New, sophisticated drugs did not move the needs on hearts attacks, strokes: what this teaches us

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In March this year, the American College of Cardiology (ACC) and the American Heart Association (AHA), both globally recognised premier organisations in cardiovascular medicine, handed down their newest dyslipidemia guideline, and gave universal Lipoprotein(a) screening in every adult a ‘Class I’ recommendation -- the strongest tier there is. The High-Sensitivity C-Reactive Protein (hsCRP) test got a lighter endorsement: checked selectively, alongside coronary calcium scoring, to sharpen risk estimates when they’re uncertain. These two long-debated biomarkers, were both freshly blessed by the field’s governing societies.

Then arrived the irony. On July 31, pharma major Novo Nordisk’s ziltivekimab — a drug built to block the inflammatory pathway behind elevated C-Reactive Protein (CRP) — fully hit its target in a Phase 3 clinical trial and still didn’t move the needle on heart attacks or strokes. Five weeks later, pelacarsenm, a drug that lowers high levels of Lp(a) failed the same way. Within six months of the guideline telling every clinician to start checking these numbers, the two flagship drugs built to act on them came up empty.

It’s a familiar shape for cardiology. Heart disease mortality fell almost every year through the back half of the last century — statins, blood pressure control, smoking cessation, better acute care — and that decline has visibly slowed this past decade, even as the drug arsenal has never been more sophisticated. LDL (’bad cholesterol’) is already driven remarkably low in anyone on a serious statin; medicine needed a new lever, and reached for the two candidates the guidelines had just endorsed. Neither has delivered yet.

On September 4, Novartis announced pelacarsen missed the primary endpoint of Lp(a)HORIZON , the first cardiovascular outcomes trial ever run for a drug built to lower lipoprotein(a). Pelacarsen is an antisense drug — a short, lab-made strand of genetic material injected monthly, designed to intercept the liver’s instructions for building Lp(a) before it’s ever made, rather than mopping up what’s already circulating. In 8,323 patients with established heart disease, it cut Lp(a) by roughly 80%. And yet, there was no reduction in heart attacks or stroke.

Lp(a) was drilled into me in medical school as one of the ‘unfair’ risk factors — a number you’re essentially born with, indifferent to diet or willpower, and loaded disproportionately onto South Asian patients, who as a population carry some of the highest mean Lp(a) levels of any group studied. It helped explain a pattern every cardiology rotation eventually shows you: South Asian patients with premature, multi-vessel disease and normal LDL numbers. That teaching isn’t wrong, and this trial doesn’t overturn it — Lp(a) is a real, heritable, biologically active risk factor. What it disputes is narrower: whether lowering it, this late and this fast, changes what happens next.

Here’s the plain version of how a heart attack builds.