Comparisons of Exacerbations and Mortality Among Regular Inhaled Therapies for Patients with Stable Chronic Obstructive Pulmonary Disease: Systematic Review and Bayesian Network Meta-Analysis

Abstract

Background: Recent large randomised controlled trials (RCTs) have shown different results for the treatment of stable chronic obstructive pulmonary disease (COPD). Additionally, outcomes other than symptoms and lung function have not been fully compared among regular inhaled therapies in a systematic review. In this systematic review and Bayesian network meta-analysis, we compared the risk of exacerbation, mortality, and other adverse events, including cardiovascular disease-related death and pneumonia, among regular inhaled drugs in patients with stable COPD. Methods: A systematic literature search was conducted to identify RCTs that included stable COPD patients who used regular inhaled therapies for 12 weeks or more. Eligible interventions were long-acting beta agonist (LABA), long-acting muscarinic antagonist (LAMA), inhaled corticosteroid (ICS), or combinations of these treatments. Bayesian network meta-analysis was used to synthesise evidence by the direct and indirect comparison of six different drug classes and placebo. Sensitivity and regression analyses were also performed. Findings: In total, 211 RCTs with 218,713 patients were included. Compared with placebo, all drug classes significantly reduced total exacerbations and moderate to severe exacerbations. Moreover, compared to placebo, ICS/LAMA/LABA and ICS/LABA were associated with a significantly lower risk of mortality. ICS/LAMA/LABA was the most beneficial treatment for reducing exacerbations and mortality in most sensitivity analyses and regression analyses even after adjustments for symptoms, exacerbation history and lung function. ICS-containing therapy increased the risk of pneumonia, but ICS/LAMA/LABA and ICS/LABA reduced the risk of cardiovascular disease-related mortality compared with placebo. Interpretation: All regular inhaled drugs reduced exacerbations, and ICS/LAMA/LABA was the most efficacious treatment for reducing the risk of exacerbation and all-cause and cardiovascular disease-related mortality. Funding Statement: This study was funded by the SNUH Research Fund (grant no. 23-2017-0020). Declaration of Interests: All authors declare no conflicts of interest for the present study. Ethics Approval Statement: This systematic review followed the guidance of the Preferred Reporting Items for SRs and Meta-analyses (PRISMA) extension statement for reporting SRs that incorporates NMAs of health care interventions and the BayesWatch guidelines for reporting results that apply Bayesian methods. We registered the final protocol in International Prospective Register of Systematic Reviews (PROSPERO, CRD42017069087).