Antiphospholipid syndrome (APS) has a close association with ischemic stroke; however, the optimal treatment strategy for APS-related stroke has yet to be established. The clinical guidelines suggest using warfarin for APS-related stroke, but these suggestions are largely based on retrospective studies from the 1990s and expert opinion, rather than high-quality clinical trials. Moreover, the evidence on the role of antiplatelet drugs other than aspirin (e.g., clopidogrel) in APS-related stroke is particularly limited. Considering the relatively young age of patients with APS and the high clinical burden of using warfarin, it is necessary to verify whether warfarin is essential. Thus, the investigators aim to compare clopidogrel-based antiplatelet therapy and warfarin as a secondary preventive medication for patients with APS-related stroke. APS-STROKE is an exploratory, multicenter, prospective, randomized, open, blinded-endpoint clinical trial. Adult patients with definite APS who have a history of ischemic stroke will be included. Patients with high-risk APS (triple positivity or persistently high titers of anti-cardiolipin or anti-β2-glycoprotein I antibodies), systemic lupus erythematous, or indications for continued antiplatelet or anticoagulant therapy will be excluded. Eligible patients will be 1:1 randomized to receive clopidogrel-based antiplatelet therapy or warfarin. Patients assigned to the clopidogrel-based antiplatelet therapy group will be permitted to use additional antiplatelet drugs other than clopidogrel at the investigator's discretion. The primary outcome is a composite of any death, major adverse cardiovascular events, systemic thromboembolic events, and major bleeding during a follow-up period of at least 4 years. This study would provide valuable information for determining the optimal secondary prevention strategy for APS-related stroke.

Inclusion Criteria:

• Age 19 years or older
• History of ischemic stroke (cerebral infarction, transient ischemic attack, or retinal arterial ischemic event)
• Patients who meet the laboratory diagnostic criteria for antiphospholipid syndrome (APS)
• Patients or guardians who agree to the study protocol and sign with informed consent

Exclusion Criteria:

• Patients with high-risk antiphospholipid antibody profile (triple positivity; persistent high-titers exceeding 80 U/mL of anti-cardiolipin or anti-β2 glycoprotein I antibodies)
• Systemic lupus erythematous
• Patients unable to discontinue previously taken anticoagulants or antiplatelet agents (e.g., atrial fibrillation, valvular heart disease, or a history of percutaneous coronary intervention)
• Women who are pregnant, breastfeeding, or intending to become pregnant during the study period
• Deemed unsuitable for participation in the study for more than four years, as per the investigators' discretion

Prospective, Randomized, Open-label, Blinded Endpoint (PROBE) trial