In patients with symptomatic intracranial atherosclerotic stenosis, adjunctive PCSK9i therapy (alirocumab) significantly reduced intracranial stenosis and improved low-density lipoprotein cholesterol control over 6 months compared to high-intensity statin alone.
Key Findings
Results
Add-on PCSK9 inhibitor therapy produced significantly greater reduction in intracranial artery stenosis compared to high-intensity statin alone at 6 months.
Median stenosis reduction was 7.1% (IQR, 3.6–12.8%) in the PCSK9i group versus -1.2% (IQR, -4.9–4.5%) in controls (P<0.001)
The baseline-adjusted mean difference estimated using a generalized linear model was 8.9 percentage points (95% CI, 5.1–12.6)
Stenosis was measured by high-resolution vessel-wall magnetic resonance imaging
60 of 62 enrolled participants completed the study per protocol
Methods
The PCSK9 inhibitor used was alirocumab 75 mg every 2 weeks added to high-intensity statin therapy for 6 months.
Prospective, randomized, open-label, blinded-end point (PROBE) trial design
62 patients with symptomatic intracranial atherosclerotic stenosis were randomized 1:2 to PCSK9i plus statin or statin alone
Median age was 66 years; 77% of participants were men
Trial registration: NCT05001984
Results
LDL cholesterol target of <55 mg/dL was achieved in a significantly higher proportion of patients in the PCSK9i group compared to controls.
85% of the PCSK9i group achieved LDL-C <55 mg/dL versus 13% of controls (P<0.01)
LDL-C target achievement was a prespecified secondary outcome
This reflects substantially improved lipid control with the addition of alirocumab
Results
Both groups showed significant reduction in plaque enhancement volume, but the difference between groups was not statistically significant.
Mean plaque enhancement volume reduction was 4.3 mm³ in the PCSK9i group versus 4.0 mm³ in controls (P=0.79)
Plaque enhancement volume was a prespecified secondary outcome measured by high-resolution vessel-wall MRI
The lack of between-group difference suggests statin therapy alone may be sufficient for reducing plaque inflammation/enhancement
Results
Recurrent stroke rates were numerically lower in the PCSK9i group compared to controls, but the difference did not reach statistical significance.
Recurrent stroke occurred in 5% of the PCSK9i group versus 13% of controls (P=0.34)
The trial was not powered to detect differences in clinical stroke recurrence
Recurrent stroke events were a prespecified secondary outcome
Results
No serious adverse events were reported in either treatment group during the 6-month study period.
Safety was a prespecified secondary assessment
The finding applied to both the PCSK9i plus statin group and the statin-alone group
This supports the safety profile of alirocumab as adjunctive therapy in this population
What This Means
This research suggests that adding a PCSK9 inhibitor drug (alirocumab) to standard statin therapy may help shrink artery narrowing in the brain caused by plaque buildup. In this small clinical trial of 62 patients who had recently had a stroke due to intracranial atherosclerosis — a condition where arteries inside the skull become dangerously narrowed — those who received the add-on treatment showed an average 7.1% reduction in arterial narrowing over 6 months, compared to a slight worsening of 1.2% in those on statins alone. Additionally, far more patients in the PCSK9i group reached the recommended LDL ('bad') cholesterol target of below 55 mg/dL (85% vs. 13%).
The study also found that both groups experienced similar reductions in plaque inflammation as measured by MRI imaging, suggesting that statins alone may adequately reduce plaque activity even if they don't shrink the physical narrowing as effectively. Fewer patients in the PCSK9i group had another stroke (5% vs. 13%), though the study was too small to confirm whether this difference was meaningful or due to chance.
This research matters because intracranial atherosclerosis is a leading cause of stroke worldwide, particularly in Asian populations, and current treatments often fail to prevent recurrence. The findings suggest that PCSK9 inhibitors could offer an additional tool for reducing arterial narrowing and lowering cholesterol levels in these high-risk patients, with no serious safety concerns observed. Larger trials will be needed to confirm whether these changes in artery narrowing translate into fewer strokes over time.
Pan Y, Tsai Y, Weng H, Lee J, Yang J, Lin L, et al.. (2026). Add-On PCSK9 Inhibitor Therapy for Acute Stroke Attributable to Intracranial Atherosclerosis: A Randomized Clinical Trial.. Journal of the American Heart Association. https://doi.org/10.1161/JAHA.125.048729