PCSK9 Inhibitor Evolocumab Reduces First Major Cardiovascular Events in High-Risk Patients Without Prior Heart Attack or Stroke

The international VESALIUS-CV clinical trial revealed that evolocumab, a PCSK9 inhibitor medication, significantly reduces the risk of first major cardiovascular events in adults with atherosclerotic cardiovascular disease or diabetes who have no history of heart attack or stroke. These findings were presented at the American Heart Association's Scientific Sessions 2025 and simultaneously published in The New England Journal of Medicine.

Over a median follow-up period of 4.6 years, participants receiving evolocumab experienced a 25% reduction in the risk of coronary heart disease death, heart attack, or ischemic stroke compared to those receiving placebo. The study also demonstrated a 19% reduction in the risk of coronary heart disease death, heart attack, ischemic stroke, or arterial revascularization. Additional benefits included a 27% reduction in cardiovascular death, heart attack, or ischemic stroke and a 36% reduction in heart attack specifically.

Lead study author Erin A. Bohula, M.D., D.Phil., emphasized the significance of these results, stating that this represents the first demonstration of improved cardiovascular outcomes with a PCSK9 inhibitor in patients without previous heart attack or stroke who were already receiving high-intensity lipid-lowering regimens. The study included 12,257 adults with an average age of 66 years from 33 countries, conducted at 745 healthcare sites between June 2019 and November 2021.

The lipid sub-study revealed dramatic cholesterol improvements, with evolocumab reducing LDL-C levels by nearly 55% from a median of 115 mg/dL at enrollment to 45 mg/dL at 48 weeks. In contrast, placebo group participants maintained elevated LDL-C levels around 109 mg/dL. This substantial reduction aligns with findings from the Cholesterol Treatment Trialists' Collaboration and supports intensive LDL-C lowering to targets around 40 mg/dL for cardiovascular prevention.

Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality globally, affecting millions through conditions including coronary heart disease, cerebrovascular disease, peripheral artery disease, and aortic atherosclerotic disease. The study population included patients with qualifying atherosclerosis without prior heart attack or stroke and those with high-risk diabetes, representing a substantial portion of the global population at elevated cardiovascular risk.

The consistency of results across key subgroups, including participants with high-risk diabetes without qualifying ASCVD who represented one-third of the study population, strengthens the potential applicability of these findings. Dr. Bohula noted that the longer follow-up period in VESALIUS-CV compared to prior PCSK9 inhibitor trials may have captured the full clinical benefit, as there is typically a delay in measurable cardiovascular benefits from LDL-C lowering.

While evolocumab is FDA-approved for treating high LDL-C levels, insurance coverage barriers may limit access for some patients. The study authors suggest that together with data from genetic studies of PCSK9 variants and other outcomes research, these findings support long-term PCSK9 inhibitor use for improving cardiovascular morbidity and potentially mortality over time. Additional information about cardiovascular health and cholesterol management is available through resources like the American Heart Association's health information on Prevention and Treatment of High Cholesterol.

Study limitations included a small percentage of patients not receiving cholesterol-lowering treatment at study initiation and limited racial and ethnic diversity in the participant population, with researchers recommending future studies across more diverse populations to confirm broader applicability. The findings nevertheless represent a significant advancement in preventive cardiovascular medicine, offering new strategies for reducing first cardiovascular events in high-risk populations worldwide.