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
- Conditions
- Ischaemic Stroke
- Interventions
- 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®)
- Registration Number
- NCT03148457
- Lead Sponsor
- Insel Gruppe AG, University Hospital Bern
- 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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 2013
- 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
-
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Early treatment Early treatment with Rivaroxaban (Xarelto®), Dabigatran (Pradaxa®), Apixaban (Eliquis®) or Edoxaban (Lixiana®) Early treatment of patients with ischaemic stroke related to atrial fibrillation (AF) with direct oral anticoagulations (DOACs). Late treatment Late treatment with Rivaroxaban (Xarelto®), Dabigatran (Pradaxa®), Apixaban (Eliquis®) or Edoxaban (Lixiana®) Treatment with direct oral anticoagulations (DOACs) according the current standard practice in patients with acute ischemic stroke related to atrial fibrillation (AF).
- Primary Outcome Measures
Name Time Method Composite of major bleeding, recurrent ischaemic stroke, systemic embolism and/or vascular death 30 ± 3 days after randomisation
- Secondary Outcome Measures
Name Time Method Myocardial infarction 90 days after randomisation All-cause mortality 90 days after randomisation Vascular death 30 days, 90 days after randomisation Major cardiovascular events defined as composite of stroke, myocardial infarct, heart failure or cardiovascular death 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 NIHSS 90 days after randomisation Transient ischemic attack 30 days, 90 days after randomisation Modified Rankin Scale (mRS) 30 days, 90 days after randomisation Silent brain lesions 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 90 days after randomisation Undetermined stroke 30 days, 90 days after randomisation Compliance 30 days after randomisation
Trial Locations
- Locations (98)
Universitätsklinikum Tulln
🇦🇹Tulln, Austria
All India Institute Of Medical Sciences
🇮🇳New Delhi, Delhi, India
Medizinische Universität Graz
🇦🇹Graz, Austria
Kepler Universitätsklinikum, Klinik für Neurologie 1
🇦🇹Linz, Austria
Kepler Universitätsklinikum, Klinik für Neurologie 2
🇦🇹Linz, Austria
Cliniques Universitaires Saint-Luc
🇧🇪Bruxelles, Belgium
Medizinische Universität Wien
🇦🇹Wien, Austria
Onze-Lieve-Vrouw Ziekenhuis VZW
🇧🇪Aalst, Belgium
AZ Groeninge
🇧🇪Kortrijk, Belgium
Antwerp University Hospital
🇧🇪Edegem, Belgium
CHC - Saint Joseph
🇧🇪Liège, Belgium
Cliniques de l'Europe - Site Ste-Elisabeth
🇧🇪Uccle, Belgium
Helsinki University Hospital
🇫🇮Helsinki, Finland
Siun sote - North Karelia social and health services
🇫🇮Joensuu, Finland
Universitätsklinikum Leipzig
🇩🇪Leipzig, Sachsen, Germany
Vivantes Klinikum Neukölln
🇩🇪Berlin, Germany
St. Josef-Hospital Bochum
🇩🇪Bochum, Germany
Klinik und Poliklinik für Neurologie Köln
🇩🇪Cologne, Germany
Universitätsklinikum Erlangen
🇩🇪Erlangen, Germany
Universitätsklinikum Frankfurt
🇩🇪Frankfurt, Germany
Universitätsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Universitätsklinikum Schleswig-Holstein
🇩🇪Lübeck, Germany
Neurologische Universitätsklinik Heidelberg
🇩🇪Heidelberg, Germany
Mannheim University Hospital
🇩🇪Mannheim, Germany
Klinikum der Universität München
🇩🇪München, Germany
Universitäsklinikum Tübingen
🇩🇪Tübingen, Germany
Dept. of Medicine, University of Thessaly
🇬🇷Larissa, Thessaly, Greece
St. James's Hospital
🇮🇪Dublin, Ireland
Christian Medical College & Hospital
🇮🇳Ludhiāna, Punjab, India
Sree Chitra Tirunal Institute for Medical Sciences and Technology
🇮🇳Trivandrum, Kerala, India
Mater Misericordiae University Hospital
🇮🇪Dublin, Ireland
St. Vincent's University Hospital
🇮🇪Dublin, Ireland
Tallaght University Hospital
🇮🇪Dublin, Ireland
Shaare Zedek Medical Center
🇮🇱Jerusalem, Israel
University Hospital Waterford
🇮🇪Waterford, Ireland
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Sheba Medical Centre
🇮🇱Ramat Gan, Israel
Kansai Medical University
🇯🇵Hirakata, Japan
St. Marianna Medical University Hospital
🇯🇵Kawasaki, Japan
Kumamoto University
🇯🇵Kumamoto, Japan
National Cerebral and Cardiovascular Center
🇯🇵Osaka, Japan
Jichi Medical University
🇯🇵Tochigi, Japan
The Jikei University Hospital
🇯🇵Tokyo, Japan
Vestre Viken Health Trust - Drammen Hospital
🇳🇴Drammen, Norway
Coimbra University Hospital
🇵🇹Coimbra, Portugal
Ålesund sjukehus
🇳🇴Ålesund, Norway
Košice Medical University
🇸🇰Košice, Slovakia
Dept. of Neurology, Universitätsspital Basel
🇨🇭Basel, Basel Stadt, Switzerland
Hospital de Santa Maria
🇵🇹Lisbon, Portugal
Fakultná Nemocnica Trnava
🇸🇰Trnava, Slovakia
Dept. of Neurology, Kantonsspital Chur
🇨🇭Chur, Graubünden, Switzerland
Dept. of Neurology, Kantonsspital Aarau
🇨🇭Aarau, Aargau, Switzerland
Dept. of Neurology, Universitätsspital Lausanne
🇨🇭Lausanne, Waadt, Switzerland
Dept. of Neurology, Hôpital de Zone de Nyon
🇨🇭Nyon, Waadt, Switzerland
Kantonsspital Baden
🇨🇭Baden, Switzerland
Dept. of Neurology, Kantonsspital Sion
🇨🇭Sion, Wallis, Switzerland
Dept. of Neurology, Kantonsspital Fribourg
🇨🇭Fribourg, Switzerland
Dept. of Neurology, Bern University Hospital
🇨🇭Bern, Switzerland
Kantonsspital Münsterlingen
🇨🇭Münsterlingen, Switzerland
Dept. of Neurology, Universitätsspital Genf
🇨🇭Geneve, Switzerland
Hôpital neuchâtelois
🇨🇭Neuchâtel, Switzerland
Ospedale Regionale di Lugano (EOC)
🇨🇭Lugano, Switzerland
Dept. of Neurology, Kantonsspital St.Gallen
🇨🇭St.Gallen, Switzerland
Kantonsspital Winterthur
🇨🇭Winterthur, Switzerland
Dept. of Neurology, Universitätsspital Zürich
🇨🇭Zurich, Switzerland
St George's University Hospitals NHS Foundation Trust
🇬🇧Tooting, London, United Kingdom
University Hospital Monklands
🇬🇧Airdrie, United Kingdom
Royal United Hospitals Bath
🇬🇧Bath, United Kingdom
Southmead Hospital Bristol
🇬🇧Bristol, United Kingdom
Countess of Chester Hospital
🇬🇧Chester, United Kingdom
Ninewells Hospital
🇬🇧Dundee, United Kingdom
University Hospital of North Durham
🇬🇧Durham, United Kingdom
Glasgow Royal Infirmary
🇬🇧Glasgow, United Kingdom
Queen Elizabeth University Hospital
🇬🇧Glasgow, United Kingdom
The James Cook University Hospital
🇬🇧Middlesbrough, United Kingdom
Morriston Hospital
🇬🇧Morriston, United Kingdom
Perth Royal Infirmary
🇬🇧Perth, United Kingdom
University Hospital of North Tees
🇬🇧Stockton-on-Tees, United Kingdom
Royal Stoke University Hospital
🇬🇧Stoke-on-Trent, United Kingdom
Weston General Hospital
🇬🇧Weston-super-Mare, United Kingdom
Wirral University Teaching Hospital
🇬🇧Wirral, United Kingdom
Ospedale Santa Maria della Misericordia
🇮🇹Perugia, Italy
Umberto Policlinico di Roma
🇮🇹Rom, Italy
Glan Clwyd Hospital
🇬🇧Rhyl, United Kingdom
UZ Leuven
🇧🇪Leuven, Belgium
Lalitha Super Speciality Hospitals
🇮🇳Kothapeta, Guntur, India
Oslo University Hospital, Ullevål
🇳🇴Oslo, Norway
Hospital de Egas Moniz
🇵🇹Lisboa, Portugal
Narayana Hrudayalaya Bangalore
🇮🇳Bengaluru, Karnataka, India
Government Medical College Thiruvananthapuram
🇮🇳Thiruvananthapuram, Kerala, India
Krankenhaus der Barmherzigen Brüder Eisenstadt
🇦🇹Eisenstadt, Austria
Universitätsklinikum St. Pölten
🇦🇹St.Pölten, Austria
University Hospital Gent
🇧🇪Gent, Belgium
Cork University Hospital
🇮🇪Cork, Ireland
Klinik Hirslanden Zürich
🇨🇭Zürich, Switzerland
Amrita Institute of Medical Sciences
🇮🇳Kochi, Kerala, India
Akershus University Hospital
🇳🇴Lørenskog, Norway
Dept. of Neurology, Kantonsspital Luzern
🇨🇭Luzern, Switzerland