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Published ahead of print on September 5, 2008, doi:10.1164/rccm.200804-494OC

Am. J. Respir. Crit. Care Med., Volume 178, Number 10, November 2008, 1009-1016

A more recent version of this article appeared on November 15, 2008
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Submitted on April 1, 2008
Accepted on September 5, 2008

The Safety of Long Acting Beta Agonists Among Patients with Asthma Using Inhaled Corticosteroids

Roman Jaeschke1*, Paul M O'Byrne2, Filip Mejza3, Parameswaran Nair2, Wiktoria Lesniak3, Jan Brozek4, Lehana Thabane5, Ji Cheng6, Holger J Schunemann7, Malcom R Sears2, and Gordon Guyatt8

1 Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Polish Institute of EBM, Krakow, Poland, 2 Department of Medicine, McMaster University, Hamilton, Ontario, Canada, 3 Polish Institute of EBM, Krakow, Poland; II Katedra Chorob Wewnetrznych, Jagiellonian University School of Medicine, Krakow, Poland, 4 Polish Institute of EBM, Krakow, Poland; II Katedra Chorob Wewnetrznych, Jagiellonian University School of Medicine, Krakow, Poland; Italian National Cancer Institute, Rome, Italy, 5 Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Hamilton, Ontario, Canada, 6 Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Hamilton, Ontario, Canada, 7 Italian National Cancer Institute, Rome, Italy; Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; CLARITY Research Group in the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada, 8 Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; CLARITY Research Group in the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

* To whom correspondence should be addressed. E-mail: Jaeschke{at}mcmaster.ca.

Background: 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. Methods: We conducted a systematic review and meta-analysis 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. We used random effects model to pool results from different studies as odds ratio [OR] (95% confidence interval) (OR < 1.0 favors LABA). Findings: 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 observation in LABA groups) there were 3 asthma-related deaths and 2 asthma-related non-fatal intubations (all in LABA groups, no more than 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 8 deaths in control groups respectively. Interpretation: In patients with asthma using inhaled corticosteroids 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 beta agonists, randomized trials, toxicity, adverse events, systematic review




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