Heterogeneity in MACE Definitions and Its Impact on Treatment Effect Estimates in Coronary Stent Trials: A Meta-Epidemiological Study.

BACKGROUND: Major adverse cardiac events (MACE) are widely used composite endpoints in cardiovascular trials. However, heterogeneity in MACE definitions may influence treatment effect estimates, with potential implications for clinical decision-making. This study explored variability in MACE definitions across coronary stent trials and assessed the influence of individual components on effect estimates. METHODS: We systematically searched PubMed and Embase (via Ovid) from inception to March 5, 2026, for meta-analyses and extracted eligible coronary stent randomized controlled trials (RCTs) from their forest plots. Data on MACE definitions, outcomes, and trial characteristics were extracted. Consistency between MACE outcomes and individual component outcomes was assessed. Meta-regression analyses assessed the associations between MACE components and treatment effect estimates. RESULTS: Among 301 included RCTs, 62.79% reported individual component results, and substantial heterogeneity was observed in MACE definitions. Among trials with comparable MACE and component results, 8.96% had non-significant MACE results despite significant mortality differences, whereas 14.81% had significant MACE results despite no significant differences in any individual component. In addition, 52.72% showed opposite effect directions between MACE and at least one component. Meta-regression further showed that inclusion of mortality, myocardial infarction, stent thrombosis, target lesion revascularization, coronary artery bypass grafting, and overall revascularization was associated with lower estimated effects, whereas inclusion of stroke was associated with higher estimated effects. CONCLUSIONS: Substantial heterogeneity exists in MACE definitions, impacting treatment effect estimates in coronary stent trials. Standardized reporting of composite and individual component outcomes is essential to improve the interpretation of trial findings and reliability of evidence synthesis.