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

Abstract

For years, the safety of using long-acting β-agonists (LABAs) in patients with asthma has been uncertain after marketing trials in which increased risk of death was identified. In 2010, the US Food and Drug Administration mandated the 4 companies marketing LABAs to perform randomized controlled trials comparing the safety of inhaled corticosteroids (ICSS) alone versus ICS-LABA combination therapy in adolescents and adults with asthma. This study is a combined analysis of these 4 trials.Adolescents (12–17 years of age) and adults with persistent asthma were enrolled into 1 of the 4 trials being conducted. Analyses were performed on the basis of intention-to-treat study data from 36 010 patients enrolled in these 4 trials.Consistent trial methods were used by all 4 companies to allow for a final combined analysis of the 4 trials by an independent joint oversight committee. Adolescents and adults with persistent asthma were enrolled into a 26-week, multicenter, parallel, randomized, double-blind, noninferiority trial. Patients were randomly assigned to receive combination therapy (ICS + LABA) or an ICS alone. The prespecified primary outcome was a composite of asthma-related intubation or death. A joint adjudication committee whose members were unaware of study assignments made the determination as to whether an event was asthma related or not. The joint oversight committee performed post hoc secondary combined analyses looking at serious asthma-related events (hospitalization, intubation, or death). The committee also compared efficacy between the 2 groups by measuring rate of asthma exacerbations, defined as an asthma deterioration that required use of systemic corticosteroids, hospitalization, or emergency department visit with use of systemic corticosteroids.Among the 36 010 patients examined, there were 3 asthma-related intubations (2 in the ICS alone group, 1 in the ICS-LABA group) and 2 asthma-related deaths (both in ICS-LABA group). Because of the small number of events, researchers focused on composite end points, finding no significant increase in the risk of serious asthma-related events associated with combination therapy compared with ICSs alone (relative risk: 1.10; 95% CI: 0.85–1.44). When further examining specific subgroups of patients who might be at increased risk for serious asthma-related events (on the basis of age, race, smoking history, obesity), the results remained consistent. There was a significant reduction in predefined asthma exacerbations seen in the combination therapy group compared with the ICS group, with 2100 patients in the ICS group (11.7%) and 1768 in the combination therapy group (9.8%) having at least 1 asthma exacerbation (relative risk: 0.83; 95% CI: 0.78–0.89; P < .001).Combination therapy with ICS-LABA for the treatment of asthma did not result in significantly higher risk of serious asthma-related events compared with treatment with inhaled glucocorticoid alone. Combination therapy did, however, result in significantly fewer asthma exacerbations.Initial concerns surrounding the safety of LABAs primarily originated from the Salmeterol Nationwide Surveillance Study and the Salmeterol Multicenter Asthma Research Trial, in which, asthma patients who were taking a LABA were not necessarily required to also use ICSs (which is now considered standard of care). So, the question remained whether the consistent use of an ICS in combination with the LABA would have lessened the risk of serious asthma-related events. The 4 mandated trials analyzed in this study (completed by AstraZeneca, GlaxoSmithKline, Merck, and Novartis) all met the primary safety objective with consistent results. This led to the US Food and Drug Administration’s removal of the boxed warning on ICS-LABA combination products in December 2017. Furthermore, the significant reduction in asthma exacerbations observed in the combination therapy group demonstrates there is benefit to using combination products in the asthma population.