Edoxaban Fails to Improve Stroke Risk, Increases Bleeding Risk After Intracranial Hemorrhage

Edoxaban did not significantly lower stroke or systemic embolism in patients with atrial fibrillation (AF) after intracranial hemorrhage (ICrH), and even increased bleeding in this population, according to data from the ENRICH-AF trial.1

These data were presented at the World Stroke Congress (WSC) 2026 in Seoul, South Korea, by Ashkan Shoamanesh, MD, associate professor of medicine and the Marta and Owen Boris Chair in Stroke Research and Care at McMaster University. ENRICH-AF was described as the “ultimate safety test” of anticoagulation for AF patients upon its initiation.1,2

“Direct oral anticoagulation reduces the risk of ischemic stroke in ICrH survivors with AF and might increase the risk of recurrent ICrH, but the net clinical benefit remains uncertain,” Shoamanesh and colleagues wrote. “We hypothesized that factor Xa inhibition with edoxaban would provide net benefit by reducing stroke (ischemic or hemorrhagic) or systemic embolism (SE) compared with avoiding anticoagulation in ICrH survivors with high-risk AF.”1

ENRICH-AF was a prospective, randomized open-label, blinded end-point, investigator-initiated study aiming to define the efficacy and safety of edoxaban versus non-anticoagulant medical therapy in high-risk patients with AF and previous ICrH. Patients were eligible for inclusion if they were ≥45 years of age with a previous ICrH, documented AF, and a CHA2DS2-VASc score ≥2. Patients with an ICrH within 14 days, secondary macrovascular, neoplastic, or infectious causes of ICrH, and a need for ongoing oral anticoagulant therapy for indications other than AF, among other criteria, were excluded.2

Patients were enrolled in a 1:1 ratio to receive either edoxaban 30 or 60 mg or non-anticoagulant medical therapy, the latter of which was determined by the local investigator and included either no antithrombotic therapy or antiplatelet monotherapy. The primary outcomes were incidence of stroke or systemic embolism from randomization to the common study end date – for an average of 3 years – and major hemorrhage as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria. Secondary endpoints included ischemic stroke, cardiovascular death, and hemorrhagic stroke, among others.2

A total of 948 patients were enrolled in the trial, with a mean age of 77 years. Over an average 28-month follow-up, Shoamanesh and colleagues recorded no significant reduction in the primary composite endpoint with edoxaban versus no anticoagulation (11.8% vs. 12.8%; HR, 0.88; 95% CI, 0.61-1.26; P = .48). Additionally, the primary safety outcome of ISTH major bleeding occurred in 11.6% of patients receiving edoxaban versus 5.2% receiving no anticoagulation (HR, 2.23; 95% CI, 1.39-3.59; P <.001).3

“Our findings do not support the use of edoxaban in unselected patients with AF after intracranial hemorrhage, but highlight the need for an individualized decision-making approach,” Shoamanesh stated in an earlier interview. “Ongoing trials, including the double-blinded, randomized ASPIRE trial comparing apixaban vs. aspirin, will add to the evidence base. Additionally, a prospective, individual participant data meta-analysis of all trials (COCROACH) will ultimately provide useful additional insights on how best to individualize optimal stroke prevention in this very vulnerable patient population.”4

References

1. Shoamanesh A. Edoxaban for Stroke Prevention in Intracranial Hemorrhage Survivors With Atrial Fibrillation (ENRICH-AF): An Open-Label, Blinded-Endpoint, Parallel Group Randomized Trial. Presented at the World Stroke Congress (WSC) 2026, Seoul, South Korea. October 21-23, 2026.

2. Population Health Research Institute. EdoxabaN foR IntraCranial Hemorrhage Survivors With Atrial Fibrillation (ENRICH-AF) (ENRICH-AF). ClinicalTrials.gov Identifier: NCT03950076. Updated September 1, 2026. Accessed October 23, 2026. https://clinicaltrials.gov/study/NCT03950076?term=NCT03950076&rank=1

3. Brooks A. ENRICH-AF: A Dosing Clue Emerges After Edoxaban's Miss, With Ashkan Shoamanesh, MD. HCPLive. August 30, 2026. October 23, 2026. https://www.hcplive.com/view/enrich-af-a-dosing-clue-emerges-after-edoxaban-s-miss-with-ashkan-shoamanesh-md

4. European Society of Cardiology. Safer stroke prevention strategies are needed for patients with atrial fibrillation after intracranial haemorrhage. Published August 29, 2026. Accessed October 23, 2026. https://www.escardio.org/news/press/press-releases/safer-stroke-prevention-strategies-are-needed-for-patients-with-atrial-fibrillation-after-intracranial-haemorrhage/