SYSTEMATIC REVIEW article
Front. Cardiovasc. Med.
Sec. Clinical and Translational Cardiovascular Medicine
Effect of triple inhaled therapy on MACE and cardiovascular events in COPD: a systematic review and meta-analysis
Provisionally accepted
Alberto Calderon Montero1,2*
Vivencio Barrios1,3Javier de Miguel Diez1,4Clara Calderón-Ferrer5,6Milan Joshi7- 1Servicio Madrileño de Salud (SERMAS). Consejería de Salud. Comunidad de Madrid, Madrid, Spain
- 2Cerro del Aire Primary Health Center, Majadahonda, Spain
- 3Cardiology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain
- 4Pneumology Department, Hospital General Universitario Gregorio Maranon, Madrid, Spain
- 5Universidad Complutense de Madrid, Madrid, Spain
- 6Chemistry, Madrid, Spain
- 7Statician, Birmingham City University, Birmingham, United Kingdom
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Background: Although some meta-analyses show that triple inhaled therapy (TT) reduces all-cause mortality compared to 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 january 15, 2025. All randomized clinical trial (RCTs) evaluating TT versus DT and reporting MACE and cardiovascular outcomes were included. We assessed risk of bias and conducted a random effect meta-analysis estimating summary relative risk (RR) with 95% confidence intervals, evaluating heterogeneity using I². A network meta-analysis (NMA) was undertaken. Results: From 781 citations, 5 RCTs were selected (7855 patients receiving TT, 7003 LABA/ICS, 5059 LAMA/LABA). The risk of bias was moderate in 3 and low in 2 RCTs. TT reduced MACE by a non-significant 11% vs LAMA/LABA (0.89; 0.70-1.12, 4 RCTs, I²=0%) and increased by a non-significant 26% vs LABA/ICS (1.26; 0.97-1.64, 4 RCTs, I²=0%). TT reduced cardiovascular mortality by 50% (0.50; 0.31-0.80, 3 RCTs, I²=0%) and increase non-fatal stroke by 92% (1.92; 1.09-3.39, 2 RCTs, I²=0%) compared to LAMA/LABA. TT shows a favourable trend on myocardial ischaemia outcomes. For cardiovascular mortality, 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 cardiovascular mortality compared to LAMA/LABA dual therapy, without significant reduction on MACE.
Keywords: MACE, cardiovascular events, Triple inhaled therapy, COPD, Meta-analysis
Received: 23 Sep 2025; Accepted: 30 Oct 2025.
Copyright: © 2025 Calderon Montero, Barrios, de Miguel Diez, Calderón-Ferrer and Joshi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Alberto Calderon Montero, acalderonmontero@gmail.com
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