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The Safety of Long-Acting β-Agonists among Patients with Asthma Using Inhaled Corticosteroids

Systematic Review and Metaanalysis

Roman Jaeschke^1,2, Paul M. O'Byrne¹, Filip Mejza^2,3, Parameswaran Nair¹, Wiktoria Leniak^2,3, Jan Broek^2,3,4, Lehana Thabane^5,6, Ji Cheng⁶, Holger J. Schünemann^4,5,7, Malcolm R. Sears¹ and Gordon Guyatt^1,5,7

¹ Department of Medicine, McMaster University, Hamilton, Ontario, Canada; ² Polish Institute of Evidence-Based Medicine, Krakow, Poland; ³ II Katedra Chorób Wewntrznych, Jagiellonian University School of Medicine, Krakow, Poland; ⁴ Italian National Cancer Institute, Rome, Italy; ⁵ Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; ⁶ Biostatistics Unit, Father Sean O'Sullivan Research Centre, St. Joseph's Healthcare, Hamilton, Ontario, Canada; and ⁷ CLARITY Research Group, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

Correspondence and requests for reprints should be addressed to Roman Jaeschke, M.D., 301 James Street South, Fontbonne Building, Room F506, Hamilton, ON, L8P 3B6 Canada. E-mail: jaeschke{at}mcmaster.ca

Rationale: Inhaled long-acting β-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 β-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; 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.

Key Words: long-acting β-agonists • randomized trials • toxicity • adverse events • systematic review

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject There are data suggesting that long-acting β-agonists (LABAs) increase mortality in patients with asthma. However, this issue has not been optimally evaluated in patients receiving concomitant corticosteroids. What This Study Adds to the Field 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.