Two in five cardiovascular events are not the patient's first

Design

prespecified analysis of a randomised double-blind placebo-controlled trial, negative binomial regression for total events

Population

12,257 patients with atherosclerosis or high-risk diabetes, no prior MI or stroke, LDL-C 90 mg/dL or above on optimised lipid-lowering therapy; median 4.6 years

Primary outcome

total (first and subsequent) 4-point and 3-point major adverse cardiovascular events

Effect

total 4-point MACE IRR 0.80 (95% CI 0.71-0.90); 55 total events prevented per 1,000 patients over 5 years (95% CI 36-74)

VESALIUS-CV randomised 12,257 patients with qualifying atherosclerosis or high-risk diabetes, no prior myocardial infarction or stroke, and LDL cholesterol at or above 90 mg/dL on optimised therapy, to evolocumab or placebo. Over a median 4.6 years there were 1,654 first four-point events and 1,107 subsequent ones — 67% more events than a first-event analysis counts. This prespecified analysis used negative binomial regression to capture all of them.

Evolocumab reduced first four-point events by 19% (HR 0.81, 95% CI 0.73-0.89), subsequent events by 25% (IRR 0.75, 0.61-0.91) and total events by 20% (IRR 0.80, 0.71-0.90). For three-point events the reductions were 25%, 37% and 27% respectively. Translated into absolute terms, the projection is 31 first and 24 subsequent four-point events prevented per 1,000 patients over five years — 55 in total (95% CI 36-74). Results held across statin intensity and across the presence or absence of qualifying atherosclerosis.

The practical point is about how benefit is counted rather than about the drug. Time-to-first-event analysis discards everything after the index event, which is precisely the burden that fills clinics and beds. Where a PCSK9 inhibitor is being justified — and in Indian practice that justification is usually financial — the total-event number is the honest one to put in the argument, and it is roughly twice the first-event number.

• Quote total-event benefit, not first-event benefit, when arguing for a PCSK9 inhibitor
• Recheck LDL on maximum tolerated statin plus ezetimibe before assuming a patient needs this class
• Primary prevention here means no prior infarct or stroke, not absence of atherosclerosis — these patients had established disease or high-risk diabetes
• Cost and cold-chain remain the practical barriers in India; confirm access before raising the option with a patient

Why it matters

First-event analysis has been quietly understating what lipid lowering is worth in exactly the patients whose funding is hardest to justify.

Don't overread it

This is a prespecified secondary analysis of total events, not an independent trial result.

The statistics, in plain English

An incidence rate ratio counts all events a patient has, so it can differ from a hazard ratio that stops at the first. Here the two agree closely (0.80 and 0.81), which means the drug is not simply delaying a first event but reducing the whole stream. The confidence interval on subsequent events (0.61-0.91) is wider because fewer patients contribute to it.

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