Adding formoterol to budesonide in a fixed-dose combination does not increase serous asthma-related events in adolescents and adults, according to a report published online Sept. 1 in the New England Journal of Medicine.
This finding from a multicenter randomized double-blind clinical trial involving 11,693 patients should allay safety concerns about adding long-acting beta-agonists to inhaled glucocorticoids in moderate to severe asthma. Previously, two large studies linked such additive therapy to increased asthma-related deaths and other serious outcomes, but other clinical trials and numerous meta-analyses found no such increase.
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In 2009, the Food and Drug Administration mandated that the four manufacturers of long-acting beta-agonists available in the United States conduct postmarketing safety analyses of these agents. The current trial is AstraZeneca’s response to the mandate, said Stephen P. Peters, MD, PhD, of Wake Forest University, Winston-Salem N.C., and his associates.
They assessed patients aged 12 years and older who had taken daily asthma medication for at least 1 year before enrollment and had a history of at least one exacerbation during that year. These participants were enrolled at 534 medical centers in 25 countries during 2011-2015 and randomly assigned to receive either budesonide plus formoterol (5,846 patients) or budesonide alone (5,847 patients) through an inhaler twice daily for 26 weeks. The primary endpoint was a composite of asthma-related death, intubation, and hospitalization.
A total of 43 patients in the combined-therapy group had 49 serious asthma-related events, while 40 patients in the budesonide-only group had 45 such events. This is a nonsignificant difference and establishes the noninferiority of the combined treatment regarding this outcome, the investigators said (N Engl J Med. 2016 Sept 1. doi: 10.1056/NEJMoa1511190).
In addition, 539 (9.2%) of the patients in the combined-therapy group reported 637 asthma exacerbations, while 633 in the budesonide-only group had 762 exacerbations. Thus, the risk of having an asthma exacerbation was 16.5% lower with combined therapy (HR, 0.84).
Both study groups had a clinically relevant improvement in asthma control as measured by the ACQ-6, and the combined therapy yielded a significantly greater benefit. The percentage of patients who had a clinically relevant improvement in asthma control at the conclusion of treatment also favored budesonide plus formoterol (58.7% vs. 54.4%). And the combined-therapy group also had a greater mean number of symptom-free days, had fewer night-time awakenings, and used fewer doses of rescue medications, Dr. Peters and his associates said.
Given that asthma-related deaths are rare, none of the four individual manufacturer-sponsored postmarketing studies required by the FDA can be powered for a separate analysis of that endpoint. “Any between-group differences in asthma-related death will need to be evaluated in the context of pooled data from the four studies, once they are all completed,” the investigators added.
Dr. Peters and his associates reported ties to numerous industry sources.