Effect Modification by Acute Coronary Syndrome Prevalence on Non-Invasive Ventilation Efficacy in Acute Cardiogenic Pulmonary Edema: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Non-invasive ventilation (NIV) reduces mortality in patients with acute cardiogenic pulmonary edema (ACPE). However, the 3CPO trial reported null results. Therefore, we hypothesized that the prevalence of acute coronary syndrome (ACS) would influence the effectiveness of NIV. A systematic literature review was conducted to identify randomized controlled trials (RCTs) comparing NIV and standard oxygen therapy in patients with ACPE from PubMed, CENTRAL, and Embase databases through December 2025. Random-effects meta-analysis and REML meta-regression were utilized, and evidence quality was evaluated using GRADE. (PROSPERO: CRD420251142245). Fourteen RCTs (<i>n</i> = 1967) were included in the analysis. NIV significantly reduced hospital mortality (RR 0.75, 95% CI 0.58-0.96; I² = 0%) and endotracheal intubation (RR 0.49, 95% CI 0.35-0.68). Meta-regression revealed that study-level ACS prevalence was significantly associated with the magnitude of NIV's mortality effect (β₁ = -0.023 per 1% increase in ACS, <i>p</i> = 0.008; R² = 46.2%). The equilibrium point occurred at an ACS prevalence of 14.1% (95% CI 5.2-23.0%). At 3CPO's ACS prevalence of 27%, the model predicted an RR of 0.75 (95% CI 0.58-0.97). The observed 3CPO RR was 0.97 (95% CI 0.66-1.43); the confidence intervals overlap substantially, and 3CPO was underpowered for mortality as an isolated endpoint. The mortality benefit of NIV appears to be associated with the prevalence of ACS among treated patients, though this ecological finding requires confirmation at the individual-patient level.