Republished: Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Postgraduate medical journal (Impact Factor: 1.45). 04/2014; 90(1062):205-207. DOI: 10.1136/postgradmedj-2011-201275rep
Source: PubMed


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.

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    • "Although the currently reported clinical trials evaluating the AB/IB Respimat SMI have reported no significant differences in adverse events, recent evaluations of tiotropium delivered by Respimat SMI suggest an increased risk of mortality.61–63 Singh et al61 performed a meta-analysis of placebo-controlled, parallel-group, randomized trials of tiotropium delivered by Respimat SMI in patients with COPD and found an increased risk of mortality, with a relative risk (RR) of 1.52 (95% CI, 1.06, 2.15). "
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and its treatment is critical to improve quality of life, reduce symptoms, and diminish the frequency of COPD exacerbations. Due to the harmful environmental effects of pressurized metered-dose inhalers (pMDIs) containing chlorofluorocarbons (CFCs), newer systems for delivering respiratory medications have been developed. A search of the literature in the PubMed database was undertaken using the keywords "COPD," "albuterol," "ipratropium bromide," and "Respimat® Soft Mist Inhaler™"; pertinent references within the identified citations were included. The environmental effect of CFC-pMDIs, the invention of the Respimat® Soft Mist Inhaler™ (SMI) (Boehringer Ingelheim, Ingelheim, Germany), and its use to deliver the combination of albuterol and ipratropium bromide for the treatment of COPD were reviewed. The adverse environmental effects of CFC-pMDIs stimulated the invention of novel delivery systems including the Respimat SMI. This review presents its development, internal mechanism, and use to deliver the combination of albuterol and ipratropium bromide. CFC-pMDIs contributed to the depletion of the ozone layer and the surge in disorders caused by harmful ultraviolet B radiation. The banning of CFCs spurred the development of novel delivery systems for respiratory medications. The Respimat SMI is an innovative device that produces a vapor of inhalable droplets with reduced velocity and prolonged aerosol duration that enhance deposition within the lower airway and is associated with improved patient satisfaction. Clinical trials have demonstrated that the Respimat SMI can achieve effects equivalent to pMDIs but with lower medication doses. The long-term safety and efficacy remain to be determined. The Respimat SMI delivery device is a novel, efficient, and well-received system for the delivery of aerosolized albuterol and ipratropium bromide to patients with COPD; however, the presence of longer-acting, less frequently dosed respiratory medications provide patients and providers with other therapeutic options.
    International Journal of COPD 04/2013; 8:221-30. DOI:10.2147/COPD.S31246 · 3.14 Impact Factor
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    • "These cardiovascular deaths were concentrated among patients with pre-existing arrhythmias and cardiovascular disease. There is biologic and clinical evidence that the cardiovascular risk of inhaled anticholinergics is particularly concentrated among patients with chronic obstructive pulmonary disease who also have concomitant cardiovascular disease [31]. Although a subsequent trial reported an increased risk of angina and arrhythmias [32], it reported no increased risk of myocardial infarction and composite stroke [32]. "
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    ABSTRACT: Randomized controlled trials are the principal means of establishing the efficacy of drugs. However pre-marketing trials are limited in size and duration and exclude high-risk populations. They have limited statistical power to detect rare but potentially serious adverse events in real-world patients. We summarize the principal methodological challenges in the reporting, analysis and interpretation of safety data in clinical trials using recent examples from systematic reviews. The principle challenges include the lack of an evidentiary gold standard, the limited statistical power of randomized controlled trials and resulting type 2 error, the lack of adequate ascertainment of adverse events and limited generalizability of safety trials that exclude high risk patients. We discuss potential solutions to these challenges. Evaluation of drug safety requires careful examination of data from heterogeneous sources. Meta-analyses of drug safety should include appropriate statistical methods and assess the optimal information size to avoid type 2 errors. They should evaluate outcome reporting biases and missing data to ensure reliable and accurate interpretation of findings. Regulatory and academic partnerships should be fostered to provide an independent and transparent evaluation of drug safety.
    Trials 08/2012; 13(1):138. DOI:10.1186/1745-6215-13-138 · 1.73 Impact Factor
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    ABSTRACT: Background Tiotropium delivered at a dose of 5 g with the Respimat inhaler showed efficacy similar to that of 18 g 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. Methods 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 g or 5 g, as compared with tiotropium HandiHaler at a once-daily dose of 18 g. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 g or 2.5 g vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 g vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease. ResultsDuring 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 g vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 g 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 g 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. Conclusions Tiotropium Respimat at a dose of 5 g or 2.5 g had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 g in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR number, NCT01126437.)
    New England Journal of Medicine 08/2013; 369(16). DOI:10.1056/NEJMoa1303342 · 55.87 Impact Factor
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