Comparisons of Efficacy and Safety between Triple (Inhaled Corticosteroid/Long-Acting Muscarinic Antagonist/Long-Acting Beta-Agonist) Therapies in Chronic Obstructive Pulmonary Disease: Systematic Review and Bayesian Network Meta-Analysis

Abstract

<b><i>Background:</i></b> Various combinations of inhaled corticosteroid (ICS), long-acting muscarinic antagonist (LAMA), and long-acting beta-agonist (LABA) have been used as triple therapy for stable chronic obstructive pulmonary disease (COPD). <b><i>Objective:</i></b> Our study was conducted to answer whether there were significant differences among various combinations in efficacy, for reducing exacerbation or mortality, and in safety, for increasing cardiovascular events or pneumonia. <b><i>Method:</i></b> We searched parallel-group randomized controlled trials (RCTs) comparing ICS/LAMA/LABA with other inhaled drugs in patients with stable COPD for at least 12 weeks in PubMed, EMBASE, the Cochrane Library, and clinical trial registries from inception to December 31, 2019. We conducted a network meta-analysis with Bayesian statistics using a random-effects model with heterogeneous variance structure (PROSPERO, CRD42019126757). <b><i>Results:</i></b> Nine different combinations of ICS/LAMA/LABA were identified in 21 RCTs containing 29,892 patients with moderate to very severe COPD. We could not find any significant evidence suggesting a better treatment for reducing total exacerbations or all-cause mortality among ICS/LAMA/LABA combinations. There were also no significant differences in moderate to severe exacerbation, COPD-related mortality, or cardiovascular disease-related mortality among ICS/LAMA/LABA combinations, and the risk of major adverse cardiovascular events was not different. A significantly lower risk of pneumonia was found in fluticasone propionate (FP)/glycopyrrolate/salmeterol (SAL) than FP/tiotropium/SAL {median odds ratio [OR] (95% credible interval [CrI]) = 0 [0–0.72]} and FP/umeclidinium/SAL {median OR (95% Crl) = 0 [0–0.97]}. <b><i>Conclusion:</i></b> There were no significant differences in clinical outcomes, including acute exacerbation and all-cause mortality among various ICS/LAMA/LABA combinations in patients with moderate to very severe COPD.