NEW ORLEANS — The first global randomized trial of the PCSK9 inhibitor evolocumab for the prevention of a primary major adverse cardiovascular event (MACE) found a relative reduction in risk similar in magnitude to that previously seen for secondary prevention. 

The VESALIUS-CV trial showed a risk reduction over a median of 4.6 years of follow-up of 19% and 25% (P < .001 for both) for the dual composite primary MACE endpoints. These were accompanied by a 20% reduction (P = .0005) in all-cause death, a result characterized as “nominal” because it was not among the prespecified composite endpoints.

“The reduction in MACE in this trial supports intensive LDL-C lowering in high-risk patients whether or not they have had a prior event,” said Erin A. Bohula, MD, DPhil, an associate physician in cardiovascular medicine at Brigham and Women’s Hospital in Boston, who led the study.

The findings were presented at the 2025 Scientific Sessions of the American Heart Association and published simultaneously in The New England Journal of Medicine.

‘False Dichotomy’

The results challenge the “false dichotomy” that traditionally divides high-risk patients with from those without a prior myocardial infarction or other type of MACE, according to Pamela B. Morris, MD, the chair of cardiovascular disease prevention at the Medical University of South Carolina in Charleston. 

Atherosclerotic cardiovascular disease (ASCVD) can be understood as a continuum, and events define worsening but not different disease. The results of VESALIUS-CV demonstrate that aggressive lowering of LDL-C alters the disease course with or without a prior event in high-risk patients.

The new data imply that “more intensive lipid lowering, even earlier in the course of disease, is better to reduce ischemic events,” Morris said.

VESALIUS-CV enrolled 12,257 patients who were randomized 1:1 to receive 140 mg of evolocumab (Amgen) or placebo administered subcutaneously every 2 weeks. 

The VESALIUS-CV subjects were randomly assigned at 774 enrolling sites in 33 countries. The median baseline LDL-C was 122 mg/dL (> 90 mg/dL was required for entry). The median age was 66 years. Patients were eligible if they had been diagnosed with coronary artery disease, ASCVD, peripheral artery disease, or high-risk diabetes, but were excluded for any prior ASCVD event.

One of the dual endpoints was a three-point MACE defined by myocardial infarction (MI), coronary heart disease death, or ischemic stroke. The event rate at the end of follow-up was 6.2% in the evolocumab group and 8% in the placebo arm, providing a relative risk reduction of 25% (HR, 0.75; 95% CI, 0.65-0.86). 

The second of the dual primary endpoints was a four-point MACE created by adding ischemic-driven arterial revascularization to the other three. The 13.4% and 16.2% event rates in the evolocumab and placebo groups, respectively, provided a risk reduction of 19% (HR, 0.81; 95% CI, 0.73-0.89).

Validation of the Lipid Hypothesis

The reductions in risk are wholly consistent with the lipid hypothesis described more than 25 years ago, linking each incremental reduction in LDL-C with a proportionate reduction in risk of events, Bohula said. While levels of LDL-C fell modestly in the placebo arm over the course of the trial, they fell abruptly in the evolocumab arm, reaching a median absolute reduction of 63 mg/dL and a median 55% reduction relative to placebo at week 48 (P < .0001). 

The average LDL-C reached at week 48 in the evolocumab arm was approximately 45 mg/dL and remained near that level for the remainder of the study. The average LDL-C in the placebo group did not fall below 90 mg/dL. 

The proportion of lipid-lowering and risk reductions in VESALIUS-CV was nearly identical to trials conducted with other lipid-lowering agents over several decades, according to Bohula.

With the exception of death from coronary heart disease, for which the 11% risk reduction (HR, 0.89; P = .39) did not reach statistical significance, all other events in the composite endpoints were significantly reduced, the researchers found. So, too, were various combinations of events that were employed as prespecified secondary endpoints. Although not all statistically significant, a greater reduction in events for evolocumab vs placebo was seen across all subgroups, they reported.

For secondary prevention of MACE, target LDL-C has been progressively lowered following trials with increasingly more potent lipid-lowering agents, according to both Bohula and Morris. 

In secondary prevention, high-potency statin trials first led to targets of 70 mg/dL in many guidelines, Bohula reported. Following the introduction of PCSK9 inhibitors, the targets were lowered to 55 mg/dL. Most recently, some European guidelines are calling for a target of 40 mg/dL for those at extreme risk.

The VESALIUS-CV data suggest current LDL-C targets in primary prevention should also be lower, according to Amit Khera, MD, clinical chief of cardiology at the University of Texas Southwestern Medical School in Dallas.

Relative to the risk reduction in patients with a history of MI or other cardiovascular event, “we are seeing a similar effect in this primary prevention cohort,” he said. The “nominal reduction” in risk for all-cause death reported in the secondary prevention ODYSSEY OUTCOMES trial of alirocumab, another PCSK9 inhibitor, is now being echoed in VESALIUS-CV. 

Morris called the VESALIUS-CV trial “practice-changing,” suggesting that it will refocus clinicians on earlier intervention in the continuum of progressive cardiovascular disease even in the advance of MACE. She also predicted that the same type of benefit will be produced by other drugs with commensurate LDL-C lowering, such as inclisiran.

“There is no reason to think that these results are not generalizable,” she said.

The VESALIUS-CV trial received financial support from Amgen. Bohula has received research funding from Amgen as well as CeleCor, Esperion, Kowa, Novo Nordisk, and Servier. Morris and Khera reported no relevant financial relationships.