Use of the PCSK9 inhibitor evolocumab on a background of high-intensity cholesterol lowering regimen has been shown to reduce the risk of major adverse cardiovascular events (MACE) in patients at high cardiovascular risk but who have no history of myocardial infarction (MI) or stroke.
This is the headline finding from the VESALIUS-CV trial, a randomised, double-blind trial involving more than 12,000 patients with atherosclerotic cardiovascular disease (ASCVD) or high-risk diabetes who were randomly assigned to receive the drug—which goes by the brand name Repatha (Amgen)—or a placebo. Investigators followed the patients out to a median of 4.6 years and found that patients who received evolocumab had a 25% reduction in the risk of coronary heart disease death, MI, or ischaemic stroke and a 19% reduction in the aforementioned composite or ischaemia-driven arterial revascularisation.
Results of the phase 3 trial, which was sponsored by Amgen and conducted by the Thrombolysis In Myocardial Infarction (TIMI) Study Group, were presented during a late-breaking trials session at the American Heart Association (AHA) 2025 scientific sessions (7–10 November, New Orleans, USA) and simultaneously published in the New England Journal of Medicine.
A previous TIMI trial—FOURIER—had demonstrated that evolocumab reduced the risk of MACE in patients with established atherosclerotic disease who had a history of major cardiovascular events such as MI or stroke.
“We know that lowering LDL with PCSK9 inhibitors, including evolocumab, has been shown to reduce the risk of cardiovascular events in patients with a prior major ASCVD event, such as MI or stroke,” presenting author Erin Bohula (Harvard Medical School, Boston, USA), an investigator in the TIMI Study Group, commented during a press conference at AHA 2025. “However, what we don’t know is if there is clinical benefit of PCSK9 inhibition in patients without a prior MI or stroke.”
Patients qualified for inclusion in VESALIUS-CV if they had an LDL-cholesterol of at least 90mg/dL (or met non-high-density lipoprotein cholesterol or apolipoprotein B criteria), met study inclusion criteria for atherosclerosis (including the presence of coronary artery, peripheral arterial or cerebrovascular disease) or high-risk diabetes, and had at least one other cardiovascular risk factor.
The study included 12,257 patients, with an average age of 66 years old. At the start of the study, about two-thirds of the participants met the inclusion criteria for atherosclerosis (without a prior MI or stroke), and 50% met inclusion criteria for diabetes. Investigators reported that the average LDL-cholesterol level was 122mg/dL. Seventy-two percent of participants were on a high-intensity lipid-lowering regimen. Participants were randomised to one of the two treatment groups: 140mg of evolocumab injected under the skin every two weeks, or a placebo also injected every two weeks, for the duration of the trial.
At AHA 2025, Bohula reported that the use of evolocumab resulted in a 25% relative risk reduction in the three-point MACE composite of coronary heart disease death, MI or ischaemic stroke, whilst a broader composite that also included any ischaemia-driven arterial revascularisation resulted in a 19% relative risk reduction. Findings for the dual primary endpoints were consistent across key subgroups, including in participants with high-risk diabetes without qualifying ASCD, which represented one-third of the total study population.
Nominally lower rates of death from cardiovascular causes (2.8% versus 3.6%, respectively) and death from all causes (7.9% versus 9.7%, respectively) were noted in the evolocumab group compared to the placebo group, Bohula detailed, adding that “interestingly, the curves diverge quite late, at about 1.5 years, which is consistent with what we’ve seen with the statin trials”.
A sub-study that evaluated participants’ lipids measures over time, demonstrated that the median LDL-cholesterol at enrolment was 115mg/dL, and was lowered by nearly 55% in the evolocumab group at 48 weeks, resulting in a median LDL-cholesterol level of 45mg/dL. In contrast, LDL-cholesterol levels remained elevated among those in the placebo group, at a median of 109mg/dL.
“The VESALIUS-CV results support intensive LDL-cholesterol lowering—one could argue maybe to a range of around 40mg/dL—even in patients without a prior event,” said Bohula of the results, explaining that this number may be significant as recent guidelines for extreme risk patients suggest shooting for a target below 40mg/dL.
Speaking to Cardiovascular News, Marc Sabatine (Brigham and Women’s Hospital and Harvard Medicine School, Boston, USA), chair of the TIMI Study Group, agreed that the study’s results, taken alongside those of FOURIER, help to inform strategies for LDL-cholesterol lowering as a strategy for primary prevention.
“It’s always worthwhile to try to prevent a heart attack or stroke, as these represent irreversible loss of heart or brain tissue. FOURIER and now VESALIUS-CV show that getting LDL-cholesterol to ~1mmol/L (~40 mg/dL) is worthwhile in individuals with known atherosclerosis or at high risk. Epidemiological and imaging studies suggest coronary plaque grows when LDL-cholesterol is above ~70mg/dL. Thus, for individuals in whom you have confirmed they do not have atherosclerosis, I would advocate targeting an LDL-cholesterol of 70mg/dL or lower.”
As for which tools are best suited for the job, be they statins, PCSK9 inhibitors such as evolocumab, or otherwise, Sabatine comments that the choice is likely to be guided by cost and patient preference—including whether they prefer an injectable or oral drug delivery—above all.
On the wider significance of the findings, and whether VESALIUS-CV builds the case for preventive strategies that address LDL-cholesterol earlier in life, Sabatine seems convinced.
“It makes more sense to treat earlier to prevent heart attacks and strokes than to wait until they happen and only then treat intensively,” he explains. “From a population health perspective, if we kept LDL-cholesterol of 70mg/dL or lower from adulthood on, could largely eliminate coronary artery disease. Indeed, in pre-industrial societies still in existence, their LDL-cholesterol is often around or below this level and they have almost no coronary disease.”
Further data from the trial are expected at the upcoming American College of Cardiology (ACC) scientific sessions (28–30 March, New Orleans, USA), with the results of an analysis of the effect of evolocumab in patients without significant atherosclerosis to be presented in a late-breaking trials session on day one of the meeting.
