Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD: ETHOS study

Original: N Engl J Med 2020; 383: 35-48

Author(s): Rabe KF, Martinez FJ, Ferguson GT et al.

Reviewer: Stylianos Loukides, e-Learning Director

Published: 05 Jul, 2020

The ETHOS study randomized 8509 patients in a 1:1:1:1 manner to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 μg or 160 μg of Budesonide], a LAMA [18 μg of Glycopyrrolate], and a LABA [9.6 μg of Formoterol]) or one of two dual therapies (18 μg of Glycopyrrolate plus 9.6 μg of Formoterol or 320 μg of Budesonide plus 9.6 μg of Formoterol). In this study, patients were recruited if they were symptomatic despite receiving at least two maintenance inhaled therapies, had a postbronchodilator FEV1 of 25 to 65%pred, a smoking history of at least 10 pack-years, and a documented history of at least one moderate or severe COPD exacerbation (if their FEV1 was <50%pred) or at least two moderate or at least one severe COPD exacerbation (if their FEV1 was ≥50%pred) in the year before screening. Interestingly most of the study subjects were lacking an exacerbation history. The primary end point was the annual rate of moderate or severe COPD exacerbations.

The results have shown that exacerbation rate was significantly lower with 320-μg–Budesonide triple therapy than with Glycopyrrolate/Formoterol (24% lower: rate ratio (RR), 0.76; 95% confidence interval [CI], 0.69 to 0.83; p<0.001) or Budesonide/Formoterol (13% lower: RR, 0.87; 95% CI, 0.79 to 0.95; p = 0.003). Similarly, the rate was significantly lower with 160-μg–Budesonide triple therapy than with Glycopyrrolate/Formoterol (25% lower: RR, 0.75; 95% CI, 0.69 to 0.83; p<0.001) or Budesonide/Formoterol (14% lower: RR, 0.86; 95% CI, 0.79 to 0.95; p = 0.002). In the noninferiority analysis of the annual rate of severe exacerbations that was performed in the per-protocol population (all patients with postrandomization data obtained before any major protocol deviations), 160-μg–budesonide triple therapy was shown to be noninferior to budesonide–formoterol (rate ratio, 0.82; 95% CI, 0.68 to 1.00); however, differences between the 160-μg–budesonide triple-therapy group and either dual-therapy group were not significant.

The risk of death from any cause in the 160-μg–budesonide triple-therapy group was lower than that in the glycopyrrolate–formoterol group (39 vs. 49 deaths; hazard ratio, 0.79; 95% CI, 0.52 to 1.20) but higher than that in the budesonide–formoterol group (39 vs. 34 deaths; hazard ratio, 1.13; 95% CI, 0.72 to 1.80). The triple-therapy regimens showed a benefit over the dual-therapy regimens with respect to the annual rate of moderate or severe exacerbations in both eosinophil subgroups (<150 and ≥150 cells per cubic millimeter). The final conclusion was that In this randomized trial patients with moderate-to-very-severe COPD, single-inhaler triple therapy with an inhaled glucocorticoid (budesonide, 320 μg or 160 μg twice daily) plus LAMA–LABA (glycopyrrolate–formoterol) resulted in significantly lower rates of moderate or severe exacerbations than dual therapy with LAMA–LABA or inhaled glucocorticoid–LABA. In addition, both triple-therapy regimens significantly improved patient-reported outcomes as compared with either dual-therapy regimen.

###2 major comments:

  • The aforementioned encouraging results regarding the efficacy of triple therapy in patients with COPD pose a great risk for the treating physician of selecting this therapy for all COPD patients, in a “one size fits all” manner. However, having in mind that overtreatment might increase the risk of adverse events without providing a clear benefit to the patient it is important to specify the exact reasons and patient characteristics which would make triple therapy a reasonable choice.
  • Since data from most clinical trial populations show that blood eosinophil counts impact the effect of ICS regarding the prevention of COPD exacerbations, it seems that blood eosinophil count might serve as a potential and useful biomarker for the prognosis and guidance of treatment with ICS as an add on therapy, in patients with stable COPD.
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