Comparison of clopidogrel-based antiplatelet therapy versus warfarin as a secondary prevention strategy for AntiPhospholipid Syndrome-related STROKE (APS-STROKE): Rationale and design of a prospective, randomized, open-label, blinded-endpoint trial: Rationale and design of a prospective, randomized, open-label, blinded-endpoint trial

Background: Antiphospholipid syndrome (APS) is closely associated with ischemic stroke. However, optimal treatment for APS-related stroke remains unestablished, as current guidelines are based on outdated studies and expert opinion rather than high-quality clinical trials. Evidence on antiplatelet agents other than aspirin, such as clopidogrel, in APS-related stroke is particularly limited. Given the relatively young age of patients with APS and the burden of warfarin use, verifying its necessity is crucial. This study compares clopidogrel-based antiplatelet therapy and warfarin for secondary prevention in APS-related stroke. Methods: APS-STROKE is an exploratory, multicenter, prospective, randomized, open, blinded-endpoint clinical trial. Adult patients with definite APS and a history of ischemic stroke or transient ischemic attack (TIA) 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 erythematosus, or other major indications for continued antiplatelet or anticoagulant therapy will be excluded. Participants will be randomized 1:1 to receive clopidogrel-based antiplatelet therapy or warfarin. More than 200 patients are planned for inclusion across 32 stroke centers. The primary endpoint is a composite of any death, major adverse cardiovascular events, systemic thromboembolic events, and major bleeding during at least 4 years of follow-up. Secondary endpoints include major adverse cardiovascular events, ischemic stroke, any bleeding, major bleeding, intracranial bleeding, clinically relevant non-major bleeding, any death, and thrombosis-related death. Conclusion: This study will provide valuable information on the optimal secondary prevention strategy for APS-related stroke. Trial registration: ClinicalTrials.gov: NCT05995600; CRIS: KCT0008900.