Add-on PCSK9 Inhibitor Therapy for Acute Stroke Due to Intracranial Atherosclerosis: A Randomized Clinical Trial

BackgroundIntracranial atherosclerotic stenosis (ICAS) is a major cause of ischemic stroke with high recurrence rates despite intensive therapy. The efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) as adjunctive treatment in ICAS remains unclear. MethodsWe conducted a prospective, randomized, open-label, blinded-endpoint trial involving 62 patients with symptomatic ICAS. Participants were randomized 1:2 to receive either a PCSK9i (alirocumab 75 mg every two weeks) plus high-intensity statin or high-intensity statin alone for six months. The primary outcome was the change in intracranial artery stenosis measured by high-resolution vessel-wall magnetic resonance imaging. Secondary outcomes included plaque enhancement volume, low-density lipoprotein cholesterol (LDL-C) target achievement (<55 mg/dL), recurrent stroke events, modified Rankin Scale, and safety assessments. ResultsAmong 62 participants (median age, 66 years; 68% men), 60 completed the study per protocol. At 6 months, median stenosis reduction was greater in the PCSK9i group (7.1%; 95% CI, 3.6-12.8%) than in controls (- 1.2%; 95% CI, -4.9-4.5%) (p < 0.01). Both groups showed significant reduction in plaque enhancement volume, but between-group difference was not significant (4.3 vs 4.0 mm3; p = 0.28). LDL-C <55 mg/dL was achieved in 85% of the PCSK9i group vs 13% of controls (p < 0.01). Recurrent stroke occurred in 5% vs 13% of patients (p = 0.39). No serious adverse events were reported in either group. ConclusionIn patients with symptomatic ICAS, adjunctive PCSK9i therapy significantly reduced intracranial stenosis and improved LDL-C control over 6 months. While both treatment strategies reduced plaque enhancement, PCSK9i provided additional benefit in stenosis regression. Larger and longer-term studies are warranted to confirm these findings and clarify optimal LDL-C targets for ICAS management. Trial RegistrationClinicalTrials.gov Identifier: NCT05001984