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Meta-Analysis: Effect of Long-Acting β-Agonists on Severe Asthma Exacerbations and Asthma-Related Deaths
- Shelley R. Salpeter, MD;
- Nicholas S. Buckley;
- Thomas M. Ormiston, MD; and
- Edwin E. Salpeter, PhD
- From Santa Clara Valley Medical Center, San Jose, California, and Cornell University, Ithaca, New York.
Abstract
Background: Long-acting β-agonists may increase the risk for fatal and nonfatal asthma exacerbations.
Purpose: To assess the risk for severe, life-threatening, or fatal asthma exacerbations associated with long-acting β-agonists.
Data Sources: 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.
Study Selection: 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.
Data Extraction: 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).
Data Synthesis: 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%).
Limitations: The small number of deaths limited the reliability in assessing this risk, and 28 studies did not report information on the outcomes of interest.
Conclusions: Long-acting β-agonists have been shown to increase severe and life-threatening asthma exacerbations, as well as asthma-related deaths.
Article and Author Information
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Acknowledgments: The authors thank Christopher Stave for coordinating the trials search.
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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.
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Requests for Single Reprints: Shelley R. Salpeter, MD, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128; e-mail, Salpeter{at}stanford.edu.
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Current Author Addresses: Drs. S. Salpeter and Ormiston: Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128.
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Mr. Buckley: 215 Brookwood Road, Woodside, CA 94062.
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Dr. E. Salpeter: Cornell University, Space Sciences Building, Ithaca, NY 14853.
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