Article    Full Text of this article Free    PDF of this article (PDFs free after 6 months) All Versions of this Article:    144/12/904 (most recent)    0000605-200606200-00126v1    Figures/Tables List    CME course  Services    Send comment/rapid response letter    Published comments/rapid response letters    Notify a friend about this article    Alert me when this article is cited    Add to Personal Archive    Download to Citation Manager    ACP Search                            Get Permissions  Google Scholar    Search for Related Content  PubMed Articles in PubMed by Author:    Salpeter, S. R.    Salpeter, E. E.    Related Articles in PubMed    PubMed Citation    PubMed

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

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 asthmarelated 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

 

Author and Article Information

From Santa Clara Valley Medical Center, San Jose, California, and Cornell University, Ithaca, New York.

See also: The Role of Long-Acting ß-Agonists in the Management of Asthma: Analysis, Meta-Analysis, and More Analysis by J. Glassroth.

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.

This article has been cited by other articles:

				K. M. Stockl, L. Le, A. S. M. Harada, and S. Zhang Use of controller medications in patients initiated on a long-acting {beta}2-adrenergic agonist before and after safety alerts Am. J. Health Syst. Pharm., August 15, 2008; 65(16): 1533 - 1538. [Abstract] [Full Text] [PDF]

				J. F. Donohue, N. A. Hanania, C. Fogarty, S. C. Campbell, M. Rinehart, and K. Denis-Mize Long-term safety of nebulized formoterol: Results of a twelve-month open-label clinical trial Therapeutic Advances in Respiratory Disease, August 1, 2008; 2(4): 199 - 208. [Abstract] [PDF]

				E. Bateman, H. Nelson, J. Bousquet, K. Kral, L. Sutton, H. Ortega, and S. Yancey Meta-analysis: Effects of Adding Salmeterol to Inhaled Corticosteroids on Serious Asthma-Related Events Ann Intern Med, July 1, 2008; 149(1): 33 - 42. [Abstract] [Full Text] [PDF]

				K. B. Weiss Drug Safety and Salmeterol: The Controversy Continues Ann Intern Med, July 1, 2008; 149(1): 56 - 57. [Full Text] [PDF]

				A. M. Wood and R. A. Stockley Editorial: Unifying the genetics, co-morbidities and management of COPD Therapeutic Advances in Respiratory Disease, June 1, 2008; 2(3): 113 - 117. [PDF]

				S Joos, A Miksch, J Szecsenyi, B Wieseler, U Grouven, T Kaiser, and A Schneider Montelukast as add-on therapy to inhaled corticosteroids in the treatment of mild to moderate asthma: a systematic review Thorax, May 1, 2008; 63(5): 453 - 462. [Abstract] [Full Text] [PDF]

				J.F. Donohue, N.A. Hanania, K.A. Sciarappa, E. Goodwin, D.R. Grogan, R.A. Baumgartner, and J.P. Hanrahan Arformoterol and salmeterol in the treatment of chronic obstructive pulmonary disease: A one year evaluation of safety and tolerance Therapeutic Advances in Respiratory Disease, April 1, 2008; 2(2): 37 - 48. [Abstract] [PDF]

				N. A. Hanania Targeting Airway Inflammation in Asthma: Current and Future Therapies Chest, April 1, 2008; 133(4): 989 - 998. [Abstract] [Full Text] [PDF]

				B. Adelsberg Review: LABAs are better than leukotriene receptor antagonists when added to inhaled corticosteroids in recurrent asthma Arch. Dis. Child. Ed. Pract., April 1, 2008; 93(2): 71 - 71. [Full Text] [PDF]

				S. R. Salpeter Response Can Fam Physician, November 1, 2007; 53(11): 1886 - 1886. [Full Text] [PDF]

				S. Cohen, J. Taitz, and A. Jaffe Paediatric prescribing of asthma drugs in the UK: are we sticking to the guideline? Arch. Dis. Child., October 1, 2007; 92(10): 847 - 849. [Abstract] [Full Text] [PDF]

				M. A. Grippi and C. Mulrow Trials That Matter: Minimizing Treatment of Mild, Persistent Asthma Ann Intern Med, September 4, 2007; 147(5): 344 - 345. [Full Text] [PDF]

				D. W. Harrington and M. T. Munekata Update in General Internal Medicine Ann Intern Med, July 17, 2007; 147(2): 104 - 116. [Full Text] [PDF]

				P. Ernst, A. McIvor, F. M. Ducharme, L.-P. Boulet, M. FitzGerald, K. R. Chapman, T. Bai, and for the Canadian Asthma Guideline Group Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids. Ann Intern Med, November 7, 2006; 145(9): 692 - 694. [Abstract] [Full Text] [PDF]

				H. S. Nelson and P. M. Dorinsky Safety of long-acting beta-agonists. Ann Intern Med, November 7, 2006; 145(9): 706 - 706. [Full Text] [PDF]

				D. Ryan Safety of long-acting beta-agonists. Ann Intern Med, November 7, 2006; 145(9): 707 - 707. [Full Text] [PDF]

				M. J. Lindberg Safety of long-acting beta-agonists. Ann Intern Med, November 7, 2006; 145(9): 706 - 707. [Full Text] [PDF]

				S. W. Stoloff Safety of long-acting beta-agonists. Ann Intern Med, November 7, 2006; 145(9): 707 - 707. [Full Text] [PDF]

				G. P. Currie Safety of long-acting beta-agonists. Ann Intern Med, November 7, 2006; 145(9): 707 - 708. [Full Text] [PDF]

				J M FitzGerald and P G Gibson Asthma exacerbations {middle dot} 4: Prevention. Thorax, November 1, 2006; 61(11): 992 - 999. [Abstract] [Full Text] [PDF]

				R. J Lipchik Addition of salmeterol to usual asthma pharmacotherapy may increase respiratory related deaths or life threatening experiences Evid. Based Med., October 1, 2006; 11(5): 139 - 139. [Full Text] [PDF]

				Effects of Long-Acting {beta}-Agonists in Children with Asthma Journal Watch Pediatrics and Adolescent Medicine, September 6, 2006; 2006(906): 1 - 1. [Full Text]

				Long-Acting Inhaled {beta}-Agonists and Mortality Journal Watch (General), July 18, 2006; 2006(718): 3 - 3. [Full Text]

				A. Tonks What's new in the other general journals. BMJ, June 24, 2006; 332(7556): 1500 - 1501. [Full Text] [PDF]

				J. Glassroth The Role of Long-Acting {beta}-Agonists in the Management of Asthma: Analysis, Meta-Analysis, and More Analysis Ann Intern Med, June 20, 2006; 144(12): 936 - 937. [Full Text] [PDF]

Rapid Responses: