LOS ANGELES – Fluticasone-salmeterol inhalers (Advair) are as safe as and more effective than fluticasone monotherapy inhalers are for patients with moderate to severe asthma, according to a large, randomized trial from its drug maker, GlaxoSmithKline, presented at the annual meeting of the American Academy of Allergy, Asthma and Immunology and simultaneously published online March 6 in the New England Journal of Medicine.
The study is the first of several that the Food and Drug Administration required from Glaxo and other manufacturers in 2010 to evaluate the safety of long-acting beta-2 agonists (LABAs) such as salmeterol when used in combination with inhaled corticosteroids, after it became clear that LABAs, when used alone, increase the risk of serious asthma complications, including death (N Engl J Med. 2016 Mar 6. doi: 10.1056/NEJMoa1511049).
Dr. David Stempel
Current black box warnings on fluticasone-salmeterol (Advair), Merck’s mometasone-formoterol inhaler (Dulera), and AstraZeneca’s budesonide-formoterol combo (Symbicort)note that data are “inadequate to determine” if concomitant steroids mitigate the risk of LABAs.
Merck and AstraZeneca’s studies are ongoing, but Glaxo’s initial results seem reassuring. “I think what this study really does is provide evidence to answer the question that FDA was asking about safety. This is [also] the first really large study to show a decrease in exacerbations with [fluticasone-salmeterol],” principal investigator Dr. David Stempel, with Glaxo’s Respiratory Clinical Development program in Durham, N.C., said at the annual meeting.
However, because “patients with a history of life-threatening or unstable asthma” – including those who, at any point, had been intubated for asthma – “were excluded from the study, our results cannot be extrapolated to such patients,” the researchers wrote.
The inclusion criteria were otherwise broad: Adults and adolescents at least 12 years old, with a history of severe asthma exacerbations requiring the use of inhaled glucocorticoids or hospitalization in the previous year, but not in the month before enrollment, were included. There were 5,834 subjects randomized to fluticasone-salmeterol and 5,845 to fluticasone alone, both for 26 weeks. Adherence to the study medications was 95%.
There were 36 serious asthma-related events – endotracheal intubation or hospitalization – in 34 patients (0.58%) in the fluticasone-salmeterol group, and 38 events in 33 patients (0.56%) in the fluticasone-only group. The hazard ratio for serious asthma-related events with fluticasone-salmeterol was 1.03 (95% confidence interval, 0.64-1.66), indicating that the safety of the combination was comparable with that of fluticasone monotherapy (P = .003). There were no asthma-related deaths in the trial, and two intubations in the fluticasone-only group.
The risk of a severe asthma exacerbation was 21% lower with fluticasone-salmeterol (HR, 0.79; 95% CI 0.70-0.89). While 480 fluticasone-salmeterol patients (8%) had at least one severe asthma exacerbation, at least one severe exacerbation occurred in 597 fluticasone-only patients (10%; P less than 0.001). “The difference was most prominent among adolescents, in whom the risk was 35% lower,” the investigators wrote.
“We found that ... the risk of serious asthma-related events was no greater when salmeterol was delivered by inhaler in a fixed-dose combination with fluticasone propionate than when fluticasone was administered alone,” and the “clinical benefits of fluticasone-salmeterol were significant,” they concluded.
The trial, which was designed with FDA guidance, excluded patients with life-threatening or unstable asthma in order to “mimic the population in which the (original LABA safety) signal was seen” in earlier studies; “the signal wasn’t seen specifically in that population.” Even so, “very few patients were eliminated due to a history of life-threatening asthma,” Dr. Stempel said.
It’s unclear why concomitant steroids reduce the risk. “LABA monotherapy may mask underlying disease by providing a temporary reduction in symptoms but ultimately placing patients at risk for serious exacerbations. When you give short- or long-acting bronchodilators, patients feel better, but you’re not treating the underlying disease; corticosteroids treat the underlying inflammatory component,” he said
The company will soon publish results from a similar fluticasone-salmeterol safety trial in children 4-11 years old. “I hope were finished” after that, “but we have to have a discussion with FDA to see what’s next.” The agency might want to pool data from the incoming trials to look at LABA-containing inhalers as a class. “It’s too premature to know where we’ll go with the box warning, but there’s a lot more information now than was available when the box first appeared in 2003,” Dr. Stempel said.
The work was funded by GlaxoSmithKline, and the authors are current or former employees.