Design: Prespecified total-events analysis of a randomised, double-blind, placebo-controlled trial (VESALIUS-CV)
Population: 12,257 patients with atherosclerosis or high-risk diabetes, no prior MI or stroke, LDL-C ≥90 mg/dL on optimised therapy
Primary outcome: Total (first and subsequent) 4-point and 3-point MACE
Effect: Total 4-P MACE IRR 0.80 (95% CI 0.71–0.90); 55 fewer events per 1,000 over 5 years (36–74)

VESALIUS-CV randomised 12,257 patients with atherosclerosis or high-risk diabetes, no prior MI or stroke, and LDL cholesterol of 90 mg/dL or more despite optimised lipid-lowering therapy, to evolocumab or placebo. The main trial showed fewer first events. This prespecified analysis counted every event, first and subsequent, over a median 4.6 years.

There were 1,654 first four-point MACE (coronary death, MI, ischaemic stroke, ischaemia-driven revascularisation) and 1,107 later ones. Evolocumab reduced first events by 19% (HR 0.81, 95% CI 0.73 to 0.89), subsequent events by 25% (IRR 0.75, 0.61 to 0.91) and total events by 20% (IRR 0.80, 0.71 to 0.90). For three-point MACE, total events fell by 27% (IRR 0.73, 0.63 to 0.86). The projected benefit was 55 fewer four-point events per 1,000 patients over five years (95% CI 36 to 74). Results were consistent by statin intensity.

This extends PCSK9 inhibition from secondary prevention to high-risk patients before a first MI or stroke, and shows the benefit grows when repeat events are counted. In India, cost limits access; the case for maximising statin and ezetimibe first is unchanged, and this identifies who gains most if more is possible.

In a high-risk patient without prior MI or stroke whose LDL cholesterol stays at or above 90 mg/dL on statin and ezetimibe, consider a PCSK9 inhibitor.
High-risk diabetes, even without established atherosclerosis, was a qualifying group, not only coronary disease.
Counting repeat events, evolocumab was projected to prevent about 55 events per 1,000 patients over five years, 31 of them first events.
Maximise statin intensity and add ezetimibe before a PCSK9 inhibitor; the trial population was already on optimised therapy.

Why it matters

The threshold for intensive LDL lowering no longer waits for the first heart attack or stroke.

The statistics, in plain English

An incidence rate ratio of 0.80 means 20% fewer events in total, counting people who had more than one. '55 per 1,000 over 5 years' is the absolute benefit; its 95% CI (36 to 74) does not approach zero. The subsequent-event estimate is described as an association because randomisation protects only the first event.