Benefit–Harm Analysis of Earlier Initiation of Triple Therapy for Prevention of Acute Exacerbation in Patients with Chronic Obstructive Pulmonary Disease

Rationale: Reducing the risk of exacerbation is a fundamental goal in managing stable COPD. Guidelines recommend triple therapy (inhaled corticosteroids, long-acting muscarinic antagonists, and long-acting beta-agonists ICS/LAMA/LABA) only as a step-up from dual therapy (LAMA/LABA) for patients at continued high risk of exacerbation, due to the trade-off of an increased risk of pneumonia associated with ICS-containing therapies. However, there is little evidence on the optimum timing of initiating triple therapy. Objectives: To perform a benefit-harm analysis to evaluate the net benefit of earlier initiation of triple therapy for the prevention of acute exacerbations in patients with COPD, compared to standard timing recommended in current guidelines. Methods: We used a validated whole disease microsimulation model of COPD in the Canadian general population aged ≥40 years to determine the benefit-harm of earlier initiation of triple therapy over a 20-year time horizon, compared to standard care. We assessed net change in quality-adjusted life-years (QALYs) from the reduction in risk of acute exacerbations and the increased risk of treatment-related pneumonia in subgroups of patients with COPD defined by exacerbation history, symptoms, and disease severity. Model parameters were determined from clinical trials and other published literature. Key parameters were varied in one-way sensitivity analysis. Results: In patients at high risk of acute exacerbation (54.7% female, mean age 74.0, 68% GOLD grade I-II), earlier initiation of triple therapy was associated with a net QALY gain of 4.8 per 100 COPD patients over 20 years, compared to standard care. The net QALY gain increased to 5.9 per 100 patients in the subgroup of patients with a high symptom burden (mMRC>1). Earlier initiation remained net beneficial in all subgroup and sensitivity analysis scenarios. Conclusions: Modeling suggests that earlier initiation of triple therapy is likely to be net beneficial for patients at high risk of acute exacerbation, with an even greater benefit to patients with a high symptom burden. Further clinical research is needed to verify these findings in empirical studies.