• Stroke [ Time Frame: From randomization until the common study end date (median 2 years) ]
  composite of ischemic, hemorrhagic and unspecified
• Major hemorrhage [ Time Frame: From randomization until the common study end date (median 2 years) ]
  as defined byt the International Society on Thrombosis and Haemostasis (ISTH) criteria

• Ischemic stroke [ Time Frame: From randomization until the common study end date (median 2 years) ]
  development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute ischemic stroke.
• cardiovascular death [ Time Frame: From randomization until the common study end date (median 2 years) ]
  Death related to cardiovascular cause
• hemorrhagic stroke [ Time Frame: From randomization until the common study end date (median 2 years) ]
  development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute intraparenchymal, intraventricular or subarachnoid hemorrhage
• Disabling/fatal stroke [ Time Frame: From randomization until the common study end date (median 2 years) ]
  Disabling stroke is defined as stroke resulting in a clinical outcome that is associated with a modified Rankin scale of 4 or 5. Fatal stroke is defined as death occurring within 30 days of stroke.
• composite of all stroke, myocardial infarction, systemic thromboembolism, or all-cause death [ Time Frame: From randomization until the common study end date (median 2 years) ]
  Components of composite outcome (adjudicated) includes stroke (ischemic, hemorrhagic, and undefined stroke, TIA with positive neuroimaging),myocardial infarction, systemic thromboembolism or all-cause death. Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred
• net clinical benefit (composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area) [ Time Frame: From randomization until the common study end date (median 2 years) ]
  Net clinical benefit is a composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area
• modified Rankin Scale [ Time Frame: 12 months ]
  mRS as measured at 12 month visit
• All intracranial hemorrhage (intracerebral hemorrhage, intraventricular hemorrhage, subdural hematoma, subarachnoid hemorrhage) [ Time Frame: From randomization until the common study end date (median 2 years) ]
  Intracranial hemorrhage as defined by Signs or symptoms associated with an epidural, subdural, subarachnoid, intraparenchymal or intraventricular hemorrhage on computed tomography (CT) or MRI scan, or as demonstrated by surgery or autopsy.
• Fatal intracranial hemorrhage [ Time Frame: From randomization until the common study end date (median 2 years) ]
  Inctracranial hemorrhage defined as Signs or symptoms associated with an epidural, subdural, subarachnoid, intraparenchymal or intraventricular hemorrhage on computed tomography (CT) or MRI scan, or as demonstrated by surgery or autopsy with death occurring within 30 days of stroke
• Subdural hemorrhage [ Time Frame: From randomization until the common study end date (median 2 years) ]
  Subdural hemorrhage as defined as Signs or symptoms associated with a subdural hemorrhage on computed tomography (CT) or MRI scan, or as demonstrated by surgery or autopsy
• Hospitalization for any cause [ Time Frame: From randomization until the common study end date (median 2 years) ]
  Minimum of one overnight stay in hospital.

• Ischemic stroke [ Time Frame: From randomization until the common study end date (median 2 years) ]
• cardiovascular death [ Time Frame: From randomization until the common study end date (median 2 years) ]
• hemorrhagic stroke [ Time Frame: From randomization until the common study end date (median 2 years) ]
• Disabling/fatal stroke [ Time Frame: From randomization until the common study end date (median 2 years) ]
• composite of all stroke, myocardial infarction, systemic thromboembolism, or all-cause death [ Time Frame: From randomization until the common study end date (median 2 years) ]
• net clinical benefit (composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area) [ Time Frame: From randomization until the common study end date (median 2 years) ]
• modified Rankin Scale [ Time Frame: 12 months ]
  mRS as measured at 12 month visit
• All intracranial hemorrhage (intracerebral hemorrhage, intraventricular hemorrhage, subdural hematoma, subarachnoid hemorrhage) [ Time Frame: From randomization until the common study end date (median 2 years) ]
• Fatal intracranial hemorrhage [ Time Frame: From randomization until the common study end date (median 2 years) ]
• Subdural hemorrhage [ Time Frame: From randomization until the common study end date (median 2 years) ]
• Hospitalization for any cause [ Time Frame: From randomization until the common study end date (median 2 years) ]

• Intracranial Hemorrhages
• Atrial Fibrillation

• Drug: Edoxaban
  Edoxaban 60mg (or 30mg as determined by clinical criteria)
  Other Names:

  • Lixana
  • Savaysa
• Other: Non-anticoagulant medical therapy
  Non-anticoagulant medical therapy as determined by the local investigator includes i) No antithrombotic therapy ii) Antiplatelet monotherapy, including de novo indication for antiplatelet monotherapy during course of the study

• Experimental: Edoxaban 60/30mg daily
  Edoxaban 60/30 mg daily (lower dose depending on clinical criteria)
  Intervention: Drug: Edoxaban
• Active Comparator: Non-anticoagulant medical therapy
  Non-anticoagulant medical therapy: no antithrombotic therapy or antiplatelet monotherapy (at discretion of local investigator)
  Intervention: Other: Non-anticoagulant medical therapy

Inclusion Criteria:

1. Written informed consent provided
2. Age ≥45 years, at the time of signing the informed consent
3. Previous intracranial hemorrhage (symptomatic, spontaneous and non-traumatic intraparenchymal, intraventricular, and/or cSAH, and symptomatic spontaneous or non-penetrating traumatic subdural hemorrhages) on or off antithrombotic therapy, and confirmed to have stabilized on neuroimaging.
4. Documented atrial fibrillation (paroxysmal, persistent, permanent)
5. CHA2DS2-VASc score ≥2

Exclusion Criteria:

1. Recent intracranial hemorrhage (within 14 days)
2. Secondary macrovascular, neoplastic or infectious causes of intracranial hemorrhage (except for antithrombotic treatment or non-penetrating traumatic subdural hemorrhages)
3. Traumatic or aneurysmal cSAH
4. Need for ongoing oral anticoagulant therapy for indication other than AF (e.g. mechanical heart valve, venous thromboembolic disease)
5. Need for ongoing antiplatelet therapy for indication where edoxaban would not be a suitable substitute
6. Plans for left atrial appendage occlusion
7. Estimated creatinine clearance (CrCl) < 15 mL/min or other creatinine clearance following local product monograph (Canada < 30mL/min)
8. Platelet count less than 100,000mm3 at enrollment or other bleeding diathesis
9. Persistent, uncontrolled hypertension (systolic BP averaging >150 mmHg)
10. Chronic use of NSAID
11. Clinically significant active bleeding, including gastrointestinal bleeding
12. 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
13. Antiphospholipid antibody syndrome
14. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk
15. Known hypersensitivity to edoxaban
16. Estimated inability to adhere to study procedures
17. Pregnancy or breastfeeding
18. Estimated life expectancy < 6 months at the time of enrollment

19. 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)

    • Post menopausal female subjects must be amenorrheic for ≥12 months prior to screening or ≥6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) prior to screening. Women of childbearing potential must have negative serum pregnancy test within 7 days prior to randomization or urine pregnancy testing within 24 hours of randomization. Heterosexually active women of childbearing potential must use highly effective methods of contraception for 32 days after discontinuation (duration of study drug plus 30 days duration of one ovulatory cycle).