Comparisons of exacerbations and mortality among regular inhaled therapies for patients with stable chronic obstructive pulmonary disease: Systematic review and Bayesian network meta-analysis.

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, , 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 0.59-0.93, P[OR > 1] = 0.004; and OR = 0.86, 95% CrI 0.76-0.98, P[OR > 1] = 0.015, respectively). The results minimally changed, even in various sensitivity and covariate-adjusted meta-regression analyses. ICS/LAMA/LABA tended to lower the risk of cardiovascular mortality but did not show significant results. ICS/LAMA/LABA increased the probability of pneumonia (OR for triple therapy = 1.56; 95% CrI 1.19-2.03; P[OR > 1] = 1.000). The main limitation is that there were few RCTs including only less symptomatic patients or patients at a low risk. Conclusions These findings suggest that triple therapy can potentially be the best option for stable COPD patients in terms of reducing exacerbation and all-cause mortality. Author summaryWhy was this study done? Pharmacologic inhaled therapies are cornerstones for treating patients with stable chronic obstructive pulmonary disease (COPD) to improve their health condition and reduce the future risk of exacerbation and mortality while minimizing significant drug-related adverse events. However, the best inhaled therapy for reducing exacerbation, mortality, and adverse events is unknown. As previous evidence is not enough to determine which inhaled therapy is expected to be most beneficial, a new attempt using a network meta-analysis (NMA) is needed to provide clinicians useful information in choosing one of the various inhaled therapies. NMAs with Bayesian statistics can compare drugs directly and indirectly, calculate the rank of the drugs in terms of efficacy and safety, and are suitable for analysing rare events, such as mortality. What did the researchers do and find? We conducted a systematic review (SR) and Bayesian NMA of 219 trials involving 228,710 patients to compare exacerbation, mortality, and adverse events among all regular inhaled drug classes, including inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting beta-agonist (LABA), LAMA/LABA, ICS/LABA, LAMA, LABA, ICS, and placebo. In our NMA, ICS/LAMA/LABA was the most effective treatment for reducing total exacerbations and all-cause mortality. ICS/LABA also reduces all-cause mortality compared with placebo in our NMA. All drug classes reduced the exacerbation risk compared with placebo. What do these findings mean? All regular inhaled drug classes are beneficial for stable COPD patients in terms of decreasing the exacerbation risk. Compared with the other drug classes, triple therapy with ICS/LAMA/LABA could potentially be the best option for high-risk patients with stable COPD in terms of reducing both exacerbation and all-cause mortality.