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Review | Clinician's Corner

Inhaled Anticholinergics and Risk of Major Adverse Cardiovascular Events in Patients With Chronic Obstructive Pulmonary Disease:  A Systematic Review and Meta-analysis

Sonal Singh, MD, MPH; Yoon K. Loke, MBBS, MD; Curt D. Furberg, MD, PhD
JAMA. 2008;300(12):1439-1450. doi:10.1001/jama.300.12.1439.
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Published online

Context 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.

Objective To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke.

Data Sources 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.

Study Selection Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events.

Data Extraction 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 I2 statistic.

Data Synthesis After a detailed screening of 103 articles, 17 trials enrolling 14 783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7311 patients (1.2%) receiving control therapy (RR, 1.58 [95% confidence interval {CI}, 1.21-2.06]; P < .001, I2 = 0%). Among individual components of the primary end point, inhaled anticholinergics significantly increased the risk of MI (RR, 1.53 [95% CI 1.05-2.23]; P = .03, I2 = 0%) and cardiovascular death (RR, 1.80 [95% CI, 1.17-2.77]; P = .008, I2 = 0%) without a statistically significant increase in the risk of stroke (RR, 1.46 [95% CI, 0.81-2.62]; P = .20, I2 = 0%). All-cause mortality was reported in 149 of the patients treated with inhaled anticholinergics (2.0%) and 115 of the control patients (1.6%) (RR, 1.26 [95% CI, 0.99-1.61]; P = .06, I2 = 2%). A sensitivity analysis restricted to 5 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, 1.27-2.36]; P < .001, I2 = 0%).

Conclusion Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

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Figure 1. Study Selection
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Figure 2. Meta-analysis of Randomized Controlled Trials of Inhaled Anticholinergics vs Control for Major Adverse Cardiovascular Outcomes Composite
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Cardiovascular outcomes composite indicates cardiovascular death, myocardial infarction, and stroke. Size of the data markers indicates weight of the study. CI indicates confidence interval.

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Figure 3. Meta-analysis of Long-Term Randomized Controlled Trials of Inhaled Anticholinergics vs Control for Major Adverse Cardiovascular Outcomes Composite
Graphic Jump Location

Cardiovascular outcomes composite indicates cardiovascular death, myocardial infarction, and stroke. Long-term indicates longer than 6 months to 5 years. Size of the data markers indicates weight of the study. CI indicates confidence interval.

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Figure 4. Meta-analysis of Short-Term Randomized Controlled Trials of Inhaled Anticholinergics vs Control for Major Adverse Cardiovascular Outcomes Composite
Graphic Jump Location

Cardiovascular outcomes composite indicates cardiovascular death, myocardial infarction, and stroke. Short-term indicates 6 weeks to 6 months. Size of the data markers indicates weight of the study. CI indicates confidence interval.

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