Medications Commonly Prescribed for COPD Associated With Increased Risk of Cardiovascular Death, Heart Attack or Stroke

The use of inhaled anticholinergic agents (medications that help reduce bronchospasm) by patients with chronic obstructive pulmonary disease (COPD) is associated with a significantly increased risk of heart attack, stroke of cardiovascular death, according to a meta-analysis of randomized trials published in the September 24 issue of JAMA.


COPD is the fourth leading cause of chronic illness and death in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide. Inhaled anticholinergic agents (including ipratropium bromide or tiotropium bromide) are widely used in patients with COPD, but their effect on the risk of cardiovascular outcomes is unknown, according to background information in the article. Inhaled tiotropium is the most widely prescribed medication for COPD, with more than 8 million patients worldwide having used it since its approval in 2002.


Sonal Singh, M.D., M.P.H., of Wake Forest University School of Medicine, Winston-Salem, N.C., and colleagues conducted a meta-analysis to determine cardiovascular risks (myocardial infarction [MI; heart attack], stroke, and cardiovascular death) associated with the long-term use of inhaled anticholinergics. After identifying and a detailed screening of 103 articles, 17 randomized trials enrolling 14,783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years.


The analysis indicated that inhaled anticholinergics significantly increased the risk, by 58 percent, of cardiovascular death, heart attack, or stroke (1.8 percent vs. 1.2 percent for controls). Among individual components of the primary outcome, inhaled anticholinergics significantly increased the risk of heart attack by 53 percent (1.2 percent vs. 0.8 percent for controls) and also significantly increased (by 80 percent) the risk of cardiovascular death (0.9 percent vs. 0.5 percent for controls).


All-cause death was reported in 149 of the patients treated with inhaled anticholinergics (2.0 percent) and 115 of the control patients (1.6 percent). A sensitivity analysis restricted to 5 long-term trials (greater than 6 months) confirmed the significantly increased risk (73 percent) of cardiovascular death, heart attack, or stroke (2.9 percent of patients treated with anticholinergics vs. 1.8 percent of the control patients).


“Chronic obstructive pulmonary disease is an independent risk factor for cardiovascular hospitalization and cardiovascular death. Cardiovascular death is a more frequent cause of death in patients with COPD than respiratory causes, with the proportion of cardiovascular deaths increasing with the severity of the disease,” the authors write.


“Clinicians need to closely monitor patients with COPD who are taking long-term anticholinergics for the development of cardiovascular events. Clinicians and patients should carefully consider these potential long-term cardiovascular risks of inhaled anticholinergics in the treatment of COPD, and decide whether these risks are an acceptable trade-off in return for their symptomatic benefits.”


JAMA. 2008;300[12]:1439-1450.