Triple Treatment Reduces COPD Exacerbations

Inhaled triple therapy with budesonide, glycopyrrolate, and formoterol showed a signal of reducing all-cause mortality in patients with moderate to severe chronic obstructive pulmonary disease (COPD) at higher (320 μg) budesonide doses in newly reported findings from the large, multicenter, 52-week ETHOS trial.

Two doses of the glucocorticoid -- 160 μg and 320 μg -- were evaluated in the trial, which compared twice-daily doses of the triple therapy with dual treatment with the long-acting muscarinic antagonist (LAMA) glycopyrrolate and the long-acting β2 agonist (LABA) formoterol or formoterol and budesonide, reported Klaus Rabe, MD, of the Airway Research Center North in Grosshansdorf, Germany.

Rabe presented the findings at an American Thoracic Society 2020 virtual session on clinical trials held in advance of the full virtual program scheduled for August; they were also published in the New England Journal of Medicine.

At both budesonide doses, twice-daily treatment with the single inhaler triple therapy was associated with significantly lower rates of moderate to severe COPD exacerbations, compared with the dual treatments.

Treatment with either triple-therapy regimen was also associated with significantly improved patient-reported outcomes, compared with dual therapy, the AstraZeneca-funded trial showed.

But only the 320-μg budesonide triple-therapy group showed a signal of a lower risk for death from any cause, with patients treated with the higher-dose budesonide triple therapy having a 46% lower death risk than patients in the glycopyrrolate-formoterol dual-therapy group.

Rabe noted that the trial was the first to examine two doses of a glucocorticoid in fixed-dose triple therapy, compared with dual LABA/LAMA or inhaled corticosteroid (ICS)/LABA treatments.

Rabe characterized the 46% reduction in all-cause mortality risk as "quite a sizable reduction given the [large] size of this trial." Each of the study's four treatment arms included roughly 2,100 patients.

Although mortality was numerically about 50% greater in the low-dose group, the wide confidence interval "precluded any definitive conclusions regarding a dose-response relationship," the researchers said.

Rabe said the optimal glucocorticoid dose in triple-combination therapy for COPD remains to be determined.

The trial included 8,509 patients with moderate to severe COPD randomized in similar numbers to treatment with twice-daily inhaled, fixed-dose triple therapy (160-μg or 320-μg budesonide/18-μg glycopyrrolate/9.6-μg formoterol), or dual therapy with 18-μg glycopyrrolate/9.6-μg formoterol or 320-μg budesonide/9.6-μg formoterol.

The primary endpoint was the annual rate of moderate to severe COPD exacerbations; a secondary endpoint was time to death from any cause.

Subgroup analyses included inhaled use of glucocorticoid at screening and patient blood eosinophil count. The annual rates of moderate or severe exacerbations were:

• 1.08 in the 320-μg budesonide triple-therapy group

• 1.07 in the 160-μg budesonide triple-therapy group

• 1.42 in the glycopyrrolate-formoterol group

• 1.24 in the budesonide-formoterol group

Compared with the dual glycopyrrolate-formoterol group, the exacerbation rate was significantly lower with 320-μg budesonide triple therapy (24% lower: rate ratio 0.76, 95% CI 0.69-0.83, P<0.001).

Triple therapy with the higher budesonide dose was also associated with a lower exacerbation risk than budesonide-formoterol (13% lower: rate ratio 0.87, 95% CI 0.79-0.95, P=0.003).

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), the researchers reported.

The incidence of any adverse event was similar across the treatment groups (range 61.7% to 64.5%), while the incidence of confirmed pneumonia ranged from 3.5% to 4.5% in the groups that included inhaled glucocorticoid use. The pneumonia incidence was 2.3% in the glycopyrrolate-formoterol group.

Rabe noted that previously reported studies of fixed ICS/LABA/LAMA therapy for COPD, including IMPACT, TRILOGY, and TRIBUTE, also showed a lower rate of moderate to severe exacerbations with triple therapy.

It has been suggested that the observed benefit for triple therapy may result from the discontinuation of inhaled glucocorticoids in patients using them prior to trial entry, but the ETHOS subgroup analysis of patients taking steroids before the trial did not support this, he said. "Our subanalysis makes it quite clear that the superiority of the triple combination in high and low [budesonide] doses was irrespective of ICS at screening."

The researchers concluded that while triple therapy with higher-dose budesonide appeared to be associated with lower all-cause mortality compared with other treatments, triple therapy with the lower budesonide dose showed greater efficacy for reducing exacerbations and improving quality of life compared with the dual treatment with twice the steroid dose.

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