September 1, 2026Circulation2 citations
Effects of Evolocumab on Mortality Outcomes in Patients Without Previous Myocardial Infarction or Stroke: A Prespecified Analysis of the VESALIUS-CV Randomized Clinical Trial
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Key Result
Evolocumab reduced all-cause mortality compared with placebo (7.9% vs 9.7%; HR 0.80; 95% CI 0.70-0.91; P=0.0005) in high-risk patients without previous myocardial infarction or stroke.
Key Points
- Evaluate the impact of evolocumab on all-cause and cause-specific mortality in high-risk patients with atherosclerosis or diabetes who have no prior history of myocardial infarction or stroke.
- Conducted a prespecified mortality analysis of the VESALIUS-CV double-blind randomized clinical trial (NCT03872401) in 12,257 patients (median age 66 years [IQR 60–71], 43% women) with elevated atherogenic lipids and qualifying atherosclerosis or high-risk diabetes.
- Assessed all-cause, cardiovascular, non-cardiovascular, and undetermined mortality over a median follow-up of 4.6 years (IQR 4.0–5.2), using multistate modeling to estimate the impact of nonfatal cardiovascular events on subsequent non-cardiovascular deaths.
- All-cause mortality was significantly lower in the evolocumab group than in the placebo group: 434 deaths (5-year Kaplan-Meier rate 7.9%) versus 539 deaths (9.7%) (hazard ratio 0.80; 95% CI, 0.70–0.91; P=0.0005).
- Evolocumab demonstrated consistent mortality risk reductions across cardiovascular deaths (2.8% vs 3.6%; HR 0.79; 95% CI, 0.64–0.98), non-cardiovascular deaths (4.2% vs 5.0%; HR 0.85; 95% CI, 0.71–1.01), and undetermined deaths (1.1% vs 1.4%; HR 0.64; 95% CI, 0.45–0.92).
- Multistate modeling demonstrated that 78% (bootstrap IQR 71–92%) of the reduction in non-cardiovascular deaths with evolocumab was driven by the prevention of antecedent nonfatal cardiovascular events.
Study Design
Type
RCT (n=12,257)
Blinding
Double-blind
Randomization
randomized
Multicenter
Yes
Structured PICO
Does evolocumab reduce all-cause mortality in high-risk patients with atherosclerosis or high-risk diabetes without previous myocardial infarction or stroke?
P
Population
12,257 patients (median age 66, 43% women) with qualifying atherosclerosis or high-risk diabetes without previous MI or stroke, followed for a median of 4.6 years.
I
Intervention
Evolocumab
C
Comparator
Placebo
O
Outcome
All-cause mortalityhard clinical
Evolocumab significantly reduces all-cause mortality in high-risk patients without prior myocardial infarction or stroke, largely driven by the prevention of nonfatal cardiovascular events.
Main Result
Hazard Ratio: 0.8 (95% CI 0.7–0.91)
Absolute Event Rate: 7.9% vs 9.7%
p-value: p=0.0005
Abstract
BACKGROUND: Evolocumab, a PCSK9 (proprotein convertase subtilisin–kexin type 9) inhibitor, significantly reduced the risk of cardiovascular events in patients without previous myocardial infarction or stroke in the VESALIUS-CV trial (Effect of Evolocumab in Patients at High Cardiovascular Risk without Prior Myocardial Infarction or Stroke). However, mortality results have yet to be fully characterized. METHODS: VESALIUS-CV was a double-blind study of 12 257 patients (median age, 66 years interquartile range, 60–71; 43% women) with qualifying atherosclerosis or high-risk diabetes without previous myocardial infarction or stroke, and low-density lipoprotein-cholesterol ≥90 mg/dL (or non–high-density lipoprotein-C ≥120 mg/dL or apolipoprotein B ≥80 mg/dL) who were randomized to evolocumab or placebo. Prespecified mortality outcomes of interest included all-cause mortality, subtypes of death (including cardiovascular CV and non-CV), and timing of events. Non-CV mortality was further investigated using multistate modeling to assess the contribution of prevention of nonfatal CV events (myocardial infarction, ischemic stroke, and ischemia-driven arterial revascularization) to non-CV mortality. RESULTS: Over a median of 4.6 years (interquartile range, 4.0-5.2), 973 (7.9%) patients died: 351 (36%) of CV causes, 497 (51%) of non-CV causes, and 125 (13%) of undetermined cause. All-cause mortality rates were 20% lower with evolocumab compared with placebo: 434 deaths (5-year Kaplan-Meier rate of 7.9%) with evolocumab versus 539 deaths (9.7%) with placebo (hazard ratio, 0.80, 95% CI, 0.70–0.91; P =0.0005). There was consistency of benefit for CV death (156 deaths 2.8% versus 195 3.6%; hazard ratio, 0.79; 95% CI, 0.64–0.98), non-CV death (229 4.2% versus 268 5.0%; hazard ratio, 0.85; 95% CI, 0.71–1.01), and deaths of undetermined cause (49 1.1% versus 76 1.4%; hazard ratio, 0.64; 95% CI, 0.45–0.92). Results were consistent regardless of age, sex, region, race, qualifying atherosclerosis or high-risk diabetes, baseline low-density lipoprotein-cholesterol, or background lipid therapy. Postrandomization nonfatal myocardial infarction, ischemic stroke, and ischemia-driven arterial revascularization were associated with increased risk of subsequent non-CV death within the next 4 years, with the majority occurring during the first year after the event. Multistate modeling suggested the observations regarding non-CV death with evolocumab was largely (78%; bootstrap interquartile range, 71–92%) driven by the prevention of antecedent nonfatal CV events. CONCLUSIONS: These results support using evolocumab to improve survival in high-risk patients who have not experienced a previous myocardial infarction or stroke, including those with high-risk diabetes without qualifying atherosclerosis with low-density lipoprotein-cholesterol ≥ 90 mg/dl (or non-high-density lipoprotein-cholesterol ≥ 120 mg/dl or apolipoprotein B ≥ 80 mg/dl). REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03872401.
Expert Takes6 quotes
1/6
“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. 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.”
Dr. Jay Bradner, Executive Vice President, Research and Development, Artificial Intelligence and DataAmgengemini_groundedSupportiveView source
Cite This Study
Giugliano et al. (2026) conducted an RCT in Qualifying atherosclerosis or high-risk diabetes without previous myocardial infarction or stroke (n=12,257). Evolocumab vs. Placebo was evaluated on All-cause mortality (HR 0.80, 95% CI 0.70-0.91, p=0.0005). Evolocumab reduced all-cause mortality compared with placebo (7.9% vs 9.7%; HR 0.80; 95% CI 0.70-0.91; P=0.0005) in high-risk patients without previous myocardial infarction or stroke.