Signal for Cardiovascular Harm With Triple Inhaler Therapy

Chronic obstructive pulmonary disease (COPD) remains a leading cause of death and disability worldwide. Many inhaler combinations have proven to reduce the risk of exacerbation and hospitalization with COPD. These include long-acting β2-agonists (LABA), long-acting muscarinic antagonists (LAMA), and inhaled corticosteroids (ICS).

Patients with COPD frequently have comorbidities like hypertension, atrial fibrillation, and heart failure. Prior studies have identified conflicting outcomes regarding the cardiovascular safety of the various inhaler combinations in patients with COPD. In this installment of Talking Therapeutics, we explore a recently published large database analysis of Korean patients with COPD.

Talking Point: Clear Signal for Harm With Triple Therapy

A study analyzed COPD patients from the Health Insurance Review and Assessment Service database in Korea. The cohort was eventually divided into 3 arms: the LAMA/LABA group (n=28,322), the ICS/LABA group (n=11,812), and the triple group (LAMA/ICS/LABA therapy, n=6174).

The authors primary finding was from a multivariable Cox analyses demonstrating that, compared to ICS/LABA therapy, triple therapy was independently associated with the development of ischemic heart disease (HR: 1.22, 95% CI: 1.04–1.43), heart failure (HR: 1.45, 95% CI: 1.14–1.84), arrhythmia (HR: 1.72, 95% CI: 1.41–2.09), and atrial fibrillation/flutter (HR: 2.31, 95% CI: 1.64–3.25), whereas the LAMA/LABA therapy did not show a significant association.

The authors also found that the annual incidence of ischemic heart disease, heart failure, arrhythmia, and atrial fibrillation/flutter occurred most frequently in the first year and decreased as therapeutic duration became longer.

Talking Point: No Cause for Panic Yet

LAMAs and LABAs can stress the cardiovascular system through dysregulation of the autonomic nervous system. While numerously randomized trials like TORCH, UPLIFT, and FLAME failed to show cardiovascular harm, fewer than 20% of real-world patients would meet the strict inclusion/exclusion criteria for these trials. The signal for harm seen in this Korean study is, therefore, still relevant.

While it’s important to consider the potential cardiovascular harms of triple therapy for COPD, there are known benefits that cannot be denied to patients based on this study. Triple therapy with LAMA/LABA/ICS is superior to LABA/ICS at preventing COPD exacerbations and improving quality of life in patients with moderate-to-severe COPD. This therapy should still be used in these patients pending additional cardiovascular safety data.