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 Although exacerbation and mortality are the most important clinical outcomes of stable chronic obstructive pulmonary disease (COPD), the drug classes that are the most efficacious in reducing exacerbation and mortality among all possible inhaled drugs have not been determined. Methods and findings We performed a systematic review (SR) and Bayesian network meta-analysis (NMA). We searched Medline, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, the European Union Clinical Trials Register, and the official websites of pharmaceutical companies (from inception to July 9, 2019). The eligibility criteria were as follows: (1) parallel-design randomized controlled trials (RCTs); (2) adults with stable COPD; (3) comparisons among long-acting muscarinic antagonists (LAMAs), long-acting beta-agonists (LABAs), inhaled corticosteroids (ICSs), combined treatment (ICS/LAMA/ LABA, LAMA/LABA, or ICS/LABA), or a placebo; and (4) study duration � 12 weeks. This study was prospectively registered in International Prospective Register of Systematic Reviews (PROSPERO; CRD42017069087). In total, 219 trials involving 228,710 patients were included. Compared with placebo, all drug classes significantly reduced the total exacerbations and moderate to severe exacerbations. ICS/LAMA/LABA was the most efficacious treatment for reducing the exacerbation risk (odds ratio [OR] = 0.57; 95% credible interval [CrI] 0.50-0.64; posterior probability of OR > 1 [P(OR > 1)] < 0.001). In addition, in contrast to the other drug classes, ICS/LAMA/LABA and ICS/LABA were associated with a significantly higher probability of reducing mortality than placebo (OR = 0.74, 95% CrI 0.

Reduction in All-Cause Mortality with Fluticasone Furoate/Umeclidinium/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease

“…This finding was consistently observed in the on-treatment analyses, the analyses that included offtreatment data, and in sensitivity tipping point analyses. These data extend previous studies that suggested a reduction in mortality using ICS-containing medications in patients with COPD (5,6,8,13,14). We confirm a survival benefit to ICScontaining therapy in a predefined, prospective analysis.…”

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

“…Recent large RCTs [9, 12-17] and meta-analyses [18, 35-38] have shown a superior impact of ICSs/LAMAs/LABAs in improving lung function, reducing acute exacerbation, and increasing symptoms compared with LAMAs/LABAs or ICSs/LABAs, without an increase in the incidence of adverse events. Although experts expect each ICS/LAMA/LABA to yield similar benefits and adverse events, the supporting scientific evidence is not available.…”

“…ICSs/LAMAs/LABAs had significant benefits for the reduction of acute exacerbations [9, 12-15], symptoms [15, 16], and rescue medication use [17], and the improvement of lung function [13, 15, 16] compared with ICSs/LABAs or LAMAs/LABAs in randomized controlled trials (RCTs). Furthermore, we previously showed that triple therapy reduced all-cause mortality compared with other dual or single treatments [18]. Currently, ICSs/LAMAs/LABAs are recommended for some patients with persistent breathlessness or who experienced exacerbations, despite the dual therapies [4].…”

Comparisons of exacerbations and mortality among LAMA/LABA combinations in stable chronic obstructive pulmonary disease: systematic review and Bayesian network meta-analysis

“…Recently, LAMA/LABA combination therapy has been introduced as a more potent treatment than LAMA or LABA alone. Studies and meta-analyses have shown that such combination therapy has a greater effect than monotherapy on lung function, symptoms, quality of life, and acute exacerbations [6][7][8][9][10][11][12][13][14]. In addition, LAMA/LABA combination therapy is associated with less frequent moderate to severe exacerbations than inhaled corticosteroid (ICS)/ LABA combination [8,9,15], although a large trial contradicted these results [16].…”