Although evolocumab, a PCSK9 inhibitor, reduces major adverse cardiovascular events (MACE) in patients with prior myocardial infarction (MI), stroke, or peripheral artery disease, its efficacy in preventing first cardiovascular events in patients without such history remained uncertain.
The international, double-blind, placebo-controlled VESALIUS-CV trial (NCT03872401) enrolled 12,257 adults with established atherosclerosis or diabetes mellitus, LDL-C ≥90 mg/dL, and no previous MI or stroke. Participants were randomized 1:1 to subcutaneous evolocumab 140 mg every 2 weeks or matching placebo on background statin therapy. Two hierarchical primary endpoints were evaluated: (1) 3-point MACE (coronary heart disease death, MI, or ischemic stroke) and (2) 4-point MACE (3-point MACE plus ischemia-driven coronary, cerebral, or peripheral arterial revascularization). Median follow-up was 4.6 years.
Baseline characteristics were balanced: median age 66 years, 43% women, 93% White, median LDL-C 139 mg/dL. Evolocumab lowered LDL-C by 66.3% (median 29 mg/dL at week 12) versus minimal change with placebo. A first 3-point MACE occurred in 336 patients (5-year Kaplan–Meier estimate 6.2%) in the evolocumab group versus 443 (8.0%) in placebo (hazard ratio 0.75; 95% CI 0.65–0.86; P<0.001), representing a 25% relative risk reduction and absolute risk reduction of 1.8%. The 4-point MACE occurred in 747 (13.4%) versus 907 (16.2%) patients (HR 0.81; 95% CI 0.73–0.89; P<0.001), a 19% relative and 2.8% absolute reduction. Individual components showed consistent benefit: MI (HR 0.73), ischemic stroke (HR 0.75), and revascularization (HR 0.80). No significant differences emerged in safety outcomes, including new-onset diabetes, neurocognitive events, injection-site reactions, or allergic reactions.
Among high-risk patients with atherosclerosis or diabetes but without prior MI or stroke, evolocumab significantly reduced the risk of first major cardiovascular events compared with placebo, with a safety profile comparable to prior trials. These findings extend the benefit of intensive LDL-C lowering with PCSK9 inhibition to primary prevention populations at elevated risk.
