PCSK9 Inhibitors for Secondary Prevention in Patients with Prior Stroke: A PRISMA-Guided Systematic Review

Survivors of ischemic stroke face a persistently high risk of recurrent cerebrovascular and cardiovascular events. Intensive lipid-lowering therapy is central to secondary prevention, yet substantial residual risk remains despite statins ± ezetimibe. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab and alirocumab, produce large additional reductions in LDL cholesterol (LDL-C) and may mitigate recurrent stroke. This study aims to synthesize randomized and high-quality evidence on efficacy and safety of PCSK9 inhibitors for secondary prevention in adults with a prior ischemic stroke or Transient Ischemic Attack (TIA) using a PRISMA-guided approach.

PubMed/MEDLINE and the Cochrane Library (inception to September 7, 2025) were searched for Randomized Controlled Trials (RCTs), prespecified subgroup analyses, and systematic reviews/meta-analyses reporting stroke outcomes with PCSK9 inhibitors. Outcomes included total/ischemic/hemorrhagic stroke, Major Adverse Cardiovascular Events (MACE), mortality, and safety signals (e.g., neurocognition, intracranial hemorrhage). A systematic review with narrative synthesis was conducted; no de novo meta-analysis was performed due to heterogeneity in stroke outcome definitions, secondary endpoint reporting, and overlap across existing pooled analyses.

Of 535 records identified, seven studies met inclusion criteria: two large cardiovascular outcomes RCTs-FOURIER (evolocumab) and ODYSSEY OUTCOMES (alirocumab), plus five systematic reviews/meta-analyses. Both RCTs reduced ischemic stroke and MACE without increasing hemorrhagic stroke; prespecified analyses in participants with prior ischemic stroke were directionally consistent, though underpowered for stroke-specific endpoints. Meta-analyses (>45,000 participants) confirm reduced total/ischemic stroke with no signal for intracranial hemorrhage. Current guidelines recommend adding a PCSK9 inhibitor in very-high-risk patients not achieving LDL-C goals on maximally tolerated statins ± ezetimibe.

PCSK9 inhibitors produce large, durable LDL-C reductions and are associated with fewer atherosclerotic events, with a consistent signal toward fewer ischemic strokes, although stroke was largely a secondary endpoint in the available trials.

PCSK9 inhibitors produce large, durable LDL-C reductions and are linked to fewer atherosclerotic events, with a favorable signal for ischemic stroke and no observed excess in hemorrhagic or cognitive harms. These findings, though derived mainly from secondary endpoints, support use in high-risk secondary prevention when LDL-C remains above target on optimal therapy. Clinical benefit will be greatest in patients with higher baseline risk and deeper LDL-C lowering. Further stroke-specific trials, extended follow-up in older populations, and harmonized outcome definitions are needed to strengthen certainty and optimize patient selection and value.