Intracranial HemorrhagesPhase 4ENRICH-AFNCT03950076
EdoxabaN foR IntraCranial Hemorrhage Survivors With Atrial Fibrillation (ENRICH-AF)
A Phase 4 study testing Edoxaban and Non-anticoagulant medical therapy in people with Intracranial Hemorrhages and Atrial Fibrillation, run by Population Health Research Institute at 152 sites in 15 countries.
Trial 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)… Read more about this study
- Who is it for?
- Ages 45 years and older
- Conditions the study is for
- Intracranial Hemorrhages, Atrial Fibrillation
- What is being tested?
- Edoxaban and Non-anticoagulant medical therapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 948 participants
- Where
- 152 sitesin 15 countries
- Study dates
- 20 Sep 2019to 22 Jul 2026
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Written informed consent provided
- Age ≥45 years, at the time of signing the informed consent
- 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
- Documented atrial fibrillation (paroxysmal, persistent, permanent)
- CHA2DS2-VASc score ≥2
Who cannot join
- 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)
- 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
- 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
Show all 21Show fewer
- Estimated creatinine clearance (CrCl) < 15 mL/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)
- 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).
Trial locations and contacts
152 sites in 15 countries.
152 sites in 15 countries
United Kingdom27 sites
Aberdeen Royal Infirmary, NHS Grampian
Aberdeen
Nevill Hall Hospital
Abergavenny
NHS Lanarkshire Health Board - Monklands Hospital
Airdrie
Arrowe Park Hospital
Birkenhead
The Royal Bournemouth Hospital
Bournemouth
Bradford Teaching Hospitals NHS Foundation Trust, at Bradford Royal Infirmary
Bradford
Cambridge University Hospitals NHS Foundation Trust
Cambridge
University Hospital of Wales
Cardiff
East Suffolk and North Essex NHS Foundation Trust, at Colchester Hospital
Colchester
Edinburgh Royal Infirmary
Edinburgh
Queen Elizabeth Hospital - Gateshead Health NHS Foundation Trust
Gateshead
Glasgow Royal Infirmary
Glasgow
Queen Elizabeth University Hospital
Glasgow
Gloucestershire Royal Hospital
Gloucester
LNWUH - Northwick Park Hospital
Harrow
Calderdale and Huddersfield NHS Foundation Trust
Huddersfield
Victoria Hospital Kirkcaldy
Kirkcaldy
Homerton University Hospital
London
King's Mill Hospital
Mansfield
The South Tees Hospitals NHS Foundation Trust
Middlesbrough
Morriston Hospital
Morriston
Royal Preston Hospital
Preston
Royal Berkshire NHS Foundation Trust
Reading
Royal Cornwall Hospital
Truro
Hillingdon Hospital
Uxbridge
Southend University Hospital Southend University Hospital NHS Foundation Trust
Westcliff-on-Sea
Yeovil District Hospital
Yeovil
Canada18 sites
Brandon Regional Health Centre
Brandon
University of Calgary / Foothills Medical Centre
Calgary
Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean
Chicoutimi
University of Alberta Hospital
Edmonton
Nova Scotia Health Authority
Halifax
Hamilton Health Sciences
Hamilton
Kingston General Hospital
Kingston
London Health Science Centre - University Hospital
London
CHUM Centre Hospitalier de l'Université de Montréal
Montreal
McGill University Health Centre
Montreal
The Ottawa Hospital Research Institute
Ottawa
The Rhema Research Institute
Owen Sound
CHUL Pavillon Enfant-Jésus
Québec
University of Saskatchewan
Saskatoon
Thunder Bay Regional Health Sciences Centre
Thunder Bay
Sunnybrook Health Science Centre
Toronto
University Health Network - Toronto Western Hospital
Toronto
Canadian Cardiac Research Centre
Windsor
India17 sites
Zydus Hospitals & Healthcare Research Pvt. Ltd.
Ahmedabad
Shree Krishna Hospital and Pramukhswami Medical College
Anand
Bangalore Baptist Hospital
Bangalore
Fortis Hospital Ltd
Bangalore
Mazumdar Shaw Medical Center - Unit of Narayana Health
Bangalore
St. John's Medical College Hospital
Bangalore
Post Graduate Institute of Medical Education &Research
Chandigarh
Sikkim Manipal Institute of Medical Sciences
Gangtok
GNRC Hospitals
Guwahati
Bangur Institute of Neurosciences
Kolkata
Caritas Hospital
Kottayam
Christian Medical College & Hospital
Ludhiāna
Dhadiwal Hospital in coalition with Shreeji Healthcare
Nashik
Bharati Vidyapeeth (DTU) Medical College & Hospital
Pune
Nanjappa Hospital
Shimoga
Sree Chitra Tirunal Institute for Medical Sciences and Technology
Thiruvananthapuram
Rhythm Heart Institute
Vadodara
Spain16 sites
Coruña University Hospital
A Coruña
University Hospital of Albacete
Albacete
Instituto de Investigacion Sanitaria Biocruces
Barakaldo
Hospital Clinic de Barcelona
Barcelona
Hospital de La Santa Creu Isant Pau
Barcelona
Hospital del Mar
Barcelona
Hospital Universitari Vall d'Hebron
Barcelona
Complejo Hospitalario Universitario de Cáceres
Cáceres
Hospital Donostia - Osidonostialdea
Donostia / San Sebastian
Hospital u Arnau de Vilanova de Lleida
Lleida
Hospital General Universitario Gregorio Marañon
Madrid
Hospital Ramón y Cajal
Madrid
La Paz Univerity Hospital
Madrid
Hospital Universitario Central de Asturias-Finba
Oviedo
Hospital Universitario son Espases
Palma de Mallorca
Hospital Universitari i Politécnic La Fe.
Valencia
Germany14 sites
Charité - University Medicine Berlin
Berlin
Dresden University Hospital "Carl Gustav Carus"
Dresden
Universitätsklinikum Essen
Essen
Klinikum Friedrichshafen
Friedrichshafen
University Medicine Goettingen
Goettigen
Martha-Maria Hospital
Halle
Universitätsklinikum Hamburg-Eppendorf
Hamburg
Klinikum Main-Spessart, Krankenhaus Lohr
Lohr
Klinik fur Neurologie, UKSH campus Lubeck
Lübeck
Medical Faculty Mannheim, Heidelberg University
Mannheim
Westfalische Wilhelms-Universitat Munster
Münster
Klinikum Osnabrück; Neurologie
Osnabrück
Department of Neurology, Klinikum Vest
Recklinghausen
Universitätsklinikum Tübingen
Tübingen
United States10 sites
The University of Texas at Austin, Dell Medical School
Austin, Texas, 78701
Texas Tech University Health Sciences Center at El Paso
El Paso, Texas, 79905
Alexian Brothers Medical Center
Elk Grove Village, Illinois, 60007
Baylor St. Luke's Medical Center
Houston, Texas, 77030
Presence Care Transformation Corporation
Lisle, Illinois, 60532
Tulane University Medical Center
New Orleans, Louisiana, 70112
The Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Allegheny General Hospital
Pittsburgh, Pennsylvania, 15218
New York Presbyterian - Queens
Queens, New York, 11355
MultiCare Institute for Research & Innovation
Tacoma, Washington, 98405
Belgium10 sites
Erasme Hospital
Brussels
UZ Brussel
Brussels
Universitair Ziekenhuis Antwerpen (UZA)
Edegem
Ziekenhuis Oost-Limburg
Genk
Jessa Hospital
Hasselt
Groeninge Hospital
Kortrijk
UZ Leuven
Leuven
Clinique CHC MontLégia
Liège
AZ Damiaan
Ostend
AZ Delta
Roeselare
Nepal9 sites
Chitwan Everest Asptalal Private limited
Bharatpur
Chitwan Medical College Teaching Hospital
Bharatpur
Nobel Medical College & Teaching Hospital
Biratnagar
B P Koirala Institute of Health Sciences
Dharān
B & C Medical College Teaching Hospital & Research Centre Pvt. Ltd.
Jhapa
Annapurna Neurological institute and allied sciences
Kathmandu
Grande International Hospital
Kathmandu
Kathmandu Medical College
Kathmandu
Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences (UDMNINAS)
Kathmandu
China8 sites
Beijing Anzhen Hospital, Capital Medical University
Beijing
Punan Hospital
Shanghai
Shanghai Blue Cross Brain Hospital
Shanghai
Shanghai East Hospital, Tongji University
Shanghai
Shanghai Fengcheng Hospital
Shanghai
Xinhua Hospital, Chongming Branch
Shanghai
Yangpu Hospital, Tongji University
Shanghai
The First People's Hospital of Shenyang
Shenyang
Egypt8 sites
Fayoum General Hospital
Al Fayyum
Mansoura University Hospital
Al Mansurah
Alexandria University Hospital
Alexandria
Beni Suef University Hospital
Banī Suwayf
Ain Shams Specialized Hospital
Cairo
Ain Shams University Hospital
Cairo
Tanta University Hospital
Tanta
Zagazig University Hospital
Zagazig
Argentina5 sites
Stat Research S.A.
Buenos Aires, C1023AAB
Hospital Italiano de Buenos Aires
Buenos Aires, C1199 CABA
Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI)
Buenos Aires, C1428 CABA
Hospital Policial Churruca-Visca
Buenos Aires, C1437 JCP
Centro Instituto Neurologico Salta
Salta
Austria4 sites
Medical University of Innsbruck
Innsbruck
Institut für Akutneurologie und Stroke Unit (IANS), Landeskrankenhaus Feldkirch
Rankweil
Medical University of Vienna, Dept. of Neurology
Vienna
Salzkammergutklinikum Vöcklabruck
Vöcklabruck
Czechia3 sites
St. Anne's University Hospital
Brno
Neurological Department, General Hospital of Jihlava
Jihlava
Cerebrovaskularni poradna s.r.o.
Ostrava
Switzerland2 sites
University Hospital Basel
Basel
Inselspital, University Hospital Bern
Bern
About this study
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.
Read the 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.
- Conditions
- Intracranial Hemorrhages, Atrial Fibrillation
- Being tested
- Edoxaban, Non-anticoagulant medical therapy
- Keywords
- Edoxaban, Intracranial Hemorrhage, Hemorrhagic Stroke
- Medical subject headings
- Intracranial Hemorrhages, Atrial Fibrillation, Hemorrhagic Stroke
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EdoxabanDrug
Also called Lixiana, Savaysa
Edoxaban 60mg (or 30mg as determined by clinical criteria)
Non-anticoagulant medical therapyOther
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
| Study group | Role | What they receive |
|---|---|---|
| Edoxaban 60/30mg daily | Experimental | Edoxaban 60/30 mg daily (lower dose depending on clinical criteria) Receives: Drug: Edoxaban |
| Non-anticoagulant medical therapy | Active comparator | Non-anticoagulant medical therapy: no antithrombotic therapy or antiplatelet monotherapy (at discretion of local investigator) Receives: Other: Non-anticoagulant medical therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Stroke or Systemic Embolism
Stroke (composite of ischemic, hemorrhagic and unspecified) or systemic embolism
Measured: From randomization until the common study end date (average of 3 years)
Major hemorrhage
as defined byt the International Society on Thrombosis and Haemostasis (ISTH) criteria
Measured: From randomization until the common study end date (median 2 years)
Secondary outcomes (11)
Ischemic stroke
development of an acute neurologic deficit in conjunction with brain imaging consistent with acute/subacute ischemic stroke.
Measured: From randomization until the common study end date (median 2 years)
Cardiovascular death
Death related to cardiovascular cause
Measured: 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
Measured: 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.
Measured: 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
Measured: 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
Measured: From randomization until the common study end date (median 2 years)
modified Rankin Scale
mRS as measured at 12 month visit
Measured: 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.
Measured: 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
Measured: 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
Measured: From randomization until the common study end date (median 2 years)
Hospitalization for any cause
Minimum of one overnight stay in hospital.
Measured: From randomization until the common study end date (median 2 years)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 May 2019
- Study start20 Sep 2019
- Primary completion22 Jul 2026
- Study completion22 Jul 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Intracranial HemorrhagesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Prospective, randomized, open, blinded end-point (PROBE), multicenter international trial
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 948 participants (actual)
Sponsor and investigators
- Lead sponsor
- Population Health Research Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ashkan Shoamanesh, MD, FRCPC, Principal investigator, Population Health Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03950076
- Sponsor's protocol ID
- ENRICH-AF
- Acronym
- ENRICH-AF
- Status last verified
- Aug 2026
- First submitted
- 10 May 2019
- Last updated
- 1 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Shoamanesh A; ENRICH-AF Steering Committee. Anticoagulation in patients with cerebral amyloid angiopathy. Lancet. 2023 Oct 21;402(10411):1418-1419. doi: 10.1016/S0140-6736(23)02025-1. Epub 2023 Oct 12. No abstract available.
PubMed 37839419Cochrane 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.
PubMed 36700520Li 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.
PubMed 34022170