Cardioselective beta-blockers do not prevent exacerbations of chronic obstructive pulmonary disease: a meta-analysis of randomized trials

This systematic review and meta-analysis will assess whether adding an oral cardioselective beta-blocker (bisoprolol, metoprolol or another beta1-selective agent) to usual care changes exacerbations, hospitalizations, mortality or safety in adults with chronic obstructive pulmonary disease (COPD) who are not taking a beta-blocker and in whom the drug is not prescribed for an established cardiac indication. Observational studies suggested that beta-blockers reduce COPD exacerbations and death, but the randomized trials published since 2019 have reported neutral or conflicting results, and no published meta-analysis has pooled them. We will include randomized controlled trials with at least 6 months of follow-up that compare a cardioselective beta-blocker with placebo or usual care. The primary outcome is time to first moderate or severe exacerbation. Secondary outcomes include the annualized exacerbation rate, exacerbations requiring hospitalization, all-cause, respiratory and cardiovascular mortality, serious adverse events, cardiovascular events, discontinuation of the study drug (overall and for respiratory reasons) and COPD Assessment Test (CAT) score. Effect estimates will be pooled with a random-effects model (REML with the Hartung-Knapp-Sidik-Jonkman adjustment), complemented by trial sequential analysis, a Bayesian analysis and an analysis of effect modification by sex. Risk of bias will be assessed with RoB 2 and certainty of evidence with GRADE.