Shelley R. Salpeter, MD; Nicholas S. Buckley; Thomas M. Ormiston, MD; Edwin E. Salpeter, PhD
Acknowledgments: The authors thank Christopher Stave for coordinating the trials search.
Potential Financial Conflicts of Interest: None of the authors have had any relationships with a pharmaceutical company that manufactures a β-agonist or other respiratory medications. Dr. Shelley Salpeter has consulted on legal cases involving β-agonists but has never given expert testimony and has no contracts with law firms.
Requests for Single Reprints: Shelley R. Salpeter, MD, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128; e-mail, Salpeter@stanford.edu.
Current Author Addresses: Drs. S. Salpeter and Ormiston: Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128.
Mr. Buckley: 215 Brookwood Road, Woodside, CA 94062.
Dr. E. Salpeter: Cornell University, Space Sciences Building, Ithaca, NY 14853.
Long-acting β-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 β-agonists.
English- and non–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 β-agonist use in patients with asthma. All trials allowed the use of as-needed short-acting β-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 33 826 participants found that long-acting β-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 β-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.
Study flow diagram.
Table. Studies Included in Primary Analysis*
Effect of long-acting β-agonists compared with placebo on odds ratio of hospitalizations for asthma exacerbation.
Effect of long-acting β-agonists compared with placebo on odds ratio of life-threatening asthma exacerbations.
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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.
Asthma, Pulmonary/Critical Care.
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