Evolocumab in Patients without a Previous Myocardial Infarction or Stroke

BACKGROUND: The proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab reduces the risk of major adverse cardiovascular events (MACE) among patients with a previous myocardial infarction, stroke, or symptomatic peripheral artery disease. The effect of evolocumab on the risk of MACE among patients without a previous myocardial infarction or stroke is unknown. METHODS: We conducted an international, double-blind, randomized, placebo-controlled trial of evolocumab in patients with atherosclerosis or diabetes and without a previous myocardial infarction or stroke who had a low-density lipoprotein cholesterol level of at least 90 mg per deciliter. Patients were randomly assigned in a 1:1 ratio to receive evolocumab at a dose of 140 mg every 2 weeks or placebo. The two primary end points were a composite of death from coronary heart disease, myocardial infarction, or ischemic stroke (3-point MACE) and a composite of 3-point MACE or ischemia-driven arterial revascularization (4-point MACE). RESULTS: A total of 12,257 patients were randomly assigned to receive evolocumab (6129 patients) or placebo (6128) and were included in the efficacy analyses. The median age of the patients was 66 years, 43% were women, and 93% were White. The median follow-up was 4.6 years. A 3-point MACE event occurred in 336 patients (5-year Kaplan-Meier estimate, 6.2%) in the evolocumab group, as compared with 443 (8.0%) in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). A 4-point MACE event occurred in 747 patients (5-year Kaplan-Meier estimate, 13.4%) in the evolocumab group, as compared with 907 (16.2%) in the placebo group (hazard ratio, 0.81; 95% CI, 0.73 to 0.89; P<0.001). No evidence of a between-group difference was seen in the incidence of safety events. CONCLUSIONS: PCSK9 inhibition with evolocumab led to a lower risk of first cardiovascular events than placebo among patients with atherosclerosis or diabetes and without a previous myocardial infarction or stroke. (Funded by Amgen; VESALIUS-CV ClinicalTrials.gov number, NCT03872401.).