Single-Inhaler Triple vs LABA-ICS Therapy for COPD: Comparative Safety in Real-World Clinical Practice.

Background: Recent treatment guidelines for COPD have replaced the long-acting beta₂-agonist (LABA) and inhaled corticosteroid (ICS) combination with single-inhaler triple therapy that adds a long-acting muscarinic antagonist (LAMA) (LAMA-LABA-ICS). However, the corresponding trials reported numerically higher incidences of cardiovascular adverse events with triple therapy compared with LABA-ICS.

Research question: Does single-inhaler triple therapy increase the incidence of major adverse cardiovascular events, compared with LABA-ICS, in a real-world clinical practice setting?

Study design and methods: We identified a cohort of patients with COPD, ≥ 40 years of age, treated during 2017-2021, from the UK's Clinical Practice Research Datalink. Among LAMA-naïve patients, initiators of single-inhaler triple therapy were matched 1:1 to LABA-ICS users on time-conditional propensity scores. They were compared on the incidence of major adverse cardiovascular events (MACEs), defined as hospitalization for myocardial infarction or stroke, or all-cause-mortality, over 1 year.

Results: The cohort included 10,255 initiators of triple therapy and 10,255 matched users of LABA-ICS. The incidence rate of MACEs was 11.3 per 100 per year with triple therapy compared with 8.7 per 100 per year for LABA-ICS. The corresponding adjusted hazard ratio (HR) of MACEs with triple therapy was 1.28 (95% CI, 1.05-1.55), relative to LABA-ICS; however, the increase was mainly in the first 4 months (HR, 1.41; 95% CI, 1.14-1.74). The HR of all-cause death was 1.31 (95% CI, 1.06-1.62), whereas for acute myocardial infarction and stroke hospitalization it was 1.00 (95% CI, 0.56-1.79) and 1.06 (95% CI, 0.48-2.36), respectively, with triple therapy, relative to LABA-ICS.

Interpretation: In a real-world setting of COPD treatment, patients who initiated single-inhaler triple therapy had an increased incidence of MACEs compared with similar patients treated with an LABA-ICS inhaler. This small increase was due to the all-cause mortality component, occurring mainly in the first 4 months after treatment initiation.