Effect of triple inhaled therapy on cardiovascular and all-cause mortality compared with dual inhaled therapy in COPD: A systematic review and meta-analysis

Abstract

Background

There is uncertainty about the role of triple inhaled therapy with LAMA/LABA/ICS (long-acting muscarinic antagonist/long-acting β2-agonist/inhaled glucocorticoids) in chronic obstructive pulmonary disease (COPD) on cardiovascular mortality. We estimated the effect of triple inhaled therapy (TT) compared with dual inhaled therapy (DT, including either LAMA/LABA or LABA/ICS) on all-cause and cardiovascular mortality in an evidence synthesis,

Methods

Following prospective registration (https://osf.io/gtfvm), a comprehensive search strategy of PubMed, Scopus, and Embase was performed, without language or time restrictions until September 30, 2024. All randomized clinical trials (RCTs) evaluating TT vs. DT and reporting cardiovascular or all-cause mortality were included. We assessed risk of bias and conducted a random effect meta-analysis estimating summary relative risk (RR) with 95% confidence intervals (CI), evaluating heterogeneity using I². A network meta-analysis (NMA) was undertaken to hierarchically rank the therapies using P-score.

Results

From 781 citations, 5 RCTs were selected. There were 3 three-arm RCTs comparing TT vs. LABA/ICS vs. LAMA/LABA, 1 two-arm RCT comparing TT vs. LABA/ICS, and 1 two-arm RCT comparing TT vs. LAMA/LABA (total of 7855 patients receiving TT, 7003 LABA/ICS and 5059 LAMA/LABA). The risk of bias was moderate in 2 (40%), and low in 3 (60%) RCTs. TT reduced cardiovascular mortality by 48% vs. LAMA/LABA (RR 0.52, 95% CI 0.32–0.86, 3 RCTs, I² = 0%) and by a non-significant 11% vs. LABA/ICS (RR 0.89, 95% CI 0.57–1.37, 3 RCTs, I² = 0%). TT reduced all-cause mortality by 34% vs. LAMA/LABA (RR 0.66, 95% CI 0.48–0.90, 4 RCTs, I² = 23.7%) and by 10% vs. LABA/ICS (RR 0.90, 95% CI 0.71–1.13, 4 RCTs, I² = 0%). For both cardiovascular and all-cause mortality, NMA P-score showed that TT ranked first (81%/91%), LABA/ICS ranked second (58%/57%) and LAMA/LABA ranked last (11%/<1%) in effectiveness.

Conclusions

In patients with moderate to very severe COPD and previous exacerbations, TT inhaled significantly reduces cardiovascular and all-cause mortality compared to LAMA/LABA dual therapy, but not when compared to LABA/ICS.