Ensifentrine vs placebo for chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized clinical trials

Introduction: To evaluate the efficacy and safety of ensifentrine in chronic obstructive pulmonary disease (COPD). Methods: We searched electronic databases and registries until 25 January 2025, for randomized clinical trials (RCTs) comparing ensifentrine vs placebo in patients with COPD. Primary outcomes include forced expiratory volume in one second (FEV₁) area under the curve (AUC), peak FEV₁, and morning trough FEV₁. Results: Ten RCTs involving 2,589 patients were included. Compared with placebo, ensifentrine improved FEV₁ AUC by 104.24 ml (95% CI, 74.03 to 133.44; moderate certainty) on day 1 and by 90.37 ml (95% CI, 54.94 to 125.81; moderate certainty) at study end. Ensifentrine increased peak FEV₁ by 140.99 ml on day 1 (95% CI, 107.48 to 174.5; moderate certainty) and by 118.98 ml at the final assessment (95% CI, 86.49 to 151.47; moderate certainty). Ensifentrine improved morning trough FEV₁ by 42.15 ml (95% CI, 19.87 to 64.43; high certainty). Dose-response analysis showed a bell-shaped curve for all outcomes. Ensifentrine did not significantly differ from placebo in adverse events or improvements in COPD symptoms and quality of life. Conclusions: Compared with placebo, ensifentrine improved lung function in COPD. Larger RCTs are needed to integrate this bronchodilator benefit with patient-centered outcomes. PROSPERO registration: CRD42024571928.