UPDATED: Phase 3 VESALIUS-CV Trial Demonstrates Evolocumab Reduces Cardiovascular Events in High-Risk Adults Without Prior Heart Attack or Stroke

[Editor's Note: This article has been updated with complete results from the VESALIUS-CV trial reported at the 2025 American Heart Association Scientific Sessions and published simultaneously in the New England Journal of Medicine on November 8, 2025.]

In adults without prior myocardial infarction or stroke enrolled in the phase 3 VESALIUS-CV trial, participants treated with evolocumab (Repatha; Amgen) were at significantly reduced risk of major adverse cardiovascular events (MACE), according to full results of the study presented in a late-breaking session at the 2025 American Heart Association Scientific Sessions and simultaneously published in the New England Journal of Medicine.¹

In the trial of 12,257 adults followed for a median of 4.6 years, evolocumab reduced the risk of the primary composite endpoint of death from coronary heart disease, myocardial infarction, or ischemic stroke by 25% compared to placebo (hazard ratio 0.75; 95% CI, 0.65-0.86; P <.001), with events occurring in 6.2% versus 8.0% of participants. The expanded primary endpoint that included ischemia-driven revascularization showed a 19% risk reduction (HR 0.81; 95% CI, 0.73-0.89; P <.001), occurring in 13.4% versus 16.2% of patients.¹

Evolocumab is now the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to demonstrate event reduction in both primary and secondary prevention settings.

"Building on the success of FOURIER, in which we showed that adding evolocumab to statin therapy in patients with a prior heart attack or stroke reduced the risk of subsequent major adverse cardiovascular events, we now show that in the much larger population of patients with atherosclerosis or diabetes, but without a prior heart attack or stroke, that adding evolocumab to their lipid regimen substantially reduces their risk of MACE," Marc S. Sabatine, MD, MPH, chair of the TIMI Study Group and the Lewis Dexter, MD, Endowed Chair in Cardiovascular Medicine at Brigham and Women's Hospital, said in a statement.² "In both FOURIER and VESALIUS-CV, patients in the evolocumab arm achieved median LDL-C levels in the range of approximately 30 to 45 mg/dL, supporting such a target across a broad range of patients."²

The VESALIUS-CV Trial

The global, double-blind, randomized trial enrolled 12,257 high-risk adults with atherosclerosis or diabetes but without previous myocardial infarction or stroke who had LDL cholesterol levels of at least 90 mg/dL. Participants were randomly assigned to receive evolocumab 140 mg every 2 weeks or matching placebo. Median age of the cohort was 66 years, 43% were women, and 93% self identified as White. Approximately 92% were already receiving lipid-lowering therapy, with 72% on high-intensity therapy and 68% on high-intensity statins. The median baseline LDL cholesterol level was 122 mg/dL.

Primary Endpoints Statistically Significant

Both primary endpoints were met with statistically and clinically significant reductions. For the 3-point MACE endpoint (death from coronary heart disease, myocardial infarction, or ischemic stroke), events occurred in 336 patients (6.2%) in the evolocumab group versus 443 patients (8.0%) in the placebo group. For the 4-point MACE endpoint (3-point MACE plus ischemia-driven arterial revascularization), events occurred in 747 patients (13.4%) in the evolocumab group versus 907 patients (16.2%) in the placebo group.

Significant risk reductions were also observed for multiple secondary endpoints, including a:

A 27% lower risk of cardiovascular death, myocardial infarction, or ischemic stroke (HR 0.73; 95% CI, 0.64-0.84; P <.001)

A 27% lower risk of death from coronary heart disease or myocardial infarction (HR 0.73; 95% CI, 0.62-0.87; P <.001)

A 36% lower risk of myocardial infarction (HR 0.64; 95% CI, 0.52-0.79; P <.001)

A 21% lower risk of ischemia-driven arterial revascularization (HR 0.79; 95% CI, 0.70-0.88; P <.001)

Death from coronary heart disease showed no significant difference between groups (HR 0.89; 95% CI, 0.68-1.16; P =.39). However, exploratory analyses showed apparent reductions in death from cardiovascular causes (HR 0.79; 95% CI, 0.64-0.98) and death from any cause (HR 0.80; 95% CI, 0.70-0.91).

Lipid Lowering Effects

In a lipid substudy of 2,014 participants, evolocumab reduced LDL cholesterol by 55% at 48 weeks compared to placebo (least-squares mean percentage change −55%; 95% CI, −59 to −52), for an absolute difference of −63 mg/dL. The median LDL cholesterol level at 48 weeks was 45 mg/dL in the evolocumab group versus 109 mg/dL in the placebo group.

Favorable Safety Profile

No new safety signals were observed, and no evidence of between-group differences was seen in the incidence of adverse events leading to discontinuation or serious adverse events.

"These results mark an important milestone in the fight against cardiovascular disease, the leading cause of death worldwide. The benefit across endpoints and established safety profile underscore Repatha's role as a cornerstone therapy in comprehensive lipid management," Jay Bradner, MD, executive vice president of Research and Development at Amgen, said in an earlier press release.³

The VESALIUS-CV findings build on the FDA's earlier 2025 expansion of evolocumab's approved use to include adults at increased risk for major adverse cardiovascular events due to uncontrolled LDL cholesterol. The results also extend evidence beyond the FOURIER trial, which in 2017 showed evolocumab reduced cardiovascular events in patients with established atherosclerotic cardiovascular disease and prior events.¹

Cardiovascular disease remains the leading cause of death worldwide, with approximately 75% of heart attacks and strokes occurring as first-time events. Despite optimized lipid-lowering therapy, more than 80% of high-risk patients remain above guideline-recommended LDL cholesterol targets.^4,5

"Repatha is known as a highly effective LDL-C lowering treatment and is now the first and only PCSK9 inhibitor shown to reduce cardiovascular events in high-risk adults without prior heart attack or stroke," Bradner added in the release. "These additional data demonstrate that Repatha has the potential to reach tens of millions more patients earlier in their journey, before a life-altering event occurs,"

Evolocumab was first approved in 2015 and is currently indicated to reduce the risk of major adverse cardiovascular events in adults, and as an adjunct to diet and exercise for adults and pediatric patients with familial hypercholesterolemia. It has been studied in more than 57,000 patients across 51 trials.

References:

1. Bohula EA, Marston NA, Bhatia AK, et al. Evolocumab in patients without a previous myocardial infarction or stroke. N Engl J Med. Published online November 8, 2025. doi:10.1056/NEJMoa2514428
2. Amgen’s Repatha cuts risk of first major adverse cardiovascular events by 25% in landmark phase 3 VESALIUS-CV trial. News release. Amgen. November 8, 2025. Accessed Novemeber 10, 2025. https://www.amgen.com/newsroom/press-releases/2025/11/amgens-repatha-cuts-risk-of-first-major-adverse-cardiovascular-events-by-25-in-landmark-phase-3-vesaliuscv-trial
3. Landmark phase 3 trial (VESALIUS-CV) meets primary endpoints in a cardiovascular primary prevention study of 12,000 patients. Amgen. October 2, 2025. Accessed October 2, 2025. https://investors.amgen.com/news-releases/news-release-details/landmark-phase-3-trial-vesalius-cv-meets-primary-endpoints
4. Martin SS, Aday AW, Allen NB, et al. 2025 heart disease and stroke statistics: a report of US and global data from the American Heart Association. Circulation. 2025;151(8):e41-e660. doi:10.1161/CIR.0000000000001303
5. Le H, Huang X, Khan SS, et al. Very high prevalence of nonoptimally controlled traditional risk factors at the onset of cardiovascular disease. J Am Coll Cardiol. 2025;86(14). doi:10.1016/j.jacc.2025.07.014