Clinical Question: Does the use of beta agonists by patients wth chronic obstructive pulmonary disease (COPD) increase the risk of adverse cardiovascular events?

Setting: Outpatient (any)

Study Design: Meta-analysis (randomized controlled trials)

Allocation to Groups: Uncertain

Synopsis: There has long been concern that beta agonists may increase the risk of adverse cardiovascular events, particularly in patients with COPD. Observational studies have found an association, although they cannot prove causation. This study is a meta-analysis of randomized, placebo-controlled trials of beta agonists (primarily albuterol and salmeterol) in the treatment of asthma or COPD.

The authors did an appropriate search of MEDLINE but did not report searching the Cochrane Controlled Trials Register, even though they used the Cochrane MetaView software to do their meta-analysis. They identified two kinds of studies: single-dose trials in which patients received a single dose of a beta agonist and heart rate or potassium levels were measured, and longer duration trials in which at least one adverse cardiovascular event was measured. Adverse cardiovascular events included a wide variety of events, from the relatively benign (e.g., sinus tachycardia) to the more serious, major events (e.g., ventricular tachycardia, atrial fibrillation, syncope, myocardial infarction, congestive heart failure, cardiac arrest, sudden death). Two reviewers independently abstracted data, the quality of studies was evaluated, and analysis was appropriate.

The authors found 13 single-dose trials that included 232 patients and 20 trials of longer duration that included 6,623 patients who met the study criteria. The average length of the longer duration trials was 4.7 months. The single-dose trials showed a minor increase in heart rate (mean: 9.1 beats per minute; 95 percent confidence interval [CI], 5.3 to 12.9) and a clinically unimportant decrease in the level of serum potassium. Results of the longer duration trials showed an increased risk of any adverse cardiovascular event (relative risk [RR], 2.5; 95 percent CI, 1.6 to 4.0), largely caused by an increase in the risk of sinus tachycardia. The likelihood of major cardiovascular events increased but was not statistically significant (RR, 1.6; 95 percent CI, 0.8 to 3.4). In absolute terms, 1,742 patients in the beta-agonist group had 15 major events, compared with seven events among 1,347 patients in the placebo group. Although the study designs were different for the trials of longer duration, the results were statistically homogeneous.

Bottom Line: This study provides some evidence that use of beta agonists increases the risk of adverse cardiovascular events in patients taking them for asthma or COPD. Most of these events are trivial (e.g., sinus tachycardia), and the absolute increase in the risk of a major cardiovascular event is low (i.e., approximately one additional event for every 200 patients over a six-month period). (Level of Evidence: 1a–)