tiotropium-bromide and Cardiovascular-Diseases

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

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

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

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

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

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

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

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

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

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

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

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 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

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

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

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

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

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

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

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

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

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

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

The aim of this study was to examine the risk of cardiovascular diseases among users of both inhaled (ipratropium bromide or tiotropium bromide) and oral (oxybutynin and propantheline, solifenacin, tolterodine) anticholinergics.. A retrospective study was undertaken on data obtained from the Food and Drug Administration (FDA) from subjects who had received either an inhaled or oral form of an anticholinergic drug and experienced some side effect during the period from 1988 to 2009. The recorded data included: patient's age, sex, list of drugs and side effects. Side effect rates for the anticholinergic drugs were compared using univariate (Chi-square) and multivariate (logistic regression) methods.. The files from the FDA held data for 36 491 different subjects, of whom 2610 (7.15%) experienced a cardiovascular or neurovascular side effect. Subjects were classified as taking the oral (45%) or inhaled (55%) class of the drug, with only 109 subjects (0.3%) taking drugs in both forms. Side effect rates differed between anticholinergic drugs. Stroke and hypertension were significantly more common for subjects taking oral anticholinergic drug compared with tiotropium, while other reported vascular side effects (cardiac ischaemia or arrhythmiascardiac failure, cardiac arrest) tended to be more commonly associated with the use of inhaled anticholingerics. These differences persisted after adjustment for age and gender.. This observational study of recorded side effects showed that, except for stroke and hypertension, patients who were treated with an inhaled anticholinergic drug appeared to be at higher risk of developing neurovascular or cardiovascular side effects, than those treated with an oral drug. However, physicians should also be aware that oral anticholinergic drugs may have similar adverse impacts on health. Further studies on the association between anticholinergic drugs and cardiovascular and neurovascular side effects are recommended.

Topics: Administration, Inhalation; Administration, Oral; Aged; Aged, 80 and over; Bronchodilator Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Cholinergic Antagonists; Female; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Retrospective Studies; Risk; Scopolamine Derivatives; Stroke; 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

Topics: Cardiovascular Diseases; Humans; Meta-Analysis as Topic; Pioglitazone; Randomized Controlled Trials as Topic; Rosiglitazone; Scopolamine Derivatives; Thiazolidinediones; 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

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

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

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

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

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