The VESALIUS-CV Trial: Evolocumab in High-Risk Primary Prevention

For decades, aggressive lipid-lowering therapy has been reserved largely for patients who have already experienced a heart attack or stroke. The VESALIUS-CV trial (NCT03872401) is challenging that paradigm. At ACC 2026, Pharmacy Times spoke with Nicholas Marston, MD, MPH, cardiologist at Brigham and Women's Hospital, about what a key subgroup analysis reveals about the potential of PCSK9 inhibition earlier in the cardiovascular disease continuum.

Pharmacy Times: Can you begin with an overview of the VESALIUS-CV trial? What was the motive for the trial?

Nicholas Marston, MD, MPH: VESALIUS-CV was a large cardiovascular outcomes trial enrolling approximately 12,000 patients at high cardiovascular risk who had not yet experienced a prior MI or stroke. Patients qualified for the trial either through documented atherosclerosis or high-risk diabetes, and all had an LDL cholesterol of 90 mg/dL or higher. They were randomized to either evolocumab (Repatha; Amgen) or placebo and followed for a median of 4 and a half years. The primary end points were coronary heart disease death, MI, or stroke, with a second primary endpoint that also included ischemia-driven revascularization. The subgroup we presented here at ACC represented about 30% of the overall trial and consisted of patients with no significant atherosclerosis. That's an important group because these are patients in whom we don't typically intensify lipid-lowering therapy.

Pharmacy Times: Can you walk us through the magnitude of benefit and how clinicians should interpret it?

Marston: In the overall trial, we saw a 25% reduction in cardiovascular events. In this subgroup of patients without known significant atherosclerosis, we saw a 31% relative risk reduction in both the 3-point and 4-point MACE end points. That's a substantial effect. And importantly, we're preventing first events here. This is high-risk primary prevention, which represents a meaningful shift toward earlier treatment and something that distinguishes VESALIUS-CV from prior trials in this space.

Pharmacy Times: What were the standout efficacy and safety findings?

Marston: Beyond the 31% relative risk reduction in the primary end point, we also observed a nominal reduction in mortality end points—a 32% reduction in cardiovascular death and a 24% reduction in all-cause mortality. That's something we haven't seen before with this class of medicines, so it's genuinely exciting to see a mortality signal. The safety profile was also favorable and consistent with what has been established for evolocumab in prior trials.

Pharmacy Times: How did the results compare with earlier trials like FOURIER (NCT01764633) in terms of both efficacy and patient population?

Marston: FOURIER was a secondary prevention population and all patients had prior MI or stroke and more established atherosclerotic cardiovascular disease. Here, we're treating high-risk primary prevention patients earlier in the disease process, trying to prevent first events rather than recurrent ones. The trial design was similar, but VESALIUS-CV ran considerably longer, with a median follow-up of 4 and a half years compared to just 2.2 years in FOURIER. I think that extended duration is what allowed us to see the larger effect, particularly on mortality. We didn't see a mortality benefit in FOURIER, and I believe that's largely because the follow-up was too short. With more than twice the duration in VESALIUS-CV, that benefit emerged.

Pharmacy Times: How could these results change the way we approach prevention for patients earlier in the disease continuum?

Marston: Currently, the recommendation for high-risk diabetic patients in primary prevention is to be on a statin and target an LDL below 70 mg/dL. In this trial, we intensified lipid-lowering by adding evolocumab—a PCSK9 monoclonal antibody—and achieved a mean LDL of 44 mg/dL, which is the target we typically reserve for secondary prevention. I think the clinical implication is clear: we should be more aggressive with high-risk primary prevention patients with diabetes. That means not just targeting below 70 mg/dL with a statin, but adding a PCSK9 inhibitor to get them closer to 40 mg/dL.