Shelley R. Salpeter, MD; Nicholas S. Buckley; Thomas M. Ormiston, MD; Edwin E. Salpeter, PhD
Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-Analysis: Effect of Long-Acting β-Agonists on Severe Asthma Exacerbations and Asthma-Related Deaths. Ann Intern Med. 2006;144:904-912. doi: 10.7326/0003-4819-144-12-200606200-00126
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Published: Ann Intern Med. 2006;144(12):904-912.
Long-acting Î²-agonists may increase the risk for fatal and nonfatal asthma exacerbations.
To assess the risk for severe, life-threatening, or fatal asthma exacerbations associated with long-acting Î²-agonists.
English- and nonâ€“English-language searches of MEDLINE, EMBASE, and Cochrane databases; the U.S. Food and Drug Administration Web site; and references of selected reviews through December 2005.
Randomized, placebo-controlled trials that lasted at least 3 months and evaluated long-acting Î²-agonist use in patients with asthma. All trials allowed the use of as-needed short-acting Î²-agonists.
Outcomes measured were Peto odds ratio (OR) and risk difference of severe exacerbations requiring hospitalization, life-threatening exacerbations requiring intubation and ventilation, and asthma-related deaths. The OR for asthma-related deaths was obtained from the Salmeterol Multi-center Asthma Research Trial (SMART).
Pooled results from 19 trials with 33Â 826 participants found that long-acting Î²-agonists increased exacerbations requiring hospitalization (OR, 2.6 [95% CI, 1.6 to 4.3]) and life-threatening exacerbations (OR, 1.8 [CI, 1.1 to 2.9]) compared with placebo. Hospitalizations were statistically significantly increased with salmeterol (OR, 1.7 [CI, 1.1 to 2.7]) and formoterol (OR, 3.2 [CI, 1.7 to 6.0]) and in children (OR, 3.9 [CI, 1.7 to 8.8]) and adults (OR, 2.0 [CI, 1.1 to 3.9]). The absolute increase in hospitalization was 0.7% (CI, 0.1% to 1.3%) over 6 months. The risk for asthma-related deaths was increased (OR, 3.5 [CI, 1.3 to 9.3]), with a pooled risk difference of 0.07% (CI, 0.01% to 0.1%).
The small number of deaths limited the reliability in assessing this risk, and 28 studies did not report information on the outcomes of interest.
Long-acting Î²-agonists have been shown to increase severe and life-threatening asthma exacerbations, as well as asthma-related deaths.
Long-acting β-agonists may help improve asthma symptoms, but they also may increase risks for adverse outcomes.
This meta-analysis summarizes data from 19 randomized, placebo-controlled trials involving 33 826 participants with asthma. Compared with placebo, long-acting β-agonists increased severe exacerbations requiring hospitalization (odds ratio, 2.6 [95% CI, 1.6 to 4.3]), life-threatening exacerbations (odds ratio, 1.8 [CI, 1.1 to 2.9]), and asthma-related deaths (odds ratio, 3.5 [CI, 1.3 to 9.3]; risk difference, 0.07%). Risks were similar for salmeterol and formoterol and in children and adults.
Several trials did not report information about potential harms, and the number of reported deaths was small.
SMART = Salmeterol Multi-center Asthma Research Trial.
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