Real-world comparative effectiveness of evolocumab versus ezetimibe in adults with atherosclerotic cardiovascular disease: an active-comparator new-user study

Background Evolocumab and ezetimibe are both guideline-recommended options for patients unable to reach LDL-C goals on statin therapy. While both have been shown to lower cardiovascular risk, head-to-head outcomes data are lacking. Methods We conducted an active-comparator, new-user cohort, target trial emulation study using the U.S. Komodo Health Healthcare Map® database among patients with ASCVD and any prior statin use who initiated evolocumab or ezetimibe during 2017–2024. Follow-up continued through June 2026. Using inverse probability weighting for treatment and informative censoring, we estimated the 4-year cumulative risks of fatal or nonfatal MI for each treatment group and compared hazards using a hazard ratio (HR) estimator that incorporated baseline LDL-C, where available, and accounted for missing baseline LDL-C, where not available. Results The cohort included 64,421 evolocumab initiators and 479,682 ezetimibe initiators. After weighting, all baseline covariates were balanced (standardized mean differences <0.1). Among patients with available baseline LDL-C (41.4% of the cohort), weighted 4-year cumulative risk of fatal or nonfatal MI was 5.88% (95% CI: 4.77% – 7.00%) with evolocumab and 7.76% (95% CI: 7.31% – 8.20%) with ezetimibe. In the full study cohort, evolocumab initiation was associated with a lower rate of fatal or nonfatal MI than ezetimibe initiation (HR = 0.80; 95% CI: 0.70 – 0.91). Conclusions In this large, real-world comparative effectiveness study, initiating evolocumab, as compared with ezetimibe, was associated with a 20% lower rate of fatal and nonfatal MI over 4 years. These findings may inform the clinical selection of non-statin therapies when LDL-C goals are not achieved with statin therapy alone.