Comparative effectiveness of probucol versus ezetimibe in statin-treated patients with established atherosclerotic cardiovascular disease

Introduction Statins remain the cornerstone of therapy for atherosclerotic cardiovascular disease (ASCVD). When statin monotherapy is insufficient, ezetimibe is typically recommended as adjunctive therapy. Probucol, an agent with unique antioxidative properties, serves as an alternative therapeutic option. However, its comparative effectiveness against ezetimibe on major clinical outcomes in the real-world setting remains unclear. Purpose To compare the 1-year clinical effectiveness of probucol versus ezetimibe on all-cause mortality and cardiovascular events in patients with established ASCVD receiving statin therapy. Methods A target trial emulation (TTE) study was conducted using data from a large-scale electronic medical record database from January 2008 to December 2024. The study included hospitalized patients with established ASCVD who were newly prescribed either probucol or ezetimibe in combination with statins. Propensity score matching (PSM) was utilized to balance baseline characteristics between groups. The primary outcome was 1-year all-cause mortality. Secondary outcomes included 1-year cardiovascular mortality, acute myocardial infarction (AMI), stroke, and a composite of these events. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Additionally, subgroup analyses stratified by key clinical features and multiple sensitivity analyses were performed to validate the robustness of the findings. Results A total of 40,661 eligible patients were identified. After PSM, 12,886 patients were included in the final analysis (6,443 in the probucol group and 6,443 in the ezetimibe group). At 1-year follow-up, the primary outcome of all-cause mortality did not differ significantly between the probucol and ezetimibe groups (HR: 0.80, 95% CI: 0.62 - 1.13; P = 0.082). Similarly, no significant differences were observed for the composite endpoint (HR: 1.00, 95% CI: 0.81 - 1.25; P = 0.972). Results for specific secondary outcomes were also comparable, including cardiovascular mortality (HR: 0.83, 95% CI: 0.59 - 1.17; P = 0.285), AMI (HR: 0.78, 95% CI: 0.52 - 1.16; P = 0.218), and stroke (HR: 1.19, 95% CI: 0.85 - 1.66; P = 0.314). Results remained consistent across sensitivity analyses and pre-specified subgroups. Conclusion In this large-scale study of patients with established ASCVD, probucol demonstrated comparable 1-year effectiveness to ezetimibe regarding all-cause mortality and cardiovascular events. These findings suggest that probucol may serve as a viable alternative strategy for lipid management in this high-risk population.