Atrial Fibrillation, Intracranial Hemorrhages
Conditions
Keywords
Edoxaban, Intracranial Hemorrhage, Hemorrhagic Stroke
Brief summary
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) or systemic embolism in high-risk atrial fibrillation (CHA2DS2-VASc ≥2) patients with previous intracranial hemorrhage.
Detailed description
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/systemic embolism 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.
Interventions
DRUGEdoxaban
Edoxaban 60mg (or 30mg as determined by clinical criteria)
OTHERNon-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
Sponsors
Population Health Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Masking description
open label study where outcomes assessor is blinded to treatment allocation
Intervention model description
Prospective, randomized, open, blinded end-point (PROBE), multicenter international trial
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
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 non-lobar intraparenchymal or intraventricular hemorrhage, and symptomatic spontaneous or non-penetrating traumatic subdural hemorrhages) on or off antithrombotic therapy 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. Isolated subarachnoid hemorrhage (convexity or basal); subarachnoid blood tracking onto convexity secondary to an intraventricular hemorrhage or as part of a multicompartment bleed in cases of traumatic subdural hemorrhages are eligible 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 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) 20. Lobar intraparenchymal hemorrhage * 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stroke or Systemic Embolism | From randomization until the common study end date (average of 3 years) | Stroke (composite of ischemic, hemorrhagic and unspecified) or systemic embolism |
| Major hemorrhage | From randomization until the common study end date (median 2 years) | as defined byt the International Society on Thrombosis and Haemostasis (ISTH) criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ischemic stroke | 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 | From randomization until the common study end date (median 2 years) | Death related to cardiovascular cause |
| Composite of all stroke, myocardial infarction, systemic thromboembolism, or all-cause death | 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) | 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 | 12 months | mRS as measured at 12 month visit |
| All intracranial hemorrhage (intracerebral hemorrhage, intraventricular hemorrhage, subdural hematoma, subarachnoid hemorrhage) | 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 | 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 | 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 |
| Hemorrhagic stroke | 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 |
| Hospitalization for any cause | From randomization until the common study end date (median 2 years) | Minimum of one overnight stay in hospital. |
| Disabling/fatal stroke | 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. |
Countries
Argentina, Austria, Belgium, Canada, China, Czechia, Egypt, Germany, India, Nepal, Portugal, Spain, Switzerland, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORAshkan Shoamanesh, MD, FRCPC
Population Health Research Institute
Outcome results
None listed