The OCEANIC-STROKE trial, a large Phase 3 randomized controlled trial enrolling 12,327 adults across 37 countries and published in the New England Journal of Medicine, delivers compelling evidence that asundexian (50 mg daily), a selective Factor XIa inhibitor, reduces recurrent ischemic stroke by 26% (6.2% vs 8.4%), major cardiovascular events by 17%, and disabling/fatal strokes by 31% when added to standard antiplatelet therapy, with no increase in major bleeding. This high-quality RCT (double-blind, event-driven, representative sample with 25% over age 75 and balanced stroke subtypes) stands in stark contrast to decades of failed intensification strategies. What the original MedicalXpress coverage and similar early reports miss is the historical pattern of near-universal trade-offs: MATCH, CHARISMA, and SPS3 trials using intensified antiplatelets consistently hit bleeding walls; WARSS and ESPRIT showed warfarin added little net benefit over aspirin in non-cardioembolic stroke due to hemorrhage; NAVIGATE-ESUS and RE-SPECT ESUS with DOACs in embolic stroke of undetermined source either lacked efficacy or increased bleeding. Asundexian changes the equation by targeting the contact pathway amplification loop that drives pathological thrombosis far more than normal hemostasis. Synthesizing the primary NEJM report with the preceding PACIFIC-STROKE Phase 2 trial (Lancet Neurology, 2022; n=1,800; showed directional reduction in covert infarcts with clean safety) and a 2023 Nature Reviews Cardiology synthesis on FXI inhibitors reveals a consistent biological narrative: unlike platelet inhibitors or thrombin/factor Xa blockers, FXIa inhibition preserves fibrin formation at vascular injury sites while attenuating feedback loops on damaged endothelium or atherosclerotic plaque. No significant conflicts of interest beyond standard industry sponsorship (Bayer) were evident; the independent PHRI coordination adds credibility. Original coverage also underplayed absolute risk reduction (approximately 2.2% for stroke over median ~11-month follow-up, NNT ~45) and the potential for this agent in high-bleeding-risk subgroups where physicians currently withhold intensification. This breakthrough validates a 20-year hypothesis that selective contact-pathway inhibition can finally break the efficacy-bleeding coupling that has limited secondary prevention since the aspirin era. If replicated in ongoing analyses and real-world registries, asundexian could shift guidelines, reduce the estimated 500,000+ annual recurrent strokes globally in non-cardioembolic patients, and open combination strategies previously deemed too dangerous. Limitations include the need for longer-term data on rare events and cost-effectiveness once approved, but the consistency across age, sex, severity, and etiology subgroups is genuinely practice-changing.