Tiotropium and risk for fatal and nonfatal cardiovascular events in patients with chronic obstructive pulmonary disease: systematic review with meta-analysis

Respir Med. 2009 Oct;103(10):1421-9. doi: 10.1016/j.rmed.2009.05.020. Epub 2009 Jun 24.


Background: There are safety concerns regarding the use of anticholinergics in the COPD patient population. The purpose of this review was to evaluate the cardiovascular risk of regular use of inhaled tiotropium bromide in patients with COPD of any severity.

Methods: Systematic searches were conducted in MEDLINE, EMBASE, the Cochrane Controlled Trials Register, manufactures' trial register, and FDA databases, without language restriction. Primary outcomes were a composite of major adverse cardiovascular events, cardiovascular mortality, and nonfatal myocardial infarction (MI) or stroke during the treatment period. Relative risks (RR) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I2 statistic.

Results: Nineteen randomized controlled trials (18,111 participants) were selected. There was no difference in the incidence of adverse cardiovascular events (RR=0.96; 95% CI, 0.82-1.12, I2=6%). Among individual components of the composite outcome, tiotropium did not significantly increase the risk of cardiovascular death (RR=0.93; 95% CI, 0.73-1.20, I2=1%), nonfatal MI (RR=0.84; 95% CI, 0.64-1.09, I2=0%), and nonfatal stroke (RR=1.04; 95% CI, 0.78-1.39, I2=0%). A smoking history of > or = 55 pack-years presented a trend to a higher rate of cardiovascular adverse events in patients receiving tiotropium.

Conclusions: Compared with control (placebo or salmeterol), tiotropium did not significantly increase the risk of adverse major cardiovascular events among COPD patients. Subgroup analysis suggested that smoking history can modify the risk of cardiovascular adverse events.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Administration, Inhalation
  • Bronchodilator Agents / adverse effects*
  • Bronchodilator Agents / therapeutic use
  • Humans
  • Myocardial Infarction / chemically induced*
  • Myocardial Infarction / mortality
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / mortality
  • Randomized Controlled Trials as Topic
  • Risk Assessment
  • Scopolamine Derivatives / administration & dosage
  • Scopolamine Derivatives / adverse effects*
  • Stroke / chemically induced*
  • Stroke / mortality
  • Tiotropium Bromide


  • Bronchodilator Agents
  • Scopolamine Derivatives
  • Tiotropium Bromide