tiotropium-bromide and Stroke

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

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

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

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

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

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

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

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

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

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

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

A recent communication from the United States Food and Drug Administration highlighted a possible increased risk of stroke associated with use of the relatively new inhaled anticholinergic drug, tiotropium bromide. Using the United Kingdom General Practice Research Database, we set out to assess the risk of stroke in individuals exposed to inhaled tiotropium bromide and two other inhaled treatments for airways disease.. We used the self-controlled case-series that reduces confounding and minimizes the potential for biases in the quantification of risk estimates.. Of 1043 people with a diagnosis of incident stroke who had had at least one prescription for tiotropium bromide, 980 satisfied inclusion criteria. The age-adjusted incidence rate ratio for all-cause stoke in individuals exposed to tiotropium bromide (n = 980), ipratropium bromide (n = 4181) and fluticasone propionate/salmeterol xinafoate (n = 1000) was 1.1 [95% confidence interval (CI) 0.9, 1.3], 0.8 (95% CI 0.7, 0.9) and 1.0 (95% CI 0.9, 1.2), respectively.. We found no evidence of an increased risk of all-cause stroke for individuals exposed to commonly prescribed inhaled treatments for chronic obstructive pulmonary disease.

Topics: Administration, Inhalation; Aged; Albuterol; Androstadienes; Bronchodilator Agents; Cholinergic Antagonists; Dose-Response Relationship, Drug; Drug Combinations; Female; Fluticasone; Humans; Ipratropium; Male; Middle Aged; Risk Factors; Salmeterol Xinafoate; Scopolamine Derivatives; Stroke; Tiotropium Bromide; United Kingdom