EdoxabaN for IntraCranial Hemorrhage Survivors with Atrial Fibrillation (ENRICH-AF)

Phase 4

Active, not recruiting

• Conditions: Intracranial Hemorrhages; Atrial Fibrillation
• Interventions: Other: Non-anticoagulant medical therapy; Drug: Edoxaban

• Registration Number: NCT03950076
• Lead Sponsor: Population Health Research Institute

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.

Study Timeline

• Study First Submitted: 2019-05-10
• Study First Submitted QC: 2019-05-13
• Study First Posted: 2019-05-15
• Study Start: 2019-09-20
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-14
• Last Update Posted: 2025-01-16
• Primary Completion: 2026-04
• Study Completion: 2026-10

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 948

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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Non-anticoagulant medical therapy	Non-anticoagulant medical therapy	Non-anticoagulant medical therapy: no antithrombotic therapy or antiplatelet monotherapy (at discretion of local investigator)
Edoxaban 60/30mg daily	Edoxaban	Edoxaban 60/30 mg daily (lower dose depending on clinical criteria)

Primary Outcome Measures

Name	Time	Method
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
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

Secondary Outcome Measures

Name	Time	Method
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
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
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.
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
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
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
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.
modified Rankin Scale	12 months	mRS as measured at 12 month visit

Trial Locations

Locations (152)

Alexian Brothers Medical Center; 🇺🇸 Elk Grove Village, Illinois, United States

Presence Care Transformation Corporation; 🇺🇸 Lisle, Illinois, United States

Tulane University Medical Center; 🇺🇸 New Orleans, Louisiana, United States

New York Presbyterian - Queens; 🇺🇸 Queens, New York, United States

The Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Allegheny General Hospital; 🇺🇸 Pittsburgh, Pennsylvania, United States

The University of Texas at Austin, Dell Medical School; 🇺🇸 Austin, Texas, United States

Texas Tech University Health Sciences Center at El Paso; 🇺🇸 El Paso, Texas, United States

Baylor St. Luke's Medical Center; 🇺🇸 Houston, Texas, United States

MultiCare Institute for Research & Innovation; 🇺🇸 Tacoma, Washington, United States

Stat Research S.A.; 🇦🇷 Buenos Aires, Argentina

Hospital Italiano de Buenos Aires; 🇦🇷 Buenos Aires, Argentina

Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI); 🇦🇷 Buenos Aires, Argentina

Hospital Policial Churruca-Visca; 🇦🇷 Buenos Aires, Argentina

Centro Instituto Neurologico Salta; 🇦🇷 Salta, Argentina

Medical University of Innsbruck; 🇦🇹 Innsbruck, Austria

Institut für Akutneurologie und Stroke Unit (IANS), Landeskrankenhaus Feldkirch; 🇦🇹 Rankweil, Austria

Medical University of Vienna, Dept. of Neurology; 🇦🇹 Vienna, Austria

Salzkammergutklinikum Vöcklabruck; 🇦🇹 Vocklabruck, Austria

Erasme Hospital; 🇧🇪 Brussel, Belgium

UZ Brussel; 🇧🇪 Brussel, Belgium

Universitair Ziekenhuis Antwerpen (UZA); 🇧🇪 Edegem, Belgium

Ziekenhuis Oost-Limburg; 🇧🇪 Genk, Belgium

Jessa Hospital; 🇧🇪 Hasselt, Belgium

Groeninge Hospital; 🇧🇪 Kortrijk, Belgium

UZ Leuven; 🇧🇪 Leuven, Belgium

Clinique CHC MontLégia; 🇧🇪 Liège, Belgium

AZ Damiaan; 🇧🇪 Oostende, Belgium

AZ Delta; 🇧🇪 Roeselare, Belgium

Brandon Regional Health Centre; 🇨🇦 Brandon, Canada

University of Calgary / Foothills Medical Centre; 🇨🇦 Calgary, Canada

Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean; 🇨🇦 Chicoutimi, Canada

University of Alberta Hospital; 🇨🇦 Edmonton, Canada

Nova Scotia Health Authority; 🇨🇦 Halifax, Canada

Hamilton Health Sciences; 🇨🇦 Hamilton, Canada

Kingston General Hospital; 🇨🇦 Kingston, Canada

London Health Science Centre - University Hospital; 🇨🇦 London, Canada

CHUM Centre Hospitalier de l'Université de Montréal; 🇨🇦 Montreal, Canada

McGill University Health Centre; 🇨🇦 Montréal, Canada

The Ottawa Hospital Research Institute; 🇨🇦 Ottawa, Canada

The Rhema Research Institute; 🇨🇦 Owen Sound, Canada

CHUL Pavillon Enfant-Jésus; 🇨🇦 Québec, Canada

University of Saskatchewan; 🇨🇦 Saskatoon, Canada

Thunder Bay Regional Health Sciences Centre; 🇨🇦 Thunder Bay, Canada

Sunnybrook Health Science Centre; 🇨🇦 Toronto, Canada

University Health Network - Toronto Western Hospital; 🇨🇦 Toronto, Canada

Canadian Cardiac Research Centre; 🇨🇦 Windsor, Canada

Beijing Anzhen Hospital, Capital Medical University; 🇨🇳 Beijing, China

Punan Hospital; 🇨🇳 Shanghai, China

Shanghai Blue Cross Brain Hospital; 🇨🇳 Shanghai, China

Shanghai East Hospital, Tongji University; 🇨🇳 Shanghai, China

Shanghai Fengcheng Hospital; 🇨🇳 Shanghai, China

Xinhua Hospital, Chongming Branch; 🇨🇳 Shanghai, China

Yangpu Hospital, Tongji University; 🇨🇳 Shanghai, China

The First People's Hospital of Shenyang; 🇨🇳 Shenyang, China

St. Anne's University Hospital; 🇨🇿 Brno, Czechia

Neurological Department, General Hospital of Jihlava; 🇨🇿 Jihlava, Czechia

Cerebrovaskularni poradna s.r.o.; 🇨🇿 Ostrava, Czechia

Alexandria University Hospital; 🇪🇬 Alexandria, Egypt

Beni Suef University Hospital; 🇪🇬 Banī Suwayf, Egypt

Ain Shams Specialized Hospital; 🇪🇬 Cairo, Egypt

Ain Shams University Hospital; 🇪🇬 Cairo, Egypt

Fayoum General Hospital; 🇪🇬 Fayoum, Egypt

Mansoura University Hospital; 🇪🇬 Mansoura, Egypt

Tanta University Hospital; 🇪🇬 Tanta, Egypt

Zagazig University Hospital; 🇪🇬 Zagazig, Egypt

Charité - University Medicine Berlin; 🇩🇪 Berlin, Germany

Dresden University Hospital "Carl Gustav Carus"; 🇩🇪 Dresden, Germany

Universitätsklinikum Essen; 🇩🇪 Essen, Germany

Klinikum Friedrichshafen; 🇩🇪 Friedrichshafen, Germany

University Medicine Goettingen; 🇩🇪 Goettigen, Germany

Martha-Maria Hospital; 🇩🇪 Halle, Germany

Universitätsklinikum Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Klinikum Main-Spessart, Krankenhaus Lohr; 🇩🇪 Lohr, Germany

Klinik fur Neurologie, UKSH campus Lubeck; 🇩🇪 Lübeck, Germany

Medical Faculty Mannheim, Heidelberg University; 🇩🇪 Mannheim, Germany

Westfalische Wilhelms-Universitat Munster; 🇩🇪 Münster, Germany

Klinikum Osnabrück; Neurologie; 🇩🇪 Osnabrück, Germany

Department of Neurology, Klinikum Vest; 🇩🇪 Recklinghausen, Germany

Universitätsklinikum Tübingen; 🇩🇪 Tuebingen, Germany

Zydus Hospitals & Healthcare Research Pvt. Ltd.; 🇮🇳 Ahmedabad, India

Shree Krishna Hospital and Pramukhswami Medical College; 🇮🇳 Anand, India

Bangalore Baptist Hospital; 🇮🇳 Bangalore, India

Fortis Hospital Ltd; 🇮🇳 Bangalore, India

Mazumdar Shaw Medical Center - Unit of Narayana Health; 🇮🇳 Bangalore, India

St. John's Medical College Hospital; 🇮🇳 Bangalore, India

Post Graduate Institute of Medical Education &Research; 🇮🇳 Chandigarh, India

Sikkim Manipal Institute of Medical Sciences; 🇮🇳 Gangtok, India

GNRC Hospitals; 🇮🇳 Guwahati, India

Bangur Institute of Neurosciences; 🇮🇳 Kolkata, India

Caritas Hospital; 🇮🇳 Kottayam, India

Christian Medical College & Hospital; 🇮🇳 Ludhiāna, India

Dhadiwal Hospital in coalition with Shreeji Healthcare; 🇮🇳 Nashik, India

Bharati Vidyapeeth (DTU) Medical College & Hospital; 🇮🇳 Pune, India

Nanjappa Hospital; 🇮🇳 Shimoga, India

Sree Chitra Tirunal Institute for Medical Sciences and Technology; 🇮🇳 Thiruvananthapuram, India

Rhythm Heart Institute; 🇮🇳 Vadodara, India

Chitwan Everest Asptalal Private limited; 🇳🇵 Bharatpur, Nepal

Chitwan Medical College Teaching Hospital; 🇳🇵 Bharatpur, Nepal

Nobel Medical College & Teaching Hospital; 🇳🇵 Biratnagar, Nepal

B P Koirala Institute of Health Sciences; 🇳🇵 Dharān Bāzār, Nepal

B & C Medical College Teaching Hospital & Research Centre Pvt. Ltd.; 🇳🇵 Jhapa, Nepal

Annapurna Neurological institute and allied sciences; 🇳🇵 Kathmandu, Nepal

Grande International Hospital; 🇳🇵 Kathmandu, Nepal

Kathmandu Medical College; 🇳🇵 Kathmandu, Nepal

Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences (UDMNINAS); 🇳🇵 Kathmandu, Nepal

CHULN-Hospital Santa Maria; 🇵🇹 Lisboa, Portugal

Coruña University Hospital; 🇪🇸 A Coruña, Spain

University Hospital of Albacete; 🇪🇸 Albacete, Spain

Instituto de Investigacion Sanitaria Biocruces; 🇪🇸 Barakaldo, Spain

Hospital Clinic de Barcelona; 🇪🇸 Barcelona, Spain

Hospital de La Santa Creu Isant Pau; 🇪🇸 Barcelona, Spain

Hospital del Mar; 🇪🇸 Barcelona, Spain

Hospital Universitari Vall d'Hebron; 🇪🇸 Barcelona, Spain

Complejo Hospitalario Universitario de Cáceres; 🇪🇸 Cáceres, Spain

Hospital Donostia - Osidonostialdea; 🇪🇸 Donostia, Spain

Hospital u Arnau de Vilanova de Lleida; 🇪🇸 Lleida, Spain

Hospital General Universitario Gregorio Marañon; 🇪🇸 Madrid, Spain

Hospital Ramón y Cajal; 🇪🇸 Madrid, Spain

La Paz Univerity Hospital; 🇪🇸 Madrid, Spain

Hospital Universitario Central de Asturias-Finba; 🇪🇸 Oviedo, Spain

Hospital Universitario son Espases; 🇪🇸 Palma De Mallorca, Spain

Hospital Universitari i Politécnic La Fe.; 🇪🇸 Valencia, Spain

University Hospital Basel; 🇨🇭 Basel, Switzerland

Inselspital, University Hospital Bern; 🇨🇭 Bern, Switzerland

Aberdeen Royal Infirmary, NHS Grampian; 🇬🇧 Aberdeen, United Kingdom

Nevill Hall Hospital; 🇬🇧 Abergavenny, United Kingdom

NHS Lanarkshire Health Board - Monklands Hospital; 🇬🇧 Airdrie, United Kingdom

Arrowe Park Hospital; 🇬🇧 Birkenhead, United Kingdom

The Royal Bournemouth Hospital; 🇬🇧 Bournemouth, United Kingdom

Bradford Teaching Hospitals NHS Foundation Trust, at Bradford Royal Infirmary; 🇬🇧 Bradford, United Kingdom

Cambridge University Hospitals NHS Foundation Trust; 🇬🇧 Cambridge, United Kingdom

University Hospital of Wales; 🇬🇧 Cardiff, United Kingdom

East Suffolk and North Essex NHS Foundation Trust, at Colchester Hospital; 🇬🇧 Colchester, United Kingdom

Edinburgh Royal Infirmary; 🇬🇧 Edinburgh, United Kingdom

Queen Elizabeth Hospital - Gateshead Health NHS Foundation Trust; 🇬🇧 Gateshead, United Kingdom

Glasgow Royal Infirmary; 🇬🇧 Glasgow, United Kingdom

Queen Elizabeth University Hospital; 🇬🇧 Glasgow, United Kingdom

Gloucestershire Royal Hospital; 🇬🇧 Gloucester, United Kingdom

LNWUH - Northwick Park Hospital; 🇬🇧 Harrow, United Kingdom

Calderdale and Huddersfield NHS Foundation Trust; 🇬🇧 Huddersfield, United Kingdom

Victoria Hospital Kirkcaldy; 🇬🇧 Kirkcaldy, United Kingdom

Homerton University Hospital; 🇬🇧 London, United Kingdom

King's Mill Hospital; 🇬🇧 Mansfield, United Kingdom

The South Tees Hospitals NHS Foundation Trust; 🇬🇧 Middlesbrough, United Kingdom

Morriston Hospital; 🇬🇧 Morriston, United Kingdom

Royal Preston Hospital; 🇬🇧 Preston, United Kingdom

Royal Berkshire NHS Foundation Trust; 🇬🇧 Reading, United Kingdom

Royal Cornwall Hospital; 🇬🇧 Truro, United Kingdom

Hillingdon Hospital; 🇬🇧 Uxbridge, United Kingdom

Southend University Hospital Southend University Hospital NHS Foundation Trust; 🇬🇧 Westcliff-on-Sea, United Kingdom

Yeovil District Hospital; 🇬🇧 Yeovil, United Kingdom