Meta-analysis: Effect of Long-Acting Beta-Agonists on Severe Asthma Exacerbations and Asthma-Related Deaths

Ann Intern Med. 2006 Jun 20;144(12):904-12. doi: 10.7326/0003-4819-144-12-200606200-00126. Epub 2006 Jun 5.

Abstract

Background: Long-acting beta-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 beta-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 beta-agonist use in patients with asthma. All trials allowed the use of as-needed short-acting beta-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 beta-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 beta-agonists have been shown to increase severe and life-threatening asthma exacerbations, as well as asthma-related deaths.

Publication types

  • Meta-Analysis

MeSH terms

  • Adrenergic beta-Agonists / administration & dosage
  • Adrenergic beta-Agonists / adverse effects*
  • Adult
  • Albuterol / administration & dosage
  • Albuterol / adverse effects
  • Albuterol / analogs & derivatives
  • Anti-Asthmatic Agents / administration & dosage
  • Anti-Asthmatic Agents / adverse effects*
  • Asthma / drug therapy*
  • Asthma / mortality*
  • Bronchodilator Agents / administration & dosage
  • Bronchodilator Agents / adverse effects
  • Child
  • Drug Administration Schedule
  • Ethanolamines / administration & dosage
  • Ethanolamines / adverse effects
  • Female
  • Formoterol Fumarate
  • Hospitalization / statistics & numerical data*
  • Humans
  • Male
  • Randomized Controlled Trials as Topic
  • Recurrence
  • Risk Factors
  • Salmeterol Xinafoate
  • Treatment Outcome

Substances

  • Adrenergic beta-Agonists
  • Anti-Asthmatic Agents
  • Bronchodilator Agents
  • Ethanolamines
  • Salmeterol Xinafoate
  • Albuterol
  • Formoterol Fumarate