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Editorials |

Anticholinergic Drugs for the Treatment of COPD Are Safe… Are They?

Klaus F. Rabe, MD, PhD
Author and Funding Information

From the Department of Pulmonology, Leiden University Medical Center.

Correspondence to: Klaus F. Rabe, MD, PhD, Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands; e-mail: k.f.rabe@lumc.nl


Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Professor Rabe has consulted, participated in advisory boardmeetings, and received lecturefees from AstraZeneca, Boehringer, ChiesiPharmaceuticals, Pfizer, Novartis, Nycomed, Medical Specialties Distributors, and GlaxoSmithKline. Professor Rabe holds no stock or other equities in pharmaceutical companies. The Department of Pulmonology, and thereby Professor K. F. Rabe as head of the department, has received grants from Novartis, AstraZeneca, Boehringer Ingelheim, Nycomed, Roche and GlaxoSmithKline in the years 2005 until 2009.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;137(1):1-3. doi:10.1378/chest.09-2466
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COPD is increasingly recognized as a complex systemic disorder with a whole range of comorbidities, especially cardiovascular, contributing significantly to COPD morbidity and mortality.1 Among the most frequently prescribed inhaled medications for this disorder are anticholinergic agents, such as short-acting ipratropium bromide, available for 20 years, and the long-acting drug tiotropium bromide, introduced in 2002, which has been shown to improve airflow, hyperinflation, exercise tolerance, exacerbations of COPD, and health-related quality of life with once-daily dosing2-8 in patients with COPD. Since these drugs are poorly absorbed by the gastrointestinal tract and the lungs, systemic adverse effects such as tachycardia are considered unlikely,9 and prescription habits might have been biased toward administering this class of drugs to patients with a higher perceived cardiovascular risk. However, for many years a link between anticholinergic drugs and an increased risk of mortality, especially from cardiovascular disease, has been reported10-14 and debated. Although there seems no reasonable explanation based on the pharmacology that short-acting anticholinergics would affect the cardiovascular system differently than long-acting drugs, a pattern seems to evolve favoring tiotropium over ipratropium also in terms of safety. Three recent publications again highlighted potential concerns in relation to short-acting anticholinergic ipratropium bromide and cardiovascular safety in patients with COPD. The metaanalysis by Singh et al14 seemed to indicate an increased risk for myocardial infarctions with a risk ratio (RR) of 1.53, (1.05-2.23) and cardiovascular death RR 1.80, (1.17-2.77) in patients randomized to inhaled anticholinergics. Similarly, two observational studies found an increased risk between anticholinergic use and cardiovascular events13 and cardiovascular-related mortality.12 The retrospective, nested case-control study by Lee et al12 focused on overall and cause-specific mortality examining the association between several respiratory medications and the risk of death in patients with newly diagnosed COPD. As a critical comment, this study likely contains relevant differences in baseline risk between the treatment groups, and there was no information available on smoking or lung function. The study by Singh et al14 selected 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, myocardial infarction, or stroke; the secondary outcome was all-cause mortality. The conclusion was that inhaled anticholinergics significantly increased the risk of the composite cardiovascular end point, myocardial infarction, and cardiovascular death, without a statistically significant increase in the risk of stroke. The study has been criticized for integrating placebo controlled trials with active controlled trials and because the analysis did not take into account differential discontinuation. Interestingly, also in this analysis, most of the evidence was provided by the Lung Health Study, which was conducted using ipratropium.

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