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REVIEW
Meta-Analysis: Effect of Long-Acting ß-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
20 June 2006 | Volume 144 Issue 12 | Pages 904-912
Background: Long-acting ß-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 ß-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 ß-agonist use in patients with asthma. All trials allowed the use of as-needed short-acting ß-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 ß-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 ß-agonists have been shown to increase severe and life-threatening asthma exacerbations, as well as asthma-related deaths.
Editors' Notes
Context
- Long-acting ß-agonists may help improve asthma symptoms, but they also may increase risks for adverse outcomes.
Contribution
- This meta-analysis summarizes data from 19 randomized, placebo-controlled trials involving 33 826 participants with asthma. Compared with placebo, long-acting ß-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.
Cautions
- Several trials did not report information about potential harms, and the number of reported deaths was small.
—The Editors
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Author and Article Information
From Santa Clara Valley Medical Center, San Jose, California, and Cornell University, Ithaca, New York.
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 ß-agonist or other respiratory medications. Dr. Shelley Salpeter has consulted on legal cases involving ß-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{at}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.
Related articles in Annals:
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Editorials
The Role of Long-Acting ß-Agonists in the Management of Asthma: Analysis, Meta-Analysis, and More Analysis
Jeffrey Glassroth
- Annals 2006 144: 936-937.
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