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

Background Only few randomized controlled trials (RCTs) for head-to-head comparison have been conducted between various combinations of long-acting muscarinic antagonists (LAMAs) and long-acting beta-agonists (LABAs). Our study was conducted to compare acute exacerbation and all-cause mortality among different LAMA/LABA regimens using Bayesian network meta-analysis (NMA). Methods We searched Medline, EMBASE, and the Cochrane library (search date: July 1, 2019). We included parallel-group RCTs comparing LAMA/LABA combinations with other inhaled drugs in the stable COPD for >= 48 weeks. Two different network geometries were used. The geometry of network (A) had nodes of individual drugs or their combination, while that of network (B) combined all other treatments except LAMA/LABA into each drug class. This study was prospectively registered in PROSPERO; CRD42019126753. Results We included 16 RCTs involving a total of 39,065 patients with stable COPD. Six combinations of LAMA/LABA were identified: tiotropium/salmeterol, glycopyrrolate/indacaterol, umeclidinium/vilanterol, tiotropium/olodaterol, aclidinium/formoterol, and glycopyrrolate/formoterol. We found that umeclidinium/vilanterol was associated with a lower risk of total exacerbations than other LAMA/LABAs in the NMA using network (A) (level of evidence: low or moderate). However, the significant differences were not present in the NMA of network (B). There were no significant differences among the LAMA/LABA combinations in terms of the number of moderate to severe exacerbations, all-cause mortality, major adverse cardiovascular events, or pneumonia. Conclusions The present NMA including all available RCTs provided that there is no strong evidence suggesting different benefits among LAMA/LABAs in patients with stable COPD who have been followed up for 48 weeks or more. Trial registration: This study was prospectively registered in PROSPERO; CRD42019126753.