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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)

This study is currently recruiting participants.
Verified November 2017 by University Hospital Inselspital, Berne
Sponsor:
ClinicalTrials.gov Identifier:
NCT03148457
First Posted: May 11, 2017
Last Update Posted: November 15, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
University Hospital Inselspital, Berne
  Purpose

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.


Condition Intervention
Ischaemic Stroke 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®)

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by University Hospital Inselspital, Berne:

Primary Outcome Measures:
  • Composite of major bleeding, recurrent ischaemic stroke, systemic embolism and/or vascular death [ Time Frame: 30 ± 3 days after randomisation ]

Secondary Outcome Measures:
  • Modified Rankin Scale (mRS) [ Time Frame: 30 days, 90 days after randomisation ]
  • Major bleeding [ Time Frame: 30 days, 90 days after randomisation ]
  • Non-major bleeding [ Time Frame: 30 days, 90 days after randomisation ]
  • Recurrence of stroke [ Time Frame: 30 days, 90 days after randomisation ]
  • Systemic embolism [ Time Frame: 30 days, 90 days after randomisation ]
  • Vascular death [ Time Frame: 30 days, 90 days after randomisation ]
  • All-cause mortality [ Time Frame: 90 days after randomisation ]
  • Myocardial infarction [ Time Frame: 90 days after randomisation ]
  • Major cardiovascular events defined as composite of stroke, myocardial infarct, heart failure or cardiovascular death [ Time Frame: 90 days after randomisation ]
  • Silent brain lesions [ Time Frame: 90 days after randomisation ]
    If CT/MRI is performed in clinical routine

  • Favourable outcome defined as mRS ≤ 2 and shift analysis adjusted to premorbid mRS [ Time Frame: 90 days after randomisation ]
  • NIHSS [ Time Frame: 90 days after randomisation ]
  • Transient ischemic attack [ Time Frame: 30 days, 90 days after randomisation ]
  • Undetermined stroke [ Time Frame: 30 days, 90 days after randomisation ]
  • Compliance [ Time Frame: 30 days after randomisation ]

Estimated Enrollment: 2000
Actual Study Start Date: November 6, 2017
Estimated Study Completion Date: October 31, 2021
Estimated Primary Completion Date: August 30, 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)
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).

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03148457


Contacts
Contact: Miriam Paulisch, PhD +41 31 632 67 80 miriamhelen.paulisch@insel.ch
Contact: Stefanie Lerch, PhD +41 31 632 73 09 stefanie.lerch@insel.ch

Locations
Switzerland
Dept. of Neurology, Kantonsspital Aarau Recruiting
Aarau, Aargau, Switzerland, 5001
Principal Investigator: Krassen Nedeltchev, Prof. Dr. med.         
Dept. of Neurology, Universitätsspital Basel Recruiting
Basel, Basel Stadt, Switzerland, 4031
Principal Investigator: Leo Bonati, Prof. Dr. med.         
Dept. of Neurology, Kantonsspital Chur Recruiting
Chur, Graubünden, Switzerland, 7000
Principal Investigator: Sylvan Albert, Dr. med.         
Dept. of Neurology, Kantonsspital Lugano Recruiting
Lugano, Tessin, Switzerland, 6900
Principal Investigator: Carlo Cereda, Dr. med.         
Dept. of Neurology, Universitätsspital Lausanne Recruiting
Lausanne, Waadt, Switzerland, 1011
Principal Investigator: Patrik Michel, Prof. Dr. med.         
Dept. of Neurology, Hôpital de Zone de Nyon Recruiting
Nyon, Waadt, Switzerland, 1260
Principal Investigator: Julian Niederhäuser, Dr. med.         
Dept. of Neurology, Kantonsspital Sion Recruiting
Sion, Wallis, Switzerland, 1951
Principal Investigator: Christophe Bovin, Dr. med.         
Dept. of Neurology, Bern University Hospital Recruiting
Bern, Switzerland, 3010
Contact: Miriam Paulisch, Dr. phil. nat.    +41 31 632 67 80    miriamhelen.paulisch@insel.ch   
Principal Investigator: Urs Fischer, Prof. Dr. med.         
Dept. of Neurology, Kantonsspital Fribourg Recruiting
Fribourg, Switzerland, 1708
Principal Investigator: Andrea Humm, PD Dr. med.         
Dept. of Neurology, Universitätsspital Genf Recruiting
Geneve, Switzerland, 1205
Principal Investigator: Fabienne Perren, Prof. Dr. med.         
Dept. of Neurology, Kantonsspital Luzern Recruiting
Luzern, Switzerland, 6000
Principal Investigator: Martin Müller, Prof. Dr. med.         
Dept. of Neurology, Kantonsspital St.Gallen Recruiting
St.Gallen, Switzerland, 9000
Principal Investigator: Jochen Vehoff, Dr. med.         
Dept. of Neurology, Universitätsspital Zürich Recruiting
Zurich, Switzerland, 8091
Principal Investigator: Christoph Globas, Dr. med.         
Sponsors and Collaborators
University Hospital Inselspital, Berne
Investigators
Principal Investigator: Urs Fischer, Prof. Dr. med. Dept. of Neurology, Inselspital Bern
  More Information

Responsible Party: University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier: NCT03148457     History of Changes
Other Study ID Numbers: 2017-00588
First Submitted: April 7, 2017
First Posted: May 11, 2017
Last Update Posted: November 15, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by University Hospital Inselspital, Berne:
Stroke
Direct oral anticoagulation
Apixaban
Dabigatran
Rivaroxaban
Edoxaban
Therapy initiation
Major bleeding
Atrial fibrillation

Additional relevant MeSH terms:
Stroke
Atrial Fibrillation
Ischemia
Cerebral Infarction
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Arrhythmias, Cardiac
Heart Diseases
Pathologic Processes
Brain Infarction
Brain Ischemia
Rivaroxaban
Apixaban
Edoxaban
Dabigatran
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action