Comparative effectiveness and safety of escalating to triple therapy versus switching to dual bronchodilators after discontinuing LABA/ICS in patients with COPD: a retrospective cohort study

Abstract

Background: The latest guidelines discourage the use of long-acting beta₂-agonists/inhaled corticosteroids (LABA/ICS) for chronic obstructive pulmonary disease (COPD). However, there is a lack of evidence regarding the optimal subsequent treatment after discontinuing LABA/ICS.

Objectives: To compare the effectiveness and safety of switching from LABA/ICS to triple therapy (LABA/long-acting muscarinic antagonists (LAMA)/ICS) or to dual bronchodilators (LABA/LAMA) in COPD patients.

Design: This was a new-user, active-comparator, and propensity score-matched cohort study analyzing the Taiwanese nationwide healthcare insurance claims.

Methods: We recruited COPD patients switching from LABA/ICS to triple therapy or to dual bronchodilators from 2015 to 2019. The primary effectiveness outcome was the annual rate of exacerbations, and safety outcomes included severe pneumonia and all-cause mortality. Stratification by prior exacerbations was conducted.

Results: After matching, each group comprised 1892 patients, 55% of whom experienced no exacerbations in the prior year. Treatment with LABA/LAMA/ICS versus LABA/LAMA showed comparable annual rate of moderate-to-severe exacerbations (incidence rate ratio, 1.04; 95% confidence interval (CI), 0.91-1.19). However, switching to LABA/LAMA/ICS was associated with increased risks of severe pneumonia (hazard ratio (HR), 1.65; 95% CI, 1.30-2.09) and all-cause death (HR, 1.39; 95% CI, 1.09-1.78). In patients with⩾2 prior exacerbations, LABA/LAMA/ICS versus LABA/LAMA was related to a 21% reduced rate of exacerbations but with a twofold increased pneumonia risk and a 49% elevated risk of all-cause mortality.

Conclusion: Switching from LABA/ICS to triple therapy versus dual bronchodilators in COPD patients was associated with similar rates of annual exacerbations but was related to elevated risks of severe pneumonia and all-cause mortality. Among frequent exacerbators, triple therapy was associated with lower rates of exacerbation but was accompanied by increased risks of pneumonia and mortality compared to LABA/LAMA. Careful consideration of the examined safety events is necessary when switching from LABA/ICS to triple therapy in COPD management.

Keywords: COPD; comparative effectiveness and safety; dual therapy; observational study; triple therapy.

Figure 1.

Flowchart showing the selection of the base and study cohorts. COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; LABA, inhaled long-acting β2 agonists; LAMA, inhaled long-acting muscarinic antagonists.

Figure 2.

Forest plots showing the (a) sensitivity analyses and (b) subgroup analyses of the annual rate of exacerbation. ^aHRs with 95% CIs were estimated to study the outcomes of competing risk models, GERD, and high-dimensional PS matching. ^bp < 0.05. CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; GERD, gastroesophageal reflux disease; HR, hazard ratio; IRR, incidence rate ratio; PS, propensity score.

Figure 3.

Bar charts illustrating (a) the annual rate of COPD moderate-to-severe exacerbations and (b) incidence rate of first hospitalization for pneumonia stratified by prior exacerbation(s). ^ap < .05. ^bp < .001. CI, confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; ICS, inhaled corticosteroids; IRR, incidence rate ratio; LABA, inhaled long-acting β2 agonists; LAMA, inhaled long-acting muscarinic antagonists.