Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis

Sonal Singh, Yoon K. Loke, Curt D. Furberg

Research output: Contribution to journalArticle

Abstract

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]; P2=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]; P2=0%). Conclusion: Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

Original languageEnglish (US)
Pages (from-to)1439-1450
Number of pages12
JournalJournal of the American Medical Association
Volume300
Issue number12
DOIs
StatePublished - Sep 24 2008
Externally publishedYes

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Cholinergic Antagonists
Chronic Obstructive Pulmonary Disease
Meta-Analysis
Stroke
Myocardial Infarction
Confidence Intervals
Ipratropium
Mortality
Information Storage and Retrieval
Statistical Models
MEDLINE
Registries
Therapeutics
Randomized Controlled Trials
Databases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease : A systematic review and meta-analysis. / Singh, Sonal; Loke, Yoon K.; Furberg, Curt D.

In: Journal of the American Medical Association, Vol. 300, No. 12, 24.09.2008, p. 1439-1450.

Research output: Contribution to journalArticle

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title = "Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis",
abstract = "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]; P2=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]; P2=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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AU - Loke, Yoon K.

AU - Furberg, Curt D.

PY - 2008/9/24

Y1 - 2008/9/24

N2 - 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]; P2=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]; P2=0%). Conclusion: Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

AB - 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]; P2=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]; P2=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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