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N Engl J Med. 2018 Jun 28;378(26):2497-2505. doi: 10.1056/NEJMoa1716868.

Combined Analysis of Asthma Safety Trials of Long-Acting β2-Agonists.

Author information

1
From the Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Pulmonary Division, Department of Medicine, University of Cape Town, Cape Town, South Africa (E.D.B.); the Division of Medical Ethics, Department of Population Health, New York University School of Medicine, New York (A.L.C.); the Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque (H.W.K.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (P.M.O.); LungenClinic Grosshansdorf and Christian Albrechts University Kiel, Kiel, and Airway Research Center North, German Center for Lung Research, Grosshansdorf - both in Germany (K.F.R.); and the Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA (V.M.C.).

Abstract

BACKGROUND:

Safety concerns regarding long-acting β2-agonists (LABAs) in asthma management were initially identified in a large postmarketing trial in which the risk of death was increased. In 2010, the Food and Drug Administration (FDA) mandated that the four companies marketing LABAs for asthma perform prospective, randomized, controlled trials comparing the safety of combination therapy with a LABA plus an inhaled glucocorticoid with that of an inhaled glucocorticoid alone in adolescents (12 to 17 years of age) and adults. In conjunction with the FDA, the manufacturers harmonized their trial methods to allow an independent joint oversight committee to provide a final combined analysis of the four trials.

METHODS:

As members of the joint oversight committee, we performed a combined analysis of the four trials comparing an inhaled glucocorticoid plus a LABA (combination therapy) with an inhaled glucocorticoid alone. The primary outcome was a composite of asthma-related intubation or death. Post hoc secondary outcomes included serious asthma-related events and asthma exacerbations.

RESULTS:

Among the 36,010 patients in the intention-to-treat study, there were three asthma-related intubations (two in the inhaled-glucocorticoid group and one in the combination-therapy group) and two asthma-related deaths (both in the combination-therapy group) in 4 patients. In the secondary analysis of serious asthma-related events (a composite of hospitalization, intubation, or death), 108 of 18,006 patients (0.60%) in the inhaled-glucocorticoid group and 119 of 18,004 patients (0.66%) in the combination-therapy group had at least one composite event (relative risk in the combination-therapy group, 1.09; 95% confidence interval [CI], 0.83 to 1.43; P=0.55); 2100 patients in the inhaled-glucocorticoid group (11.7%) and 1768 in the combination-therapy group (9.8%) had at least one asthma exacerbation (relative risk, 0.83; 95% CI, 0.78 to 0.89; P<0.001).

CONCLUSIONS:

Combination therapy with a LABA plus an inhaled glucocorticoid did not result in a significantly higher risk of serious asthma-related events than treatment with an inhaled glucocorticoid alone but resulted in significantly fewer asthma exacerbations.

PMID:
29949492
DOI:
10.1056/NEJMoa1716868
[Indexed for MEDLINE]
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