Alirocumab shrank intracranial stenosis on MRI — but the trial is small

Design

prospective, randomised, open-label, blinded-endpoint trial, 1:2 allocation, 6 months

Population

62 patients with symptomatic intracranial atherosclerotic stenosis, median age 66, 77% men

Primary outcome

change in intracranial artery stenosis on high-resolution vessel-wall MRI at 6 months

Effect

median reduction 7.1% vs −1.2%; baseline-adjusted difference 8.9 percentage points (95% CI 5.1-12.6); LDL below 55 mg/dL in 85% vs 13%

An open-label, blinded-endpoint trial randomised 62 patients with symptomatic intracranial atherosclerotic stenosis 1:2 to alirocumab 75 mg fortnightly plus high-intensity statin, or high-intensity statin alone, for six months. The primary outcome was change in stenosis on high-resolution vessel-wall MRI. Median age was 66; 77% were men; 60 completed per protocol.

Median stenosis reduction was 7.1% (IQR 3.6-12.8) with the PCSK9 inhibitor against −1.2% (IQR −4.9 to 4.5) with statin alone; the baseline-adjusted mean difference was 8.9 percentage points (95% CI 5.1-12.6). LDL cholesterol below 55 mg/dL was reached by 85% against 13%. Plaque enhancement volume fell in both groups with no difference between them. Recurrent stroke was 5% against 13% (P = 0.34). No serious adverse events were reported.

Intracranial atherosclerosis is among the most common causes of stroke in South and East Asian populations and has stubbornly resisted everything beyond aggressive medical therapy, so a regression signal on imaging is worth noting. But 62 patients, open-label treatment allocation, and an imaging primary endpoint together mean this is a reason to run a larger trial, not to start prescribing. The stroke numbers — three events against eight — are exactly the kind that look persuasive and prove nothing.

• Do not add a PCSK9 inhibitor for intracranial stenosis outside a trial on the strength of this
• Do check that high-intensity statin and the LDL target are actually being achieved — 13% in the control arm were at goal
• Vessel-wall MRI stenosis is a surrogate; no trial has yet shown it tracks stroke prevention in this population
• Intracranial atherosclerosis is proportionally a much larger cause of stroke in Indian practice than in Western cohorts, which is why this question matters here

Why it matters

It raises the possibility that intracranial plaque regresses under deep LDL lowering, in a disease where nothing has moved for years.

Don't overread it

Sixty-two patients, open-label, imaging endpoint — the stroke difference is not evidence of stroke prevention.

The statistics, in plain English

The primary endpoint is a change in measured stenosis, not a clinical event. An 8.9-percentage-point adjusted difference with an interval of 5.1 to 12.6 is a real imaging effect, but the recurrent stroke comparison (5% vs 13%, P = 0.34) involves so few events that it is compatible with harm as well as benefit. Open-label allocation also means the control arm's LDL achievement of 13% may partly reflect how the arms were managed rather than what the drugs do.

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