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

IF 0.9 Q4 PRIMARY HEALTH CARE

Medicina de Familia-SEMERGEN Pub Date : 2025-03-25 DOI:10.1016/j.semerg.2025.102478

A. Calderón-Montero , M. García Fernández , M.E. García-Velasco , M. Joshi , K. Khan , C. Calderón-Ferrer , M. Núñez-Núñez

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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.

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与双重吸入治疗相比，三联吸入治疗对COPD患者心血管和全因死亡率的影响：一项系统回顾和荟萃分析

背景：慢性阻塞性肺疾病（COPD）患者采用LAMA/LABA/ICS（长效毒蕈碱拮抗剂/长效β2激动剂/吸入糖皮质激素）三联吸入治疗对心血管死亡率的影响尚不确定。在一项证据合成中，我们估计了三重吸入治疗（TT）与双重吸入治疗（DT，包括LAMA/LABA或LABA/ICS）对全因死亡率和心血管死亡率的影响。方法：在前瞻性注册（https://osf.io/gtfvm）之后，在2024年9月30日之前，在没有语言或时间限制的情况下，对PubMed、Scopus和Embase进行了全面的搜索策略。所有评估TT与DT并报告心血管或全因死亡率的随机临床试验（rct）均被纳入。我们评估了偏倚风险，并进行了随机效应荟萃分析，估计了95%置信区间（CI）的总相对风险（RR），使用I2评估异质性。采用网络荟萃分析（NMA）使用P-score对治疗进行分层排序。结果从781篇文献中筛选出5篇rct。有3项比较TT、LABA/ICS和LAMA/LABA的3组随机对照试验，1项比较TT和LABA/ICS的2组随机对照试验，1项比较TT和LAMA/LABA的2组随机对照试验（共7855例接受TT、7003例接受LABA/ICS和5059例接受LAMA/LABA的患者）。2项rct的偏倚风险为中等（40%），3项rct的偏倚风险为低（60%）。与LAMA/LABA相比，TT降低了48%的心血管死亡率（RR 0.52, 95% CI 0.32-0.86, 3个rct， I2 = 0%），与LABA/ICS相比，TT降低了11% （RR 0.89, 95% CI 0.57-1.37, 3个rct， I2 = 0%）。与LAMA/LABA相比，TT使全因死亡率降低34% (RR 0.66, 95% CI 0.48-0.90, 4个rct， I2 = 23.7%)，与LABA/ICS相比，TT使全因死亡率降低10% （RR 0.90, 95% CI 0.71-1.13, 4个rct， I2 = 0%）。对于心血管和全因死亡率，NMA p -评分显示TT的有效性排名第一（81%/91%），LABA/ICS排名第二（58%/57%），LAMA/LABA排名最后（11%/<1%）。结论在中度至极重度COPD患者中，与LAMA/LABA双重治疗相比，吸入TT可显著降低心血管和全因死亡率，但与LABA/ICS相比无显著降低。

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