VESALIUS-CV: Mortality benefit in high-risk primary prevention patients

November 2026

Evolocumab reduced the risk of all-cause mortality, with consistent results for cardiovascular and non-cardiovascular death, in patients with atherosclerosis or high-risk diabetes without previous myocardial infarction or stroke. These findings further support intensive low-density lipoprotein-cholesterol lowering in these high-risk patient groups.

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 2026;154: DOI: 10.1161/CIRCULATIONAHA.126.082436

STUDY SUMMARY

Objective

To investigate the effect of evolocumab on mortality outcomes in the VESALIUS-CV trial (Effect of Evolocumab in Patients at High Cardiovascular Risk without Prior Myocardial Infarction or Stroke).

 

 

Study design

Prespecified analysis of the VESALIUS-CV trial, a randomized, double-blind trial of patients with qualifying atherosclerosis or high-risk diabetes without previous myocardial infarction (MI) or stroke, who were randomly allocated to treatment with evolocumab 140 mg every 2 weeks or matching placebo (1).    

 

 

Study population

The trial enrolled men (aged 50–79 years) and women (55–79 years) with qualifying atherosclerosis or high-risk diabetes, no previous MI or stroke, and low-density lipoprotein cholesterol (LDL-C) ≥90 mg/dL (or non–high density lipoprotein-cholesterol ≥120 mg/dL or apolipoprotein B ≥80 mg/dL). Overall, 12,257 patients (median age 66 years, 43% women, 93% White) were randomized and included in the analysis.

 

 

Main study variables

The prespecified mortality outcomes were i) all-cause mortality and ii) subtypes of death (including cardiovascular [CV] and non-CV).

 

 

Methods

The analysis plan for mortality end points was prespecified for all-cause mortality and deaths attributable to CV, non-CV, and undetermined cause. The analysis was intention-to-treat using Kaplan-Meier methods and Cox proportional hazard models, stratified by region and baseline LDL-C. All-cause mortality was also evaluated using a prespecified landmark analysis in 1-year increments. As the cumulative incidence curves indicated an inflection point at 1.5 years, the landmark analysis was presented at this time point.

 

Key results

Over the median follow-up of 4.6 years (interquartile range, 4.0–5.2 years) 973 (7.9%) patients died. Compared with survivors, patients who died tended to be older (median age 68 vs. 65 years), male (67% vs. 57%), with a higher prevalence of high-risk diabetes (61% vs. 48%) and kidney dysfunction at baseline. Lipid profiles were generally similar between survivors and nonsurvivors.  

 

Treatment with evolocumab was associated with 20% reduction in all-cause mortality (p=0.0005, Table 1), with similar benefit for CV and non-CV deaths. Because CV and all-cause mortality followed coronary heart disease death (which did not differ between treatment groups: hazard ratio 0.89, 95% confidence interval [CI] 0.68 – 1.16; p=0.39) in the prespecified hierarchy of the secondary end points, p-values for mortality end points were considered nominal and exploratory.  There was no reduction in mortality end points in the first 1.5 years (Hazard ratio 0.99; 95% CI 0.78–1.25), followed by a 27% reduction thereafter (Hazard ratio 0.73; 95% CI 0.63–0.85; p interaction 0.039).

 

Reductions in mortality associated with evolocumab treatment were consistent across key subgroups, including age, sex, geographic region, baseline LDL-C, background lipid therapy, and qualifying disease state

 

Table 1. Results of Kaplan-Meier mortality analysis at 5 years

Outcome

No. (%) of deaths

Hazard ratio

p-value

 

Evolocumab

Placebo

(95% CI)

 

All-cause death

434 (7.9)

539 (9.7)

0.80 (0.70–0.91)

0.0005

CV death

156 (2.8)

195 (3.6)

0.79 (0.64–0.98)

0.031

Non-CV death

229 (4.2)

268 (5.0)

0.85 (0.71–1.01)

0.065

Undetermined

49 (1.1)

76 (1.4)

0.64 (0.45–0.92)

0.014

Author conclusions

These results support using evolocumab to improve survival in high-risk patients who have not experienced a previous MI or stroke, including those with high-risk diabetes without qualifying atherosclerosis with LDL-C ≥ 90 mg/dL (or non-high-density lipoprotein-cholesterol ≥ 120 mg/dL or apolipoprotein B ≥80 mg/dL).

Comment

In this prespecified analysis of the VESALIUS-CV trial, treatment with evolocumab added to standard lipid lowering therapy was associated with improved survival in high-risk primary prevention patients with qualifying lipid levels (LDL-C ≥ 90 mg/dL or non-high-density lipoprotein-cholesterol ≥ 120 mg/dL or apolipoprotein B ≥80 mg/dL). Time to event analyses indicated that this mortality benefit was not observed until at least 1.5 years on evolocumab treatment, consistent with findings observed in trials with statin therapy (2).  ODYSSEY OUTCOMES with alirocumab in patients with an acute coronary syndrome or FOURIER with evolocumab in patients with stable atherosclerotic cardiovascular disease did not show a benefit on mortality, but both trials were of relatively short duration (3,4). However, further analyses from ODYSSEY OUTCOMES were suggestive of a survival benefit in patients treated with alirocumab for at least 3 years (5). Additionally, extended follow-up in the open-label extension to FOURIER (FOURIER-OLE trial) suggested that a longer duration of evolocumab treatment may improve survival, with evidence of divergence in mortality curves after about 2 years (6). Together, these findings add to evidence that reduction in the cumulative LDL-C burden is the key determinant for a mortality benefit from LDL-C lowering therapy.

It should, however, be borne in mind that VESALIUS-CV was not powered for mortality end points. While this analysis was prespecified in the protocol and analysis plan, in the hierarchy of secondary end points, coronary heart disease death ranked above other mortality end points, and therefore the results should be viewed as exploratory rather than definitive. Despite these considerations, the nominal P value of 0.0005 for all-cause mortality is noteworthy and suggests that this is likely not a chance finding.

Taken together, the results from this latest analysis from VESALIUS-CV further support intensive LDL-C lowering to reduce both cardiovascular risk and improve survival in high-risk primary prevention patients, including those with diabetes without qualifying atherosclerosis.

References

  1. Marston NA, Bohula EA, Bhatia AK, et al; VESALIUS-CV Investigators. Evolocumab to reduce first major cardiovascular events in patients without known significant atherosclerosis and with diabetes: results from the VESALIUS-CV Trial. JAMA 2026;335:1400–1407
  2. Baigent C, Keech A, Kearney PM, et al; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278.
  3. Schwartz GG, Steg PG, Szarek M, et al; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–107.
  4. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med.2017;376:1713-22.
  5. Steg PG, Szarek M, Bhatt DL, et al. Effect of alirocumab on mortality after acute coronary syndromes. Circulation 2019;140:103–12.
  6. O’Donoghue ML, Giugliano RP, Wiviott SD, et al. Long-term evolocumab in patients with established atherosclerotic cardiovascular disease. Circulation 2022;146:1109–19.

Key words: VESALIUS-CV; mortality; prespecified analysis; evolocumab; primary prevention