Evolocumab Cuts Death Risk for a First Heart Attack or Stroke

A prespecified secondary analysis of the VESALIUS-CV trial (NCT03872401) found that evolocumab (Repatha; Amgen), a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, was associated with a 20% relative reduction in all-cause mortality among high-risk patients with qualifying atherosclerosis or diabetes who had not experienced a prior myocardial infarction (MI) or stroke.¹

The findings, which were presented in a late-breaking science session at the European Society of Cardiology Congress 2026 in Munich, Germany, and published in Circulation, provide evidence of a mortality benefit with evolocumab in a high-risk population without a history of MI or stroke. The analysis also adds to evidence supporting intensive low-density lipoprotein cholesterol (LDL-C) lowering earlier in the course of cardiovascular disease.

"For people at high risk of a heart attack or stroke, lowering LDL-C or 'bad' cholesterol with Repatha may do more than help prevent these events; it may also reduce the risk of dying from heart disease and its serious consequences," said Jay Bradner, MS, executive vice president, Research and Development, Artificial Intelligence and Data at Amgen, in a statement.² "This is especially significant given cardiovascular disease remains the leading cause of death worldwide. The totality of these data is practice-changing and reinforces the importance of identifying high-risk patients early and lowering LDL-C aggressively and consistently with Repatha."

VESALIUS-CV was a double-blind, placebo-controlled trial that randomized 12,257 patients (median age, 66 years; 43% women) with qualifying atherosclerosis or high-risk diabetes, no previous MI or stroke, and an LDL-C level of at least 90 mg/dL—or comparable non–high-density lipoprotein cholesterol or apolipoprotein B thresholds—to receive evolocumab 140 mg subcutaneously every 2 weeks or placebo.¹ Patients received the study drug in addition to optimized background lipid-lowering therapy. Over a median follow-up of 4.6 years, 973 patients (7.9%) died: 36% from cardiovascular causes, 51% from noncardiovascular causes, and 13% from undetermined causes.

All-Cause Mortality Dropped 20%, With Benefit Emerging After 1.5 Years

All-cause mortality occurred in 434 patients in the evolocumab group vs 539 patients in the placebo group, corresponding to 5-year Kaplan-Meier rates of 7.9% and 9.7%, respectively (HR, 0.80; 95% CI, 0.70-0.91; P = .0005). The reduction was also observed for cardiovascular mortality (HR, 0.79; 95% CI, 0.64-0.98). Mortality from noncardiovascular causes was numerically lower with evolocumab (HR, 0.85; 95% CI, 0.71-1.01), as were deaths from undetermined cause (HR, 0.64; 95% CI, 0.45-0.92).

The mortality benefit emerged gradually. A landmark analysis found no difference between treatment groups during the first 1.5 years (HR, 0.99), followed by a 27% relative reduction in mortality after 1.5 years (HR, 0.73; P for interaction = .039).

Among cause-specific cardiovascular deaths, evolocumab showed directionally favorable effects for acute MI, stroke, and heart failure, but not sudden cardiac death. Among noncardiovascular causes of death, infection and malignancy were the most common categories.

A multistate model examined whether nonfatal cardiovascular events occurring after randomization were associated with subsequent mortality. Patients who experienced a postrandomization MI, ischemic stroke, or ischemia-driven revascularization had substantially higher subsequent mortality risk. The model estimated that approximately 78% of the treatment effect on noncardiovascular mortality could be statistically attributed to preventing these antecedent nonfatal cardiovascular events. This finding suggests that preventing a first cardiovascular event may have downstream effects on survival, although the multistate analysis is model-based and does not establish a direct causal effect of evolocumab on noncardiovascular causes of death.

The mortality findings were generally consistent across prespecified subgroups, including age, sex, region, race, baseline LDL-C, background lipid-lowering therapy, and qualifying disease category. The treatment effect was also consistent among patients with high-risk diabetes without qualifying atherosclerosis.

An editorial accompanying the primary VESALIUS-CV results in The New England Journal of Medicine described the trial as an important advance in understanding intensive LDL-C lowering among patients at high cardiovascular risk without prior MI or stroke.³

“Although PCSK9 inhibitors had been shown to reduce the risk of atherosclerotic cardiovascular disease events among patients with previous myocardial infarction or stroke, this new trial has shown their clinical benefit in patients without previous myocardial infarction or stroke,” wrote the authors. “With a longer follow-up than earlier PCSK9 inhibitor trials … numerically fewer deaths were observed in the evolocumab group than in the placebo group. Although this result was not significant owing to the hierarchical testing approach, it is likely to reflect a true signal.”

Overall, the findings extend the evidence base for PCSK9 inhibition beyond populations with established cardiovascular events, including patients with high-risk diabetes without qualifying atherosclerosis.¹ However, the mortality benefit emerged after approximately 1.5 years of treatment, and the analysis was conducted in a selected high-risk population, so the findings should be interpreted within the trial's eligibility criteria and alongside other evidence on the benefits, risks, and long-term value of PCSK9 inhibition.

"These analyses reinforce that a patient's first major cardiovascular event is not merely an isolated occurrence but often a transition to a higher-risk state," said Marc S. Sabatine, MD, MPH, chair of the TIMI Study Group and the Lewis Dexter, MD, Endowed Chair in Cardiovascular Medicine at Mass General Brigham Heart & Vascular Institute, in a statement.² "Evolocumab reduced not only first cardiovascular events but also subsequent events during the course of the study, the latter of which almost doubled the number of events prevented. By preventing these events, evolocumab can alter the patient's trajectory, with lower rates of all-cause mortality and consistent effects for both cardiovascular and noncardiovascular mortality. Together, these data support the large clinical benefit of intensive LDL-C lowering with evolocumab down to ~40 mg/dL to help prevent cardiovascular morbidity and mortality."

References

1. Giugliano RP, Bohula EA, Bellavia A, et al. Effects of evolocumab on mortality outcomes in patients without previous myocardial infarction or stroke: a prespecified analysis of the VESALIUS-CV randomized clinical trial. Circulation. Published online August 31, 2026. doi:10.1161/CIRCULATIONAHA.126.082436
2. Amgen’s Repatha reduces risk of death in patients at high risk for a first heart attack or stroke. News release. Amgen. August 31, 2026. Accessed August 31, 2026. https://www.amgen.com/newsroom/press-releases/2026/08/amgens-repatha-reduces-risk-of-death-in-patients-at-high-risk-for-a-first-heart-attack-or-stroke
3. VESALIUS-CV: evolocumab vs. placebo in patients without previous MI or stroke. American College of Cardiology. November 8, 2025. Accessed August 31, 2026. https://www.acc.org/latest-in-cardiology/articles/2025/11/03/16/19/sat-1010am-vesalius-aha-2025