Key Points
- In high-risk patients without known significant atherosclerosis and with diabetes, evolocumab reduced the risk of a first major cardiovascular event.
- LDL-C reduction was profound at approximately 51%, achieving levels near 40-45 mg/dL.
- This is the first randomized controlled trial that demonstrates that a PCSK-9 inhibitor improves outcomes in a primary-prevention population.
- The medication safety profile was consistent with prior studies, with no major new concerns.
Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of cardiovascular prevention, with statins forming the foundation of therapy. While PCSK-9 inhibitors such as evolocumab have demonstrated outcome benefits in secondary prevention, their role in primary prevention, particularly among high-risk individuals without prior myocardial infarction (MI) or stroke, remained uncertain. The VESALIUS- CV trial showed that 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. A prespecified analysis of this study assessed whether evolocumab could prevent a first major cardiovascular event (MACE) in patients without known significant atherosclerosis. The main trial results were presented at ACC with simultaneous publication in JAMA.
VESALIUS-CV (ClinicalTrials.gov: NCT03872401) was a global, randomized, double-blind, placebo-controlled phase 3 trial enrolling 12,257 patients with atherosclerosis or high-risk diabetes but no prior MI or stroke. Participants had elevated atherogenic lipoproteins despite optimized lipid-lowering therapy and were randomized 1:1 to evolocumab 140 mg subcutaneously every 2 weeks or placebo. The dual primary endpoints included composites of coronary heart disease (CHD) death, MI, or ischemic stroke (3-P MACE), and an expanded composite including revascularization (4-P MACE). Median follow-up was 4.8 years.
This predefined subgroup included 3655 patients (1849 in the evolocumab group and 1806 in the placebo group) with a median age of 65 years (57%female). Among those in the lipid sub study, the median LDL-C level at 48 weeks was 52mg/dL in the evolocumab group vs 111mg/dL in the placebo group (P < .001). A 3-P MACE event occurred in 83 patients (5-year Kaplan-Meier estimate, 5.0%) in the evolocumab group compared with 117 patients (5-year Kaplan-Meier estimate, 7.1%) in the placebo group (hazard ratio [HR], 0.69 [95%CI, 0.52-0.91]; P = .009; between-group difference, 2.1%[95%CI, 0.4%-3.8%]). A 4-P MACE event occurred in 127 patients (5-year Kaplan-Meier estimate, 7.6%) in the evolocumab group compared with 178 patients (5-year Kaplan-Meier estimate, 10.5%) in the placebo group (HR, 0.69 [95%CI, 0.55-0.86]; P = .001; between-group difference, 2.9%[95%CI, 0.9%-4.9%]). There were 136 deaths (5-year Kaplan-Meier estimate, 7.8%) in the evolocumab group compared with 172 deaths (5-year Kaplan-Meier estimate, 10.1%) in the placebo group (HR, 0.76 [95%CI, 0.61-0.95]).
VESALIUS-CV extends the paradigm of intensive lipid lowering into earlier stages of cardiovascular disease, demonstrating that aggressive LDL-C reduction can prevent first events in high-risk populations. One key limitation is the relatively homogeneous study population and underrepresentation of diverse racial and ethnic groups, which may affect generalizability. Additionally, considerations regarding cost, access, and long-term adherence remain important for widespread implementation. However, these study findings support a broader role for PCSK9 inhibitors alongside statins, particularly in patients with residual risk despite guideline-directed therapy.