Am Fam Physician. 2006 Oct 15;74(8):1426-1428.
Current asthma guidelines recommend augmenting therapy with long-acting beta agonists (LABAs) in patients whose symptoms are not adequately controlled with an inhaled corticosteroid. However, the recent Salmeterol Multi-center Asthma Research Trial (SMART) associated the use of the LABA salmeterol (Serevent) with an increased risk of asthma-related death, causing the U.S. Food and Drug Administration to issue warnings about salmeterol and similar medications. Because severe exacerbations and deaths from asthma are rare, the risks associated with LABA use are uncertain. To assess these risks more accurately, Salpeter and colleagues conducted a meta-analysis of randomized, placebo-controlled trials of LABAs in patients with asthma.
The authors searched multiple databases and reference lists to identify randomized controlled trials that compared the effects of LABAs versus placebo for at least 12 weeks. Outcomes of interest were asthma exacerbations requiring hospitalization or intubation and ventilation, and asthma-related deaths. Although 47 trials met inclusion criteria, only 19 trials that published outcomes or supplied unpublished outcomes data were included in the meta-analysis. These trials were conducted from 1998 to 2006 and involved a total of 33,826 participants. Follow-up intervals ranged from 12 to 52 weeks; 12 of the trials lasted only 12 weeks. All trials permitted the use of short-acting beta agonists as needed for symptom relief.
Compared with placebo, patients with asthma using LABAs were 2.6 times more likely to be hospitalized (95% confidence interval [CI], 1.6 to 4.3) and 1.8 times more likely to require intubation and ventilation (95% CI, 1.1 to 2.9). Asthma-related deaths occurred in three of 14 trials (five trials did not provide data on asthma-related deaths); two of the trials reported a single death. In the SMART trial, there were 13 deaths in the LABA group and three in the placebo group, translating to one excess death per 1,000 patient years. Assuming that no deaths occurred in the trials that did not provide data on deaths, patients using LABAs had a 0.06 percent increase in absolute risk of asthma-related death after six months of treatment.
The authors conclude that LABA use results in statistically significant increases in severe and life-threatening asthma exacerbations and asthma-related deaths. Because salmeterol was prescribed to approximately 3.5 million adults in the United States in 2004, it could potentially be responsible for up to 80 percent of asthma-related deaths. The authors theorize that LABAs may worsen asthma control in susceptible patients by desensitizing and down-regulating beta-adrenergic receptors that subsequently fail to respond to short-acting or “rescue” beta agonist use.
Salpeter SR, et al. Meta-analysis: effect of long-acting beta agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med. June 20, 2006;144:904–12.
editor’s note: For family physicians who were puzzled by the appearance of the initial U.S. Food and Drug Administration warnings about salmeterol in 2005, the study by Salpeter and colleagues demonstrates an apparent gap between clinical trials and clinical practice. Put simply, if LABAs worsen asthma control, then why do the overwhelming majority of patients who use them seem to improve? In an editorial in the same issue, Glassroth advocates an approach that strikes a balance between evidence and pragmatism: maximize the inhaled corticosteroid dose before starting a LABA, monitor these patients closely, and be quick to withdraw the LABA or substitute another medication if the patient does not improve.1 Hopefully, future studies will tell physicians which patients with asthma are at highest risk for these rare life-threatening events.—k.w.l.
1. Glassroth J. The role of long-acting beta agonists in the management of asthma: analysis, meta-analysis, and more analysis. Ann Intern Med. 2006;144:936–7.
Copyright © 2006 by the American Academy of Family Physicians.
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