Asthma patients on salmeterol, a long-acting beta-agonist (LABA), plus fluticasone inhaled corticosteroid (ICS) combination therapy did not have a greater risk of serious asthma-related events compared with patients receiving fluticasone alone, according to the recent AUSTRI* study.

While previous studies have raised doubts about the safety of salmeterol for asthma treatment due to increased death risk, the current findings suggest it is safe as an add-on therapy to ICS.

“Not only was there no difference in the safety profile between the two arms of study, there was [also] less incidence of severe asthma exacerbation in the [LABA/ICS] combination arm compared to steroid alone arm,” said Dr. Ong Kian Chung, a consultant respiratory specialist from the KC Ong Chest & Medical Clinic in Mount Elizabeth Medical Centre, Singapore, who was unaffiliated with the study.

“The combination arm was more efficacious in controlling asthma in this manner, as is currently known.”

The debate about the safety of salmeterol arose from two large clinical trials that showed more asthma-related deaths among patients receiving salmeterol than those on placebo. [Chest2006;129:15-26; BMJ 1993;306:1034-1037; N Engl J Med 2016;374:1887-1888]

The results prompted the US Food and Drug Administration to mandate LABA manufacturers to include a black box warning in their product inserts. [N Engl J Med 2016;374:1887-1888]

However, a meta-analysis suggested that the risk of asthma-related deaths increased only when salmeterol was dispensed in a separate casing and not necessarily when used as a combination therapy with an ICS. [Thorax 2010; 65:39-43]

To address this issue, the multicenter double-blind AUSTRI study randomized 11,679 patients (aged ≥12 years) with persistent asthma to receive either fluticasone propionate plus salmeterol in combination or fluticasone propionate alone in a single masked inhaler twice daily for 26 weeks. [N Engl J Med 2016;374:1822-1830]

The frequency of serious asthma-related events, including hospitalization, endotracheal intubation, or death, was similar in both arms (36 events in 34 patients for fluticasone-salmeterol versus 38 events in 33 patients for fluticasone alone).

The risk of developing serious asthma-related events in the fluticasone-salmeterol arm was no greater than the fluticasone alone arm (hazard ratio [HR], 1.03, 95 percent confidence interval [CI], 0.64-1.66, p=0.003), which demonstrated noninferiority.

Adherence to medications was high in each treatment arm (95.1 percent for both).

Furthermore, patients receiving fluticasone-salmeterol had 21 percent lower risk of a severe asthma exacerbation compared with patients treated with fluticasone only (HR, 0.79, 95 percent CI, 0.70-0.89), with 8 percent of the patients on fluticasone-salmeterol experiencing at least one severe exacerbation episode compared with 10 percent in the fluticasone alone arm (p<0.001).

“It is clear that among patients with asthma who have not had life-threatening episodes in the past and are highly adherent to their drug regimen, it is likely that the use of salmeterol together with fluticasone in a single inhaler is safe,” said Dr. Fernando Martinez, a paediatric pulmonologist from the Arizona Respiratory Center at the University of Arizona in Tuscon, Arizona, US, who was unaffiliated with the study, in a separate commentary. [N Engl J Med 2016;374:1887-1888]

He also suggested that the black-box warning on LABA should be lifted for this group of patients.

Ong agreed, noting that negative reaction to LABA was uncommon in his clinical experience and the adverse effects known to be associated with LABA such as palpitations or hand tremors were rare among his 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,” said Martinez.

But not all patients may benefit. Martinez noted that patients with life-threatening asthma were excluded from the patient group, although the reasons for this were not explained in the study.

“It is bewildering that the patients at highest risk for the composite primary outcome were purposely left out,” he said, and cautioned that the same precautions should still be maintained when using fluticasone-salmeterol in patients with life-threatening or unstable asthma.