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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Atrial Fibrillation; Intracranial Hemorrhages
• Intervention / Treatment: Drug: Edoxaban; Other: Non-anticoagulant medical therapy

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 Type: Interventional
• Enrollment (Actual): 948
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1023AAB
    • STAT Research S.A.
  • Buenos Aires, Argentina, C1199 CABA
    • Hospital Italiano de Buenos Aires
  • Buenos Aires, Argentina, C1428 CABA
    • Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI)
  • Buenos Aires, Argentina, C1437 JCP
    • Hospital Policial Churruca-Visca
  • Salta, Argentina
    • Centro Instituto Neurologico Salta
• Austria
  • Innsbruck, Austria
    • Medical University of Innsbruck
  • Rankweil, Austria
    • Institut für Akutneurologie und Stroke Unit (IANS), Landeskrankenhaus Feldkirch
  • Vienna, Austria
    • Medical University of Vienna, Dept. of Neurology
  • Vöcklabruck, Austria
    • Salzkammergutklinikum Vöcklabruck
• Belgium
  • Brussels, Belgium
    • Erasme Hospital
  • Brussels, Belgium
    • UZ Brussel
  • Edegem, Belgium
    • Universitair Ziekenhuis Antwerpen (UZA)
  • Genk, Belgium
    • Ziekenhuis Oost-Limburg
  • Hasselt, Belgium
    • Jessa Hospital
  • Kortrijk, Belgium
    • Groeninge Hospital
  • Leuven, Belgium
    • UZ Leuven
  • Liège, Belgium
    • Clinique CHC MontLégia
  • Ostend, Belgium
    • AZ Damiaan
  • Roeselare, Belgium
    • AZ Delta
• Canada
  • Brandon, Canada
    • Brandon Regional Health Centre
  • Calgary, Canada
    • University of Calgary / Foothills Medical Centre
  • Chicoutimi, Canada
    • Centre intégré universitaire de santé et de services sociaux du Saguenay-Lac-Saint-Jean
  • Edmonton, Canada
    • University of Alberta Hospital
  • Halifax, Canada
    • Nova Scotia Health Authority
  • Hamilton, Canada
    • Hamilton Health Sciences
  • Kingston, Canada
    • Kingston General Hospital
  • London, Canada
    • London Health Science Centre - University Hospital
  • Montreal, Canada
    • McGill University Health Centre
  • Montreal, Canada
    • CHUM Centre Hospitalier de l'Université de Montréal
  • Ottawa, Canada
    • The Ottawa Hospital Research Institute
  • Owen Sound, Canada
    • The Rhema Research Institute
  • Québec, Canada
    • CHUL Pavillon Enfant-Jésus
  • Saskatoon, Canada
    • University of Saskatchewan
  • Thunder Bay, Canada
    • Thunder Bay Regional Health Sciences Centre
  • Toronto, Canada
    • Sunnybrook Health Science Centre
  • Toronto, Canada
    • University Health Network - Toronto Western Hospital
  • Windsor, Canada
    • Canadian Cardiac Research Centre
• China
  • Beijing, China
    • Beijing Anzhen Hospital, Capital Medical University
  • Shanghai, China
    • Shanghai East Hospital, Tongji University
  • Shanghai, China
    • Punan Hospital
  • Shanghai, China
    • Shanghai Blue Cross Brain Hospital
  • Shanghai, China
    • Shanghai Fengcheng Hospital
  • Shanghai, China
    • Xinhua Hospital, Chongming Branch
  • Shanghai, China
    • Yangpu Hospital, Tongji University
  • Shenyang, China
    • The first people's hospital of Shenyang
• Czechia
  • Brno, Czechia
    • St. Anne's University Hospital
  • Jihlava, Czechia
    • Neurological Department, General Hospital of Jihlava
  • Ostrava, Czechia
    • Cerebrovaskularni poradna s.r.o.
• Egypt
  • Al Fayyum, Egypt
    • Fayoum General Hospital
  • Al Mansurah, Egypt
    • Mansoura University Hospital
  • Alexandria, Egypt
    • Alexandria University Hospital
  • Banī Suwayf, Egypt
    • Beni suef University hospital
  • Cairo, Egypt
    • Ain Shams University Hospital
  • Cairo, Egypt
    • Ain Shams Specialized Hospital
  • Tanta, Egypt
    • Tanta University Hospital
  • Zagazig, Egypt
    • Zagazig University Hospital
• Germany
  • Berlin, Germany
    • Charité - University Medicine Berlin
  • Dresden, Germany
    • Dresden University Hospital "Carl Gustav Carus"
  • Essen, Germany
    • Universitätsklinikum Essen
  • Friedrichshafen, Germany
    • Klinikum Friedrichshafen
  • Goettigen, Germany
    • University Medicine Goettingen
  • Halle, Germany
    • Martha-Maria Hospital
  • Hamburg, Germany
    • Universitätsklinikum Hamburg-Eppendorf
  • Lohr, Germany
    • Klinikum Main-Spessart, Krankenhaus Lohr
  • Lübeck, Germany
    • Klinik fur Neurologie, UKSH campus Lubeck
  • Mannheim, Germany
    • Medical Faculty Mannheim, Heidelberg University
  • Münster, Germany
    • Westfälische Wilhelms-Universität Münster
  • Osnabrück, Germany
    • Klinikum Osnabrück; Neurologie
  • Recklinghausen, Germany
    • Department of Neurology, Klinikum Vest
  • Tübingen, Germany
    • Universitätsklinikum Tübingen
• India
  • Ahmedabad, India
    • Zydus Hospitals & Healthcare Research Pvt. Ltd.
  • Anand, India
    • Shree Krishna Hospital and Pramukhswami Medical College
  • Bangalore, India
    • St. John's Medical College Hospital
  • Bangalore, India
    • Bangalore Baptist Hospital
  • Bangalore, India
    • Fortis Hospital Ltd
  • Bangalore, India
    • Mazumdar Shaw Medical Center - Unit of Narayana Health
  • Chandigarh, India
    • Post Graduate Institute of Medical Education &Research
  • Gangtok, India
    • Sikkim Manipal Institute of Medical Sciences
  • Guwahati, India
    • GNRC Hospitals
  • Kolkata, India
    • Bangur Institute of Neurosciences
  • Kottayam, India
    • Caritas Hospital
  • Ludhiāna, India
    • Christian Medical College & Hospital
  • Nashik, India
    • Dhadiwal Hospital in coalition with Shreeji Healthcare
  • Pune, India
    • Bharati Vidyapeeth (DTU) Medical College & Hospital
  • Shimoga, India
    • Nanjappa Hospital
  • Thiruvananthapuram, India
    • Sree Chitra Tirunal Institute for Medical Sciences and Technology
  • Vadodara, India
    • Rhythm Heart Institute
• Nepal
  • Bharatpur, Nepal
    • Chitwan Everest Asptalal Private limited
  • Bharatpur, Nepal
    • Chitwan Medical College Teaching Hospital
  • Biratnagar, Nepal
    • Nobel Medical College & Teaching Hospital
  • Dharān, Nepal
    • B P Koirala Institute of Health Sciences
  • Jhapa, Nepal
    • B & C Medical College Teaching Hospital & Research Centre Pvt. Ltd.
  • Kathmandu, Nepal
    • Kathmandu Medical College
  • Kathmandu, Nepal
    • Annapurna Neurological institute and allied sciences
  • Kathmandu, Nepal
    • Grande International Hospital
  • Kathmandu, Nepal
    • Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences (UDMNINAS)
• Portugal
  • Lisbon, Portugal
    • CHULN-Hospital Santa Maria
• Spain
  • A Coruña, Spain
    • Coruña University Hospital
  • Albacete, Spain
    • University Hospital of Albacete
  • Barakaldo, Spain
    • Instituto de Investigacion Sanitaria Biocruces
  • Barcelona, Spain
    • Hospital Clinic de Barcelona
  • Barcelona, Spain
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain
    • Hospital del Mar
  • Barcelona, Spain
    • Hospital de La Santa Creu Isant Pau
  • Cáceres, Spain
    • Complejo Hospitalario Universitario de Cáceres
  • Donostia / San Sebastian, Spain
    • Hospital Donostia - Osidonostialdea
  • Lleida, Spain
    • Hospital u Arnau de Vilanova de Lleida
  • Madrid, Spain
    • Hospital General Universitario Gregorio Marañón
  • Madrid, Spain
    • Hospital Ramon y Cajal
  • Madrid, Spain
    • La Paz Univerity Hospital
  • Oviedo, Spain
    • Hospital Universitario Central de Asturias-Finba
  • Palma de Mallorca, Spain
    • Hospital Universitario Son Espases
  • Valencia, Spain
    • Hospital Universitari i Politécnic La Fe.
• Switzerland
  • Basel, Switzerland
    • University Hospital Basel
  • Bern, Switzerland
    • Inselspital, University Hospital Bern
• United Kingdom
  • Aberdeen, United Kingdom
    • Aberdeen Royal Infirmary, NHS Grampian
  • Abergavenny, United Kingdom
    • Nevill Hall Hospital
  • Airdrie, United Kingdom
    • NHS Lanarkshire Health Board - Monklands Hospital
  • Birkenhead, United Kingdom
    • Arrowe Park Hospital
  • Bournemouth, United Kingdom
    • The Royal Bournemouth Hospital
  • Bradford, United Kingdom
    • Bradford Teaching Hospitals NHS Foundation Trust, at Bradford Royal Infirmary
  • Cambridge, United Kingdom
    • Cambridge University Hospitals NHS Foundation Trust
  • Cardiff, United Kingdom
    • University Hospital of Wales
  • Colchester, United Kingdom
    • East Suffolk and North Essex NHS Foundation Trust, at Colchester Hospital
  • Edinburgh, United Kingdom
    • Edinburgh Royal Infirmary
  • Gateshead, United Kingdom
    • Queen Elizabeth Hospital - Gateshead Health NHS Foundation Trust
  • Glasgow, United Kingdom
    • Glasgow Royal Infirmary
  • Glasgow, United Kingdom
    • Queen Elizabeth University Hospital
  • Gloucester, United Kingdom
    • Gloucestershire Royal Hospital
  • Harrow, United Kingdom
    • LNWUH - Northwick Park Hospital
  • Huddersfield, United Kingdom
    • Calderdale and Huddersfield NHS Foundation Trust
  • Kirkcaldy, United Kingdom
    • Victoria Hospital Kirkcaldy
  • London, United Kingdom
    • Homerton University Hospital
  • Mansfield, United Kingdom
    • King's Mill Hospital
  • Middlesbrough, United Kingdom
    • The South Tees Hospitals NHS Foundation Trust
  • Morriston, United Kingdom
    • Morriston Hospital
  • Preston, United Kingdom
    • Royal Preston Hospital
  • Reading, United Kingdom
    • Royal Berkshire NHS Foundation Trust
  • Truro, United Kingdom
    • Royal Cornwall Hospital
  • Uxbridge, United Kingdom
    • Hillingdon Hospital
  • Westcliff-on-Sea, United Kingdom
    • Southend University Hospital Southend University Hospital NHS Foundation Trust
  • Yeovil, United Kingdom
    • Yeovil District Hospital
• United States
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • Alexian Brothers Medical Center
    • Lisle, Illinois, United States, 60532
      • Presence Care Transformation Corporation
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Medical Center
  • New York
    • Queens, New York, United States, 11355
      • New York Presbyterian - Queens
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Hospital of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15218
      • Allegheny General Hospital
  • Texas
    • Austin, Texas, United States, 78701
      • The University of Texas at Austin, Dell Medical School
    • El Paso, Texas, United States, 79905
      • Texas Tech University Health Sciences Center at El Paso
    • Houston, Texas, United States, 77030
      • Baylor St. Luke's Medical Center
  • Washington
    • Tacoma, Washington, United States, 98405
      • MultiCare Institute for Research & Innovation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
Stroke or Systemic Embolism	Stroke (composite of ischemic, hemorrhagic and unspecified) or systemic embolism	From randomization until the common study end date (average of 3 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)

Collaborators and Investigators

• Sponsor: Population Health Research Institute
• Investigators: Principal Investigator: Ashkan Shoamanesh, MD, FRCPC, Population Health Research Institute

Publications and helpful links

General Publications

• Cochrane A, Chen C, Stephen J, Ronning OM, Anderson CS, Hankey GJ, Al-Shahi Salman R. Antithrombotic treatment after stroke due to intracerebral haemorrhage. Cochrane Database Syst Rev. 2023 Jan 26;1(1):CD012144. doi: 10.1002/14651858.CD012144.pub3.
• Li L, Poon MTC, Samarasekera NE, Perry LA, Moullaali TJ, Rodrigues MA, Loan JJM, Stephen J, Lerpiniere C, Tuna MA, Gutnikov SA, Kuker W, Silver LE, Al-Shahi Salman R, Rothwell PM. Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies. Lancet Neurol. 2021 Jun;20(6):437-447. doi: 10.1016/S1474-4422(21)00075-2.

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2019
• Primary Completion (Estimated): May 13, 2026
• Study Completion (Estimated): May 13, 2026

Study Registration Dates

• First Submitted: May 10, 2019
• First Submitted That Met QC Criteria: May 13, 2019
• First Posted (Actual): May 15, 2019

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Edoxaban; Intracranial Hemorrhage; Hemorrhagic Stroke
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Hemorrhage; Stroke; Pathological Conditions, Signs and Symptoms; Hemorrhagic Stroke; Atrial Fibrillation; Intracranial Hemorrhages; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Anticoagulants; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; edoxaban
• Other Study ID Numbers: ENRICH-AF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No