New findings from the 8000-plus patient ETHOS trial shows triple inhaler therapy siginificantly betters patient mortality and symptoms over 52 weeks versus dual therapy.
Klaus F. Rabe, MD
Twice-daily budesonide/glycopyrrolate/formoterol significantly lowered exacerbations in patients with moderate or severe chronic obstructive pulmonary disease (COPD) versus a pair of double therapy inhalers, according to new findings.
In new results from the Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) trial, investigators reported results showed a fixed dose of either 160 or 320 mcg inhaled budesonide with long-acting meta antagonist (LAMA) glycopyrrolate plus long-acting beta agonist (LABA) formoterol reduced COPD exacerbations over 52 weeks at a notably greater rate than glycopyrrolate-formoterol or budesonide-formoterol.
The findings, presented during the American Thoracic Society (ATS) 2020 Virtual Sessions, show benefit of inhaled corticosteroid (ICS) plus LAMA/LABA pertain to quality of life and mortality metrics in patients with COPD, as well as that of exacerbation rates.
Investigators, led by Klaus F. Rabe, MD, of the Airway Research Center North in Germany, conducted the 52-week, phase 3, randomized trial funded by AstraZeneca.
Their patient population included 8509 patients aged 40-80 years old with moderate to very severe COPD and at least 1 exacerbation in the last year. Patients were randomized 1:1:1:1 to either twice-daily inhaled doses of the triple therapy (160 or 320 mcg budesonide/ 18 mcg glycopyrrolate/ 9.6 mcg formoterol), or one of the 2 dual therapy options. Patients administered budesonide in the dual therapy treatment arm were given 320 mcg.
Doses were administered twice daily over a 52-week period.
Rabe and colleagues sought a primary endpoint of annual rate of moderate or severe exacerbations, as per mean number per patient per year, as analyzed in the modified intention-to-treat population with the use of on-treatment data only.
Secondary endpoints included time to first exacerbation, change from baseline in average daily rescue medication use over 24 weeks, rate of patients with a St. George’s Respiratory Questionnaire (SGRQ) response, and time to death from any cause.
Mean patient age in all treatment arms was 64.6±7.6, with approximately three-fifths of patients being male. About two-fifths were current smokers.
Investigators observed annual moderate or severe exacerbation rates of 1.08 and 1.07 in patients treated with 320 mcg and 160 mcg budesonide plus LAMA/LABA, respectively. Among patients treated with LAMA/LABA or ICS/LABA, annual exacerbations were 1.42 and 1.24, respectively.
They confirmed that exacerbation rates were significantly lower with 320 mcg budesonide plus LAMA/LABA than with LAMA/LABA—a 24% reduction (RR, 0.76; 95% CI, 0.69-0.83; P <.001). The 13% reduction between this treatment arm and patients on ICS/LABA was also deemed significant (RR, 0.87; 95% CI, 0.79-0.95; P = .003).
Lower-dose budesonide (160 mcg) plus LAMA/LABA was also associated with similar, significantly reduced annual exacerbations than LAMA/LABA (RR, 0.75; 95% CI, 0.69-0.83; P <.001) and ICS/LABA (RR, 0.86; 95% CI, 0.79-0.95; P = .002).
A lower mortality rate was observed in patients with COPD treated with 320 mcg budesonide plus LAMA/LABA versus those treated with dual therapy.
“This is the second trial to show a benefit of triple therapy over dual therapy with LAMA/LABA with respect to mortality among patients with COPD,” investigators wrote.
In an interview with HCPLive regarding the findings, Rabe emphasized results show a continued evidence for the treatment regimen in patients with COPD—and noted it could even come to influence current guidance around patient care.
"If you look at the guidelines, you’ll realize there’s possibility to add a bronchodilator regime, primarily,” he explained. “There’s very good reasons, and it’s debated, to give someone a triple therapy—2 bronchodilators plus a steroid.”
Though previous findings evidencing the mortality benefit of triple therapy versus dual therapy have been marked by suggestions that patients switched from LAMA/LABA are required to discontinue inhaled glucocorticoids, Rabe and colleagues noted their large swath of ETHOS data shows patients benefitted similarly with triple therapy regardless of their inhaled glucocorticoid use history.
The rate of patients to experience an adverse event in any of the 4 treatment arms ranged from 61.7% to 64.5%, with pneumonia being a pronounced burden among patients on ICS.
The team concluded that triple therapy of budesonide/glycopyrrolate/formoterol benefitted patients with COPD and a history of exacerbations when compared to dual therapies, additionally showing association with bettered quality of life scoring, symptom reduction, and reduced risk of mortality.
“We also showed that triple therapy with a 160-mcg dose of budesonide was an effective treatment option for COPD,” they wrote. “This lower-dose inhaled glucocorticoid triple-therapy regimen showed greater efficacy than the higher-dose inhaled glucocorticoid-LABA regimen, with lower rates of exacerbations, greater reductions in symptoms, and greater improvement in health-related quality of life.”
The study, “Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD,” was published online in The New England Journal of Medicine.