Patients without prior MI or stroke get cardioprotection from evolocumab

The proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab, when added to background lipid-lowering therapy, helps reduce the risk of major adverse cardiovascular events (MACE) in patients with atherosclerosis or diabetes who have no history of myocardial infarction (MI) or stroke, according to the randomized VESALIUS-CV trial.

Over a median follow-up of 4.6 years, the composite of death from coronary heart disease, MI, or ischaemic stroke (3-point MACE) occurred in 6.2 percent of patients in the evolocumab arm vs 8 percent of patients in the placebo arm, corresponding to a significant 25-percent risk reduction (hazard ratio [HR], 0.75, 95 percent confidence interval [CI], 0.65–0.86; p<0.001). [N Engl J Med 2025;doi:10.1056/NEJMoa2514428]

Similarly, the expanded 4-point MACE composite outcome, which included the 3-point MACE and ischaemia-driven arterial revascularization, occurred in fewer patients who received evolocumab vs placebo (13.4 percent vs 16.2 percent), for a 19-percent risk reduction (HR, 0.81, 95 percent CI, 0.73–0.89; p<0.001).

The beneficial effect of treatment on both MACE endpoints was consistent across subgroups defined by demographics, qualifying disease category, baseline low-density lipoprotein cholesterol (LDL-C) values, statin intensity, and use of ezetimibe. No safety issues emerged with evolocumab.

“To date, PCSK9 inhibitors have been studied in the highest-risk populations—patients with a major, previous atherosclerotic cardiovascular disease (ASCVD) event—in whom they prevented recurrent MACE,” noted first author Dr Erin Bohula from Brigham and Women’s Hospital in Boston, Massachusetts, US, who presented the trial data at the AHA Scientific Sessions. [N Engl J Med 2017;376:1713-1722; N Engl J Med 2018;379:2097-2107]

“These findings support the use of the PCSK9 inhibition to prevent a first major cardiovascular event in a population along the ASCVD continuum that is at lower risk than populations previously studied, with benefit in patients with atherosclerosis without a previous MI or stroke, as well as in patients with diabetes without qualifying atherosclerosis, who accounted for one third of the trial population,” Bohula added.

Dramatic LDL-C reduction

Notable results were also observed in the lipid substudy, in which lipid levels were tracked over time in a subset of 2,014 patients.

Patients in the substudy started with a median LDL-C level of 115 mg/dL. Evolocumab pushed it down by 55 percent (95 percent CI, −59 to −52) or by 63 mg/dL in absolute terms at week 48 relative to placebo, and this reduction was maintained throughout the course of the trial. The median LDL-C levels at week 48 were 45 and 109 mg/dL in the respective treatment arms.

Evolocumab also resulted in greater reductions in other atherogenic lipids at 48 weeks compared with placebo, with a 47-percent reduction in non–high-density lipoprotein cholesterol and 44-percent decrease in apolipoprotein B levels.

“Guidelines have recommended progressively lower goals for LDL-C of <70 mg/dL and, more recently, <55 mg/dL in patients at very high risk. In fact, the most recent European guideline endorsed consideration of a goal below 40 mg/dL in patients at extreme risk,” according to Bohula. [Circulation 2019;139:e1046-e1081; Eur Heart J 2020;41:111-88; Atherosclerosis 2025;409:120479; Circulation 2025;151:e771-e862]

“The reduction in MACE seen in VESALIUS-CV, with an achieved LDL-C of around 40 mg/dL in the evolocumab arm, supports intensive LDL-C lowering to this level, even in patients without a prior major ASCVD event,” she added.

Study discussant Dr Pamela Morris from the Medical University of South Carolina in Charleston, South Carolina, US, echoed Bohula, saying, “What this trial demonstrates is that more intensive lipid-lowering therapy even earlier in the course of disease is better to reduce ischaemic events.”

Population at high-risk

VESALIUS-CV included 12,257 patients without a history of MI or stroke and meet criteria for at least one of the following four disease categories: coronary artery disease, atherosclerotic cerebrovascular disease, peripheral artery disease, or high-risk diabetes. High-risk diabetes was defined as long-standing (≥10 years’ duration), treated with daily insulin, or complicated by microvascular disease.

Additionally, the patients had features making them at high risk of a first ASCVD event, as follows: either 50–79 years of age (in men) or 55–79 years of age (in women); an LDL cholesterol level of ≥90 mg/dL, a non-HDL cholesterol level of ≥120 mg/dL, or an apolipoprotein B level of ≥80 mg/dL; and stable, optimized lipid-lowering therapy for at least 2 weeks.

The median age of the patients was 66 years, 43 percent were women, 93 percent White, and the median BMI 30 kg/m². Roughly two-thirds of the patients met the criteria for qualifying atherosclerosis, including 45 percent with coronary artery disease, 10 percent with cerebrovascular disease, and 17 percent with peripheral artery disease. Around 49 percent had high-risk diabetes, and one-third had high-risk diabetes without qualifying atherosclerosis. In terms of background therapy, 72.2 percent were on high-intensity lipid lowering therapy, 68 percent were taking high-intensity statins, and 19.8 percent were receiving ezetimibe.

The patients were randomly assigned to receive subcutaneous injections of evolocumab at a dose of 140 mg every 2 weeks (n=6,129) or placebo (n=6,128). The 3-point and 4-point MACE were the dual primary endpoints. Secondary endpoints consisted of composites and individual ones that were tested in a prespecified hierarchical order.

True signal of mortality benefit

Compared with placebo, evolocumab conferred significant reductions in all the secondary composite endpoints, including a 27-percent reduction in the risk of death from cardiovascular causes, MI, or ischaemic stroke (6.8 percent vs 9.1 percent; HR, 0.73, 95 percent CI, 0.64–0.84; p<0.0001).

As for the individual endpoints, evolocumab was associated with a 36-percent decrease in MI risk (HR, 0.64, 95 percent CI, 0.52–0.79; p<0.0001) and a 21-percent decrease in ischaemia-driven revascularization risk (HR, 0.79, 95 percent CI, 0.70–0.88; p<0.0001). There was no significant reduction in the risk of CHD death. A notable 20-percent reduction in the risks of CV death (2.8 percent vs 3.6 percent; HR, 0.79, 95 percent CI, 0.64–0.98; p=0.032) and all-cause death (7.9 percent vs 9.7 percent; HR, 0.80, 95 percent CI, 0.70–0.91; p=0.0005) observed with evolocumab should be considered hypothesis-generating based on hierarchical testing.

In an editorial comment published in the New England Journal of Medicine, Drs Chiadi Ndumele and Roger Blumenthal from the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease in Baltimore, Maryland, US, emphasized that the mortality benefit with evolocumab was compelling. [N Engl J Med 2025;10.1056/NEJMe2515447]

“With a longer follow-up than earlier PCSK9 inhibitor trials, which had less than 3 years of follow-up, 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,” Ndumele and Blumenthal noted. [Lancet 2010;376:1670-1681; Lancet 2005;366:1267-1278]

Bohula added that the median follow-up of 4.6 years in VESALIUS-CV, which is comparable to the average follow-up in the seminal statin trials, holds importance, given the well-described lag in the onset of cardiovascular benefit with LDL-C lowering, with the magnitude of clinical benefit increasing over time.

“Thus, the previous, shorter trials of PCSK9 inhibitors are likely to have underestimated the long-term clinical benefit… Moreover, the duration of follow-up is particularly relevant for detecting a benefit for fatal outcomes, as seen in statin trials in which the effect only became apparent after several years of follow-up,” she said. [N Engl J Med 2017;376:1713-1722; N Engl J Med 2018;379:2097-2107; Lancet 1994;344:1383-1389; N Engl J Med 1998;339:1349-1357]

Takeaways from a landmark trial

“What [VESALIUS-CV] does for us is begin to expand the populations who are likely to benefit from more intensive lipid-lowering therapy beyond those ASCVD and acute coronary syndrome patients, into those without prior MI, subclinical atherosclerosis, and high-risk diabetes, both with underlying atherosclerosis but also in primary prevention without underlying atherosclerosis,” Morris said.

Like the trial’s namesake, the 16th century Flemish physician and anatomist Andreas Vesalius, whose work fundamentally advanced understanding of the circulatory system, “the VESALIUS-CV trial advances our understanding of vascular anatomy—this time, by showing the important implications of strategies to prevent atherosclerotic cardiovascular disease,” Ndumele and Blumenthal added.

Bohula acknowledged that the trial was limited by the inclusion of patients with less-intensive or no background lipid-lowering therapy.

“However, the benefit of evolocumab therapy appeared to be consistent regardless of the intensity of statin therapy or ezetimibe use, and the percentages of patients taking high-intensity lipid-lowering therapy in this trial were greater than those observed in multiple registries around the world,” they said. [Am Heart J 2025;279:50-58; Am J Prev Cardiol 2025;23:101067; Eur J Prev Cardiol 2021;28:1279-1289]

In August, the US Food and Drug Administration expanded the approved use of evolocumab to include adults at increased risk of MACE due to uncontrolled LDL-C, preceding the release of the VESALIUS-CV trial findings.