Triple therapy with either a 320-μg or 160 μg dose of budesonide, long-acting muscarinic antagonist (LAMA), and long-acting β2-agonist (LABA) reduced chronic obstructive pulmonary disease (COPD) exacerbations compared to higher dose inhaled glucocorticoid-LABA therapy, investigators with the ETHOS trial reported.
Moreover, the 320-μg budesonide/LAMA/LABA regimen “resulted in lower all-cause mortality than LAMA-LABA therapy,” and the benefit was greatest at higher eosinophil levels, Klaus F. Rabe, MD, PhD, of Lungen Clinic, Grosshansdorf and Christian-Albrechts University, Kiel, Germany, and colleagues wrote in The New England Journal of Medicine. The results were also reported at an ATS 2020 Virtual Clinical Trials Session.
The phase III Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) trial tested the two triple-fixed dose, single inhaler regimens versus two dual therapy regimens: LAMA-LABA and inhaled glucocorticoid-LABA. The researchers recruited patients ages 40 to 80 who had a least one COPD exacerbation in the previous year.
The intention-t0-treat population included 2,137 patients in the 320-μg-budesonide triple therapy arm; 2,121 in the 160-μg-budesonide triple therapy group; 2,120 in glycophyrrolate-formoterol cohort; and 2,131 in the budesonide-formoterol group. The average age of participants across all groups was 64, about 60% were men, and roughly 40% were current smokers.
“A total of 7187 patients (83.8%) completed the trial, of whom 6654 (77.6%) completed 52 weeks of treatment (79.4% and 80.4% in the 320-μg–budesonide and 160-μg–budesonide triple-therapy groups, respectively, 74.1% in the glycopyrrolate-formoterol group, and 76.6% in the budesonide–formoterol group),” the study authors wrote.
Among the findings:
- Annual moderate-to-severe exacerbation rate was 1.08 in the higher dose budesonide triple therapy group and 1.07 in the lower dose budesonide triple therapy group.
- Annual moderate-to-severe exacerbation rate was 1.42 in the glycopyrrolate-formoterol group and 1.24 in the budesonide-formoterol group.
“The rate was significantly lower with 320-μg-budesonide triple therapy than with glycopyrrolate–formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69-0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79-0.95; P = 0.003),” Rabe and colleagues wrote. “Similarly, the rate was significantly lower with 160-μg–budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69-0.83; P<0.001) or budesonide–formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79-0.95; P = 0.002).”
Pneumonia was more common in all groups receiving inhaled glucocorticoid treatment, “(range, 2.4%-3.0%) than in the glycopyrrolate–formoterol group (1.3%) (P<0.05 for all comparisons).”
The investigators noted that the trial was not powered to detect a significant difference between the triple-dose therapy regimens, but comparisons “showed trends in favor of 320-μg–budesonide triple therapy with respect to severe exacerbations, SGRQ response, and use of rescue medication. Furthermore, despite a mortality of 1.8% overall, when the triple-therapy regimens were compared with glycopyrrolate–formoterol, a lower risk of death from any cause was observed only in the 320-μg–budesonide triple-therapy group, as shown by the 95% confidence interval.”
The ETHOS results mark the second time a randomized trial has demonstrated a benefit for triple therapy versus dual LAMA-LABA therapy — the IMPACT trial for triple therapy with fluticasone furoate–umeclidinium–vilanterol versus umeclidinium–vilanterol also showed a mortality benefit.
Rabe et al pointed out that the ETHOS findings support current GOLD recommendations that “suggest that patients with elevated eosinophil levels who continue to have exacerbations while receiving a single bronchodilator regimen with either a LAMA or a LABA should initially step up to inhaled glucocorticoid-LABA therapy… In the subgroups defined according to blood eosinophil counts, the benefits of triple therapy (with either dose of budesonide) over LAMA-LABA therapy with respect to exacerbations were greater among the patients with higher counts, a finding consistent with observations in previous studies of the response to inhaled glucocorticoids, as well as with the current GOLD recommendations.”
Be aware that this randomized trial did not detect a difference in efficacy between the 320 μg and 160 μg budesonide triple therapy doses compared to dual therapy.
Note that when the triple-therapy regimens were compared with glycopyrrolate–formoterol, a lower risk of death from any cause was observed only in the 320-μg–budesonide triple-therapy group.
Peggy Peck, Editor-in-Chief, BreakingMED™
The ETHOS trial was funded by AstraZeneca.
Rabe reported grants and personal fees from Boehringer Ingelheim, and AstraZeneca, as well as personal fees from Novartis, Chiesi Pharmaceuticals, Sanofi, Roche, and Regeneron outside the submitted work.
Cat ID: 154
Topic ID: 89,154,730,143,192,154,195,925