Weekly Journal Scan: an OCEANIC wave redefines the role of factor XIa inhibition in stroke prevention

Comment on ‘Asundexian for Secondary Stroke Prevention’ which was published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2513880. OCEANIC-STROKE is a clinically important and mechanistically challenging trial. It provides the first convincing phase-3 evidence that oral factor XIa inhibition can reduce the recurrence of ischaemic stroke when added to antiplatelet therapy after a non-cardioembolic stroke or high-risk TIA, without an apparent increase in major bleeding. However, the same drug at the same dose failed in the setting where anticoagulation is highly effective—AF-related cardioembolism.2 This apparent discrepancy represents the central biological question emerging from the OCEANIC program. In OCEANIC-AF, asundexian was inferior to apixaban for the prevention of stroke or systemic embolism, indicating that FXIa inhibition cannot replace FXa inhibition in AF.3 By contrast, the benefit observed in OCEANIC-STROKE suggests a substrate-dependent effect. FXI amplifies thrombin generation and stabilizes thrombus formation, with a limited role in physiological haemostasis.4,5 In platelet-rich arterial thrombosis, activated platelets sustain FXI-dependent thrombin amplification through inflammatory and contact pathway activation, a process that may be attenuated by FXIa inhibition without materially impairing haemostasis, consistent with genetic evidence linking reduced FXI levels to lower ischaemic stroke risk and only a mild bleeding tendency.6–8 Conversely, thrombosis in AF is driven by stasis and sustained coagulation activation within the left atrial appendage, leading to fibrin-rich clots dependent on continuous thrombin generation.9 In this setting, FXIa inhibition may be insufficient to suppress the tissue factor–FXa–thrombin axis, providing a mechanistic basis for the divergent efficacy profile of asundexian across trials.