Clinical Question

Is the combination of a long-acting beta agonist and an inhaled corticosteroid as safe and effective as an inhaled corticosteroid alone?

Bottom Line

The combination of fluticasone and salmeterol (Advair), with the steroid dose adjusted for disease severity, reduces the number of severe asthma exacerbations more than fluticasone (Flovent) alone (number needed to treat [NNT] = 50 over 26 weeks), with no difference in terms of potential harms, such as intubation or asthma-related death. (Level of Evidence = 1b)

Synopsis

This study was performed by GlaxoSmithKline at the behest of the U.S. Food and Drug Administration because of enduring concerns about the safety of long-acting beta agonists. The authors identified patients with moderate to severe asthma who had experienced at least one exacerbation in the previous year that required systemic steroids or hospitalization (but no such episode in the previous month). The 11,751 patients from 694 centers were randomized to receive fluticasone/salmeterol or fluticasone alone. The dose of fluticasone alone was stratified into three subgroups based on disease severity: 100 mcg, 250 mcg, and 500 mcg. In the combination treatment group, salmeterol (50 mcg) was combined with fluticasone at 100 mcg, 250 mcg, and 500 mcg, according to disease severity. All medications were given twice daily. Patients were 12 years and older (mean age = 43 years), and most patients were from North America or Europe. Groups were balanced at the beginning of the study, and analysis was by intention to treat. Outcomes were adjudicated by members of the research team who were masked to treatment assignment.

The primary efficacy end point was the first severe asthma exacerbation, defined as the use of systemic steroids for at least three days, asthma-related hospitalization, or an emergency department visit resulting in systemic steroid administration. There were fewer severe asthma exacerbations in the fluticasone/salmeterol group than in the group that received fluticasone alone (8% vs. 10%; P < .001; NNT = 50 over 26 weeks). The primary safety outcome (a composite of asthma-related deaths, asthma-related intubations, and asthma-related hospitalizations) was similar between groups: 36 events in the fluticasone/salmeterol group and 38 events in the fluticasone-only group. There were three deaths in the fluticasone/salmeterol group and six in the fluticasone-only group, none of which were adjudicated as being related to asthma.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Allocation: Concealed

Setting: Outpatient (any)

Reference: StempelDARaphiouIHKralKMet alAUSTRI InvestigatorsSerious asthma events with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med2016;374(19):1822–1830.