The safety of long-acting beta-agonists among patients with asthma using inhaled corticosteroids: systematic review and metaanalysis

Am J Respir Crit Care Med. 2008 Nov 15;178(10):1009-16. doi: 10.1164/rccm.200804-494OC. Epub 2008 Sep 5.


Rationale: Inhaled long-acting beta-agonists (LABAs), when used as monotherapy in asthma, may increase asthma-related hospitalizations, life threatening events requiring intubation/mechanical ventilation, and asthma-related deaths, but concomitant use of inhaled corticosteroids (ICS) may modify this effect.

Objectives: To determine the safety of long-acting beta-agonists among patients with asthma using corticosteroids.

Methods: We conducted a systematic review and metaanalysis of parallel-group, blinded, randomized, controlled trials with at least 12 weeks of treatment addressing the impact of LABA on asthma-related and total morbidity and mortality in patients concomitantly using ICS. We searched MEDLINE, EMBASE, ACPJC, and Cochrane (Central) databases, and contacted authors and sponsors.

Measurements and main results: We used a random effects model to pool results from different studies as odds ratios (ORs) (95% confidence interval [CI]) (OR < 1.0 favors LABA). The search yielded 62 relevant studies included in this analysis. Among over 29,000 participants (15,710 taking LABA, with over 8,000 patient-years observed in the LABA groups), there were three asthma-related deaths and two asthma-related, nonfatal intubations (all in LABA groups; <or= one event per study). Differences in asthma-related hospitalizations (OR, 0.74; 95% CI, 0.53-1.03) and asthma-related serious adverse events (mostly hospitalizations; OR, 0.75; 95% CI, 0.54-1.03) failed to reach statistical significance. The OR for total mortality was 1.26 (95% CI, 0.58-2.74), reflecting 14 deaths in LABA groups and eight deaths in control groups, respectively.

Conclusions: In patients with asthma using ICS, LABA did not increase the risk of asthma-related hospitalizations. There were very few asthma-related deaths and intubations, and events were too infrequent to establish LABA's relative effect on these outcomes.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Administration, Inhalation
  • Adrenal Cortex Hormones / administration & dosage*
  • Adrenergic beta-Antagonists / adverse effects*
  • Asthma / drug therapy*
  • Drug Interactions
  • Drug Therapy, Combination
  • Humans
  • Randomized Controlled Trials as Topic


  • Adrenal Cortex Hormones
  • Adrenergic beta-Antagonists