Jim Kling

March 11, 2016

LOS ANGELES — For patients with asthma, the risks for death, endotracheal intubation, and hospitalization with a combination of the long-acting beta agonist salmeterol plus the inhaled corticosteroid fluticasone are similar to those with fluticasone alone, according to results from a safety study known as AUSTRI.

"The most important thing to do is to reassure people about the efficacy and the safety of these medications," David Stempel, MD, medical director at GlaxoSmithKline, which sponsored the study, told Medscape Medical News.

The results were presented during a poster session here at the American Academy of Allergy, Asthma and Immunology 2016 Annual Meeting, and were published online simultaneously in the New England Journal of Medicine.

In the early 1990s, studies suggested an association between the risk for death or near-fatal asthma and short-acting beta agonists. However, they also suggested that the need for large volumes of these drugs was a marker for uncontrolled asthma, perhaps explaining the negative outcomes.

But two large clinical trials — SNS and SMART — showed an association between the regular use of the long-acting beta agonist salmeterol and the risk for death or near-fatal asthma. These studies were conducted before inhaled corticosteroids entered routine use in asthma care, and were therefore not designed to address whether the concurrent use of inhaled glucocorticoids alters risk, Dr Stempel and his colleagues explain.

After these study results were released, combination medications containing long-acting beta agonists were required by the US Food and Drug Administration (FDA) to carry black-box labeling, and the manufacturers were required to review their study data.

AUSTRI is one of a series of studies being carried out by Merck, AstraZeneca, and Novartis in accordance with a 2010 FDA mandate to conduct safety studies. All have similar designs, Dr Stempel reported, but AUSTRI is the first to be published or presented at a scientific conference.

AUSTRI Study

AUSTRI involved 11,679 people 12 years and older with a history of severe asthma exacerbation in the previous year, but no episodes in the previous month.

About half the patients were randomized to the combination of fluticasone plus salmeterol for 26 weeks, and about half were randomized to fluticasone monotherapy.

Sixty-seven study participants experienced 74 serious asthma-related events during the study period; 34 patients experienced 36 events in the combination group and 33 patients experienced 38 events in the monotherapy group.

The hazard ratio for a serious asthma-related event in the combination group was 1.03 (95% confidence interval [CI], 0.64 - 1.66). Results showed that the combination is noninferior to the monotherapy (P = .003).

The risk for severe asthma exacerbation was 21% lower in the combination group than in the monotherapy group (hazard ratio, 0.79; 95% CI, 0.70 - 0.89; P < .001).

The results are encouraging, said Jonathan Matz, MD, an allergist and immunologist in private practice in Baltimore, who is participating in a similar trial being run by Merck.

"My impression is that the current black-box warning is probably not warranted. The combination drug seems to be safe," he told Medscape Medical News.

Still, Dr Matz emphasized the need to wait until all the trials are complete before drawing a definitive conclusion. "I don't think anybody is surprised. Still, it's a black-box warning. When all of the trials come in, if they all say the same thing, then it will have serious weight."

Lingering Doubts

But questions remain about the AUSTRI study population; patients with life-threatening or unstable asthma were excluded.

Those are the patients most likely to experience severe adverse effects, Fernando Martinez, MD, director of the Arizona Respiratory Center in Tucson, writes in an editorial accompanying the published study.

The decision to exclude these patients is understandable, according to Stanley Szefler, MD, professor of pediatrics at the University of Colorado Denver School of Medicine, who moderated an earlier session in which the results were discussed.

Patients with severe disease could have a different phenotype, and institutional review boards might object to their inclusion because of fears about undertreatment. Nevertheless, the exclusion might have robbed the study of a home run, he said.

"In some ways, it is reassuring, but in other ways, it leaves a lingering question," Dr Szefler told Medscape Medical News.

This study was funded by GlaxoSmithKline. Dr Stempel is an employee of GlaxoSmithKline. Dr Matz is participating in a clinical trial supported by Merck. Dr Martinez reports receiving grant support from the National Institutes of Health and Johnson & Johnson. Dr Szefler has served on advisory panels and conducted clinical research for GlaxoSmithKline.

American Academy of Allergy, Asthma and Immunology (AAAAI) 2016 Annual Meeting: Abstract L3. Presented March 6, 2016.

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