Articles
Science Matters: Research Summary of the Evolocumab in Patients Without Prior Myocardial Infarction or Stroke (VESALIUS-CV) Trial
About the Author: Michael Katsnelson MD, PhD, FACC is currently a research fellow at Washington University in St. Louis School of Medicine. He specializes in advanced heart failure/transplant cardiology, and his main research interest lies in studying the role of the innate immune system in the progression of ischemic cardiomyopathy. In this article he provides a summary of a recent NEJM publication.
Background: The benefit of LDL-lowering therapy in the prevention of cardiovascular ischemic events has been well established. PCSK9 inhibitors enhance the uptake of LDL from the circulation by inhibiting the degradation of LDL receptors present on the cell surface. PCSK9 inhibitors have been studied in the context of secondary prevention in very high-risk patients who have experienced a prior MI or stroke and are unable to attain the target LDL-c level with use of statins and/or ezetimibe. The effects of PCSK9 inhibitors in patients without a prior cardiovascular ischemic event have not been well studied. The VESALIUS-CV trial tested whether evolocumab treatment would result in a reduced risk of an initial cardiovascular ischemic event in a patient population with established atherosclerosis or diabetes, but no history of prior MI or stroke.
Materials and Methods: VESALIUS-CV was a randomized placebo-controlled trial which enrolled men age 50-79 or women age 55-79 with an LDL-c level of at least 90 mg/dL, non-HLD cholesterol level of at least 120 mg/dL or an apolipoprotein-B level of at least 80 mg/dL. Enrolled patients had no personal history of MI or stroke. Patients were also required to have at least one of the following disease categories: 1) coronary artery disease, 2) atherosclerotic cerebrovascular disease, 3) peripheral artery disease or 4) high risk diabetes defined as either ≥10 years in duration, treated with daily insulin, or complicated by microvascular disease. Patients were also required to have at least one additional criterion that placed them at higher risk for cardiovascular ischemic events including age≥65, active smoking, very elevated LDL-c levels, or concomitant atherosclerosis and diabetes. Patients were randomized in a 1:1 ratio to receive either subcutaneous injection with evolocumab every 2 weeks or placebo injections at a similar time interval. The two primary endpoints of the trial included a composite of death from coronary artery disease, myocardial infarction or ischemic stroke (3-point MACE) and a composite of the above listed events plus ischemia-driven arterial revascularization in any vascular bed (4-point MACE).
Results: The trial enrolled 12,257 patients who underwent randomization and were included in the efficacy analysis. Approximately two thirds of the enrolled patients had qualifying atherosclerosis (coronary artery disease, cerebrovascular disease or peripheral artery disease). Approximately one third had high risk diabetes without qualifying atherosclerosis. At baseline, 92% of patients were on lipid lowering therapy and 72% of patients were on high intensity lipid lowering therapy. Evolocumab treatment resulted in a significantly reduced risk of both of the primary efficacy endpoints when compared with placebo. Administration of PCSK9 inhibitor resulted in a 25% lower risk of the 3-point MACE endpoint (composite of death from coronary disease, MI or ischemic stroke) and a 19% lower risk of 4-point MACE (3-point MACE plus ischemia driven revascularization in any arterial vascular bed). In a substudy of patients who underwent testing for serum lipid levels, the LDL-c declined from a median of 115 mg/dL at baseline to 45 mg/dL in the PCSK9 inhibitor treated group and 109 mg/dL in the placebo treated group following 48 weeks of therapy.
Discussion: The addition of PCSK9 inhibitor therapy to baseline lipid-lowering agents resulted in a significant decrease in the incidence of major adverse cardiovascular-related outcomes including death from coronary artery disease, myocardial infarction, ischemic stroke, or ischemia-related revascularization in any arterial vascular bed (coronary, cerebral or peripheral). The results of the trial support expanding the use of PCSK9 inhibitor therapy to those patients with evidence of atherosclerosis, but without a history of myocardial infarction or ischemic stroke. The median follow-up interval of the trial was 4.6 years, which is longer than most other studies with PCSK9 inhibitors and allowed for the assessment of the long-term clinical benefit of evolocumab. The trial suggests that a patient’s overall atherosclerotic disease burden may determine the magnitude of the protective benefit derived from lipid lowering therapies. Thus, there may be a future role for imaging techniques which can quantify an individual’s atherosclerotic burden (i.e. coronary artery calcium scoring) to determine which patients would benefit the most from PCSK9 inhibitor therapy.
Bohula EA, Marston NA, Bhatia AK, et al. Evolocumab in patients without a previous myocardial infarction or stroke. N Engl J Med 2026;394:117-127.
