Effect of triple inhaled therapy on MACE and cardiovascular events in COPD: a systematic review and meta-analysis.

Background: Although some meta-analyses show that triple inhaled therapy (TT) reduces all-cause mortality compared with dual inhaled therapy (DT), the effect on cardiovascular events is not yet well defined. We estimated the effect of TT compared with DT (LAMA/LABA or LABA/ICS) on MACE and cardiovascular outcomes in an evidence synthesis. Methods: Following prospective registration (https://osf.io/gtfvm), a comprehensive search strategy of PubMed, Scopus, and Embase was performed until 15 January 2025. All randomized clinical trials (RCTs) evaluating TT vs. DT and reporting MACE and cardiovascular outcomes were included. We assessed risk of bias and conducted a random-effects meta-analysis estimating summary relative risk (RR) with 95% confidence intervals, evaluating heterogeneity using I 2. A network meta-analysis (NMA) was undertaken. Results: From 781 citations, five RCTs were selected (7,855 patients receiving TT, 7,003 LABA/ICS, 5,059 LAMA/LABA). The risk of bias was moderate in three and low in two RCTs. TT reduced MACE by a non-significant 11% vs. LAMA/LABA (0.89; 0.70-1.12, four RCTs, I 2 = 0%) and increased by a non-significant 26% vs. LABA/ICS (1.26; 0.97-1.64, four RCTs, I 2 = 0%). TT reduced cardiovascular mortality (CVD) by 50% (0.50; 0.31-0.80, three RCTs, I 2 = 0%) and increased non-fatal stroke by 92% (1.92; 1.09-3.39, two RCTs, I 2 = 0%) compared with LAMA/LABA. TT shows a favorable trend in myocardial ischemia outcomes. For CVD, NMA showed that TT ranked first and LAMA/LABA last in effectiveness. Conclusions: In exacerbating patients with moderate to very severe COPD, TT significantly reduces CVD compared with LAMA/LABA dual therapy, without a significant reduction in MACE. Systematic Review Registration: https://doi.org/10.17605/OSF.IO/GTFVM.