Fluticasone/salmeterol appears noninferior to fluticasone alone in patients with persistent asthma

Combination therapy with fluticasone/salmeterol appeared to be noninferior to therapy with fluticasone alone for patients with persistent asthma, according to a recent industry-supported study.

Due to trial results showing worse outcomes in patients with asthma taking long-acting beta-agonists as monotherapy, the FDA placed a black-box warning on these drugs and required manufacturers to conduct trials comparing their use plus inhaled glucocorticoids with inhaled glucocorticoids alone. Researchers from GlaxoSmithKline performed a multicenter, randomized, double-blind trial in adolescents and adults to determine whether risk for serious asthma-related events was higher with a long-acting beta-agonist (salmeterol) plus an inhaled glucocorticoid (fluticasone) than with the inhaled glucocorticoid alone. The trial's primary end point was first serious asthma-related event, defined as death, endotracheal intubation, or hospitalization. The efficacy end point was first severe asthma exacerbation. GlaxoSmithKline funded the study, and the FDA provided guidance on study design. Results were published online March 6 by the New England Journal of Medicine.

Patients 12 years of age and older were eligible for the trial if they had had a severe asthma exacerbation in the year before randomization but had not had one in the previous month. Those who had a history of life-threatening or unstable asthma were excluded. A total of 11,679 patients were enrolled in the study and were stratified into 6 groups according to current asthma therapies and asthma control. Within these 6 groups, patients were randomly assigned in a 1:1 ratio to receive fluticasone/salmeterol (100 μg/50 μg, 250 μg/50 μg, or 500 μg/50 μg) or fluticasone alone (100 μg, 250 μg, or 500 μg). Study medications were administered twice daily in a masked dry-powder inhaler. All patients were also given open-label rescue albuterol or salbutamol. Overall, 5,834 patients were assigned to the fluticasone/salmeterol group and 5,845 patients were assigned to the fluticasone group. Median rate of adherence to the study drug was 95.1% in each group. Trial duration was 26 weeks.

Seventy-four serious asthma-related events occurred in 67 patients, 36 events in 34 patients in the fluticasone/salmeterol group and 38 events in 33 patients in the fluticasone group. The hazard ratio for a serious asthma-related event was 1.03 (95% CI, 0.64 to 1.66) in the fluticasone/salmeterol group (P=0.003), which reached the predefined threshold for noninferiority. Thirty-six asthma-related hospitalizations occurred in each group, and 2 patients in the fluticasone group required intubation related to asthma, but no asthma-related deaths were noted in either group. The hazard ratio for severe asthma exacerbation with fluticasone/salmeterol was 0.79 (95% CI, 0.70 to 0.89); 480 of 5,834 patients in the fluticasone/salmeterol group (8%) and 597 of 5,845 patients in the fluticasone group (10%) had at least 1 severe asthma exacerbation (P<0.001).

The authors noted that the trial was relatively short, that few serious asthma-related events occurred, and that the results may not apply to all patients with asthma, among other limitations. However, they concluded that frequency of serious asthma-related events was similar with 26 weeks of fluticasone plus fixed-dose salmeterol and with fluticasone alone in patients with moderate to severe asthma and that combination therapy yielded greater clinical benefits due to lower risk for severe asthma exacerbation.

The author of an accompanying editorial said that the trial results at first appear to be reassuring but questioned the exclusion criteria used, specifically that patients with life-threatening or unstable asthma were excluded.

“Why this decision was made is never explained, but it is bewildering that the patients at highest risk for the composite primary outcome were purposely left out,” the editorialist wrote, noting that included patients were probably more likely to adhere to therapy. Nevertheless, the editorialist said, the results of the trial indicate that fluticasone/salmeterol used in a single inhaler is most likely safe in those with high adherence and no history of life-threatening asthma episodes and that the black-box warning should be lifted for this specific combination of therapy and patients.

“This is an important result, and it stresses once again that most patients with asthma, and especially those without serious episodes, can reach high levels of symptom control and avoid frequent exacerbations by simply using their inhalers every day,” the editorialist wrote. For patients with severe and unstable disease, he said, “the safe clinical approach is to maintain the same precautions in using fluticasone-salmeterol that have been recommended until now for all patients with asthma.”