Add‐On PCSK9 Inhibitor Therapy for Acute Stroke Attributable to Intracranial Atherosclerosis: A Randomized Clinical Trial

Background Intracranial atherosclerotic stenosis 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 intracranial atherosclerotic stenosis remains unclear. Methods We conducted a prospective, randomized, open‐label, blinded‐end point trial involving 62 patients with symptomatic intracranial atherosclerotic stenosis. Participants were randomized 1:2 to receive either a PCSK9i (alirocumab 75 mg every 2 weeks) plus high‐intensity statin or high‐intensity statin alone for 6 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 target achievement (<55 mg/dL), recurrent stroke events, modified Rankin Scale, and safety assessments. Results Among 62 participants (median age, 66 years; 77% men), 60 completed the study per protocol. At 6 months, median stenosis reduction was greater in the PCSK9i group (7.1%; interquartile range, 3.6–12.8%) than in controls (−1.2%; interquartile range, −4.9–4.5%) ( 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). Both groups showed significant reduction in plaque enhancement volume, but between‐group difference was not significant (4.3 versus 4.0 mm 3 ; P =0.79). Low‐density lipoprotein cholesterol <55 mg/dL was achieved in 85% of the PCSK9i group versus 13% of controls ( P <0.01). Recurrent stroke occurred in 5% versus 13% of patients ( P =0.34). No serious adverse events were reported in either group. Conclusions In patients with symptomatic intracranial atherosclerotic stenosis, adjunctive PCSK9i therapy significantly reduced intracranial stenosis and improved low‐density lipoprotein cholesterol control over 6 months. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT05001984.