What is the efficacy and safety of edoxaban compared with non-anticoagulant medical therapy (no antithrombotic therapy or antiplatelet monotherapy) for stroke prevention in high-risk AF patients and previous intracranial haemorrhage?

Study Sites •National Hospital of Sri Lanka •Colombo South Teaching Hospital •Kurunegala Teaching Hospital •Karapitiya Teaching Hospital •Sri Jayewardenepura General Hospital •Negombo District General Hospital •National Hospital, Kandy

Participants who satisfy the eligibility criteria and complete protocol related activities relevant to screening visit will be randomly allocated in a 1:1 ratio to open label intervention edoxaban [60/30 mg daily] or non-anticoagulant medical therapy (either no antithrombotic therapy or antiplatelet monotherapy). Randomization will occur any time after 14 days since the time of the qualifying intracranial hemorrhage. Exact timing will be left to the discretion and equipoise of the local investigator.

The administration of the 60mg daily or 30mg daily will be determined by the following criteria. Dose will be 60 mg unless any of the following conditions are met in which case the dose will be 30mg.

1.Estimated Creatinine-clearance 15-49 mL/min 2.body weight greater or equal to 60 kg 3.Concomitant use of potent P-glycoprotein inhibitors (a country specific dosing guidance document will be provided).

Participants who are allocated to the open label intervention Edoxaban arm will be receiving tablet 30 mg or 60 mg once daily. For participants randomly assigned to receive non-anticoagulant medical therapy, the local site investigator will determine treatment, which may or may not include antiplatelet monotherapy but will not include oral anticoagulation or left atrial appendage occlusion.

Participants will be followed every 6 months until the common study end date. This study is event driven to accrue 123 primary events. Each participant will have an average of 24 months of follow-up period (which will range 1 to 3 years).

•Age greater than or equal to 45 years, at the time of signing the informed consent •Previous intracranial hemorrhage (symptomatic, spontaneous and non-traumatic intraparenchymal, intraventricular, and/or Convexal subarachnoid hemorrhage cSAH, and symptomatic spontaneous or non-penetrating traumatic subdural hemorrhages) on or off antithrombotic therapy (Table 2) •Documented atrial fibrillation (paroxysmal, persistent, permanent) •CHA2DS2-VASc score greater than or equal to 2

•Recent intracranial hemorrhage (within 14 days) •Secondary macrovascular, neoplastic or infectious causes of intracranial hemorrhage (except for antithrombotic treatment or non-penetrating traumatic subdural hemorrhages) •Traumatic or aneurysmal cSAH •Need for ongoing oral anticoagulant therapy for indication other than AF (e.g. mechanical heart valve, venous thromboembolic disease) •Need for ongoing antiplatelet therapy for indication where edoxaban would not be a suitable substitute •Plans for left atrial appendage occlusion •Estimated creatinine clearance (CrCl) < 15 mL/min or other creatinine clearance following local product monograph (Canada < 30mL/min) •Platelet count less than 100,000mm3 at enrollment or other bleeding diathesis •Persistent, uncontrolled hypertension (systolic BP averaging >150 mmHg) •Chronic use of NSAID •Clinically significant active bleeding, including gastrointestinal bleeding •Lesions or conditions at increased risk of clinically significant bleeding, e.g. active peptic ulcer disease with recent bleeding, patients with spontaneous or acquired impairment of hemostasis •Antiphospholipid antibody syndrome •Hepatic disease associated with coagulopathy and clinically relevant bleeding risk •Known hypersensitivity to edoxaban •Estimated inability to adhere to study procedures •Pregnancy or breastfeeding •Estimated life expectancy < 6 months at the time of enrollment •Close affiliation with the investigational site; e.g. a close relative for the investigator, dependent person (e.g., employee or student of the investigational site)