EdoxabaN foR IntraCranial Hemorrhage Survivors With Atrial Fibrillation (ENRICH-AF)

Study Overview
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Brief Summary
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To assess whether edoxaban (60/30 mg daily) compared to non-antithrombotic medical therapy (either no antithrombotic therapy or antiplatelet monotherapy) reduces the risk of stroke (composite of ischemic, hemorrhagic and unspecified stroke) in high-risk atrial fibrillation (CHA2DS2-VASc ≥2) patients with previous intracranial hemorrhage.

Detailed Description
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The EdoxabaN foR IntraCranial Hemorrhage survivors with Atrial Fibrillation (ENRICH-AF) study is a prospective, randomized open-label, blinded end-point (PROBE), investigator-initiated, study that will define 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 hemorrhage. Intracranial hemorrhage includes intracerebral hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage and subdural hematoma. Recruitment will occur at 250-300 stroke research centres in North and South America, Europe and Asia over 24 months, where 1200 adult participants with high-risk AF (CHA2DS2-VASc score ≥2) and previous spontaneous or traumatic intracranial hemorrhage (while on or off antithrombotic therapy) will be randomly assigned to receive edoxaban 60/30 mg daily or to non-anticoagulant medical therapy (no antithrombotic therapy or antiplatelet monotherapy). Consenting participants will be followed to a common study end-date in this event-driven trial once 123 primary efficacy events (stroke) have accrued; anticipated to be about 12 months after the end of recruitment. ENRICH-AF will assess the safety and efficacy of anticoagulant therapy in AF participants after intracranial hemorrhage, an area where there currently exists huge interest within the stroke and cardiology research communities. Demonstrating safety comparable with non-anticoagulant medical therapy in AF patients who are particularly at high risk for intracranial hemorrhage is likely to have a more far-reaching clinical impact than solely within the proposed study population. ENRICH-AF will be the ultimate safety test of anticoagulation of AF patients, providing reassuring evidence favoring more widespread use of anticoagulation for stroke prevention in AF patients.

Official Title
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EdoxabaN foR IntraCranial Hemorrhage Survivors With Atrial Fibrillation (ENRICH-AF)

Conditions
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Intracranial Hemorrhages, Atrial Fibrillation

Intervention / Treatment
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* Drug: Edoxaban
* Other: Non-anticoagulant medical therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent provided Age ≥45 years, at the time of signing the informed consent 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. Documented atrial fibrillation (paroxysmal, persistent, permanent) CHA2DS2-VASc score ≥2 Exclusion Criteria: 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) 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).

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, open, blinded end-point (PROBE), multicenter international trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Edoxaban 60/30mg daily<br>Edoxaban 60/30 mg daily (lower dose depending on clinical criteria) | Drug: Edoxaban<br>* Edoxaban 60mg (or 30mg as determined by clinical criteria)<br>* Other names: Savaysa;|
| Active Comparator: Non-anticoagulant medical therapy<br>Non-anticoagulant medical therapy: no antithrombotic therapy or antiplatelet monotherapy (at discretion of local investigator) | Other: Non-anticoagulant medical therapy<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stroke | composite of ischemic, hemorrhagic and unspecified | From randomization until the common study end date (median 2 years) | 
| Major hemorrhage | as defined byt the International Society on Thrombosis and Haemostasis (ISTH) criteria | From randomization until the common study end date (median 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ischemic stroke | development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute ischemic stroke. | From randomization until the common study end date (median 2 years) | 
| Cardiovascular death | Death related to cardiovascular cause | From randomization until the common study end date (median 2 years) | 
| Hemorrhagic stroke | development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute intraparenchymal, intraventricular or subarachnoid hemorrhage | From randomization until the common study end date (median 2 years) | 
| Disabling/fatal stroke | 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. | From randomization until the common study end date (median 2 years) | 
| Composite of all stroke, myocardial infarction, systemic thromboembolism, or all-cause death | 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 | 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) | Net clinical benefit is a composite of stroke, myocardial infarction, cardiovascular death, fatal bleeding, and symptomatic bleeding into a critical organ or area | From randomization until the common study end date (median 2 years) | 
| modified Rankin Scale | mRS as measured at 12 month visit | 12 months | 
| All intracranial hemorrhage (intracerebral hemorrhage, intraventricular hemorrhage, subdural hematoma, subarachnoid hemorrhage) | 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. | From randomization until the common study end date (median 2 years) | 
| Fatal intracranial hemorrhage | 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 | From randomization until the common study end date (median 2 years) | 
| Subdural hemorrhage | 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 | From randomization until the common study end date (median 2 years) | 
| Hospitalization for any cause | Minimum of one overnight stay in hospital. | From randomization until the common study end date (median 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Edoxaban, Intracranial Hemorrhage, Hemorrhagic Stroke