Triple inhaled therapy provides a small reduction in moderate exacerbations, no effect on severe exacerbations (ETHOS)

Reference

Rabe KF, Martinez FJ, Ferguson GT, et al, for the ETHOS Investigators. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD. N Engl J Med 2020;383(1):35-48.

Synopsis

Triple inhaled therapy for chronic obstructive pulmonary disease (COPD) consists of an ICS, a LAMA, and a LABA. The ICS in this study was budesonide, the LAMA was glycopyrrolate 9 mcg twice daily, and the LABA was formeterol 4.8 mcg twice daily. This study randomized 8588 patients to 1 of 4 regimens: triple therapy with 320 mcg budesonide daily, triple therapy with budesonide 160 mcg daily, dual therapy with LAMA plus LABA, and dual therapy with ICS plus LABA. Participants had COPD that was not well-controlled (FEV1 < 0.70 post-bronchodilator, and already taking at least 2 inhaled agents) and had experienced at least one moderate or severe exacerbation in the past year. Participants had a mean age of 64 years, approximately 60% were men, and 41% were current smokers. Approximately 30% had a post-bronchodilator FEV1 of 50% to 80% of predicted, 60% were 30% to 50% of predicted, and 10% were less than 30% of predicted. The primary outcome was the rate of moderate or severe exacerbations; severe involved hospitalizations, while moderate was any exacerbation treated with 3 or more days of an antibiotic or systemic corticosteroid. Groups were balanced at baseline, but allocation concealment is not described. It is unclear why "rates of exacerbation were analyzed by means of negative binomial regression" instead of a straightforward comparison of the rates of the primary outcome between groups. After 1 year, there was no clinically significant difference between groups in the rate of severe exacerbations (0.13 to 0.16 per year in the 4 groups). There was a difference in the likelihood of moderate to severe exacerbations: 1.25 and 1.23 per year in the 320 mcg and 160 mcg triple therapy groups, respectively, compared with 1.63 in the LAMA plus LABA group, and 1.47 in the ICS plus LABA group. In comparison with the ICS plus LABA combination, that is approximately 1 fewer moderate or severe exacerbation every 4 years, but of course because there was no reduction in severe exacerbations, this is entirely due to fewer moderate exacerbations. For the comparison with LAMA plus LABA, it is approximately 1 fewer moderate exacerbation every 2.5 years. Although this study was not powered to compare the budesonide doses, the results were generally similar for the 160 mcg and the 320 mcg daily doses. There were no significant differences in mortality or serious adverse events.