Edoxaban did not significantly reduce stroke or systemic embolism but increased major bleeding in high-risk patients with atrial fibrillation (AF) and a prior intracranial hemorrhage, according to results from the ENRICH-AF trial presented in a Hot Line session at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany.¹
Key Takeaways
• ENRICH-AF, a randomized trial in patients with AF and prior intracranial hemorrhage, found edoxaban did not significantly reduce stroke or systemic embolism versus no anticoagulation.
• Major bleeding occurred more than twice as often with edoxaban (11.6% vs 5.2%; HR, 2.23).
• Edoxaban reduced ischemic stroke and myocardial infarction, but this was offset by a nearly 3-fold increase in hemorrhagic stroke.
• This population has historically been excluded from landmark AF anticoagulation trials, leaving prior guidance reliant on small observational studies.
• Investigators say the findings support individualized decision-making rather than routine anticoagulation, with the ongoing ASPIRE trial and COCROACH meta-analysis expected to add further evidence.
The trial compared oral anticoagulation with edoxaban against no anticoagulation in a population historically excluded from landmark AF anticoagulation trials. Investigators designed ENRICH-AF specifically to address this evidence gap, since prior guidance for anticoagulation after intracranial hemorrhage in patients with AF has relied largely on small observational studies and post hoc analyses rather than dedicated randomized trials.² A 2025 meta-analysis of these smaller studies suggested oral anticoagulation might offer net benefit among survivors of intracranial hemorrhage with AF, a signal helping motivate the dedicated ENRICH-AF trial.²
“The ideal strategy to prevent ischaemic stroke is uncertain in patients with AF and a prior intracranial haemorrhage, as these patients have been excluded from the large landmark trials assessing oral anticoagulants,” Ashkan Shoamanesh, MD, McMaster University, principal investigator of the ENRICH-AF trial, said in a statement. “This leaves us with a challenging clinical dilemma that is becoming more frequent with our ageing population.”
Edoxaban Efficacy and ENRICH-AF Trial Design
ENRICH-AF was an investigator-initiated, open-label, blinded endpoint, event-driven trial conducted across 174 sites in 20 countries.¹ Investigators enrolled patients with high-risk AF and a prior intracranial hemorrhage and randomly assigned them in a 1:1 ratio to edoxaban 60 mg once daily, with dose adjustment to 30 mg daily per label criteria, or to no anticoagulation, defined as no antithrombotic therapy or single antiplatelet therapy at clinician discretion.¹
Following a 2023 Data and Safety Monitoring Board review, investigators stopped enrolling patients with lobar intraparenchymal hemorrhage or convexity subarachnoid hemorrhage due to safety concerns.¹
The study population included 948 patients with a mean age of 77 years, and 39% were female.¹ Over an average follow-up of 28 months, edoxaban did not significantly reduce the primary endpoint of stroke, including ischemic and hemorrhagic stroke, or systemic embolism, compared with no anticoagulation (11.8% vs 12.8%; hazard ratio [HR], 0.88; 95% CI, 0.61-1.26; P = .48).¹
Edoxaban Bleeding Risk and Clinical Implications in ENRICH-AF
Ischemic stroke and myocardial infarction were significantly reduced with edoxaban compared with no anticoagulation, but this benefit was offset by an almost 3-fold excess in hemorrhagic stroke.¹ The primary safety outcome, International Society on Thrombosis and Haemostasis major bleeding, occurred in 11.6% of patients receiving edoxaban compared with 5.2% of patients receiving no anticoagulation (HR, 2.23; 95% CI, 1.39-3.59; P <.001).¹
“Our findings do not support the use of edoxaban in unselected patients with AF after intracranial haemorrhage, but highlight the need for an individualised decision-making approach,” Shoamanesh said. “Ongoing trials, including the double-blinded, randomised 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 individualise optimal stroke prevention in this very vulnerable patient population.”
References:
European Society of Cardiology. Safer stroke prevention strategies are needed for patients with atrial fibrillation after intracranial haemorrhage. Published August 29, 2026. Accessed August 29, 2026.
D'Anna L, Bax F, Abu-Rumeileh S, et al. Oral anticoagulation versus no anticoagulation for stroke prevention in patients with intracranial haemorrhage and atrial fibrillation: an updated meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2025;96:919-927.
