Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

Serious Asthma Events with Long-Acting Beta-Agonists

N Engl J Med; ePub 2016 Mar 6; Stempel, Raphiou, et al

Publish date:: March 22, 2016

A significantly higher risk of serious asthma-related events did not exist in patients who received salmeterol in a fixed-dose combination with fluticasone vs those who received fluticasone alone. This according to a study of 11,679 patients aged ≥12 years with persistent asthma enrolled in a multicenter, randomized, double-blind trial and assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. Researchers found:

• Of the enrolled patients, 67 had 74 serious asthma-related events, with 36 events in the 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group.

• Hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 and noninferiority was achieved.

• The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group (HR=0.79), with at least 1 severe asthma exacerbation occurring in 480 of 5,834 patients (8%) in the fluticasone-salmeterol group vs 597 of 5,845 patients (10%) in the fluticasone-only group.

• There were no asthma-related deaths.

Citation: Stempel DA, Raphiou IH, Kral KM, et al. Serious asthma events with fluticasone plus salmeterol versus fluticasone alone. [Published online ahead of print March 6, 2016]. N Engl J Med. doi:10.1056/NEJMoa1511049.

Commentary: In the 1990s it was shown that high frequency use of short-acting, beta-agonists (LABA) increased the risk of severe asthma exacerbations.¹ Later, 2 trials that looked at LABAs suggested that LABA use may lead to an increase in severe asthma exacerbations.² These trials had significant methodological flaws and did not ensure that patients on LABAs also be on concomitant inhaled corticosteroids, which is the current standard of care. It was felt that the use of unopposed LABAs without the use of an inhaled steroid might mask ongoing inflammation and temporarily hide symptoms while an individual’s asthma was actually getting worse. The present study is very reassuring that when a LABA and an inhaled steroid are used in combination, as is the current standard of care, there is not an increase in serious asthma-related events. In addition, consistent with previous randomized trials, combination therapy is more effective than inhaled steroids alone at decreasing asthma exacerbations. —Neil Skolnik, MD

1. Suissa S, Ernst P, Boivin JF, et al. A cohort analysis of excess mortality in asthma and the use of inhaled beta-agonists. Am J Respir Crit Care Med. 1994; 149:604-10.

2. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129:15-26. doi:10.1378/chest.129.1.15.

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