Chest
Volume 125, Issue 6, June 2004, Pages 2309-2321
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Special Report
Cardiovascular Effects of β-Agonists in Patients With Asthma and COPD: A Meta-Analysis

https://doi.org/10.1378/chest.125.6.2309Get rights and content

Background

β-Adrenergic agonists exert physiologic effects that are the opposite of those of β-blockers. β-Blockers are known to reduce morbidity and mortality in patients with cardiac disease. β2-Agonist use in patients with obstructive airway disease has been associated with an increased risk for myocardial infarction, congestive heart failure, cardiac arrest, and acute cardiac death.

Objectives

To assess the cardiovascular safety of β2-agonist use in patients with obstructive airway disease, defined as asthma or COPD.

Methods

A meta-analysis of randomized placebo-controlled trials of β2-agonist treatment in patients with obstructive airway disease was performed, to evaluate the short-term effect on heart rate and potassium concentrations, and the long-term effect on adverse cardiovascular events. Longer duration trials were included in the analysis if they reported at least one adverse event. Adverse events included sinus and ventricular tachycardia, syncope, atrial fibrillation, congestive heart failure, myocardial infarction, cardiac arrest, or sudden death.

Results

Thirteen single-dose trials and 20 longer duration trials were included in the study. A single dose of β2-agonist increased the heart rate by 9.12 beats/min (95% confidence interval [CI], 5.32 to 12.92) and reduced the potassium concentration by 0.36 mmol/L (95% CI, 0.18 to 0.54), compared to placebo. For trials lasting from 3 days to 1 year, β2-agonist treatment significantly increased the risk for a cardiovascular event (relative risk [RR], 2.54; 95% CI, 1.59 to 4.05) compared to placebo. The RR for sinus tachycardia alone was 3.06 (95% CI, 1.70 to 5.50), and for all other events it was 1.66 (95% CI, 0.76 to 3.6).

Conclusion

β2-Agonist use in patients with obstructive airway disease increases the risk for adverse cardiovascular events. The initiation of treatment increases heart rate and reduces potassium concentrations compared to placebo. It could be through these mechanisms, and other effects of β-adrenergic stimulation, that β2-agonists may precipitate ischemia, congestive heart failure, arrhythmias, and sudden death.

Section snippets

Search Strategy

A comprehensive search of the EMBASE, MEDLINE, and CINAHL databases was performed to identify randomized placebo-controlled trials on β-agonist use in patients with obstructive airway disease, published between 1966 and June 2003. The search was performed using the terms bronchodilator, sympathomimetic, adrenergic β-agonist, albuterol, salbutamol, bitolterol, isoetharine, metaproterenol, salmeterol, terbutaline, fenoterol, formoterol, procaterol, isoproterenol, reproterol, eformoterol, or

Search Results

The electronic database search identified approximately 5,000 articles, and, of these, 185 were randomized, placebo-controlled trials of β2-agonist use in patients with obstructive airway disease. After scanning references from selected articles, an additional six potentially relevant trials were identified. Of these 191 studies, 13 single-dose trials and 20 longer duration trials met the inclusion criteria. The κ-statistic for interrater agreement on study eligibility was 0.98 (95% confidence

DISCUSSION

In summary, the initiation of β2-agonist therapy was associated with significant increases in heart rate and reductions in potassium concentrations, which are known to be common systemic effects of β-adrenergic stimulation, compared to placebo. With continued treatment, the rate of cardiovascular events was increased compared to placebo, with a significant increase in sinus tachycardia and a nonsignificant trend toward an increase in major cardiovascular events. It is possible that β2-agonists

ACKNOWLEDGMENT

We thank Donald Miller for his graphical assistance, and Christopher Stave for coordinating the trials search.

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