Evolocumab lowers chance of death in high-risk patients for first heart attack or stroke

Repatha (evolocumab) lowered the risk of death from any cause by 20% in high-risk adults without a previous heart attack or stroke, according to phase 3 data in the VESALIUS-CV trial published today in Circulation.

The findings address a gap in lipid-lowering research: cardiovascular disease (CVD) remains the leading cause of death worldwide; however, most large cholesterol-drug trials are designed to show fewer heart attacks and strokes, not necessarily fewer deaths. Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, blocks a protein that would otherwise cause the liver to break down low-density lipoprotein (LDL) receptors, allowing more LDL cholesterol (LDL-C), or “bad” cholesterol, to be cleared from the blood.

VESALIUS-CV had already shown evolocumab significantly reduced cardiovascular events in this patient population, but as the study's authors wrote, mortality results “have yet to be fully characterized” before this analysis.

The analysis was led by Robert Giugliano, M.D., a physician in the Cardiovascular Division at Brigham and Women’s Hospital and Professor of Medicine at Harvard Medical School.

VESALIUS-CV, conducted by Giugliano and his team, is a double-blind, randomized, placebo-controlled trial that enrolled 12,257 adults between June 2019 and November 2021. It included men ages 50 to 79 and women 55 to 79 with qualifying atherosclerosis or high-risk diabetes, no previous heart attack or stroke and an LDL-C of 90 mg/dL or higher. Participants had a median age of 66, and 43% were women. They were randomly assigned to 140 mg of evolocumab or placebo by injection every two weeks, added to statin or other lipid-lowering therapy, and followed for a median of 4.6 years.

All-cause mortality and death broken out by cardiovascular, noncardiovascular and undetermined cause were prespecified secondary outcomes. It was discovered that death from any cause occurred in 434 patients on evolocumab (a 5-year rate of 7.9%) compared to 539 on placebo (9.7%), a 20% relative reduction. The benefit was broadly consistent by cause: cardiovascular death fell 21% and death of undetermined cause fell 36%, while noncardiovascular death was lower but didn't reach a significant difference.

A prespecified landmark analysis found no mortality difference in the first 1.5 years but a 27% reduction after that point, a delayed pattern the authors said resembles what's been seen in statin trials. A separate, exploratory multistate model estimated that about 78% of evolocumab's effect on noncardiovascular death was explained by its prevention of nonfatal heart attacks, strokes and revascularization procedures earlier in the disease course, reflecting the elevated risk of later death that follows those events. The benefit held consistently across subgroups, including age, sex, region, race, diabetes status and background lipid therapy.

The mortality data landed alongside two global real-world studies Amgen also presented at this year’s European Society of Cardiology Congress, pointing to a gap between guideline recommendations and everyday lipid management. One found patients with coronary artery disease who hadn't had a heart attack or stroke were often undertreated and didn't reach recommended LDL-C levels. The other found women at high risk were less likely than men to receive intensive cholesterol-lowering treatment or reach LDL-C goals across regions.

These findings come about amid an expanding label: the FDA broadened Repatha's approved use in August 2025 to adults at increased cardiovascular risk from uncontrolled LDL-C, and the European Commission approved a similar expanded indication today based on the VESALIUS-CV results.

This analysis draws strength from its size, its randomized double-blind design, and the fact that all-cause and cause-specific mortality were prespecified secondary outcomes rather than findings identified after the fact. However, the authors flagged real limitations: VESALIUS-CV “was not designed nor powered for mortality end points,” and because the trial's endpoint hierarchy placed coronary heart disease death above the mortality outcomes examined here, the P values for these results are nominal and exploratory rather than confirmatory, though the authors noted a P value that low makes chance an unlikely explanation.

Additionally, the multistate model wasn't prespecified either and should be read as descriptive. The trial population was also overwhelmingly White (93%) and drawn mostly from high-income countries, which the authors said may limit how well the findings generalize, and because evolocumab was the only PCSK9 inhibitor tested, the results can't be compared directly with other drugs in its class.

“These results support the use of intensive LDL-C lowering with evolocumab, in addition to standard therapies, to improve survival in high-risk patients who have not experienced a previous CV event, including those with high-risk diabetes without qualifying atherosclerosis,” the study's authors wrote in their conclusion.