Triple Therapy for Moderate-to-Severe Chronic Obstructive Pulmonary Disease

Triple Therapy for Moderate-to-Severe Chronic Obstructive Pulmonary Disease
Taylor Grupa, Pharm.D., Essentia Health

Background: Treatment of chronic obstructive pulmonary disease (COPD) follows a stepwise approach. Triple inhaled therapy, including an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist, (LAMA) and a long-acting beta agonist (LABA), has been shown to improve lung function, symptoms, and health status while reducing exacerbations, compared to other inhaler combinations. The 2020 American Thoracic Society COPD guideline recommends use of triple inhaled therapy for patients who remain symptomatic on dual therapy who have had at least one exacerbation requiring antibiotics, oral steroids, or a hospitalization in the last year. Additionally, the 2020 GOLD guideline recommends the addition of an ICS to one or two long-acting bronchodilators in patients with history of hospitalizations due to COPD exacerbations, two or more moderate COPD exacerbations per year, concomitant asthma, or blood eosinophil count > 300 cells/microliter. Little guidance is provided in either guideline regarding dose of the ICS component of inhaled triple therapy. 

Evidence: The Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) trial investigated both efficacy and safety of two doses of ICS as part of a triple therapy combination. In this randomized, double blind, parallel-group trial, participants were randomized in 1:1:1:1 fashion to receive twice daily inhalations of low dose triple therapy (160 mcg of budesonide plus 18 mcg glycopyrrolate and 9.6 mcg formoterol), high dose triple therapy (320 mcg budesonide plus 18 mcg glycopyrrolate and 9.6 mcg formoterol), LAMA/LABA dual therapy (18 mcg glycopyrrolate and 9.6 mcg formoterol), or LABA/ICS dual therapy (320 mcg budesonide and 9.6 mcg formoterol). Patients 40-80 years of age with symptomatic, moderate-to-severe COPD were eligible if they used at least two inhaled maintenance therapies at the time of screening. The primary outcome was the annual rate of moderate or severe COPD exacerbations. 

An intention-to-treat protocol was used to analyze 8509 patients. The annual rate of moderate or severe exacerbations was significantly lower in the 320 mcg budesonide triple therapy group compared to LABA/LAMA dual therapy (RR 0.76 [95% CI 0.69-0.83], P<0.001) or LABA/ICS dual therapy (RR 0.87 [95% CI 0.79-0.95], P=0.003). Additionally, the annual rate of moderate or severe exacerbations in the low dose triple therapy group was significantly lower when compared to LABA/LAMA dual therapy (RR 0.75 [95% CI 0.69-0.83], P<0.0001) and LABA/ICS dual therapy (RR 0.86 [95% CI 0.79-0.95], P=0.002). However, there was no difference between the two triple therapy groups. During analysis of secondary outcomes, it was found that high dose triple inhaled therapy demonstrated lower risk of death from any cause, while the finding was not significant in the low dose triple inhaled therapy group. No unexpected safety concerns were observed. 

Discussion and Clinical Impact: The ETHOS trial demonstrates reduced risk of moderate or severe COPD exacerbations when using either low or high dose ICS as part of an ICS/LABA/LAMA combination. While no difference was detected between triple therapy groups, the study was not powered to detect a difference. This study also demonstrates lower all-cause mortality with use of high dose ICS as part of a triple inhaled therapy regimen. Interestingly, this study calls into question the role of ICS/LABA dual therapy combinations. Current GOLD guidelines suggest first escalating to ICS/LABA therapy for those patients who have elevated eosinophil levels and frequent exacerbations while on LABA or LAMA monotherapy, prior to initiation of triple therapy. However, the ETHOS trial demonstrated a significant reduction of exacerbations with triple inhaled therapy compared to ICS/LABA therapy, suggesting there may be greater benefit to escalating from monotherapy to triple therapy in these patients, however, only patients on dual-inhaler management COPD management were included in this trial. Escalating to dual ICS/LABA therapy with close monitoring of symptom improvement first, as the guideline would suggest, is reasonable before introducing additional medication burden and cost associated with triple inhaled therapy.


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  3. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy For Diagnosis, Management, And Prevention Of Chronic Obstructive Pulmonary Disease 2020 Report. Accessed August 12, 2020.