Inhaled anticholinergics associated with increased risk of CVD in COPD

Clinical Question

Do adults with chronic obstructive pulmonary disease who use inhaled anticholinergics have an increased risk of a major cardiovascular event?

Bottom Line

Adults with chronic obstructive pulmonary disease (COPD) treated with inhaled anticholinergics, including ipratropium (Atrovent) and tiotropium (Spiriva), are at an increased risk of adverse major cardiovascular events including myocardial infarction (MI) and cardiovascular death. However, anticholinergics improve the important patient-oriented outcome of quality of life while not increasing the risk of all-cause mortality. Clinicians should assess the risks and benefits of treatment for each individual patient. For example, consider withholding anticholinergics from patients with mild to moderate symptoms of COPD who are at high risk of a cardiovascular event, and strongly consider giving anticholinergics to patients with life-altering symptoms of COPD who are at medium risk or low risk of a cardiovascular event. (LOE = 1a)


Singh S, Loke Y, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease. A systematic review and meta-analysis. JAMA 2008;300(12):1439-1450.  [PMID:18812535]

Study Design

Meta-analysis (randomized controlled trials)


Unknown/not stated


Various (meta-analysis)


Inhaled anticholinergics, including ipratropium and tiotropium, improve quality of life in adults with COPD. Their effect on long-term mortality and morbidity is uncertain. These investigators thoroughly searched multiple databases, including MEDLINE, the Cochrane Database, and Science Citation Index, as well as manufacturers' product information sheets and bibliographies of included studies, for English-language only studies evaluating anticholinergics as therapy for adults with COPD. Inclusion criteria included only randomized controlled trials with at least 30 days of follow-up and data reporting on the incidence of serious cardiovascular events. Two authors independently searched for appropriate studies and critically assessed each individual trial for methodologic quality. Disagreements were resolved after consensus agreement with a third reviewer. The primary outcome measured was a composite of cardiovascular death, MI, or stroke. Of the initial 703 potential citations, only 17 trials (n = 14,783) met inclusion criteria. The quality of the individual trials was variable, but all were double blind. Inhaled anticholinergics significantly increased the risk of the primary composite outcome and also significantly increased the individual risks of MI (number needed to treat to harm [NNTH] = 174/year; 95% CI, 75-1835) and cardiovascular death (NNTH = 40/year; 18-185). Anticholinergics did not significantly increase the risk of all-cause mortality. The authors performed a careful analysis for both heterogeneity and publication bias and found no evidence for either.