VESALIUS-CV: Adding evolocumab to standard lipid lowering therapy prevents a first major cardiovascular event in high-risk patients
November 2025
Combining the PCKS9 inhibitor evolocumab with standard lipid lowering therapy reduced first major cardiovascular events by 25% in high cardiovascular risk adults (evidence of atherosclerosis or with high-risk diabetes) and no history of heart attack or stroke.
Bohula EA, Marston NA, Bhatia AK, et al. Evolocumab in patients without a previous myocardial Infarction or stroke. N Engl J Med 2025; DOI: 10.1056/NEJMoa2514428.
STUDY SUMMARY
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Objective |
To investigate the effect of evolocumab on the risk of major adverse cardiovascular events (MACE) among patients with atherosclerosis or diabetes and without a previous myocardial infarction (MI) or stroke.
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Study design |
VESALIUS-CV (Effect of Evolocumab in Patients at High Cardiovascular Risk without Prior Myocardial Infarction or Stroke) was a double-blind, randomized, placebo-controlled trial conducted in 33 countries. Patients were randomly assigned in a 1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks or placebo.
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Study population |
VESALIUS-CV included 12,257 patients aged 50-79 years in men or 55-79 years in women, with a low-density lipoprotein cholesterol (LDL-C) of at least 90 mg/dL, a non–high-density lipoprotein cholesterol (non-HDL-C) level of at least 120 mg/dL (3.1 mmol/L), or an apolipoprotein B level of at least 80 mg/dL. Median age was 66 years and 43% were women. Approximately two-thirds of the patients met criteria for qualifying atherosclerosis (45% with coronary artery disease, 10% with cerebrovascular disease, and 17% with peripheral artery disease), and one third had high-risk diabetes without qualifying atherosclerosis. The study population was also characterized by a high prevalence of obesity (median body mass index 30 kg/m2) and hypertension (approximately 90%). At baseline, median LDL-C was 122 mg/dL (3.16 mmol/L); 92% of the patients were on lipid-lowering therapy, and 68% were on high-intensity statin therapy.
Overall, 2014 patients participated in the lipid sub-study; median baseline LDL-C in this cohort was 115 mg/dL (2.98 mmol/L).
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Main study variables |
There were two primary endpoints: · 3-point MACE: a composite of coronary heart disease (CHD) death, MI or ischemic stroke · 4-point MACE: 3-point MACE plus ischemia-driven arterial revascularization
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Methods |
Patients were randomized according to screening LDL-C (<160 mg/dL or ≥160 mg/dL) and geographic region (North America, Europe, or other). Analysis of primary and secondary endpoints was intention-to-treat with a prespecified hierarchical order as follows: a composite of MI, ischemic stroke, or ischemia-driven arterial revascularization; a composite of CHD death, MI, or ischemia-driven arterial revascularization; a composite of cardiovascular death, MI, or ischemic stroke; a composite of CHD death or MI; and the individual end points of MI, ischemia-driven arterial revascularization, CHD death, cardiovascular death, all-cause death, and ischemic stroke. Hazard ratios with 95% confidence intervals (CI) were estimated from a Cox model.
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Key results |
The median duration of follow-up was 4.6 years. Compared with placebo, treatment with evolocumab significantly reduced the risk of the 3-point MACE (CHD death, MI or ischemic stroke) by 25%, and the 4-point MACE (3-point MACE plus ischemia-driven arterial revascularization) by 19%, as well as most secondary endpoints (Table 1). The clinical benefits of evolocumab treatment were generally consistent for the two primary end points across key subgroups.
Table 1. Key efficacy results
*p<0.001. Due to hierarchical testing, as there was no significant treatment difference in the risk of CHD death, no other endpoints were tested. In the lipid sub-study, treatment with evolocumab was associated with -55% (95% CI -59% to -52%) least-squares mean percentage change versus placebo in LDL-C, and -63 mg/dL (95% CI -67 to -59 mg/dL) least-squares mean absolute difference in LDL-C at 48 weeks. Median LDL-C at 48 weeks was 45 mg/dL (interquartile range 26 to 73 mg/dL) in the evolocumab group versus 109 mg/dL (86 to 144 mg/dL) in the placebo group. |
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Author 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. |
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Comment
Aggressive LDL-C lowering with a PCSK9 inhibitor added to conventional lipid-lowering therapy (statn with or without ezetimibe) definitively reduces the risk of subsequent cardiovascular events in patients with established atherosclerotic cardiovascular disease, as demonstrated in FOURIER and ODYSSEY OUTCOMES (1,2). However, while clinical guidelines advocate aggressive LDL-C lowering in high-risk patients without prior cardiovascular events (3,4), clinical trial evidence to support this approach has been lacking. This question has now been answered by the VESALIUS-CV trial which demonstrated a reduction in first cardiovascular events, including MI, ischemic stroke, CHD death or ischemia-driven arterial revascularization. Moreover, as the study population was characterized by a high prevalence of obesity and hypertension, the results also support aggressive LDL-C lowering to prevent first cardiovascular events in patients with cardiovascular–kidney–metabolic syndrome who are considered as high risk as per recent expert statements (5,6).
The VESALIUS-CV trial has several strengths. It was well-designed with defined primary and secondary endpoints which were adjudicated by a central independent clinical events committee, which was unaware of patients’ lipid levels. Additionally, and in contrast to FOURIER and ODYSSEY OUTCOMES, the duration of follow-up was extended (median 4.6 years). It is, however, important to note that despite the study population being characterized as high-risk, nearly one in five did not receive intensive LDL-C lowering treatment (either high-intensity statin and/or ezetimibe-statin combination therapy) at baseline as recommended by clinical guidelines (3,4). These latter findings clearly underline the need for further work to improve the implementation of guidelines in clinical practice.
Finally, it is important to note that while aggressive LDL-C lowering with a PCSK9 inhibitor in combination with conventional lipid-lowering therapy significantly reduced the risk of first cardiovascular events in high-risk patients, a high cardiovascular risk persists. Five-year Kaplan-Meier estimates indicate that over 13% of patients treated with evolocumab experienced CHD death, MI or ischemic stroke or ischemia-driven arterial revascularization, underlining the need to target other factors, both lipid and non-lipid-related, that contribute to this risk.
References
- Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: 1713-22.
- Schwartz GG, Steg PG, Szarek M et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-107.
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and
European Atherosclerosis Society (EAS). Eur Heart J 2020;41:111–88.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019; 139(25): e1046-e1081.
- Ndumele CE, Rangaswami J, Chow SL, et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation 2023; 148: 1606-35.
- Romeo S, Vidal-Puig A, Husain M, et al. Clinical staging to guide management of metabolic disorders and their sequelae: a European Atherosclerosis Society consensus statement. Eur Heart J 2025;46:3685-3713.
Key words: VESALIUS-CV; first cardiovascular events; high-risk patients; atherosclerosis, diabetes, evolocumab
