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Effects of Evolocumab on Mortality Outcomes in Patients Without Previous Myocardial Infarction or Stroke: A Prespecified Analysis of the VESALIUS-CV Randomized Clinical Trial
Robert P. GiuglianoErin A. BohulaAndrea BellaviaGaetano Maria De FerrariLawrence A. LeiterJosé Carlos NicolauAjay BhatiaSabina A. MurphyL. LiuHuei WangV. BláhaAndrejs ĒrglisJorge FerreiraA. GoudevHenrik Kjærulf JensenRóbert Gábor KissGilles MontalescotAlexander ParkhomenkoNaveed SattarPeter SinnaeveRimvydas ŠlapikasGabriel Paiva da Silva LimaMarc S. Sabatineon behalf of the VESALIUS-CV Investigators
Key result
Evolocumab reduces all-cause mortality ~20% vs placebo in high-risk patients without prior MI or stroke.
- HR 0.80
- 95% CI 0.70-0.91
- P=0.0005
- n=12,257
Why the study?
Evolocumab reduced cardiovascular events in patients without prior myocardial infarction or stroke in VESALIUS-CV, but mortality results remained to be fully characterized.
Does evolocumab reduce all-cause mortality in high-risk patients with atherosclerosis or high-risk diabetes without previous myocardial infarction or stroke?
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
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
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.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
DADr. Amit Kheran/a
“It does look to impact all-cause mortality which is the most important endpoint. So, from my perspective, VESALIUS confirms the consistent benefit of PCSK9 monoclonal inhibitors for ASCVD risk reduction, with now this possible reduction in death.”
“The results from the VESALIUS-CV trial represent the first demonstration of improved cardiovascular outcomes with a PCSK9 inhibitor, or any non-statin for that matter, in patients without a previous heart attack or stroke who are already being treated with a high-intensity lipid-lowering regimen.”
DPDr. Pamela B. MorrisMD, FACC, ACC Trustee
“VESALIUS-CV is an important and practice-changing trial. It demonstrates that more intensive lipid lowering therapy earlier in the atherosclerotic disease process is better to reduce major cardiovascular events. This trial blurs the boundaries of distinction across the atherosclerosis continuum.”
Implication
Reduces all-cause mortality in high-risk patients without prior MI or stroke; extends VESALIUS-CV event reduction to survival benefit.
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.
Coverage & sources
Journal, society, and media accounts. Useful signal, not independent expert judgment.
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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.