Early Versus Late Initiation of Direct Oral Anticoagulants in Post-ischaemic Stroke Patients With Atrial fibrillatioN (ELAN): an International, Multicentre, Randomised-controlled, Two-arm, Assessor-blinded Trial

NCT03148457 | Completed DMC

• 1 other identifier: 2017-00588
• Study Type: interventional
• Target: 2,013
• Locations: 15 countries
• Sites: 98

Brief Summary

When to start anticoagulation in patients with an acute ischaemic stroke and atrial fibrillation (AF) is a relevant unanswered question in clinical practice. Direct oral anticoagulants (DOACs) are highly effective for secondary stroke prevention in these patients, but DOACs were never initiated \<7 days after stroke onset in recent trials. The ELAN trial will determine the net benefit of early versus late initiation of DOACs in patients with acute ischaemic stroke related to AF. The main objective is to estimate the net benefit of early versus late initiation of DOACs in patients with acute ischaemic stroke related to AF. The secondary objectives are to assess all vascular events and all-cause mortality after early initiation of DOACs in patients with acute ischaemic stroke related to AF compared to late initiation.

Conditions

Ischaemic Stroke

Keywords

Stroke; Direct oral anticoagulation; Apixaban; Dabigatran; Rivaroxaban; Edoxaban; Therapy initiation; Major bleeding; Atrial fibrillation

Outcome Measures

Primary Outcomes (1)

• Composite of major bleeding, recurrent ischaemic stroke, systemic embolism and/or vascular death

  30 ± 3 days after randomisation

Secondary Outcomes (15)

• Modified Rankin Scale (mRS)

  30 days, 90 days after randomisation

• Major bleeding

  30 days, 90 days after randomisation

• Non-major bleeding

  30 days, 90 days after randomisation

• Recurrence of stroke

  30 days, 90 days after randomisation

• Systemic embolism

  30 days, 90 days after randomisation

Study Arms (2)

Early treatment

EXPERIMENTAL

Early treatment of patients with ischaemic stroke related to atrial fibrillation (AF) with direct oral anticoagulations (DOACs).

Drug: Early treatment with Rivaroxaban (Xarelto®), Dabigatran (Pradaxa®), Apixaban (Eliquis®) or Edoxaban (Lixiana®)

Late treatment

OTHER

Treatment with direct oral anticoagulations (DOACs) according the current standard practice in patients with acute ischemic stroke related to atrial fibrillation (AF).

Drug: Late treatment with Rivaroxaban (Xarelto®), Dabigatran (Pradaxa®), Apixaban (Eliquis®) or Edoxaban (Lixiana®)

Interventions

Early treatment with Rivaroxaban (Xarelto®), Dabigatran (Pradaxa®), Apixaban (Eliquis®) or Edoxaban (Lixiana®) DRUG

Early treatment will be started within 48 hours after symptom onset (minor and moderate ischaemic stroke) or at day 6 + 1 day after symptom onset (major ischaemic stroke)

Early treatment

Late treatment with Rivaroxaban (Xarelto®), Dabigatran (Pradaxa®), Apixaban (Eliquis®) or Edoxaban (Lixiana®) DRUG

Patients in the control arm will receive late treatment as per current recommendations (i.e. minor ischaemic stroke after day 3 + 1 day, moderate ischaemic stroke after day 6 + 1 day and major ischaemic stroke after day 12 + 2 day).

Late treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent according to country specific details
• Age: ≥18 years
• Acute ischemic stroke, either confirmed by MRI or CT scan (tissue based definition) or by sudden focal neurological deficit of presumed ischaemic origin that persisted beyond 24 hours and otherwise normal non-contrast CT scan. Please note: prior intravenous or endovascular treatment is allowed.
• Permanent, persistent, or paroxysmal spontaneous AF previously known or diagnosed during the index hospitalization
• Agreement of treating physician to prescribe DOACs

You may not qualify if:

• Atrial fibrillation due to reversible causes (e.g. thyrotoxicosis, pericarditis, recent surgery, myocardial infarct)
• Valvular disease requiring surgery
• Mechanical heart valve(s)
• Moderate or severe mitral stenosis. Please note that other valvular diseases and biological valves are eligible
• Vitamine K antagonist: International Normalized Ratio (INR) \<1.7
• Anti-IIa: thrombin time \<80 seconds and/or anti-IIa \<50 ng/ml
• Anti-Xa: anti-Xa \<50 ng/ml
• Subject who is contraindicated to DOACs
• Female who is pregnant or lactating or has a positive pregnancy test at time of admission
• Patients with serious bleeding in the last 6 months or is at high risk of bleeding (e.g. active peptic ulcer disease, platelet count \< 100'000/mm3 or haemoglobin \< 10 g/dl or INR ≥ 1.7, documented haemorrhagic tendencies or blood dyscrasias)
• Subject currently uses or has a recent history of illicit drug(s) or abuses alcohol (defined as regular or daily consumption of more than four alcoholic drinks per day)
• Severe comorbid condition with life expectancy \< 6 months
• Severe or moderate renal insufficiency as defined by creatinine clearance \< 50 ml/min
• Subject who requires haemodialysis or peritoneal dialysis
• Subject with aortic dissection

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead

Study Sites (98)

Krankenhaus der Barmherzigen Brüder Eisenstadt

Eisenstadt, Austria

Location

Medizinische Universität Graz

Graz, 8036, Austria

Location

Kepler Universitätsklinikum, Klinik für Neurologie 1

Linz, 4020, Austria

Location

Kepler Universitätsklinikum, Klinik für Neurologie 2

Linz, 4020, Austria

Location

Universitätsklinikum St. Pölten

Sankt Pölten, 3100, Austria

Location

Universitätsklinikum Tulln

Tulln, 3430, Austria

Location

Medizinische Universität Wien

Vienna, Austria

Location

Onze-Lieve-Vrouw Ziekenhuis VZW

Aalst, 9300, Belgium

Location

Cliniques Universitaires Saint-Luc

Brussels, 1200, Belgium

Location

Antwerp University Hospital

Edegem, 2650, Belgium

Location

University Hospital Gent

Ghent, Belgium

Location

AZ Groeninge

Kortrijk, 8500, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

CHC - Saint Joseph

Liège, 4000, Belgium

Location

Cliniques de l'Europe - Site Ste-Elisabeth

Uccle, 1180, Belgium

Location

Helsinki University Hospital

Helsinki, 00290, Finland

Location

Siun sote - North Karelia social and health services

Joensuu, Finland

Location

Universitätsklinikum Leipzig

Leipzig, Saxony, 04103, Germany

Location

Vivantes Klinikum Neukölln

Berlin, Germany

Location

St. Josef-Hospital Bochum

Bochum, 44791, Germany

Location

Klinik und Poliklinik für Neurologie Köln

Cologne, 50937, Germany

Location

Universitätsklinikum Erlangen

Erlangen, 91054, Germany

Location

Universitätsklinikum Frankfurt

Frankfurt, 60323, Germany

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, Germany

Location

Neurologische Universitätsklinik Heidelberg

Heidelberg, 69120, Germany

Location

Universitätsklinikum Schleswig-Holstein

Lübeck, 23562, Germany

Location

Mannheim University Hospital

Mannheim, 68167, Germany

Location

Klinikum der Universität München

München, 81377, Germany

Location

Universitäsklinikum Tübingen

Tübingen, Germany

Location

Dept. of Medicine, University of Thessaly

Larissa, Thessaly, 41110, Greece

Location

Lalitha Super Speciality Hospitals

Kothapeta, Guntur, 522001, India

Location

Narayana Hrudayalaya Bangalore

Bengaluru, Karnataka, 560099, India

Location

Amrita Institute of Medical Sciences

Kochi, Kerala, 682041, India

Location

Government Medical College Thiruvananthapuram

Thiruvananthapuram, Kerala, 695011, India

Location

Sree Chitra Tirunal Institute for Medical Sciences and Technology

Trivandrum, Kerala, 695011, India

Location

All India Institute Of Medical Sciences

New Delhi, National Capital Territory of Delhi, 110029, India

Location

Christian Medical College & Hospital

Ludhiana, Punjab, 141008, India

Location

Cork University Hospital

Cork, Ireland

Location

Mater Misericordiae University Hospital

Dublin, Ireland

Location

St. James's Hospital

Dublin, Ireland

Location

St. Vincent's University Hospital

Dublin, Ireland

Location

Tallaght University Hospital

Dublin, Ireland

Location

University Hospital Waterford

Waterford, Ireland

Location

Hadassah Medical Center

Jerusalem, Israel

Location

Shaare Zedek Medical Center

Jerusalem, Israel

Location

Sheba Medical Centre

Ramat Gan, Israel

Location

Ospedale Santa Maria della Misericordia

Perugia, Italy

Location

Umberto Policlinico di Roma

Rome, Italy

Location

Kansai Medical University

Hirakata, 573-1010, Japan

Location

St. Marianna Medical University Hospital

Kawasaki, Japan

Location

Kumamoto University

Kumamoto, 860-8555, Japan

Location

National Cerebral and Cardiovascular Center

Osaka, 564-8565, Japan

Location

Jichi Medical University

Tochigi, Japan

Location

The Jikei University Hospital

Tokyo, 105-0003, Japan

Location

Ålesund sjukehus

Ålesund, Norway

Location

Vestre Viken Health Trust - Drammen Hospital

Drammen, 3004, Norway

Location

Akershus University Hospital

Lørenskog, Norway

Location

Oslo University Hospital, Ullevål

Oslo, 0450, Norway

Location

Coimbra University Hospital

Coimbra, Portugal

Location

Hospital de Santa Maria

Lisbon, 1649-028, Portugal

Location

Hospital de Egas Moniz

Lisbon, Portugal

Location

Košice Medical University

Košice, 040 11, Slovakia

Location

Fakultná Nemocnica Trnava

Trnava, Slovakia

Location

Dept. of Neurology, Kantonsspital Aarau

Aarau, Canton of Aargau, 5001, Switzerland

Location

Dept. of Neurology, Universitätsspital Basel

Basel, Canton of Basel-City, 4031, Switzerland

Location

Dept. of Neurology, Universitätsspital Lausanne

Lausanne, Canton of Vaud, 1011, Switzerland

Location

Dept. of Neurology, Hôpital de Zone de Nyon

Nyon, Canton of Vaud, 1260, Switzerland

Location

Dept. of Neurology, Kantonsspital Chur

Chur, Kanton Graubünden, 7000, Switzerland

Location

Dept. of Neurology, Kantonsspital Sion

Sion, Valais, 1951, Switzerland

Location

Kantonsspital Baden

Baden, 5404, Switzerland

Location

Dept. of Neurology, Bern University Hospital

Bern, 3010, Switzerland

Location

Dept. of Neurology, Kantonsspital Fribourg

Fribourg, 1708, Switzerland

Location

Dept. of Neurology, Universitätsspital Genf

Geneva, 1205, Switzerland

Location

Dept. of Neurology, Kantonsspital Luzern

Lucerne, 6000, Switzerland

Location

Ospedale Regionale di Lugano (EOC)

Lugano, 6900, Switzerland

Location

Kantonsspital Münsterlingen

Münsterlingen, 8596, Switzerland

Location

Hôpital neuchâtelois

Neuchâtel, 2000, Switzerland

Location

Dept. of Neurology, Kantonsspital St.Gallen

Sankt Gallen, 9000, Switzerland

Location

Kantonsspital Winterthur

Winterthur, 8400, Switzerland

Location

Klinik Hirslanden Zürich

Zurich, 8032, Switzerland

Location

Dept. of Neurology, Universitätsspital Zürich

Zurich, 8091, Switzerland

Location

St George's University Hospitals NHS Foundation Trust

Tooting, London, SW17 0QT, United Kingdom

Location

University Hospital Monklands

Airdrie, United Kingdom

Location

Royal United Hospitals Bath

Bath, United Kingdom

Location

Southmead Hospital Bristol

Bristol, BS10 5NB, United Kingdom

Location

Countess of Chester Hospital

Chester, United Kingdom

Location

Ninewells Hospital

Dundee, DD2 1SG, United Kingdom

Location

University Hospital of North Durham

Durham, DH1 5TW, United Kingdom

Location

Glasgow Royal Infirmary

Glasgow, United Kingdom

Location

Queen Elizabeth University Hospital

Glasgow, United Kingdom

Location

Wirral University Teaching Hospital

Metropolitan Borough of Wirral, CH49 5PE, United Kingdom

Location

The James Cook University Hospital

Middlesbrough, United Kingdom

Location

Morriston Hospital

Morriston, SA6 6NL, United Kingdom

Location

Perth Royal Infirmary

Perth, PH1 1NX, United Kingdom

Location

Glan Clwyd Hospital

Rhyl, LL18 5UJ, United Kingdom

Location

University Hospital of North Tees

Stockton-on-Tees, TS198PE, United Kingdom

Location

Royal Stoke University Hospital

Stoke-on-Trent, ST4 6QG, United Kingdom

Location

Weston General Hospital

Weston-super-Mare, United Kingdom

Location

Related Publications (9)

• Polymeris AA, Rossel JB, Koga M, Strbian D, Vedamurthy A, Krishnan M, Branca M, Meinel T, Kristoffersen ES, Yoshimoto T, Tanaka K, Kunieda T, Yakushiji Y, Vehoff J, Matsuzono K, Slade P, Demeestere J, Salerno A, Caracciolo NG, Hemelsoet D, Engelter ST, Auer E, Horvath T, Seiffge DJ, Goeldlin M, Dawson J, Fischer U. Once- versus twice-daily direct oral anticoagulants after ischemic stroke in atrial fibrillation - A post-hoc analysis of the ELAN trial. Eur Stroke J. 2026 Jan 1;11(1):23969873251360974. doi: 10.1093/esj/23969873251360974.

  PMID: 41614485 DERIVED

• Polymeris AA, Rossel JB, Koga M, Strbian D, Vedamurthy A, Krishnan M, Branca M, Meinel T, Kristoffersen ES, Yoshimoto T, Tanaka K, Kunieda T, Yakushiji Y, Vehoff J, Matsuzono K, Slade P, Demeestere J, Salerno A, Caracciolo NG, Hemelsoet D, Engelter ST, Auer E, Horvath T, Seiffge DJ, Goeldlin M, Dawson J, Fischer U; ELAN Investigators. Once- versus twice-daily direct oral anticoagulants after ischemic stroke in atrial fibrillation - A post-hoc analysis of the ELAN trial. Eur Stroke J. 2025 Aug 11:23969873251360974. doi: 10.1177/23969873251360974. Online ahead of print.

  PMID: 40785636 DERIVED

• Wouters A, Demeestere J, Rossel JB, Devroye A, Desfontaines P, Vanacker P, Hemelsoet D, Yperzeele L, Rutgers MP, Peeters A, Vynckier J, Yoshimoto T, Tanaka K, Vehoff J, Matsuzono K, Kulyk C, Sibolt G, Slade P, Salerno A, Kunieda T, Hakim A, Rohner R, Abend S, Goeldlin M, Dawson J, Fischer U, Lemmens R; ELAN Investigators. Prior Reperfusion Strategy Does Not Modify Outcome in Early Versus Late Start of Anticoagulants in Patients With Ischemic Stroke: Prespecified Subanalysis of the Randomized Controlled ELAN Trial. Stroke. 2025 Aug;56(8):2000-2008. doi: 10.1161/STROKEAHA.125.050646. Epub 2025 May 22.

  PMID: 40402090 DERIVED

• Kneihsl M, Hakim A, Goeldlin MB, Branca M, Fenzl S, Abend S, Gattringer T, Enzinger C, Dawson J, Gesierich B, Kopczak A, Hack RJ, Cerfontaine MN, Rutten JW, Lesnik Oberstein SAJ, Pasi M, Fischer U, Duering M, Meinel TR. Topographic Localization of Chronic Cerebellar Ischemic Lesions: Implications for Underlying Cause. Stroke. 2025 Jul;56(7):1823-1831. doi: 10.1161/STROKEAHA.124.049337. Epub 2025 Apr 3.

  PMID: 40177749 DERIVED

• Polymeris AA, Branca M, Sylaja PN, Sandset EC, de Sousa DA, Thomalla G, Paciaroni M, Gattringer T, Strbian D, Trelle S, Michel P, Nedeltchev K, Bonati LH, Ntaios G, Koga M, Gdovinova Z, Lemmens R, Bornstein NM, Kelly P, Goeldlin MB, Abend S, Selim M, Katan M, Horvath T, Dawson J, Fischer U; ELAN Investigators. Net Benefit of Early Anticoagulation for Stroke With Atrial Fibrillation: Post Hoc Analysis of the ELAN Randomized Clinical Trial. JAMA Netw Open. 2025 Jan 2;8(1):e2456307. doi: 10.1001/jamanetworkopen.2024.56307.

  PMID: 39874037 DERIVED

• Kneihsl M, Hakim A, Goeldlin MB, Meinel TR, Branca M, Rohner R, Fenzl S, Abend S, Shim GC, Gumbinger C, Zhang L, Kristoffersen ES, Desfontaines P, Vanacker P, Alonso A, Poli S, Nunes AP, Caracciolo NG, Gattringer T, Kahles T, Giudici D, Demeestere J, Dawson J, Fischer U; ELAN investigators. Early vs Late Anticoagulation After Ischemic Stroke in Patients With Atrial Fibrillation and Covert Brain Infarcts. Neurology. 2025 Jan 14;104(1):e210157. doi: 10.1212/WNL.0000000000210157. Epub 2024 Dec 19.

  PMID: 39700448 DERIVED

• Goeldlin MB, Hakim A, Branca M, Abend S, Kneihsl M, Valenzuela Pinilla W, Fenzl S, Rezny-Kasprzak B, Rohner R, Strbian D, Paciaroni M, Thomalla G, Michel P, Nedeltchev K, Gattringer T, Sandset EC, Bonati L, Aguiar de Sousa D, Sylaja PN, Ntaios G, Koga M, Gdovinova Z, Lemmens R, Bornstein NM, Kelly P, Katan M, Horvath T, Dawson J, Fischer U; ELAN Investigators. Early vs Late Anticoagulation in Minor, Moderate, and Major Ischemic Stroke With Atrial Fibrillation: Post Hoc Analysis of the ELAN Randomized Clinical Trial. JAMA Neurol. 2024 Jul 1;81(7):693-702. doi: 10.1001/jamaneurol.2024.1450.

  PMID: 38805207 DERIVED

• Rohner R, Kneihsl M, Goeldlin MB, Hakim A, Branca M, Abend S, Valenzuela Pinilla W, Fenzl S, Rezny-Kasprzak B, Strbian D, Trelle S, Paciaroni M, Thomalla G, Michel P, Nedeltchev K, Gattringer T, Sandset EC, Bonati L, Aguiar de Sousa D, Sylaja PN, Ntaios G, Koga M, Gdovinova Z, Lemmens R, Bornstein NM, Kelly P, Katan M, Horvath T, Dawson J, Fischer U; ELAN Investigators. Early Versus Late Initiation of Direct Oral Anticoagulants After Ischemic Stroke in People With Atrial Fibrillation and Hemorrhagic Transformation: Prespecified Subanalysis of the Randomized Controlled ELAN Trial. Circulation. 2024 Jul 2;150(1):19-29. doi: 10.1161/CIRCULATIONAHA.124.069324. Epub 2024 May 16.

  PMID: 38753452 DERIVED

• Fischer U, Koga M, Strbian D, Branca M, Abend S, Trelle S, Paciaroni M, Thomalla G, Michel P, Nedeltchev K, Bonati LH, Ntaios G, Gattringer T, Sandset EC, Kelly P, Lemmens R, Sylaja PN, Aguiar de Sousa D, Bornstein NM, Gdovinova Z, Yoshimoto T, Tiainen M, Thomas H, Krishnan M, Shim GC, Gumbinger C, Vehoff J, Zhang L, Matsuzono K, Kristoffersen E, Desfontaines P, Vanacker P, Alonso A, Yakushiji Y, Kulyk C, Hemelsoet D, Poli S, Paiva Nunes A, Caracciolo N, Slade P, Demeestere J, Salerno A, Kneihsl M, Kahles T, Giudici D, Tanaka K, Raty S, Hidalgo R, Werring DJ, Goldlin M, Arnold M, Ferrari C, Beyeler S, Fung C, Weder BJ, Tatlisumak T, Fenzl S, Rezny-Kasprzak B, Hakim A, Salanti G, Bassetti C, Gralla J, Seiffge DJ, Horvath T, Dawson J; ELAN Investigators. Early versus Later Anticoagulation for Stroke with Atrial Fibrillation. N Engl J Med. 2023 Jun 29;388(26):2411-2421. doi: 10.1056/NEJMoa2303048. Epub 2023 May 24.

  PMID: 37222476 DERIVED

MeSH Terms

Conditions

Ischemic Stroke; Stroke; Atrial Fibrillation

Interventions

Rivaroxaban; Dabigatran; apixaban; edoxaban

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyridines; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Urs Fischer, Prof. MD

  Dept. of Neurology, Inselspital Bern

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 7, 2017
• First Posted: May 11, 2017
• Study Start: November 6, 2017
• Primary Completion: December 21, 2022
• Study Completion: May 24, 2023
• Last Updated: July 18, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

DE (12); NO (4); IT (2); PT (3); CH (18); GB (17); IN (7); BE (8); JP (6); AU (7); SL (2); IE (6); GR (1); IL (3); FI (2)