A PCSK9 inhibitor cut first heart attacks and strokes in people who had never had one

The PCSK9 inhibitor evolocumab reduced the risk of a first major cardiovascular event in patients who had atherosclerosis or diabetes but had never had a heart attack or stroke, according to the VESALIUS-CV trial published in the New England Journal of Medicine on 8 November [s1].

This fills a specific gap. Evolocumab's cardiovascular outcome evidence has until now come from patients who already had a documented event behind them [s1]. Whether the same drug prevents the first one was, in the authors' own framing, unknown [s1].

The trial

VESALIUS-CV was an international, double-blind, randomised, placebo-controlled trial in patients with atherosclerosis or diabetes, no previous myocardial infarction or stroke, and an LDL cholesterol level of at least 90 mg per decilitre [s1]. Patients were assigned 1:1 to evolocumab 140 mg every two weeks or placebo [s1].

A total of 12,257 patients were randomised — 6,129 to evolocumab and 6,128 to placebo — and included in the efficacy analyses [s1]. Median age was 66 years, 43% were women, and 93% were White [s1]. Median follow-up was 4.6 years [s1].

There were two primary endpoints. Three-point MACE was a composite of death from coronary heart disease, myocardial infarction, or ischaemic stroke; four-point MACE added ischaemia-driven arterial revascularisation [s1].

The results

Three-point MACE occurred in 336 patients in the evolocumab group, a five-year Kaplan–Meier estimate of 6.2%, versus 443 patients in the placebo group, 8.0% (hazard ratio 0.75; 95% CI 0.65 to 0.86; P<0.001) [s1].

Four-point MACE occurred in 747 evolocumab patients, a five-year estimate of 13.4%, versus 907 on placebo, 16.2% (hazard ratio 0.81; 95% CI 0.73 to 0.89; P<0.001) [s1].

No between-group difference was seen in the incidence of safety events [s1].

Reading the size of the effect

A 25% relative reduction in three-point MACE is substantial. The absolute difference is the number that determines who this is worth giving to: 1.8 percentage points over five years, from 8.0% to 6.2% [s1]. Roughly speaking, that is one event avoided for every 55 or so patients treated for five years, though the trial reports Kaplan–Meier estimates rather than a number needed to treat, and the arithmetic should be read as an approximation of the trial's own figures rather than a figure the investigators published.

That trade-off is different from the one in secondary prevention because the baseline risk is lower. FOURIER, the 2017 trial that established evolocumab's outcome benefit, enrolled 27,564 patients who already had atherosclerotic cardiovascular disease and were on statin therapy, with LDL cholesterol of 70 mg per decilitre or higher [s2]. Its primary composite endpoint — cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina, or coronary revascularisation — occurred in 9.8% of evolocumab patients versus 11.3% on placebo over a median 2.2 years (hazard ratio 0.85; 95% CI 0.79 to 0.92) [s2]. Its key secondary endpoint of cardiovascular death, MI or stroke fell from 7.4% to 5.9% (hazard ratio 0.80; 95% CI 0.73 to 0.88) [s2].

So the relative risk reductions in the two populations are broadly comparable, which is what LDL-lowering trials have generally shown: the benefit tracks the size of the LDL reduction rather than the label attached to the patient. What changes between primary and secondary prevention is how many people you must treat, for how long, to convert that relative reduction into an averted event — and therefore how the cost and the injection burden weigh against it.

The limits worth stating

Ninety-three percent of VESALIUS-CV participants were White, which constrains how confidently the result generalises to the populations carrying much of the world's atherosclerotic disease burden [s1]. The entry requirement of LDL cholesterol at or above 90 mg per decilitre means these were not patients at goal on existing therapy; the trial does not speak to people already well controlled. Median follow-up of 4.6 years is long for a trial and short for primary prevention, which is a decades-long proposition.

The trial was funded by Amgen, evolocumab's manufacturer [s1]. FOURIER was also funded by Amgen [s2].

Nothing here is a treatment recommendation. VESALIUS-CV establishes that PCSK9 inhibition prevents first events in a defined higher-risk group without prior MI or stroke; who should receive it, and in what sequence relative to statins and ezetimibe, is a guideline question that this trial informs rather than settles.