In high-risk patients with atherosclerosis or diabetes, elevated LDL-C, and no prior MI or stroke, evolocumab added to optimized lipid-lowering therapy reduced first major cardiovascular events compared with placebo, supporting earlier PCSK9 inhibition in selected high-risk primary prevention patients.
Study design
- Randomized, double-blind, placebo-controlled trial
- International, multicenter trial
- N = 12,257
- Median follow-up 4.5 years
- Patients received background optimized lipid-lowering therapy
Population
- No prior MI or stroke
- LDL-C ≥90 mg/dL
- Qualifying atherosclerosis or high-risk diabetes
- Median age 66 years
- 43% women
- Most patients already receiving lipid-lowering therapy
Interventions
- Evolocumab 140 mg SC every 2 weeks: 6,129
- Placebo SC every 2 weeks: 6,128
- Both groups received optimized lipid-lowering therapy
- Median LDL-C at 48 weeks: 45 mg/dL with evolocumab vs 109 mg/dL with placebo
Primary outcome
- Dual primary endpoint 1: CHD death, MI, or ischemic stroke
- Evolocumab reduced 3-point MACE by 25% vs placebo
- Dual primary endpoint 2: 3-point MACE plus ischemia-driven arterial revascularization
- Evolocumab reduced 4-point MACE by 19% vs placebo
- Both primary endpoints met superiority
Evolocumab vs Placebo
Primary endpoint 1: relative risk of CHD death, MI, or ischemic stroke
25% relative risk reduction
Primary endpoint 1: coronary heart disease death, myocardial infarction, or ischemic stroke.
Evolocumab vs Placebo
Primary endpoint 2: relative risk of 3-point MACE + revascularization
19% relative risk reduction
Primary endpoint 2: 3-point MACE plus ischemia-driven arterial revascularization.
Secondary outcomes
- First MI reduced by 36%
- LDL-C reduced by nearly 55% at 48 weeks
- Benefit was consistent across key subgroups
- Benefit also seen in patients with high-risk diabetes without qualifying ASCVD
- Numerically fewer deaths occurred with evolocumab, but mortality was not a primary powered endpoint
Safety
- No major new safety signal reported
- Injection-based therapy, cost, and access remain practical limitations
- Trial population was predominantly White, limiting certainty across more diverse populations
Interpretation
- VESALIUS-CV extends PCSK9 outcome benefit to high-risk patients without prior MI or stroke
- This is not routine low-risk primary prevention
- Best-fit population: high-risk diabetes or documented atherosclerosis with persistently elevated LDL-C despite optimized therapy
- The trial supports earlier LDL-C intensification rather than waiting for a first MI or stroke
- Cost-effectiveness and patient selection will determine how broadly this changes practice
Bohula, E. A., et al. (2026). Evolocumab in patients without a previous myocardial infarction or stroke. The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2514428