Key Points:
- PCSK9-inhibitors – including evolocumab – are highly effective LDL-C–lowering medications that reduce major adverse cardiovascular events (MACE) in patients who have had a previous cardiovascular (CV) event, such as a prior myocardial infarction (MI) or stroke.
- Evolocumab was associated with a significant 25% relative risk reduction in a composite of coronary heart disease death, MI, or ischemic stroke compared with placebo in this population.
- This is the first trial to demonstrate that any non-statin LDL-C–lowering therapy reduces major CV events in a primary prevention population.
Previous studies have demonstrated that the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab reduces the risk of MACE among patients with a previous myocardial infarction, stroke, or symptomatic peripheral artery disease. However, whether evolocumab helps reduce MACE in patients without a prior MI or stroke is uncertain.
On November 8th, 2025, the results of “Evolocumab in Patients without a Previous Myocardial Infarction or Stroke” (NCT03872401) were presented at the American Heart Association Scientific Sessions in New Orleans, LA, with simultaneous publication in The New England Journal of Medicine. The purpose of this trial was to determine whether evolocumab reduces MACE in a high-risk primary prevention population.
This international, double-blind, randomized, placebo-controlled trial randomized 12,257 participants with atherosclerosis or diabetes and without a previous myocardial infarction or stroke, who had an LDL-C level of ≥90 mg/dL, in a 1:1 ratio to evolocumab at a dose of 140 mg every 2 weeks or placebo. The two primary composite endpoints were 3-point MACE (death from coronary heart disease, myocardial infarction, or ischemic stroke) and 4-point MACE (3-point MACE plus ischemia-driven revascularization). The mean age of participants was 66 years, 43% were female, 93% were White, 67% had atherosclerosis, and 33% had diabetes without atherosclerosis. Over 90% were on background lipid-lowering therapy (68% on high-intensity statins), with a mean LDL-C of 122 mg/dL.
Compared to placebo, evolocumab was associated with a 19% relative risk reduction in the primary endpoint of 4-point MACE (16.2% vs. 13.4%; HR 0.81 [95% CI: 0.73, 0.89]) and a 25% relative risk reduction in 3-point MACE (8.0% vs. 6.2%; HR 0.75 [95% CI: 0.65, 0.86]) at five years. The median achieved LDL-C was 45 mg/dL. In hypothesis-generating secondary endpoints, evolocumab was also associated with reductions in CV death and all-cause death. Results were consistent across key subgroups, including those with diabetes but no atherosclerosis. Limitations include a population that was 93% White and a small proportion of patients (8%) who were not on background lipid-lowering therapy.
Erin Ann Bohula, MD, DPhil, FACC, of Brigham and Women’s Hospital in Boston, MA, concluded: “The results from the VESALIUS-CV trial represent the first demonstration of improved cardiovascular outcomes with a PCSK9 inhibitor, or any non-statin for that matter, in patients without a previous heart attack or stroke who are already being treated with a high-intensity lipid-lowering regimen.”