Results from the largest asthma safety trial in the United States suggest that combination therapies containing both inhaled corticosteroids and long-acting beta agonists (LABAs) do not significantly increase the risk of serious asthma-related events as compared with inhaled corticosteroids alone.

The report, led by the University of Wisconsin School of Medicine and Public Health (SMPH), was published on June 28, 2018 in the New England Journal of Medicine.

The findings close a long-running debate about one of the most commonly prescribed therapies for asthma management in adults. Following safety concerns in 2003, the US Food and Drug Administration (FDA) issued a public health advisory stating that LABAs – a class of medications that helps keep muscles around the airways relaxed to prevent wheezing, coughing, chest tightness and shortness of breath – should not be used as a first-line therapy for asthma.

The agency also required all products containing LABAs to carry a boxed warning (referred to in the pharmaceutical industry as a "black-box warning") for consumers and mandated the four pharmaceutical companies that sold combination drug products to conduct large trials evaluating the risk of serious asthma outcomes (hospitalizations, endotracheal intubations, and death). Each company (Astra Zeneca, GlaxoSmithKline, Merck, and Novartis) evaluated its own LABA-containing drugs: Symbicort, Advair Diskus, Dulera, and Foradil, respectively.

Each of the four studies—the protocols for which were harmonized to allow for consistent combined analysis by the independent committee—were randomized, double-blinded, and lasted six months. Enrollees had a history of at least one asthma exacerbation in the previous 12 months and were thought to be at risk for additional exacerbations. (People with severe, uncontrolled, and life-threatening asthma were excluded from the study because of safety and ethical concerns, so the results cannot be generalized to these patients.) Participants were randomly assigned to receive an inhaled glucocorticoid plus a LABA (combination therapy) or an inhaled glucocorticoid alone. In total, 36,010 patients participated in the trial, and three of the four pharmaceutical companies completed their studies and reported the results. Novartis terminated its trial early after removing its drug from the market in 2015.

An independent joint oversight committee performed the final combined analysis of the four trials. The committee was led by William Busse, MD, professor, Allergy, Pulmonary and Critical Care Medicine. The analysis found no statistically significant difference in serious asthma-related events between the groups. Further, they found a significantly lower risk for exacerbation among patients in the combination-therapy group across all four trials.

“Our report should provide assurance to physicians and patients alike that this type of combination therapy is safe for adults when used as prescribed,” said Dr. Busse. “Not only did the study show that these combination therapies do not pose a higher risk than monotherapies alone, we found that they significantly decrease the number of asthma exacerbations in adults.”

Based on these results, the FDA approved the removal of the boxed warning from LABA drugs’ labels in December 2017.  

Resources:

• Busse WW, Bateman ED, Caplan AL, Kelly HW, O'Byrne PM, Rabe KF, Chinchilli VM. 2018. Combined Analysis of Asthma Safety Trials of Long-Acting β2-Agonists. N Engl J Med. 378(26):2497-2505.
• Seymour SM, Lim R, Xia C, Andraca-Carrera E, Chowdhury BA. 2018. Inhaled Corticosteroids and LABAs - Removal of the FDA's Boxed Warning. N Engl J Med. 378(26):2461-2463.
• "Combination therapy for asthma in adults is safe, study confirms," UW SMPH, June 29, 2018
• "Removal of FDA Warning on Asthma Inhalants Follows Manufacturers' Research," MD Magazine, July 9, 2018