan and had a diagnosis of COPD (ICD-9-CM codes 491.xx, 492.xx, or 496.xx) within 12 months before initial treatment with FSC, IPA, IPR, or TIO.. In these ≥ 65-year-old patients (N=14,689), initial maintenance treatment with FSC was associated with total COPD-related cost savings (medical + pharmacy) of $295 versus IPA, $1,235 versus IPR, and $110 versus TIO (p<0.05, each comparison) over a 1-year follow-up period.. Initiation of maintenance therapy with FSC was associated with significant reduction in total costs (medical + pharmacy) relative to costs associated with the short-acting anticholinergic bronchodilators IPR and IPA and the long-acting anticholinergic bronchodilator TIO in an elderly Medicare-eligible population. These data considered in the context of the substantial efficacy and effectiveness data suggest that early introduction of maintenance treatment with FSC has both clinical and economic benefits. Limitations inherent in handling of administrative data include lack of objective clinical measures such as spirometry and smoking status. Furthermore, accuracy of diagnosis codes cannot be verified.

Topics: Aged; Albuterol; Androstadienes; Bronchodilator Agents; Disease Progression; Drug Therapy, Combination; Female; Fluticasone; Health Care Costs; Health Services; Humans; Insurance Claim Review; Ipratropium; Male; Medicare; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; United States

To determine the effect of changing anticholinergic therapy in patients with COPD from ipratropium to tiotropium on pulmonary function.. We examined records of patients prescribed high-dose ipratropium, who were subsequently converted to tiotropium. Spirometric values were obtained within 2 days of the change in medication and after 56 to 224 days of the switch to tiotropium.. 15 subjects were documented to have filled a prescription for ipratropium-containing medications the month prior to the change. Medication compliance over the 6 months prior to the switch in these patients was 72% +/- 31% (mean +/- SD) for ipratropium compared to 87% +/- 14% for tiotropium over the 6-month period after the switch (P = 0.1). FEV(1) improved from 1.12 +/- 0.39 L at baseline to 1.37 +/- 0.49 L after the change to tiotropium (P = 0.01). FVC also improved from 2.45 +/- 0.73 L at baseline to 2.72 +/- 0.69 L after the change (P = 0.04). Maximal voluntary ventilation was also increased from 39.67 +/- 10.7 L/min to 45.13 +/- 15.8 L/min (P = 0.045).. We conclude that replacing high-dose ipratropium with tiotropium therapy significantly improves pulmonary function in a clinical setting.

Topics: Aged; Aged, 80 and over; Bronchodilator Agents; Dose-Response Relationship, Drug; Female; Humans; Ipratropium; Male; Medical Audit; Middle Aged; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Topics: Administration, Inhalation; Bronchodilator Agents; Cardiovascular Diseases; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Risk Factors; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

The use of one or more long-acting bronchodilators is key in the maintenance therapy of chronic obstructive pulmonary disease (COPD). This analysis pooled the results of two double-blind studies evaluating the efficacy and safety of adding nebulized formoterol fumarate inhalation solution (FFIS) to maintenance tiotropium (TIO) treatment.. Following a run-in period of 7-14 days with once-daily TIO 18 microg, COPD subjects (> or =25% to <65% predicted forced expiratory volume in 1 second [FEV(1)]) were randomized to twice-daily FFIS 20 microg (n=145) or nebulized placebo (PLA, n=140) while continuing on maintenance TIO for 6 weeks. Efficacy was measured using serial spirometry, transition dyspnea index (TDI), rescue albuterol use, and St. George's Respiratory Questionnaire (SGRQ).. The mean standardized area under the curve for FEV(1) over 3 hours (FEV(1)AUC(0-3)), the primary efficacy variable, was significantly higher in the FFIS/TIO group than the PLA/TIO group on day 1 (140 mL difference, P<0.0001) and week 6 (192 mL difference, P<0.0001). Mean TDI scores in the FFIS/TIO and PLA/TIO groups were 1.97 and 0.67, respectively (P=0.0001). Mean albuterol use declined in the FFIS/TIO group from 2.6 to 1.5 puffs/day compared with little change in the PLA/TIO group (P<0.0001). SGRQ scores were similar between treatment groups with the exception of the symptoms score, which improved in the FFIS/TIO group (-5.8) compared with PLA/TIO (-1.0), and more FFIS/TIO-treated subjects experienced a clinically significant improvement in total SGRQ score. More PLA/TIO-treated subjects than FFIS/TIO-treated subjects experienced adverse events (AEs) (45.7% vs. 31.0%) and COPD exacerbations (7.9% vs. 3.4%).. The addition of FFIS to maintenance TIO treatment for moderate to severe COPD results in significantly improved FEV(1) and dyspnea, decreased rescue medication use, and a lower incidence of AEs and COPD exacerbations. The addition of FFIS to TIO yields clinically and statistically significant benefits for COPD patients and might be of long-term benefit.

Topics: Aged; Albuterol; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Dyspnea; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Respiratory Function Tests; Scopolamine Derivatives; Tiotropium Bromide

SAR around alkyne-quinuclidine derivatives allowed the discovery of highly potent muscarinic antagonists displaying interesting preferential slow off-rates from the M3 receptor.

Topics: Alkynes; Cholinergic Antagonists; Molecular Structure; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Structure-Activity Relationship

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Drug Combinations; Fluticasone-Salmeterol Drug Combination; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Albuterol; Androstadienes; Bronchodilator Agents; Clinical Trials as Topic; Drug Combinations; Fluticasone-Salmeterol Drug Combination; Humans; Patient Dropouts; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Albuterol; Androstadienes; Anti-Inflammatory Agents; Drug Combinations; Fluticasone-Salmeterol Drug Combination; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Survival Rate; Tiotropium Bromide

Bedtime inhalation of a novel muscarinic M3 receptor antagonist markedly lowered ambulatory blood pressure (ABP), predominantly during sleep, in a chronic obstructive pulmonary disease (COPD) patient with masked nocturnal hypertension. This is the first case demonstrating that a bronchodilator significantly lowered ABP in a COPD patient with hypertension. This case suggests that bronchodilator therapy may have potential as a new antihypertensive strategy targeting the lung in hypertensive patients with impaired lung function. This "bronchoantihypertensive" therapy seems to be more effective for reducing sleep blood pressure in hypertensive patients with COPD and sleep hypoventilatory/hypoxemic syndromes.

Topics: Administration, Inhalation; Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Bronchodilator Agents; Circadian Rhythm; Humans; Hypertension; Male; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Scopolamine Derivatives; Sleep; Tiotropium Bromide

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Bronchodilator Agents; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Research Design; Scopolamine Derivatives; Tiotropium Bromide

Chronic Obstructive Pulmonary Disease (COPD) is the fourth-leading cause of chronic morbidity and mortality in North America and its burden continues to increase. Tiotropium has been shown to reduce exacerbations, hospitalizations, symptoms, and improve health-related quality of life in patients with COPD. Its effect on mortality and its effects relative to long-acting beta-agonists (LABAs), however, remain unknown. To examine the association between tiotropium use compared to LABA use on all-cause mortality in older patients with COPD, a longitudinal, population-based cohort study was conducted in Ontario, Canada. Subjects were individuals 65 years and older discharged from hospital with a diagnosis of COPD between January 1, 2003 and March 31, 2006. The hazard of receiving a prescription for tiotropium compared to a long-acting beta-agonist on all-cause mortality at 180 days post-hospital discharge, controlling for a number of potential confounders, was eliminated. Data from 7218 eligible patients were analyzed. Of these, 1046 (14.5%) died in the follow-up period. Patients who received tiotropium were 20% less likely to die than those receiving a long-acting beta-agonist (hazard ratio 0.80, 95% confidence interval 0.70 to 0.93). In conclusion, in older patients recently discharged from hospital for COPD, receiving tiotropium was found to be associated with reduced mortality at 6 months compared to receiving a long-acting beta-agonist. This result suggests that tiotropium might also be associated with decreased mortality compared to no treatment at all. Randomized placebo-control trials are needed to confirm these findings.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Age Distribution; Aged; Aged, 80 and over; Bronchodilator Agents; Cause of Death; Cohort Studies; Continuity of Patient Care; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Longitudinal Studies; Male; Ontario; Prognosis; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Registries; Respiratory Function Tests; Risk Assessment; Scopolamine Derivatives; Severity of Illness Index; Sex Distribution; Survival Analysis; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Albuterol; Androstadienes; Bronchodilator Agents; Drug Therapy, Combination; Fluticasone; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Research Design; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Topics: Adult; Bronchodilator Agents; Combined Modality Therapy; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Forced Expiratory Volume; Glucocorticoids; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Inequalities in the use of new medications may contribute to health disparities. We analyzed socioeconomic gradients in the use of tiotropium for chronic obstructive pulmonary disease (COPD).. In a cohort of adults with COPD aged > or = 55 years identified through population-based sampling, we elicited questionnaire responses on demographics, socioeconomic status (SES; lower SES defined as high school education or less or annual household income < US $20,000), and medication use and other clinical variables. In a subset we obtained pulmonary function testing. We used multiple logistic regression analysis to estimate the associations between SES and tiotropium use in COPD, adjusting for disease severity measured by a COPD Severity Score.. Of 427 subjects, 44 (10.3%) reported using tiotropium in 2006. Adjusting for COPD severity, lower SES was associated with reduced odds of tiotropium use (OR 0.3; 95% CI 0.1-0.7; p = 0.005). Among the subset with lung function data (n = 95), after including COPD Global Obstructive Lung Disease (GOLD) Stage > or = 2 in the model, lower SES remained associated with reduced odds oftiotropium use (OR 0.03; 95% CI < 0.001-0.7; p = 0.03). Including forced expiratory volume in one second in the model as a continuous variable instead of GOLD Stage > or = 2 yielded similar results for lower SES (OR 0.1; 95% CI < 0.001-0.5; p = 0.02).. There was a strong SES gradient in tiotropium use such that there was less use with lower SES. To the extent that this is an efficacious medication for COPD, this gradient represents a potential source of health disparities.

Topics: Adult; Aged; Cholinergic Antagonists; Cohort Studies; Female; Health Status Disparities; Humans; Logistic Models; Male; Multivariate Analysis; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Scopolamine Derivatives; Severity of Illness Index; Social Class; Spirometry; Tiotropium Bromide; United States

Tiotropium is widely used for the treatment of chronic obstructive pulmonary disease (COPD), but it is not usually prescribed for patients with micturition disorder, such as benign prostatic hyperplasia (BPH), because of the potential to increase the risk of acute urinary retention through its anticholinergic effects. However, no data are available to prove a true causal relationship between tiotropium and lower urinary tract dysfunction (LUTD) using quantitative symptomatic scoring or objective parameters evaluated by uroflowmetry.. To clarify the effect of tiotropium on lower urinary tract functions in COPD patients with BPH.. This prospective pilot study comprised 25 male COPD patients with BPH as defined by the International Prostate Symptom Score (IPSS), the quality of life (QOL) index, maximum flow rate (Q-max) in uroflowmetry, and prostate volume. Patients were given tiotropium once a day for 3 months. At baseline and after treatment, lower urinary tract functions were assessed symptomatically by the IPSS and the QOL index, and objectively by urinary parameters, including Q-max, average flow rate (Q-ave), postvoid residual urine volume (PVR), and bladder voiding efficiency (BVE).. Acute urinary retention was not observed in any patients. Subjectively, no significant difference was found in the IPSS or the QOL index between baseline and after tiotropium treatment. Additionally, tiotropium treatment did not change Q-max, Q-ave, time to Q-max, or overall flow time compared to baseline (Q-max (mL/s), 9.66+/-3.63, 9.11+/-3.68 and 10.51+/-3.88, P=0.15; Q-ave (mL/s), 4.20+/-1.76, 4.14+/-1.55, and 4.71+/-1.81, P=0.31; time to Q-max (s), 12.1+/-8.0, 16.2+/-11.4, and 13.0+/-11.3, P=0.10; flow time (s), 39.4+/-19.6, 40.4+/-20.1, and 38.3+/-19.1; baseline, 1 month after treatment and 3 months after treatment, respectively). No significant increase was found in PVR or BVE (PVR (mL), 57.9+/-51.2, 55.4+/-47.2 and 66.1+/-52.7, P=0.36; BVE (%), 75.8+/-18.4, 73.3+/-19.1 and 73.9+/-17.3, P=0.67; baseline, 1 month after treatment, and 3 months after treatment, respectively).. In our preliminary study, tiotropium did not adversely affect lower urinary tract functions in COPD patients with BPH, suggesting the possibility that tiotropium can be safely given to those patients. This warrants future studies in a larger series of COPD patients to validate our observations.

Topics: Administration, Inhalation; Aged; Cholinergic Antagonists; Humans; Male; Pilot Projects; Prospective Studies; Prostatic Hyperplasia; Pulmonary Disease, Chronic Obstructive; Quality of Life; Scopolamine Derivatives; Tiotropium Bromide; Urinary Retention; Urinary Tract; Urodynamics

Topics: Acute Disease; Bronchodilator Agents; Hospitalization; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Tiotropium is used in maintenance treatment of chronic obstructive pulmonary disease (COPD), but there are no guidelines on when to start tiotropium following an exacerbation.. To determine whether the addition of tiotropium to a respiratory-therapist-directed bronchodilator protocol affects bronchodilator costs for patients hospitalized for COPD exacerbation.. We retrospectively analyzed data on the number and type of bronchodilator treatments administered to all patients admitted for COPD exacerbation during the 3-month period (January through March 2006) after tiotropium was added to our bronchodilator protocol, and compared that data to a historical control period (January through March 2004) before tiotropium was available in our hospital. We compared the costs of bronchodilator treatments, baseline patient characteristics, comorbidities, concomitant medications, length of stay, adverse events, and in-hospital deaths.. Baseline characteristics, comorbidities, and concomitant medications were similar in the 2004 control group (n = 181) and the 2006 intervention group (n = 174). The mean +/- SD number of bronchodilator treatments per admission was significantly higher in the control period (13.6 +/- 15.6) than in the intervention period (10.6 +/- 9.4). That difference correlated to a reduction in combination therapy (short-acting inhaled beta(2) agonist plus ipratropium), which decreased from a per-admission average of 6.7 +/- 14.2 in the control period to 1.9 +/- 5.1 in the intervention period. Calculated bronchodilator costs were significantly lower in the intervention period than in the control period. Length of stay also significantly decreased, from 6.5 +/- 5.0 d to 5.5 +/- 4.0 d. There were no adverse events related to tiotropium. Pulmonary-related in-hospital deaths were not significantly different between the 2 periods.. Early addition of maintenance-treatment tiotropium to a respiratory-therapist-directed bronchodilator protocol for patients hospitalized for COPD exacerbation reduced costs and produced no safety concerns.

Topics: Acute Disease; Adrenergic beta-Agonists; Aged; Aged, 80 and over; Bronchodilator Agents; Clinical Protocols; Cohort Studies; Drug Costs; Female; Hospitalization; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Therapy; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The natural history of chronic obstructive pulmonary disease (COPD) has classically been considered in terms of the rapid decrease in forced expiratory volume in 1 second (FEV(1)) and no other measure apart from smoking cessation has been demonstrated to modify the speed of this decrease. The evidence available from studies performed with tiotropium, of up to 1 year's duration, have shown that this anticholinergic drug can modify the course of COPD by acting on lung function, air entrapment, exacerbations, dyspnea and exercise tolerance, thus improving health status. This evidence has served as the basis for the design of the UPLIFT study (Understanding Potential Long-term Impacts on Function with Tiotropium), the main aim of which is to determine the effect of tiotropium on disease progression. This multicenter and multinational study has lasted for 4 years and almost 6,000 patients with COPD have participated. Data from this study are currently being analyzed and the results will shortly be made known. If the results are positive, it will be the first time that a pharmacological intervention has been able to modify the rate of FEV(1) decline, which would imply that the underlying disease is truly being modified. Positive data from the UPLIFT study would indicate that, together with smoking cessation, early treatment with tiotropium should be initiated at any stage of COPD, since both measures would have been proven to be able to modify the natural course of the disease. The probability of demonstrating maintenance of bronchodilation, as well as maintenance of the decrease in the number and severity of exacerbations found in studies conducted over a 1-year period, would represent a real change in what has been known to date about the natural course of COPD.

Topics: Bronchodilator Agents; Disease Progression; Forecasting; Humans; Multicenter Studies as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Heart; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Value of information (VOI) analysis informs decision-makers about the expected value of conducting more research to support a decision. This expected value of (partial) perfect information (EV(P)PI) can be estimated by simultaneously eliminating uncertainty on all (or some) parameters involved in model-based decision-making. This study aimed to calculate the EVPPI, before and after collecting additional information on the parameter of a probabilistic Markov model with the highest EVPPI.. The model assessed the 5-year costs per quality-adjusted life year (QALY) of three bronchodilators in chronic obstructive pulmonary disease (COPD). It had identified tiotropium as the bronchodilator with the highest expected net benefit. Total EVPI was estimated plus the EVPPIs for four groups of parameters: 1) transition probabilities between COPD severity stages; 2) exacerbation probabilities; 3) utility weights; and 4) costs. Partial EVPI analyses were performed using one-level and two-level sampling algorithms.. Before additional research, the total EVPI was Euro 1985 per patient at a threshold value of Euro 20,000 per QALY. EVPPIs were Euro 1081 for utilities, Euro 724 for transition probabilities, and relatively small for exacerbation probabilities and costs. A large study was performed to obtain more precise EQ-5D utilities by COPD severity stages. After using posterior utilities, the EVPPI for utilities decreased to almost zero. The total EVPI for the updated model was reduced to Euro 1037. With an EVPPI of Euro 856, transition probabilities were now the single most important parameter contributing to the EVPI.. This VOI analysis clearly identified parameters for which additional research is most worthwhile. After conducting additional research on the most important parameter, i.e., the utilities, total EVPI was substantially reduced.

Topics: Albuterol; Bronchodilator Agents; Cost-Benefit Analysis; Ipratropium; Markov Chains; Models, Econometric; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Randomized trials provide pivotal evidence for evaluation and approval of therapies. Nonetheless, such trials are often plagued by noncompliance, especially in the form of premature discontinuation of treatment. While intent-to-treat (ITT) analysis can provide valid tests of no-effect hypotheses, some trials may make ITT analysis impossible by ceasing follow-up when patients go off assigned treatment. Furthermore, estimates based on ITT, on-treatment, or per-protocol comparisons can seriously understate harm or benefit.. To show how g-estimation based on randomization status is a natural generalization of ITT null testing to estimating efficacy from trials with important discontinuation or noncompliance.. We contrast with an analysis of the effect of a tiotropium inhaler on the occurrence of chronic obstructive pulmonary disease (COPD) events in a six-month double-blind placebo-controlled trial of 1829 patients with good but imperfect compliance.. The covariate-adjusted point estimates, 95% confidence limits (CL), and null P-values comparing expected COPD event times in placebo versus tiotropium patients were: ITT, 1.21, CL = 1.02, 1.43, P = 0.027; on-treatment, 1.27, CL = 1.06, 1.52, P = 0.009; per-protocol, 1.36, CL = 1.13, 1.63, P = 0.001; and g-estimation, 1.31, CL = 1.03,1.72, P = 0.027. Thus g-estimation preserved the ITT test of the null, but exhibited more uncertainty about the size of the tiotropium effect than the other methods. In particular, it allowed for a much larger potential effect than did ITT analysis, but produced a much larger null P than exhibited by per-protocol analysis.. Like ITT analysis, g-estimation requires all patients be followed to the end of the trial protocol, regardless of whether they comply with the protocol. Like on-treatment and per-protocol analyses, it also requires accurate compliance information be recorded.. G-estimation should become a standard procedure for the analysis of trials with noncompliance. Software to do so is available in major packages, and the procedure is easily coded for other packages.

Topics: Bronchodilator Agents; Data Interpretation, Statistical; Double-Blind Method; Humans; Nebulizers and Vaporizers; Patient Compliance; Patient Dropouts; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

To compare the effectiveness of the long-acting anticholinergic, tiotropium with ipratropium/salbutamol in reducing the risk of exacerbations and COPD-related referrals in patients with COPD.. Data were obtained from the General Practice Research Database (GPRD). Propensity score matching was used to balance prognostic covariates between treatment groups. Incidence rate ratios and 95% confidence intervals during a 12-month follow-up period were estimated.. 4193 patients (3385, tiotropium; 808, ipratropium/salbutamol) in the GPRD met the inclusion/exclusion criteria. Patients treated with tiotropium had more severe COPD than patients treated with ipratropium/salbutamol. Following propensity score matching, 1222 tiotropium-treated patients and 633 ipratropium/salbutamol-treated patients were included in the final analysis. Incidence rate ratios (95% confidence intervals) were 0.74 (0.64-0.85; p=0.0086) for exacerbations and 0.57 (0.46-0.70; p=0.004) for COPD-related referrals/hospitalisations.. Tiotropium is associated with a reduced risk of exacerbations and COPD-related referrals and hospitalisation compared to combined ipratropium/salbutamol in patients with COPD.

Topics: Aged; Albuterol; Albuterol, Ipratropium Drug Combination; Bronchodilator Agents; Databases, Factual; Family Practice; Female; Follow-Up Studies; Hospitalization; Humans; Ipratropium; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Referral and Consultation; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; United Kingdom

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Bronchodilator Agents; Drug Therapy, Combination; Hospitalization; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Acute angle-closure glaucoma is a rare form of glaucoma occurring when the filtration mechanism for the aqueous humor is obstructed by apposition of the peripheral iris to the trabecular meshwork. It may be precipitated by pupillary dilatation in a predisposed eye. In this case report, a possible relationship between local tiotropium absorption and acute angle-closure glaucoma attack is presented.

Topics: Absorption; Acute Disease; Aqueous Humor; Dilatation; Glaucoma, Angle-Closure; Humans; Male; Middle Aged; Parasympatholytics; Pulmonary Disease, Chronic Obstructive; Pupil; Scopolamine Derivatives; Tiotropium Bromide; Trabecular Meshwork

Topics: Administration, Inhalation; Aged; Cholinergic Antagonists; Dermatitis, Photoallergic; Diagnosis, Differential; Drug Eruptions; Humans; Lichenoid Eruptions; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Patients with respiratory failure are often unable to inhale powdered aerosol medications such as long-acting beta agonists and long-acting anticholinergics, which are important treatments for chronic obstructive pulmonary disease and asthma.. To explore delivery of aerosolized powder medications via tracheostomy tube.. We designed interfaces to connect the HandiHaler and Aerolizer devices to tracheostomy tubes, and to connect the HandiHaler to a manual resuscitator bag. With these interfaces, in 23 patients, we assessed the clinical ease/difficulty of delivery and delivery time of the first 3 administrations of powder-aerosol long-acting beta agonists and long-acting anticholinergics from the HandiHaler and the Aerolizer.. The powder aerosols were readily delivered to all the patients. Nineteen of the 23 patients (83%) were able to inhale the medication on their own. In the 4 patients who were unable to effectively inhale the medication on their own, bag-assist was successful. The aerosol delivery time was usually < 3 min.. With a proper interface, powdered long-acting beta agonists and long-acting anticholinergics can be easily delivered via tracheostomy tube, even if the patient cannot inhale on his or her own. Further studies are needed to assess particle size, dose delivery, and clinical efficacy with these interfaces and device modifications.

Topics: Adrenergic beta-Agonists; Adult; Aged; Asthma; Bronchodilator Agents; Drug Delivery Systems; Ethanolamines; Formoterol Fumarate; Humans; Intubation, Intratracheal; Middle Aged; Nebulizers and Vaporizers; Powders; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Tracheostomy

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Hospitalization; Humans; Male; Middle Aged; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Tiotropium (Spiriva is an inhaled, once-daily anticholinergic medication for chronic obstructive pulmonary disease (COPD). We conducted a population-based cohort study to examine the risk of cardiovascular and respiratory hospitalizations and mortality with tiotropium. Using the Danish healthcare registries, we identified persons >/=40 years old in three counties who were hospitalized for COPD from 1/1/1977 to 12/31/2003. Respiratory and cardiovascular medications were assessed from dispensing records. Cox regression was used to compute incidence rate ratios (RR) and 95% confidence intervals (CI) for hospitalization and death between 1/1/2002 and 12/31/2003, associated with periods of tiotropium use compared to non-use, controlling for age, gender, time since COPD, concomitant respiratory and cardiovascular medications, prior hospitalizations and Charlson comorbidity index. Among persons with COPD (10,603), 75% were >/=60 years old. Follow-up was >/=18 months for 64%. Among those exposed to tiotropium compared to periods of non-use, the RR for total and cause-specific hospitalization endpoints were not elevated except for COPD hospitalization (RR = 1.52, 95% CI: 1.29, 1.79). Mortality endpoints included total mortality (RR = 0.77, 95% CI: 0.65, 0.91), respiratory mortality (RR = 0.79, 95% CI: 0.60, 1.04), sudden death (RR = 0.71, 95% CI: 0.21, 2.34), cardiac arrest (RR = 0.74, 95% CI: 0.42, 1.32), heart failure (RR = 0.84, 95% CI: 0.41, 1.75), and myocardial infarction (RR = 1.25, 95% CI: 0.49, 3.17). Compared to periods of non-use, tiotropium was associated with reduced respiratory and overall mortality and was not associated with increased cardiac mortality. An increase in COPD hospitalization is inconsistent with clinical trial data and suggests preferential prescribing due to disease severity.

Topics: Adult; Aged; Bronchodilator Agents; Cardiovascular Diseases; Cohort Studies; Denmark; Female; Hospitalization; Humans; Incidence; Male; Middle Aged; Pharmacoepidemiology; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Registries; Scopolamine Derivatives; Tiotropium Bromide

It is well known that lung cancer patients with severe chronic obstructive pulmonary disease (COPD) have a higher risk of postoperative complications than patients without COPD. However, the information regarding preoperative treatment to improve pulmonary function of the lung cancer patients with severe COPD is limited. Here, we report 3 lung cancer cases with severe COPD. Although all patients received medication without tiotropium bromide in combination with pulmonary rehabilitation for 1 or 2 months, their pulmonary function did not improve and the predicted postoperative FEV1/predicted FEV1 was below 40% in all cases. After the approval in Japan for use of tiotropium bromide in the treatment of COPD, all patients were treated with tiotropium bromide. The pulmonary function in all patients improved 2-4 weeks after the start of tiotropium bromide, and we performed lobectomy safely. Currently all patients maintain good pulmonary function without recurrence of lung cancer. We propose that treatment of tiotropium bromide might be one of the effective preoperative methods to improve pulmonary function of lung cancer patients with severe COPD.

Topics: Aged; Bronchodilator Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Pneumonectomy; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

To detect dynamic hyperinflation (DH) by evaluating reduction in inspiratory capacity (IC) during metronome-paced hyperventilation (MPH) in patients with moderate-to-severe COPD, studied before and after treatment with tiotropium.. IC and FEV(1) were measured before and immediately after MPH at two times resting the respiratory rate for 20 s in 60 COPD patients (28 men; mean age, 66 +/- 10 years [+/- SD]) before and after 30 days of treatment with tiotropium bromide, 18 mug. Patients were encouraged to maintain a constant tidal volume during MPH.. At baseline, mean FEV(1) was 1.5 +/- 0.1 L (+/- SE) [57 +/- 1.6% of predicted], mean FVC was 2.6 +/- 0.1L (77 +/- 1.8% of predicted), and mean FEV(1)/FVC was 56 +/- 1%. After 180 mug of aerosolized albuterol sulfate, mean FEV(1) was 1.7 +/- 0.1 L (63 +/- 1.5% of predicted) [p < 0.001] and mean FEV(1)/FVC was 58 +/- 1%. Compared to baseline, after 30 days and 1.5 h after tiotropium there was an increase in IC of 0.18 +/- 0.04L (p < 0.0001); FEV(1) of 0.13 +/- 0.03 L (5.6 +/- 0.8% of predicted; p = 0.0002); FVC of 0.22 +/- 0.05 L (6.5 +/- 1.3% of predicted; p < 0.001); and decrease in end-expiratory lung volume (EELV)/total lung capacity (TLC) of - 3.1 +/- 0.6% (p = 0.0001); a decrease in end-inspiratory lung volume (EILV)/TLC of - 2.9 +/- 1.3% (p = 0.03); and no change in TLC (- 0.06 +/- 0.05 L). Results following MPH-induced DH at baseline and after 30 days of tiotropium were similar, with decreases in IC (- 0.35 +/- 0.03 L; p < 0.001); FEV(1) (- 0.05 +/- 0.04 L; p = 0.2); and FVC (- 0.22 +/- 0.03 L; p < 0.0001); no change in TLC; and increases in EELV/TLC (11.8 +/- 1.0% of predicted; p < 0.0001) and EILV/TLC (4.0 +/- 1.3% of predicted, p < 0.003).. In patients with moderate-to-severe COPD, tiotropium did not reduce MPH-induced DH and reduction in IC, compared to baseline. However, because tiotropium induced bronchodilation and increased baseline IC, lower operational lung volumes may blunt the effect of MPH-induced DH. The noninvasive simplicity of MPH-induced DH provides a clinically useful screening surrogate to monitor changes in IC following treatment with tiotropium.

Topics: Aged; Albuterol; Bronchodilator Agents; Female; Forced Expiratory Volume; Functional Residual Capacity; Humans; Hyperventilation; Inspiratory Capacity; Male; Middle Aged; Plethysmography, Whole Body; Pulmonary Disease, Chronic Obstructive; Residual Volume; Scopolamine Derivatives; Smoking; Spirometry; Tiotropium Bromide; Total Lung Capacity; Treatment Outcome; Vital Capacity

Tiotropium is a once-daily inhaled anticholinergic maintenance treatment with demonstrated effectiveness in chronic obstructive pulmonary disease (COPD).. To compare persistence of tiotropium-use with other inhaled respiratory drugs in COPD in current clinical practice.. The PHARMO database includes, among others, drug-dispensing and hospital discharge records for 2> or = million subjects in the Netherlands. All probable COPD-patients were identified by new respiratory drug use (age >54 years) or COPD-hospitalisations. New users of tiotropium, ipratropium, long-acting beta-agonists (LABAs), or fixed combination of LABA and inhaled corticosteroids (LABA+ICS), in 1998-2003, were included in the study. Persistence was assessed quarterly during the first year of follow-up. Patients with a proportion of days covered (PDC) > or =80% were considered persistent. Persistence was analysed using generalised estimating equations model.. About 37% of new users of tiotropium continued treatment for 1 year, compared with 14% for ipratropium, 13% for LABA, and 17% for LABA+ICS. Multivariate analyses showed that tiotropium-users were 2-3 times more persistent with their therapy than patients using ipratropium (relative risk [RR]: 2.0; 95% confidence interval [CI]: 1.8-2.3), LABA (RR: 2.9; 95% CI: 2.4-3.6), or LABA+ICS (RR: 2.4; 95% CI: 2.1-2.8), respectively. Sub-analyses in patients with a prior hospitalisation for COPD showed that 1-year persistence rates were increased for all treatments (varying from 33% for patients using LABA+ICS to 61% for patients using tiotropium), while persistence with tiotropium was again 2-3 times higher compared with other treatments.. Persistence with tiotropium was higher compared to other inhaled respiratory drugs in COPD in clinical practice.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Adult; Aged; Bronchodilator Agents; Cohort Studies; Databases as Topic; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Ipratropium; Male; Medical Record Linkage; Middle Aged; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Unwanted side-effects of a drug therapy are well known to oral medicine specialists and other colleagues. Usually they manifest itself as dry mouth, taste disturbances, various allergic or toxic reactions on the lips and/or in the oral cavity. However, the list of the drugs which might induce unwanted reactions is everyday becoming longer as more and more drugs are introduced on the market. Certain problems when diagnosing and reporting unwanted side effects of the drugs exist as only accurate method of diagnosis is repeated drug use in controlled clinical setting where fatal consequences due to the anaphilactic shock could be avoided. We report a side effect reaction to tiotropium bromide (Spiriva) cap used with HandiHaler manifesting itself as an oral ulceration in a 65 yrs old male. On the third day of drug intake the patient developed oral ulceration two times in a period of few months. Other medications he has been using for several years. To our knowledge this is a first report as an oral side-effect of this drug used for treatment of chronic obstructive pulmonary disease (COPD).

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Humans; Male; Oral Ulcer; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Heart Failure; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

To evaluate and compare the cost-effectiveness of long-acting bronchodilators by estimating incremental costs per quality-adjusted life-year (QALY) gained in patients with moderate to severe chronic obstructive pulmonary disease.. This cost-effective analysis was conducted from a third-party payer's perspective. The study was a retrospective pooled analysis, and the effectiveness evidence was derived from a systematic review of literature published from January 1, 1980, to April 14, 2006. Incremental QALYs were estimated by converting the St George's Respiratory Questionnaire scores into EuroQoL-5D scores and using these combined scores as the summary benefit measure.. The incremental cost per additional QALY was $26,094 (range, $11,780-$77,214) for tiotropium and $41,000 (range, $23,650-$98,750) for salmeterol compared with placebo. The cost per QALY gained was lower with tiotropium compared with salmeterol or ipratropium based on either the pooled data of available trials or a head-to-head trial. Treatment with tiotropium could save $391 per year while gaining 13 quality-adjusted days compared with ipratropium.. Tiotropium appears to be more cost-effective than the alternatives and may be the preferred agent for maintenance therapy in patients with moderate to severe chronic obstructive pulmonary disease. Compared with ipratropium, tiotropium could be cost saving. Because of the wide ranges of cost-effectiveness ratios for tiotropium and salmeterol and the significant overlap between them, a large prospective head-to-head trial would help address the uncertainty and confirm the results of this analysis.

Topics: Aged; Albuterol; Bronchodilator Agents; Cost Savings; Cost-Benefit Analysis; Female; Hospitalization; Humans; Ipratropium; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

Bronchodilators, including long-acting beta(2)-adrenoceptor agonists and anticholinergic bronchodilators, are effective in the treatment of chronic obstructive pulmonary disease. Evidence suggests that the addition of a long-acting beta(2)-agonist to an inhaled corticosteroid is associated with a reduced rate of exacerbations compared with either treatment alone or placebo. However, it is not known whether a long-acting beta(2)-agonist/inhaled corticosteroid combination is more effective than an anticholinergic bronchodilator alone in reducing exacerbations. The Investigating New Standards for Prophylaxis In Reduction of Exacerbations (INSPIRE) trial will study salmeterol (a long-acting beta(2)-agonist) in combination with fluticasone propionate (an inhaled corticosteroid) compared with tiotropium bromide (an anticholinergic bronchodilator) in patients with moderate-to-severe chronic obstructive pulmonary disease. The INSPIRE study is a multicentre, randomised, double-blind, double dummy, parallel group study conducted over 104 weeks. This is the first study to use two parallel definitions of an exacerbation; an event-based exacerbation is defined as one that requires use of healthcare resources, including additional treatment and hospitalization, whereas a symptom-based exacerbation is defined as one that satisfies the 1987 Anthonisen criteria. It is also the first study to compare the long-term effects of salmeterol/fluticasone propionate with tiotropium bromide on the rate of event-based exacerbations. Endpoints include rate of exacerbations (primary endpoint), time to first exacerbation, and duration of exacerbations. Health outcomes will be assessed via the St George's Respiratory Questionnaire. If the innovative methodology of utilizing 2 definitions of exacerbation proves successful, it will set the benchmark for future studies in chronic obstructive pulmonary disease.

Topics: Adult; Aged; Aged, 80 and over; Albuterol; Androstadienes; Bronchodilator Agents; Cholinergic Antagonists; Fluticasone; Humans; Middle Aged; Multicenter Studies as Topic; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Research Design; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide

The driving force in the progression of COPD is the development of exacerbations which are mostly the result of excessive inflammation. Bronchodilatators play an important role in the treatment of COPD. The reported reduction in exacerbation rates in COPD is due to the inhibition of vagal-mediated bronchoconstriction and mucus secretion. However, recent studies have highlighted the existence of muscarinic receptors on inflammatory cells and we have explored the possibility that tiotropium bromide might also inhibit neutrophil migration. We analysed the influence of tiotropium on the release of neutrophil chemotactic activity in response to acetylcholine (ACh) and the expression of muscarinic receptors on human alveolar macrophages (AM), A549 cells, MonoMac6 cells, and human lung fibroblasts. We found significant levels of all muscarinic receptor subtypes on all analysed cells except the fibroblasts. Fibroblasts expressed predominantly M2, receptors and did not release chemotactic activity. AM, A549 cells, and MonoMac6 cells released chemotactic active mediators after incubation with ACh. The secretion could be suppressed by more than 70% after coincubation with tiotropium. Tiotropium alone did not influence the granulocyte migration. Most of the chemotactic activity could be attributed to leukotriene B4 (LTB4). The release of interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) was not induced by ACh. From this, we suggest that the suppression of the Ach-mediated release of chemotactic substances like LTB4 modulates the inflammatory reaction. This may contribute to the decreased rate of exacerbations in COPD, which was observed in clinical trials.

Topics: Acetylcholine; Aged; Cells, Cultured; Chemotactic Factors; Cholinergic Antagonists; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Humans; In Vitro Techniques; Leukotriene B4; Macrophages, Alveolar; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Reverse Transcriptase Polymerase Chain Reaction; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; C-Reactive Protein; Humans; Interleukin-6; Interleukin-8; Peroxidase; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Saliva; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD), which ranks fifth in terms of the global burden of diseases, is one of the major risk factors of post-operative pulmonary complications. Tiotropium bromide is a new inhaled bronchodilator for COPD patients with a sustained duration of action; it has superior efficacy compared to other bronchodilators. However, little is known regarding its clinical value as a preoperative treatment for COPD patients. In this study, we compared the incidence of post-operative complications between COPD patients who received with tiotropium bromide and those who did not.. Retrospective study.. For 1 month before surgery we examined 84 and 82 patients treated with tiotropium bromide (tiotropium group) and oxitropium bromide (oxitropium group), respectively, in combination with other medications. We performed a statistical comparison of clinical features, pulmonary functions, and postoperative complications between the 2 groups.. The improvements in clinical symptoms and forced expiratory volume in 1 second were better in the tiotropium group than in the oxitropium group. The incidence of post-operative pulmonary complications (refractory bronchospasm, pulmonary infection, and acute respiratory failure) was significantly lower in the tiotropium group than in the oxitropium group. Three patients in the tiotropium group complained of dry mouth; however, the symptoms could be controlled. The incidence of post-operative non-pulmonary complications was not significantly different between the 2 groups.. We propose that tiotropium bromide might be a safe and useful drug for pre-operative treatment of COPD patients.

Topics: Adult; Aged; Aged, 80 and over; Bronchodilator Agents; Female; Humans; Male; Middle Aged; Preoperative Care; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Cholinergic Antagonists; Exercise Therapy; Humans; Parasympatholytics; Physical Endurance; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Time Factors; Tiotropium Bromide

Topics: Adrenal Cortex Hormones; Albuterol; Androstadienes; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Early Diagnosis; Fluticasone; Health Education; Humans; Influenza Vaccines; Pneumococcal Vaccines; Pneumonectomy; Pulmonary Disease, Chronic Obstructive; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Severity of Illness Index; Smoking; Spirometry; Surveys and Questionnaires; Survival Analysis; Theophylline; Tiotropium Bromide; Treatment Outcome

To determine the co-morbidity and economic impact of treatment with tiotropium bromide (TB) for COPD, in a population cared for by Spanish primary care teams (PCTs) and specialist physicians, in the context of routine clinical practice.. Retrospective multi-centre study.. Four PCTs and 2 urban hospitals.. Patients with COPD receiving regular treatment with TB, during 2004.. Age and sex, episodes of co-morbidity, clinical parameters, resource use, and pharmacological groups. The costs model was established by differentiating semi-fixed from variable costs (pharmacy, tests, referrals) in the PCTs, as well as the visits, emergencies and hospital admissions occurring in the hospitals. A logistical regression analysis was made to correct the model. The costs were contrasted by analysis of covariance (ANCOVA), with the estimation of marginal means (Bonferroni adjustment).. Of 900 patients with COPD, 14.3% (n=129) received treatment with TB (95% CI, 12.0%-16.6%). The mean episodes/patient/year was 2.1 (1.4) versus 1.8 (1.3) (NS), seriousness/severity 41.3% versus 26.3% (P =.001), defined daily dose (DDD) 5928.5 (9624.1) versus 6187.7 (12471.3) (NS) and number visits/patient/year 15.1 (9.4) versus 17.3(11.9) (P=.044). After adjustments for age and sex, TB use was associated with Diabetes Mellitus (OR=1.6; 95% CI, 1.0-2.5; P=.034) and severity of patients' illness (OR=1.8; 95% CI, 1.2-2.8; P=.004). Quantification of unit cost/year was 2793.16 (3166.30) euros (3359.27 [3423.25] euros versus 2703.09 [3113.75] euros; P=.001). The adjusted patient cost/year was 2831.23 euros (SE, 217.32) with TB versus 2786.86 euros (SE, 88.53) without TB (NS).. TB is associated, as therapy complementing routine treatment, with the presence of Diabetes, and with the severity of the disease. The costs of COPD entail high resource consumption. The prescription of TB does not imply greater overall cost of the disease.

Topics: Aged; Bronchodilator Agents; Costs and Cost Analysis; Female; Health Resources; Humans; Male; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Scopolamine Derivatives; Spain; Tiotropium Bromide

Use of a long-acting inhaled bronchodilator, either an anticholinergic or a beta-adrenergic receptor agonist (beta-agonist), is recommended for maintenance treatment of chronic obstructive pulmonary disease (COPD). In COPD, the organ system most frequently requiring medical care, other than the respiratory system, is the cardiac system.. To compare the risk of total mortality and certain respiratory and cardiac adverse events among users of the two types of recommended long-acting bronchodilators, we conducted a cohort study. Specifically, the study compared the safety of the only approved long-acting anticholinergic, tiotropium bromide, with the single-ingredient long-acting beta-agonists (LABAs) salmeterol or formoterol in a broad population of users.. We used automated general practitioner data from the UK THIN (The Health Information Network) database as the data source for this study. We used Cox proportional hazards models to compute hazard ratio (HR) estimates and 95% CI controlling for propensity scores comprising various baseline demographic variables, medical therapies and illnesses.. The 1061 tiotropium users and 1801 LABA users were similar with regard to risk of total mortality (HR 0.93; 95% CI 0.59, 1.44) and most cardiac events, including angina (HR 0.77; 95% CI 0.37, 1.59), atrial fibrillation or flutter (HR 0.60; 95% CI 0.25, 1.42), myocardial infarction (HR 1.29; 95% CI 0.45, 3.66) and tachycardia (HR 0.66; 95% CI 0.29, 1.51). Though imprecise, there was evidence of a decreased risk of heart failure (HR 0.65; 95% CI 0.37, 1.12) in tiotropium users. As regards respiratory endpoints, the risk of COPD exacerbation (HR 1.15; 95% CI 0.79, 1.67) and pneumonia (HR 1.11; 95% CI 0.38, 3.26) were similar among users of each type of drug, although there was a decreased risk of asthma exacerbation (HR 0.41; 95% CI 0.26, 0.64) in tiotropium users compared with LABA users.. Users of tiotropium and single-ingredient LABA had similar risk of total mortality and cardiovascular endpoints. The decreased risk of asthma exacerbations with tiotropium may be due to residual confounding by indication. Confidence limits for most events include reduced risks for tiotropium and also small increases in risk. Nevertheless, the point estimates suggest that tiotropium was associated with a lower risk of each cardiac event except myocardial infarction. However, the small number of cases means that further studies are needed to confirm these results.

Topics: Administration, Intranasal; Adult; Aged; Aged, 80 and over; Albuterol; Bronchodilator Agents; Cardiovascular Diseases; Cohort Studies; Databases, Factual; Delayed-Action Preparations; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Medical Records Systems, Computerized; Middle Aged; Primary Health Care; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; United Kingdom

Patients with COPD are frequently prescribed inhaled corticosteroids (ICS); however, it is unclear whether the treatment with ICS might modify responses to inhaled bronchodilators. Two 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group studies of tiotropium 18 microg once daily, compared with salmeterol, 50 microg bid, had been conducted in patients with moderate-to-severe COPD. Efficacy was assessed by spirometry, transition dyspnea index (TDI), St. George's Respiratory Questionnaire (SGRQ), and exacerbations. Data from both studies were combined to form subgroups with regard to concurrent use of ICS. 796 patients receiving ICS were separately analyzed from 390 patients not receiving ICS. Mean age was 64 years, and pre-bronchodilator FEV1 was 1.06 L (ICS group) and 1.13 L (non-ICS group). Both bronchodilators increased morning mean +/- SE pre-dose FEV1 compared with placebo (ICS groups: tiotropium 110 +/- 20 mL, salmeterol 80 +/- 20 mL; non-ICS groups: tiotropium 150 +/- 30 mL, salmeterol 110 +/- 30 mL; p > 0.05 for tiotropium vs salmeterol). Improvements in TDI and SGRQ and frequency of exacerbations also tended to be more profound for tiotropium. Treatment with tiotropium in patients with moderate-to-severe COPD was superior to salmeterol in lung function, irrespective of concurrent use of ICS.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Dyspnea; Forced Expiratory Volume; Health Status; Humans; Lung; Middle Aged; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Retrospective Studies; Salmeterol Xinafoate; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Bronchodilator Agents; Cholinergic Antagonists; Drug Therapy, Combination; Humans; Patient Selection; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Airway Resistance; Bronchodilator Agents; Cholinergic Antagonists; Delayed-Action Preparations; Forced Expiratory Volume; Humans; Long-Term Care; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

In chronic obstructive pulmonary disease (COPD) patients tiotropium bromide has been shown to improve forced expiratory volume in one second (FEV1) and inspiratory capacity (IC). We investigated whether the mechanism leading to these improvements is related to small airways ventilation heterogeneity, assessed by multiple breath washout tests. Forty stable tiotropium-free COPD patients (FEV1: 27%-78% predicted) were studied before and 90 min after administration of tiotropium bromide on visit0, and following 3 and 6 weeks of tiotropium bromide treatment (visit3wks, visit6wks). After study completion, COPD patients were classified into two subgroups according to degree of hyperinflation at visit0 (Hyp-, Hyp+). The Hyp+ group showed significant increases in trough (ie, pre-dose) FEV1 and IC after 3 and 6 weeks of tiotropium bromide, and the 90 min tiotropium bromide responses of FEV1 and IC were significant at visit0 (p < or = 0.001 for both) but not during subsequent visits. The Hyp- group showed significant FEV1 increases 90 min after tiotropium bromide on all three visits (all p < 0.005) but no sustained increase in trough values. In both COPD subgroups, the grossly abnormal ventilation heterogeneity barely showed any significant improvements with tiotropium bromide in the conductive airways (without changes in trough value) and no changes at all in the acinar airways. We conclude that the sustained improvements in trough IC and FEV1 with tiotropium bromide predominantly observed in COPD patients with considerable hyperinflation, are unrelated to small airways ventilation heterogeneity.

Topics: Aged; Belgium; Bronchodilator Agents; Dose-Response Relationship, Drug; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Respiratory Mechanics; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Topics: Albuterol; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Ethics, Clinical; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Research Design; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Ethics, Clinical; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Drug Therapy, Combination; Ethanolamines; Forced Expiratory Volume; Formoterol Fumarate; Humans; Inspiratory Capacity; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD) is heterogenous syndrome characterised by irreversible progressive airflow limitation caused mainly by tobacco smoking. In the continous bronchomotor tone of normal airways has a cholinergic component mediated via muscarinic cholinergic receptors. Cholinolitic bronchodilators act by blocking muscarinic receptors participate. Tiotropium bromide is an cholinolitic bronchodilatator that antagonises muscarinic receptors and dissociates more slowly from M1 and M3 than from M2 and subsequently has a long duration of action. Tiotropium reduces the number of exacerbations, increases time to first exacerbation and improves lung function significant compared with ipratiopium. Tiotropium produces superior bronchodilation, improvements in dyspnea, health related quality of life compared to ipratropium and salmeterol in patients with COPD. The use of tiotropium is associated with sustained reduction of lung hyperinflation at rest and during exercise. Tiotropium in combination with pulmonary rehabilitation produces clinically improvement in dyspnea, health status endurance of constant work compared to pulmonary rehabilitation alone. Many studies support the use of tiotropium once-daily as first line maintenance treatment in patients with COPD.

Topics: Bronchodilator Agents; Drug Administration Schedule; Humans; Pulmonary Disease, Chronic Obstructive; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

To perform a pharmacoeconomic analysis on the treatment of chronic obstructive pulmonary disease (COPD) with the addition of tiotropium bromide.. Pharmacoeconomic modeling was performed utilizing the efficacy of tiotropium bromide from the literature on different settings and severity of COPD. Reductions in exacerbations, hospitalizations, and number of exacerbation days per year were derived from these studies. Cost of drug treatment, exacerbations, hospitalization, and loss of income were derived from local data in Singapore and reported in Singapore dollars (US$1=S$1.71). A model was constructed to calculate the impact of one-year treatment with tiotropium bromide, and the results were reported for the total incremental cost per year, cost per year needed to reduce one hospitalization in one year, and cost-savings from hospitalizations in one year. Sensitivity analysis were performed for different number of patients treated per year, differing cost of hospitalization, different cost for tiotropium bromide, different impact of tiotropium bromide on clinical outcomes, and the different amount of substitution drug utilized in the comparator group.. Using the different clinical effects and looking at the impact on treating 1000, 2000, and 10,000 patients per year, most of the results showed a high level of decrease in overall cost per year that ranged from S$145.40 to S$840.37 per patient treated. Cost per year needed to reduce one hospitalization in one year ranged from S$3217.31 to S$18,148.92. Cost-savings from hospitalizations in one year per patient treated ranged from $57.16 to $322.49. This may contribute as high as 83% of the overall cost saving. Sensitivity analysis supports the cost savings finding.. Adding tiotropium bromide for severe COPD patients would lead to a significant cost savings for the economy.

Topics: Bronchodilator Agents; Cost of Illness; Economics, Pharmaceutical; Health Care Costs; Hospitalization; Humans; Ipratropium; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Severity of Illness Index; Singapore; Tiotropium Bromide; Treatment Outcome

Generic-only pharmacy benefits may present more of a burden to patients with chronic disease conditions such as chronic obstructive pulmonary disease (COPD), where generic drug therapy choices are more limited.. To evaluate the strategies that elderly patients with COPD use to manage their out-of-pocket (OOP) prescription expenses in a generic-only pharmacy benefit compared with similar patients with a single-tier copayment or a 2-tier pharmacy benefit with coverage of brand formulary drugs.. Surveys were mailed to a sample of 3,000 Kaiser Permanente (California) patients (aged > or = 65 years) who had a diagnosis for COPD and received at least 1 prescription for a COPD-related medication during 2003. The sample was stratified by type of pharmacy benefit: generic-only, single copayment tier, and 2 copayment tiers. The survey contained questions about strategies used to reduce OOP prescription expenses, such as stop taking a prescribed medication, purchase prescriptions out of the country, or discuss OOP prescription expenses with a physician. The likelihood of using specific strategies to reduce OOP prescription expenses was modeled using logistic regression. Covariates included social support, quality of life, smoking status, socioeconomic status, total prescription costs, and demographics.. A total of 1,624 surveys were returned, for a 54% response rate. Results from logistic regressions indicate that COPD patients with a generic-only benefit are significantly more likely to report that they discussed their OOP costs with their physician (odds ratio [OR]=9.02; 95% confidence interval [CI], 6.15- 13.22), purchased their medications from another country (OR=6.70; 95% CI, 3.17-14.16) and reduced spending on food and clothing (OR=4.06; 95% CI, 2.70-6.12). They are also more likely to report that they had taken less than the prescribed amount of a regular medication (OR=1.70; 95% CI, 1.25-2.31) and that they stopped taking one or more of their regular medications (OR=1.77; CI, 1.27-2.47). Patients with low annual household incomes (<25,000 US dollars) were significantly more likely to discuss their OOP costs with their physician (OR=1.47; 95% CI, 1.08-2.00 ) and to reduce spending on food and clothing (OR=1.97; 95% CI, 1.42-2.73) than those with higher incomes. Approximately 15% of COPD patients obtained drug samples from their physicians as a method to reduce OOP costs, and there was no difference among the 3 groups in the prevalence of this cost management strategy. Overall, patients in the generic-only pharmacy benefit used an average of 3 methods to reduce OOP pharmacy costs compared with approximately 1.5 cost reduction methods used by patients in single-tier and 2-tier copayment designs who had coverage of formulary brand as well as generic drugs.. Elderly patients with COPD and a generic-drug-only pharmacy benefit are more likely to report using a variety of strategies to reduce their OOP costs compared with similar patients with single-tier copayment or 2-tier copayment pharmacy benefits. The most common strategy was discussing OOP costs with their physician, and use of this strategy was inversely related to household income. There was no difference in the proportion of COPD patients among the 3 pharmacy benefit groups that used drug samples from their physicians as a means to reduce OOP costs.

Topics: Aged; Albuterol; Albuterol, Ipratropium Drug Combination; Bronchodilator Agents; California; Cost Control; Cost Sharing; Data Collection; Drugs, Generic; Female; Humans; Insurance, Pharmaceutical Services; Ipratropium; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Delayed-Action Preparations; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The objective of the study was to assess the cost-effectiveness of two therapeutic alternatives for chronic obstructive pulmonary disease in the Greek National Health Service (NHS) setting.. A Markov probabilistic model was used to compare tiotropium with salmeterol. A Monte Carlo simulation with 5000 cases was run in the probabilistic analysis. The model was designed to compute the expected time spent in each state, the expected number of exacerbations occurring and the expected treatment cost per patient. Probabilities were extracted from clinical trials, resource utilisation and cost data from a Greek university hospital.. Quality adjusted life years were 0.70 (95% Uncertainty Interval [UI]: 0.63 to 0.77) in the tiotropium arm and 0.68 (95% UI: 0.60 to 0.75) in the salmeterol arm; a difference of 0.02 (95% UI: -0.08 to 0.13). Exacerbations reached 0.85 (95% UI: 0.80 to 0.91) in the tiotropium arm and 1.02 (95% UI: 0.84 to 1.21) in the salmeterol arm, a difference of -0.17 (95% UI: -0.37 to 0.02). Estimates of the mean annual cost per patient were euro2504 (euro2122 to euro2965) in the tiotropium arm and euro2655 (euro2111 to euro3324) in the salmeterol arm, a difference of -euro151 (-euro926 to euro580). Stochastic analysis showed that tiotropium may have an advantage in reducing exacerbations. The probability that tiotropium is cost-effective was 65% at a ceiling value of euro0 and reached 77% at a ceiling ratio of euro1000. Results stay fairly constant in various sensitivity analyses.. Even though tiotropium is more expensive to buy than salmeterol in the Greek NHS (using Greek costs there was no statistically significant difference in total costs between tiotropium and salmeterol), overall, during the course of a year, it is actually associated with a lower prevalence of exacerbations and lower treatment costs and thus may represent a viable and cost-effective alternative in the Greek NHS setting.

Topics: Albuterol; Bronchodilator Agents; Computer Simulation; Cost-Benefit Analysis; Drug Therapy, Combination; Greece; Humans; Models, Statistical; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Sensitivity and Specificity; Tiotropium Bromide

Topics: Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Aged; Female; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

A 77-year-old man was referred to hospital because of dyspnea on exertion. Although the patient had been fully medicated for chronic heart failure (CHF) caused by hypertensive heart disease, the echo-estimated left ventricular end-diastolic pressure (LVEDP) and brain natriuretic peptide (BNP) level had continued to be high for at least 2 years. Pulmonary functional examination revealed concomitant chronic obstructive pulmonary disease (COPD). Because beta-agonists were expected to exacerbate the CHF, inhalation of tiotropium, a non-beta-adrenergic bronchodilator and novel M3 muscarinic receptor antagonist, was used to treat the COPD. Not only did the pulmonary function improved but the treatment also safely ameliorated CHF signs including LVEDP and plasma BNP.

Topics: Aged; Heart Failure; Humans; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Airway medications have not been shown to reduce the loss of lung function in patients with COPD. We explored whether tiotropium 18 microg once daily could slow the rate of decline of lung function over a 1-year period.. We performed a post-hoc analysis of data from 921 ambulatory COPD patients participating in two, 1-year, double-blind, tiotropium vs. placebo-controlled trials. Serial spirometry was obtained at baseline (before first dose of study drug), on day 8, at 6 weeks, and at 3, 6, 9 and 12 months after start of the study.. Baseline demographics and lung function were comparable. Baseline FEV1 was 1.01+/-0.41 (SD) L (39+/-14% predicted). Mean decline in trough FEV1 (i.e. FEV1 23-24 h after prior use of medication) between days 8 and 344 was 58 ml/year in the placebo group and 12 ml/year in the tiotropium group (p=0.005 vs. placebo); and between days 50 and 344 was 59 ml/year in the placebo group and 19 ml/year in the tiotropium group (p=0.036 vs. placebo).. Based on a retrospective analysis of 1-year, placebo-controlled clinical trials, tiotropium was associated with a reduced rate of loss of FEV1. Longer-term trials specifically designed to study this effect are required to confirm this observation.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Male; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Scopolamine Derivatives; Smoking; Spirometry; Tiotropium Bromide

We assessed the clinical and functional changes taking place in patients diagnosed of chronic obstructive pulmonary disease (COPD) who have been treated with ipratropium bromide, three months after this medicament was replaced by the new tiotropium bromide.. A prospective intervention survey was carried out in a primary health-care area in patients who suffered from COPD who fulfilled the inclusion criteria. Before changing the treatment and three months after changing it, we carried out the following procedures: spirometry, 6 minutes walking test (6MWT) with pulsioximetry before and after the exercise, St. George Respiratory Questionnaire (SGRQ) and assessment of: patient's chronic dyspnea, degree of patient's compliance, adverse effects and degree of satisfaction with the new drug.. 24 patients (22 males and 2 females) with a mean age of 68.54 years participated in the survey. The FVC improved a 4.92% (120 ml) [p = .27] and the FEV1, 14.16% (170 ml) [p < .001]. The degree of compliance arose from 67.54% to 96.73% (p < .001), the degree of dyspnea decreased from 4.63 to 3.89 (p = .141), the 6MWT increased in 23.79 m (p = .027) and the global mark of the SGRQ reduced (improved) in 13.35 points. There were adverse effects in 5 cases (mouth dryness in 4 patients and headache in 1 of them) and 15 patients (62.5%) said the new drug was better.. Most analyzed parameters had positive changes three months after changing the treatment. Tiotropium may be a valid alternative in the treatment of patients suffering from COPD in a stable stage.

Topics: Aged; Cholinergic Antagonists; Female; Humans; Male; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Cost-Benefit Analysis; Health Expenditures; Health Promotion; Insurance, Pharmaceutical Services; New Zealand; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking; Smoking Cessation; Tiotropium Bromide

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Bronchodilator Agents; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; India; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The constant increase in health care costs, in a context of limited resources and the appearance of more costly though more effective drugs, justifies an assessment of the pharmacoeconomics of these drugs. The objective of this study was to evaluate the cost-effectiveness of one of the newest drugs for the treatment of chronic obstructive pulmonary disease (COPD)-tiotropium.. A cost-effectiveness analysis (costs and outcomes) within the framework of the Spanish National Health System was done. The alternatives to tiotropium analyzed were ipratropium and salmeterol. Direct health care costs associated with hospital treatment were calculated. Forced expiratory volume in 1 second, quality of life (with the Saint George's Respiratory Questionnaire), dyspnea transitional index, mean stay in hospital, and exacerbations were the variables used to measure effectiveness. Values for these variables were taken from the main reviews and randomized clinical trials published for tiotropium.. For COPD patients, treatment with tiotropium leads to a greater reduction in exacerbations (37% compared to ipratropium and 25% compared to salmeterol 25%), and a reduction in the number of days in hospital (33% compared to ipratropium and 14% compared to salmeterol). Therefore, use of tiotropium could save ;100 000 for the current rates of admission and lengths of hospital stay in Spain.. Tiotropium was more effective than ipratropium and salmeterol as measured by objective clinical variables (forced expiratory volume in 1 second) and subjective ones (the Saint George's Respiratory Questionnaire and dyspnea transitional index). Hospital stays were shorter and exacerbations fewer with tiotropium. In all cases, tiotropium was more cost-effective than the alternatives, thus use of tiotropium could help hospitals to save money.

Topics: Adult; Aged; Albuterol; Bronchodilator Agents; Cost-Benefit Analysis; Drug Costs; Economics, Pharmaceutical; Health Care Costs; Humans; Ipratropium; Middle Aged; National Health Programs; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Spain; Tiotropium Bromide

Topics: Bronchodilator Agents; Drug Industry; Germany; Humans; Pulmonary Disease, Chronic Obstructive; Quality Assurance, Health Care; Scopolamine Derivatives; Tiotropium Bromide

Topics: Airway Resistance; Bronchodilator Agents; Dyspnea; Exercise Test; Functional Residual Capacity; Humans; Inspiratory Capacity; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Animals; Bronchoconstriction; Bronchodilator Agents; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Biopsy, Needle; Fluorescent Antibody Technique, Direct; Follow-Up Studies; Humans; Immunohistochemistry; Lupus Erythematosus, Cutaneous; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Remission, Spontaneous; Risk Assessment; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Female; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Failure

Topics: Bronchodilator Agents; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Dyspnea; Evidence-Based Medicine; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide

Long acting inhaled bronchodilators - beta agonists and anti-cholinergic--can improve symptoms, enhance quality of life, increase exercise ability, and reduce exacerbation rates in patients with COPD. PHARMAC needs to change policy so that these patients have easy access to this effective group of drugs.

Topics: Administration, Inhalation; Albuterol; Asthma; Bronchodilator Agents; Drug Approval; Ethanolamines; Formoterol Fumarate; Humans; National Health Programs; New Zealand; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Asthma; Bronchodilator Agents; Drug Approval; Drug Evaluation; Humans; National Health Programs; New Zealand; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

The economic value of tiotropium in patients with moderate to severe COPD was analysed in a cost-effectiveness study for the Swiss public health insurance system. The results show a drop in COPD exacerbations in comparison to Ipratropium, Salmeterol and standard care (without use of anticholinergics and beta-adrenergics). The numbers-needed-to-treat of tiotropium in comparison to the other medications in order to avoid severe exacerbations amounted to 8 patients (ipratropium versus tiotropium), 13 patients (standard care versus tiotropium) and 33 patients (salmeterol versus tiotropium) during 12 months. As a result fewer episodes of hospitalisations and shorter hospital stays can be expected. The direct yearly total cost for COPD therapy is CHF 4788 for tiotropium and CHF 5820 for ipratropium. Furthermore, they amount to CHF 4881 and CHF 4920 for salmeterol and standard care. The higher acquisition cost for tiotropium is compensated by fewer exacerbations. No other medication was similarly cost-effective with regard to total cost and number of exacerbations.

Topics: Albuterol; Bronchodilator Agents; Cost-Benefit Analysis; Hospitalization; Humans; Insurance, Health; Ipratropium; Length of Stay; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate; Scopolamine Derivatives; Switzerland; Time Factors; Tiotropium Bromide

Expiratory flow limitation, air-trapping and hyperinflation are well-known problems in COPD patients. Due to dyspnea during exercise COPD patients often avoid physical activity, which is one of the most important parameters of quality of life. In studies with long-acting bronchodilators, e.g., the anticholinergic agent tiotropiumbromide, a reduction of expiratory flow limitation, hyperinflation and dyspnea could be demonstrated. This was followed by an increase in physical activity. Increase in inspiratory capacity and reduction of functional residual capacity correlated well with the improvement of exercise capacity. In conclusion, bronchodilators such as tiotropiumbromide are able to reduce hyperinflation in COPD patients.

Topics: Bronchodilator Agents; Dyspnea; Exercise; Humans; Pulmonary Disease, Chronic Obstructive; Pulmonary Ventilation; Scopolamine Derivatives; Tiotropium Bromide

To elicit efficacy of a 3-month treatment with new inhaled cholinolytic drug spiriva in patients with chronic obstructive pulmonary disease (COPD) of stage 3.. Clinical symptoms (a total score of symptoms), external respiration function (ERF), pressure in the pulmonary artery were examined in 28 patients with COPD (stage 3).. Long-acting thiotropium bromide relieved symptoms (the score decreased from 7.8 +/- 0.4 to 5.6 +/- 0.5), respiratory capacity rose from 68.8 +/- 2.4% to 75.9 +/- 2.5%, forced expiratory volume per 1 s increased from 41.9 +/- 2.6% to 46.6 +/- 3.2%, mean pressure in the pulmonary artery lowered from 29.0 +/- 0.8 to 25.1 +/- 1.2 mm Hg.. Regular therapy with long-acting thiotropium bromide in patients with COPD stage 3 reduces clinical symptoms: dyspnea, mean pressure in the pulmonary artery. It also improves bronchial permeability.

Topics: Administration, Inhalation; Cholinergic Antagonists; Female; Follow-Up Studies; Forced Expiratory Flow Rates; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Wedge Pressure; Scopolamine Derivatives; Severity of Illness Index; Tiotropium Bromide; Treatment Outcome; Vital Capacity

Topics: Bronchodilator Agents; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Research Design; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Bronchodilator Agents; Controlled Clinical Trials as Topic; Delayed-Action Preparations; Drug Therapy, Combination; Ethanolamines; Formoterol Fumarate; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Humans; Ipratropium; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Structure-Activity Relationship; Tiotropium Bromide

Tiotropium is a major advance in the management of COPD. Clinical trials have shown that this product administered once a day improves overall lung function, reduces dyspnea, improves quality of life, and reduces hospitalizations. It does have the common adverse effect of an increase in dry mouth. The once-a-day dosing and easy-to-use HandiHaler device should improve patient compliance. Overall, based on the product profile, tiotropium appears to be an effective first-line agent in the management of COPD in the nursing home.

Topics: Administration, Inhalation; Aged; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Hospitalization; Humans; Ipratropium; Nebulizers and Vaporizers; Nursing Homes; Patient Education as Topic; Pulmonary Disease, Chronic Obstructive; Quality of Life; Salmeterol Xinafoate; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Animals; Humans; Pulmonary Disease, Chronic Obstructive; Rats; Scopolamine Derivatives; Tiotropium Bromide

Topics: Bronchodilator Agents; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

To determine whether long-term symptomatic improvement occurs in COPD patients with maintenance bronchodilator therapy despite a nonsignificant short-term improvement in FEV(1) following bronchodilator inhalation obtained at a single time point.. Data obtained during two identical 1-year, placebo-controlled trials of tiotropium, 18 micro g once daily, were analyzed retrospectively to determine the associations of long-term improvements in lung function and patient health status with short-term improvements in FEV(1), as measured on the first day of treatment. Based on the presence or absence of a short-term improvement in FEV(1) of > or = 12% and > or = 200 mL, respectively, patients who had been treated with tiotropium were characterized as being responsive to tiotropium (TIO-R) or poorly responsive to tiotropium (TIO-PR).. Baseline characteristics were similar other than baseline FEV(1), which was higher in the TIO-R group than in both the TIO-PR and placebo groups (p < 0.05). Baseline FEV(1) was 1.08 L in the TIO-R group (n = 263), 0.95 L in the TIO-PR (n = 255), and 0.99 L in the placebo group (n = 328). The mean (+/- SD) morning predose FEV(1) at 1 year significantly (p < 0.001) improved in patients in both of the tiotropium treatment subgroups (TIO-R group, 212 +/- 17 mL; TIO-PR group, 94 +/- 17 mL) relative to those treated with placebo. Statistically significant improvements in both tiotropium-treated groups also were noted over 1 year for dyspnea (p < 0.001), as assessed by the transition dyspnea index (TDI) [TIO-R group, 1.36 +/- 0.23 L; TIO-PR group, 0.86 +/- 0.23 L] relative to the placebo group. Patient health status assessed by the St. George Respiratory Questionnaire (SGRQ) showed statistically significant improvements over placebo for the TIO-R and TIO-PR groups (-3.96 +/- 0.99 and -3.05 +/- 1.00 L, respectively; p < 0.005). There was a significant correlation of the first-dose short-term FEV(1) response to the end-of-trial trough response (r = 0.43), but there was only a weak correlation to TDI focal score (r = 0.17) or SGRQ total score (r= -0.12).. Tiotropium was effective in the treatment of patients with COPD, irrespective of the presence or absence of a short-term response on the first day of treatment. The short-term bronchodilator response should not be used as a definitive criterion for prescribing long-term treatment with inhaled bronchodilators.

Topics: Adrenergic beta-Agonists; Aged; Albuterol; Bronchodilator Agents; Cholinergic Antagonists; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Retrospective Studies; Scopolamine Derivatives; Tiotropium Bromide; Vital Capacity

Topics: Bronchodilator Agents; Cholinergic Antagonists; Cohort Studies; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Tiotropium Bromide

Topics: Bronchodilator Agents; Cholinergic Antagonists; Erectile Dysfunction; Female; Humans; Male; Parasympatholytics; Phosphodiesterase Inhibitors; Physician-Patient Relations; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Risk Factors; Scopolamine Derivatives; Sildenafil Citrate; Sulfones; Time Factors; Tiotropium Bromide; Vasodilator Agents

Topics: Adult; Bronchodilator Agents; Diabetes Mellitus; Forced Expiratory Volume; Humans; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Smoking; Smoking Cessation; Spirometry; Tiotropium Bromide; Weight Loss

Topics: Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials as Topic; Delayed-Action Preparations; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Topics: Administration, Inhalation; Bronchodilator Agents; Cholinergic Antagonists; Costs and Cost Analysis; Europe; Female; Forced Expiratory Volume; Germany; Humans; Male; Placebos; Prognosis; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Radiography, Thoracic; Scopolamine Derivatives; Sex Factors; Time Factors; Tiotropium Bromide

Topics: Bronchodilator Agents; Cholinergic Antagonists; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide