Comparative Efficacy and Safety of Combination Treatments for Chronic Obstructive Pulmonary Disease

Background: Treatment with a long-acting beta2-agonist (LABA) is an integral part of the guidelines for management of chronic obstructive pulmonary disease (COPD). Concurrent use of a LABA and a long-acting muscarinic antagonist (LAMA) are believed to enhance bronchodilation due to the synergistic mechanisms of action. Only recently have fixed dose combination LABA/LAMA agents been developed which has resulted in a vast amount of efficacy and safety data from clinical trials. However, data remains lacking on the effectiveness and safety of LABA/LAMA in a broader population of COPD patients. Objectives: The aims of this research were to examine real-world effectiveness and safety of LABA/LAMA compared to LABA/inhaled corticosteroid (LABA/ICS) combination treatment. A secondary goal was to develop a predictive model to identify those at risk for COPD exacerbations among patients treated with LABA/LAMA or LABA/ICS. Methods: This was a retrospective, observational study utilizing administrative claims data among COPD patients initiating LABA/LAMA or LABA/ICS. Effectiveness was measured by comparing COPD exacerbation rates using Poisson regression models adjusted for baseline covariates. We examined cardiovascular and cerebrovascular safety outcomes by measuring hospitalizations with a primary diagnosis for acute coronary syndrome, heart failure, cardiac dysrhythmia, stroke, or transient ischemic attack. Time to event was compared using Cox proportional hazards models after matching patients 1 LABA/LAMA user to 4 LABA/ICS users) on propensity score. A predictive model of COPD exacerbations among LABA/LAMA or LABA/ICS users was developed using stepwise logistic regression in a training set of the original cohort. The test characteristics of the model were evaluated in the training set and validation set of patients. Results: Patients treated with the LABA/LAMA combination had similar exacerbation rates compared to those treated with LABA/ICS (adjusted incidence rate ratio of 0.98 [95% CI: 0.95 – 1.01]). Cardiovascular events in the LABA/LAMA cohort were lower than LABA/ICS (hazard ratio [HR]=0.794 [95% CI: 0.623-0.997]) but there was no significant difference in the risk of cerebrovascular events (HR=1.166 [95% CI 0.653-1.959]). The base predictive model resulted in a sensitivity of 41.6% and specificity of 85.5%. Other exploratory models resulted in similar test characteristics. Conclusions: In this real-world, observational study, exacerbations rates and cerebrovascular events were similar among patients treated with LABA/LAMA and LABA/ICS. Patients treated with LABA/LAMA had slightly lower risk of cardiovascular events. Further studies are recommended to confirm these findings. Finally, we were not able to develop a predictive model that identified patients at high risk for COPD exacerbations among patients treated with LABA/LAMA or LABA/ICS.