Eric Bateman, MD; Harold Nelson, MD; Jean Bousquet, MD; Kenneth Kral, MS; Laura Sutton, PharmD; Hector Ortega, MD, ScD; Steven Yancey, MS
Note: Drs. Bateman, Nelson, and Bousquet did the blinded adjudication of serious adverse events in this analysis.
Grant Support: By GlaxoSmithKline.
Potential Financial Conflicts of Interest:Employment: K. Kral (GlaxoSmithKline), L. Sutton (GlaxoSmithKline), H. Ortega (GlaxoSmithKline), S. Yancey (GlaxoSmithKline). Consultancies: E. Bateman (Roche, Almirall, GlaxoSmithKline, AstraZeneca, Merck, Boehringer Ingelheim, Pfizer, Altana), H. Nelson (GlaxoSmithKline), J. Bousquet (GlaxoSmithKline). Honoraria: E. Bateman (GlaxoSmithKline, Boehringer Ingelheim, Altana, Pfizer, AstraZeneca), H. Nelson (GlaxoSmithKline), J. Bousquet (GlaxoSmithKline). Stock ownership or options (other than mutual funds): L. Sutton (GlaxoSmithKline), H. Ortega (GlaxoSmithKline), S. Yancey (GlaxoSmithKline). Expert testimony: E. Bateman (GlaxoSmithKline). Grants received: E. Bateman (GlaxoSmithKline, Chiesi, AstraZeneca, Boehringer Ingelheim, Altana, Pfizer, Sanofi-Aventis, Almirall, Schering-Plough, Lilly), H. Nelson (GlaxoSmithKline).
Requests for Single Reprints: Eric Bateman, MD, Division of Pulmonology, Department of Medicine, University of Cape Town Lung Institute, PO Box 34560, Groote Schuur 7937, Cape Town, South Africa; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Bateman: Division of Pulmonology, Department of Medicine, University of Cape Town Lung Institute, PO Box 34560, Groote Schuur 7937, Cape Town, South Africa.
Dr. Nelson: National Jewish Medical and Research Center, 140 Jackson Street, Room J224, Denver, CO 80206.
Dr. Bousquet: Hôspital Arnaud de Villeneuve, CHU Montpellier and INSERM 34295, Montpellier Cedex 5, France.
Mr. Kral, Drs. Sutton and Ortega, and Mr. Yancey: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709.
Recent analyses have suggested an increased risk for serious asthma-related adverse events in patients receiving long-acting β-agonists.
To examine whether the incidences of severe asthma-related events (hospitalizations, intubations, deaths, and severe exacerbations) differ in persons receiving salmeterol plus inhaled corticosteroids compared with inhaled corticosteroids alone.
The GlaxoSmithKline (Research Triangle Park, North Carolina) database, MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systemic Reviews (1982 to September 2007) were searched without language restriction.
Randomized, controlled trials reported in any language that compared inhaled corticosteroids plus salmeterol (administered as fluticasone propionate/salmeterol by means of a single device or concomitant administration of inhaled corticosteroids and salmeterol) versus inhaled corticosteroids alone in participants with asthma.
Three physicians independently reviewed and adjudicated blinded case narratives on serious adverse events that were reported in the GlaxoSmithKline trials.
Data from 66 GlaxoSmithKline trials involving a total of 20 966 participants with persistent asthma were summarized quantitatively. The summary risk difference for asthma-related hospitalizations from these trials was 0.0002 (95% CI, −0.0019 to 0.00231; P = 0.84) for participants receiving inhaled corticosteroids plus salmeterol (n = 35 events) versus those receiving inhaled corticosteroids alone (n = 34 events). One asthma-related intubation and 1 asthma-related death occurred among participants receiving inhaled corticosteroids with salmeterol; no such events occurred among participants receiving inhaled corticosteroids alone. A subset of 24 trials showed a decreased risk for severe asthma-related exacerbations for inhaled corticosteroids plus salmeterol versus inhaled corticosteroids alone (risk difference, −0.025 [CI, −0.036 to −0.014]; P <0.001).
The included trials involved selected patients who received careful follow-up. Only 26 trials were longer than 12 weeks. Few deaths and intubations limited the ability to measure risk for these outcomes.
Salmeterol combined with inhaled corticosteroids decreases the risk for severe exacerbations, does not seem to alter the risk for asthma-related hospitalizations, and may not alter the risk for asthma-related deaths or intubations compared with inhaled corticosteroids alone.
Guidelines recommend adding long-acting β-agonists to regimens of patients with asthma that is not controlled on inhaled corticosteroids alone. Is this safe?
This meta-analysis summarizes 66 GlaxoSmithKline trials involving 20 966 patients with persistent asthma. Trials compared twice-daily salmeterol, 50 μg, plus inhaled corticosteroids with inhaled corticosteroids alone. Combination therapy did not appear to alter risk for asthma-related hospitalizations but did decrease risk for severe exacerbations requiring systemic corticosteroids. The only cases of asthma-related death and intubation occurred in patients receiving combination therapy.
Most trials were short and originally designed to assess lung function rather than clinical outcomes.
Study flow diagram.
GSK = GlaxoSmithKline.
*Studies could contribute to more than 1 subanalysis.
Appendix Table 1. Included Studies
Salmeterol (SAL) plus inhaled corticosteroids (ICS) versus ICS alone: risk difference for asthma-related hospitalization.
*Number of events/total population.
Appendix Table 2. Sensitivity Analyses for Asthma-Related Hospitalizations with Differing Continuity Corrections
Table. Severe Asthma Exacerbations Requiring Systemic Corticosteroids
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Bateman E, Nelson H, Bousquet J, Kral K, Sutton L, Ortega H, et al. Meta-analysis: Effects of Adding Salmeterol to Inhaled Corticosteroids on Serious Asthma-Related Events. Ann Intern Med. 2008;149:33-42. doi: 10.7326/0003-4819-149-1-200807010-00229
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Published: Ann Intern Med. 2008;149(1):33-42.
Asthma, Endocrine and Metabolism, Pulmonary/Critical Care.
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