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 (ELAN)

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.

Study Overview

• Status: Completed
• Conditions: Ischaemic Stroke
• Intervention / Treatment: Drug: Early treatment with Rivaroxaban (Xarelto®), Dabigatran (Pradaxa®), Apixaban (Eliquis®) or Edoxaban (Lixiana®); Drug: Late treatment with Rivaroxaban (Xarelto®), Dabigatran (Pradaxa®), Apixaban (Eliquis®) or Edoxaban (Lixiana®)

Detailed Description

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia increasing the risk of stroke and systemic thromboembolism and thus mortality and morbidity. Anticoagulation therapy, such as with vitamin K antagonists effectively prevents strokes in patients with AF, however, increases bleeding complications leading to symptomatic intracerebral haemorrhage. Direct oral anticoagulants (DOACs) are at least as effective as vitamin K antagonists in preventing recurrent strokes, but with lower rates of symptomatic intracerebral haemorrhage. Therefore, these new agents are potentially ideal drugs to treat patients with ischaemic stroke related to AF. However, in previous trials comparing DOACs with vitamin K antagonists, therapy was initiated later than 7-14 days after onset of ischaemic stroke. Whether, earlier initiation of DOACs may prevent recurrent stroke without increasing the risk of symptomatic intracerebral haemorrhage remains to be determined.

Objectives 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.

Methods All patients of 18 years or older with an acute ischaemic stroke related to AF should be screened for this trial.

Patients in the experimental arm (early treatment) and the control arm (late treatment) will receive direct oral anticoagulants for prevention of stroke and systemic embolism in patients with AF. Depending on the size of the infarction, 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). 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).

The primary outcome is a composite of major bleeding, recurrent ischaemic stroke, systemic embolism and/or vascular death at 30 ± 3 days after randomisation.

• Study Type: Interventional
• Enrollment (Actual): 2013
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stefanie Abend, BSc; Phone Number: +41 31 632 67 80; Email: stefanie.abend@insel.ch
• Study Contact Backup: Name: Seraina Beyeler, PhD; Email: seraina.beyeler@insel.ch

Study Locations

• Austria
  • Eisenstadt, Austria
    • Krankenhaus der Barmherzigen Brüder Eisenstadt
  • Graz, Austria, 8036
    • Medizinische Universität Graz
  • Linz, Austria, 4020
    • Kepler Universitätsklinikum, Klinik für Neurologie 1
  • Linz, Austria, 4020
    • Kepler Universitätsklinikum, Klinik für Neurologie 2
  • St.Pölten, Austria, 3100
    • Universitätsklinikum St. Pölten
  • Tulln, Austria, 3430
    • Universitatsklinikum Tulln
  • Wien, Austria
    • Medizinische Universität Wien
• Belgium
  • Aalst, Belgium, 9300
    • Onze-Lieve-Vrouw Ziekenhuis VZW
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Edegem, Belgium, 2650
    • Antwerp University Hospital
  • Gent, Belgium
    • University Hospital Gent
  • Kortrijk, Belgium, 8500
    • Az Groeninge
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Liège, Belgium, 4000
    • CHC - Saint Joseph
  • Uccle, Belgium, 1180
    • Cliniques de l'Europe - Site Ste-Elisabeth
• Finland
  • Helsinki, Finland, 00290
    • Helsinki University Hospital
  • Joensuu, Finland
    • Siun sote - North Karelia social and health services
• Germany
  • Berlin, Germany
    • Vivantes Klinikum Neukölln
  • Bochum, Germany, 44791
    • St. Josef-Hospital Bochum
  • Cologne, Germany, 50937
    • Klinik und Poliklinik für Neurologie Köln
  • Erlangen, Germany, 91054
    • Universitätsklinikum Erlangen
  • Frankfurt, Germany, 60323
    • Universitatsklinikum Frankfurt
  • Hamburg, Germany
    • Universitätsklinikum Hamburg-Eppendorf
  • Heidelberg, Germany, 69120
    • Neurologische Universitätsklinik Heidelberg
  • Lübeck, Germany, 23562
    • Universitatsklinikum Schleswig-Holstein
  • Mannheim, Germany, 68167
    • Mannheim University Hospital
  • München, Germany, 81377
    • Klinikum der Universität München
  • Tübingen, Germany
    • Universitäsklinikum Tübingen
  • Sachsen
    • Leipzig, Sachsen, Germany, 04103
      • Universitatsklinikum Leipzig
• Greece
  • Thessaly
    • Larissa, Thessaly, Greece, 41110
      • Dept. of Medicine, University of Thessaly
• India
  • Delhi
    • New Delhi, Delhi, India, 110029
      • All India Institute of Medical Sciences
  • Guntur
    • Kothapeta, Guntur, India, 522001
      • Lalitha Super Speciality Hospitals
  • Karnataka
    • Bengaluru, Karnataka, India, 560099
      • Narayana Hrudayalaya Bangalore
  • Kerala
    • Kochi, Kerala, India, 682041
      • Amrita Institute of Medical Sciences
    • Thiruvananthapuram, Kerala, India, 695011
      • Government Medical College Thiruvananthapuram
    • Trivandrum, Kerala, India, 695011
      • Sree Chitra Tirunal Institute for Medical Sciences and Technology
  • Punjab
    • Ludhiāna, Punjab, India, 141008
      • Christian Medical College & Hospital
• Ireland
  • Cork, Ireland
    • Cork University Hospital
  • Dublin, Ireland
    • Mater Misericordiae University Hospital
  • Dublin, Ireland
    • St. James's Hospital
  • Dublin, Ireland
    • Tallaght University Hospital
  • Dublin, Ireland
    • St. Vincent's University Hospital
  • Waterford, Ireland
    • University Hospital Waterford
• Israel
  • Jerusalem, Israel
    • Hadassah Medical Center
  • Jerusalem, Israel
    • Shaare Zedek Medical Center
  • Ramat Gan, Israel
    • Sheba Medical Centre
• Italy
  • Perugia, Italy
    • Ospedale Santa Maria della Misericordia
  • Rom, Italy
    • Umberto Policlinico di Roma
• Japan
  • Hirakata, Japan, 573-1010
    • Kansai Medical University
  • Kawasaki, Japan
    • St. Marianna Medical University Hospital
  • Kumamoto, Japan, 860-8555
    • Kumamoto University
  • Osaka, Japan, 564-8565
    • National Cerebral and Cardiovascular Center
  • Tochigi, Japan
    • Jichi Medical University
  • Tokyo, Japan, 105-0003
    • The Jikei University Hospital
• Norway
  • Drammen, Norway, 3004
    • Vestre Viken Health Trust - Drammen Hospital
  • Lørenskog, Norway
    • Akershus University Hospital
  • Oslo, Norway, 0450
    • Oslo University Hospital, Ullevål
  • Ålesund, Norway
    • Alesund sjukehus
• Portugal
  • Coimbra, Portugal
    • Coimbra University Hospital
  • Lisboa, Portugal
    • Hospital de Egas Moniz
  • Lisbon, Portugal, 1649-028
    • Hospital de Santa Maria
• Slovakia
  • Košice, Slovakia, 040 11
    • Košice Medical University
  • Trnava, Slovakia
    • Fakultna nemocnica Trnava
• Switzerland
  • Baden, Switzerland, 5404
    • Kantonsspital Baden
  • Bern, Switzerland, 3010
    • Dept. of Neurology, Bern University Hospital
  • Fribourg, Switzerland, 1708
    • Dept. of Neurology, Kantonsspital Fribourg
  • Geneve, Switzerland, 1205
    • Dept. of Neurology, Universitätsspital Genf
  • Lugano, Switzerland, 6900
    • Ospedale Regionale di Lugano (EOC)
  • Luzern, Switzerland, 6000
    • Dept. of Neurology, Kantonsspital Luzern
  • Münsterlingen, Switzerland, 8596
    • Kantonsspital Münsterlingen
  • Neuchâtel, Switzerland, 2000
    • Hôpital neuchâtelois
  • St.Gallen, Switzerland, 9000
    • Dept. of Neurology, Kantonsspital St.Gallen
  • Winterthur, Switzerland, 8400
    • Kantonsspital Winterthur
  • Zurich, Switzerland, 8091
    • Dept. of Neurology, Universitätsspital Zürich
  • Zürich, Switzerland, 8032
    • Klinik Hirslanden Zürich
  • Aargau
    • Aarau, Aargau, Switzerland, 5001
      • Dept. of Neurology, Kantonsspital Aarau
  • Basel Stadt
    • Basel, Basel Stadt, Switzerland, 4031
      • Dept. of Neurology, Universitätsspital Basel
  • Graubünden
    • Chur, Graubünden, Switzerland, 7000
      • Dept. of Neurology, Kantonsspital Chur
  • Waadt
    • Lausanne, Waadt, Switzerland, 1011
      • Dept. of Neurology, Universitätsspital Lausanne
    • Nyon, Waadt, Switzerland, 1260
      • Dept. of Neurology, Hôpital de Zone de Nyon
  • Wallis
    • Sion, Wallis, Switzerland, 1951
      • Dept. of Neurology, Kantonsspital Sion
• United Kingdom
  • Airdrie, United Kingdom
    • University Hospital Monklands
  • Bath, United Kingdom
    • Royal United Hospitals Bath
  • Bristol, United Kingdom, BS10 5NB
    • Southmead Hospital Bristol
  • Chester, United Kingdom
    • Countess of Chester Hospital
  • Dundee, United Kingdom, DD2 1SG
    • Ninewells Hospital
  • Durham, United Kingdom, DH1 5TW
    • University Hospital of North Durham
  • Glasgow, United Kingdom
    • Glasgow Royal Infirmary
  • Glasgow, United Kingdom
    • Queen Elizabeth University Hospital
  • Middlesbrough, United Kingdom
    • The James Cook University Hospital
  • Morriston, United Kingdom, SA6 6NL
    • Morriston Hospital
  • Perth, United Kingdom, PH1 1NX
    • Perth Royal Infirmary
  • Rhyl, United Kingdom, LL18 5UJ
    • Glan Clwyd Hospital
  • Stockton-on-Tees, United Kingdom, TS198PE
    • University Hospital of North Tees
  • Stoke-on-Trent, United Kingdom, ST4 6QG
    • Royal Stoke University Hospital
  • Weston-super-Mare, United Kingdom
    • Weston General Hospital
  • Wirral, United Kingdom, CH49 5PE
    • Wirral University Teaching Hospital
  • London
    • Tooting, London, United Kingdom, SW17 0QT
      • St George's University Hospitals NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

• AF and conditions other than AF that require anticoagulation, including therapeutical dose of low-molecular-weight heparin or heparin. Please note: infratherapeutic anticoagulation at ischaemic stroke onset defined as follows is not an exclusion criteria:

  • 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
• Current participation in another investigational trial
• Dual antiplatelet therapy at baseline or strong likelihood to be treated with dual antiplatelet therapy during the course of the trial
• CT or MRI evidence of haemorrhage classified as PH1 (defined as parenchymal haemorrhage = blood clots in <30% of the infarcted area without or with slight space-occupying effect) and PH2 (defined as blood clots in >30% of the infarcted area with a substantial space-occupying effect) independently of clinical deterioration. Please note that HI1 (defined as haemorrhagic infarct = small petechiae along the margins of the infarct) and HI2 (defined as confluent petechiae within the infarcted area but no space occupying effect) are acceptable if not associated with clinical deterioration and if the treating physician feels comfortable to treat patients with DOACs.
• CT or MRI evidence of mass effect or intra-cranial tumour (except small meningioma)
• CT or MRI evidence of cerebral vasculitis
• Endocarditis
• Evidence of severe cerebral amyloid angiopathy if MRI scan performed

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early treatment; 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®); 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)
Other: Late treatment; 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®); 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Composite of major bleeding, recurrent ischaemic stroke, systemic embolism and/or vascular death	30 ± 3 days after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Vascular death		30 days, 90 days after randomisation
All-cause mortality		90 days after randomisation
Myocardial infarction		90 days after randomisation
Major cardiovascular events defined as composite of stroke, myocardial infarct, heart failure or cardiovascular death		90 days after randomisation
Silent brain lesions	If CT/MRI is performed in clinical routine	90 days after randomisation
Favourable outcome defined as mRS ≤ 2 and shift analysis adjusted to premorbid mRS		90 days after randomisation
NIHSS		90 days after randomisation
Transient ischemic attack		30 days, 90 days after randomisation
Undetermined stroke		30 days, 90 days after randomisation
Compliance		30 days after randomisation

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Investigators: Principal Investigator: Urs Fischer, Prof. MD, Dept. of Neurology, Inselspital Bern

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2017
• Primary Completion (Actual): December 21, 2022
• Study Completion (Actual): May 24, 2023

Study Registration Dates

• First Submitted: April 7, 2017
• First Submitted That Met QC Criteria: May 8, 2017
• First Posted (Actual): May 11, 2017

Study Record Updates

• Last Update Posted (Actual): July 18, 2023
• Last Update Submitted That Met QC Criteria: July 17, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Stroke; Rivaroxaban; Atrial fibrillation; Apixaban; Dabigatran; Edoxaban; Direct oral anticoagulation; Therapy initiation; Major bleeding
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arrhythmias, Cardiac; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Atrial Fibrillation; Cerebral Infarction; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Dabigatran; Apixaban; Edoxaban
• Other Study ID Numbers: 2017-00588

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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