Meta-analysis: effects of adding salmeterol to inhaled corticosteroids on serious asthma-related events

Ann Intern Med. 2008 Jul 1;149(1):33-42. doi: 10.7326/0003-4819-149-1-200807010-00229. Epub 2008 Jun 3.


Background: Recent analyses have suggested an increased risk for serious asthma-related adverse events in patients receiving long-acting beta-agonists.

Purpose: 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.

Data sources: 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.

Study selection: 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.

Data extraction: Three physicians independently reviewed and adjudicated blinded case narratives on serious adverse events that were reported in the GlaxoSmithKline trials.

Data synthesis: 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).

Limitations: 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.

Conclusion: 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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adrenal Cortex Hormones / therapeutic use*
  • Adrenergic beta-Agonists / adverse effects
  • Adrenergic beta-Agonists / therapeutic use*
  • Albuterol / adverse effects
  • Albuterol / analogs & derivatives*
  • Albuterol / therapeutic use
  • Asthma / complications
  • Asthma / drug therapy*
  • Asthma / mortality
  • Bronchodilator Agents / adverse effects
  • Bronchodilator Agents / therapeutic use
  • Drug Therapy, Combination
  • Hospitalization
  • Humans
  • Intubation, Intratracheal
  • Salmeterol Xinafoate
  • Secondary Prevention


  • Adrenal Cortex Hormones
  • Adrenergic beta-Agonists
  • Bronchodilator Agents
  • Salmeterol Xinafoate
  • Albuterol