Estimated Theoretical Benefit of Aggressive LDL Lowering in Patients With Symptomatic Intracranial Atherosclerosis

OBJECTIVES: Given the high risk of recurrent atherosclerotic vascular events in patients with stroke due to intracranial atherosclerotic disease (ICAD), we estimated the potential benefit of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in this population. METHODS: In this secondary analysis of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, we estimated the association between 30-day low-density lipoprotein (LDL) reduction and recurrent stroke or myocardial infarction (MI) beyond 30 days (primary outcome). Estimates were assessed using adjusted Cox proportional hazards regression. We applied relative LDL reduction estimates from PCSK9i trials to project adjusted incidence rate differences of the primary outcome with an equivalent LDL reduction. RESULTS: Of the 451 patients from SAMMPRIS, 378 met inclusion criteria. In adjusted Cox regression, every 10 mg/dL LDL improvement was associated with a 9% lower rate of the primary outcome (adjusted hazard ratio 0.91, 95% CI 0.83-0.997). Assuming an average projected effect of PCSK9i, estimating if half of SAMMPRIS patients were treated, PCSK9i use could reduce the annualized risk of the primary outcome by 33.2% in this trial population. DISCUSSION: Every 10 mg/dL reduction in LDL for patients with stroke due to ICAD is associated with lower rates of recurrent stroke or MI, and this theoretical framework suggests that PCSK9i can help achieve this goal. TRIAL REGISTRATION INFORMATION: Secondary analysis of NCT00576693 prospectively registered interventional clinical trial. First registered December 7, 2007. Actual study start date: October 2008. https://clinicaltrials.gov/show/NCT00576693. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that a higher absolute reduction in LDL was associated with a lower risk of recurrent cerebral infarction or MI in patients with recent stroke due to intracranial stenosis.