Clinical Question

Is triple inhaled therapy for chronic obstructive pulmonary disease (COPD) more effective than dual inhaled therapy?

Bottom Line

Triple inhaled therapy, with budesonide (Pulmicort) in a dose of either 160 mcg or 320 mcg daily plus a long-acting muscarinic antagonist (LAMA) and a long-acting beta₂ agonist (LABA), reduces moderate exacerbations (a need for an antibiotic or steroid for three or more days) more than either a LAMA plus a LABA or inhaled corticosteroid plus a LABA, but the difference is small and of questionable clinical significance. There is no clinically important difference in severe exacerbations and no difference in mortality. Another study found a mortality reduction for triple therapy, with numbers needed to treat for one year of 120 (vs. a LAMA plus a LABA) and 358 (vs. an inhaled corticosteroid plus a LABA). (Level of Evidence = 1b)

Synopsis

Triple inhaled therapy for COPD consists of an inhaled corticosteroid, a LAMA, and a LABA. The inhaled corticosteroid in this study was budesonide, the LAMA was glycopyrrolate, 9 mcg twice daily, and the LABA was formoterol (Breztri Aerosphere), 4.8 mcg twice daily. The study randomized 8,588 patients to one of four regimens: triple therapy with 320 mcg of budesonide daily, triple therapy with budesonide, 160 mcg daily, dual therapy with a LAMA plus a LABA, and dual therapy with an inhaled corticosteroid plus a LABA. Participants had COPD that was not well-controlled (forced expiratory volume in one second [FEV₁] less than 0.70 postbronchodilator, and already taking at least two 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% of participants had a postbronchodilator FEV₁ of 50% to 80% of predicted, 60% were at 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 hospitalization, whereas moderate was any exacerbation treated with three or more days of an antibiotic or systemic corticosteroid. Groups were balanced at baseline, but allocation concealment was 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 one year, there was no clinically significant difference between groups in the rate of severe exacerbations (0.13 to 0.16 per year in the four 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 inhaled corticosteroid plus LABA group. In comparison with the inhaled corticosteroid plus LABA combination, that is approximately one fewer moderate or severe exacerbation every four years, but because there was no reduction in severe exacerbations, this is due to fewer moderate exacerbations. For the comparison with a LAMA plus a LABA, it is approximately one fewer moderate exacerbation every 2.5 years. Although this study was not powered to compare the budesonide dosages, 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.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Allocation: Uncertain

Setting: Outpatient (any)

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

Editor's Note: Dr. Ebell is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell.