Clinical trial NCT03148457: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Ischaemic Stroke
Keywords: Stroke
Direct oral anticoagulation
Apixaban
Dabigatran
Rivaroxaban
Edoxaban
Therapy initiation
Major bleeding
Atrial fibrillation
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2017-05-11
Enrollment: 2013
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Composite of major bleeding, recurrent ischaemic stroke, systemic embolism and/or vascular death
timeFrame: 30 ± 3 days after randomisation
Secondary outcomes:
measure: Modified Rankin Scale (mRS)
timeFrame: 30 days, 90 days after randomisation
measure: Major bleeding
timeFrame: 30 days, 90 days after randomisation
measure: Non-major bleeding
timeFrame: 30 days, 90 days after randomisation
measure: Recurrence of stroke
timeFrame: 30 days, 90 days after randomisation
measure: Systemic embolism
timeFrame: 30 days, 90 days after randomisation
measure: Vascular death
timeFrame: 30 days, 90 days after randomisation
measure: All-cause mortality
timeFrame: 90 days after randomisation
measure: Myocardial infarction
timeFrame: 90 days after randomisation
measure: Major cardiovascular events defined as composite of stroke, myocardial infarct, heart failure or cardiovascular death
timeFrame: 90 days after randomisation
measure: Silent brain lesions
timeFrame: 90 days after randomisation
measure: Favourable outcome defined as mRS ≤ 2 and shift analysis adjusted to premorbid mRS
timeFrame: 90 days after randomisation
measure: NIHSS
timeFrame: 90 days after randomisation
measure: Transient ischemic attack
timeFrame: 30 days, 90 days after randomisation
measure: Undetermined stroke
timeFrame: 30 days, 90 days after randomisation
measure: Compliance
timeFrame: 30 days after randomisation
Other outcomes:
Locations:
city: Eisenstadt
country: Austria
facility: Krankenhaus der Barmherzigen Brüder Eisenstadt
city: Graz
country: Austria
facility: Medizinische Universität Graz
city: Linz
country: Austria
facility: Kepler Universitätsklinikum, Klinik für Neurologie 1
city: Linz
country: Austria
facility: Kepler Universitätsklinikum, Klinik für Neurologie 2
city: St.Pölten
country: Austria
facility: Universitätsklinikum St. Pölten
city: Tulln
country: Austria
facility: Universitätsklinikum Tulln
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Aalst
country: Belgium
facility: Onze-Lieve-Vrouw Ziekenhuis VZW
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Gent
country: Belgium
facility: University Hospital Gent
city: Kortrijk
country: Belgium
facility: AZ Groeninge
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: CHC - Saint Joseph
city: Uccle
country: Belgium
facility: Cliniques de l'Europe - Site Ste-Elisabeth
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Joensuu
country: Finland
facility: Siun sote - North Karelia social and health services
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Sachsen
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln
city: Bochum
country: Germany
facility: St. Josef-Hospital Bochum
city: Cologne
country: Germany
facility: Klinik und Poliklinik für Neurologie Köln
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Neurologische Universitätsklinik Heidelberg
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Mannheim
country: Germany
facility: Mannheim University Hospital
city: München
country: Germany
facility: Klinikum der Universität München
city: Tübingen
country: Germany
facility: Universitäsklinikum Tübingen
city: Larissa
country: Greece
facility: Dept. of Medicine, University of Thessaly
state: Thessaly
city: New Delhi
country: India
facility: All India Institute Of Medical Sciences
state: Delhi
city: Kothapeta
country: India
facility: Lalitha Super Speciality Hospitals
state: Guntur
city: Bengaluru
country: India
facility: Narayana Hrudayalaya Bangalore
state: Karnataka
city: Kochi
country: India
facility: Amrita Institute of Medical Sciences
state: Kerala
city: Thiruvananthapuram
country: India
facility: Government Medical College Thiruvananthapuram
state: Kerala
city: Trivandrum
country: India
facility: Sree Chitra Tirunal Institute for Medical Sciences and Technology
state: Kerala
city: Ludhiāna
country: India
facility: Christian Medical College & Hospital
state: Punjab
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Dublin
country: Ireland
facility: St. Vincent's University Hospital
city: Dublin
country: Ireland
facility: Tallaght University Hospital
city: Waterford
country: Ireland
facility: University Hospital Waterford
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Centre
city: Perugia
country: Italy
facility: Ospedale Santa Maria della Misericordia
city: Rom
country: Italy
facility: Umberto Policlinico di Roma
city: Hirakata
country: Japan
facility: Kansai Medical University
city: Kawasaki
country: Japan
facility: St. Marianna Medical University Hospital
city: Kumamoto
country: Japan
facility: Kumamoto University
city: Osaka
country: Japan
facility: National Cerebral and Cardiovascular Center
city: Tochigi
country: Japan
facility: Jichi Medical University
city: Tokyo
country: Japan
facility: The Jikei University Hospital
city: Drammen
country: Norway
facility: Vestre Viken Health Trust - Drammen Hospital
city: Lørenskog
country: Norway
facility: Akershus University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital, Ullevål
city: Ålesund
country: Norway
facility: Ålesund sjukehus
city: Coimbra
country: Portugal
facility: Coimbra University Hospital
city: Lisboa
country: Portugal
facility: Hospital de Egas Moniz
city: Lisbon
country: Portugal
facility: Hospital de Santa Maria
city: Košice
country: Slovakia
facility: Košice Medical University
city: Trnava
country: Slovakia
facility: Fakultná Nemocnica Trnava
city: Aarau
country: Switzerland
facility: Dept. of Neurology, Kantonsspital Aarau
state: Aargau
city: Basel
country: Switzerland
facility: Dept. of Neurology, Universitätsspital Basel
state: Basel Stadt
city: Chur
country: Switzerland
facility: Dept. of Neurology, Kantonsspital Chur
state: Graubünden
city: Lausanne
country: Switzerland
facility: Dept. of Neurology, Universitätsspital Lausanne
state: Waadt
city: Nyon
country: Switzerland
facility: Dept. of Neurology, Hôpital de Zone de Nyon
state: Waadt
city: Sion
country: Switzerland
facility: Dept. of Neurology, Kantonsspital Sion
state: Wallis
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Bern
country: Switzerland
facility: Dept. of Neurology, Bern University Hospital
city: Fribourg
country: Switzerland
facility: Dept. of Neurology, Kantonsspital Fribourg
city: Geneve
country: Switzerland
facility: Dept. of Neurology, Universitätsspital Genf
city: Lugano
country: Switzerland
facility: Ospedale Regionale di Lugano (EOC)
city: Luzern
country: Switzerland
facility: Dept. of Neurology, Kantonsspital Luzern
city: Münsterlingen
country: Switzerland
facility: Kantonsspital Münsterlingen
city: Neuchâtel
country: Switzerland
facility: Hôpital neuchâtelois
city: St.Gallen
country: Switzerland
facility: Dept. of Neurology, Kantonsspital St.Gallen
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: Dept. of Neurology, Universitätsspital Zürich
city: Zürich
country: Switzerland
facility: Klinik Hirslanden Zürich
city: Tooting
country: United Kingdom
facility: St George's University Hospitals NHS Foundation Trust
state: London
city: Airdrie
country: United Kingdom
facility: University Hospital Monklands
city: Bath
country: United Kingdom
facility: Royal United Hospitals Bath
city: Bristol
country: United Kingdom
facility: Southmead Hospital Bristol
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Durham
country: United Kingdom
facility: University Hospital of North Durham
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Middlesbrough
country: United Kingdom
facility: The James Cook University Hospital
city: Morriston
country: United Kingdom
facility: Morriston Hospital
city: Perth
country: United Kingdom
facility: Perth Royal Infirmary
city: Rhyl
country: United Kingdom
facility: Glan Clwyd Hospital
city: Stockton-on-Tees
country: United Kingdom
facility: University Hospital of North Tees
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
city: Weston-super-Mare
country: United Kingdom
facility: Weston General Hospital
city: Wirral
country: United Kingdom
facility: Wirral University Teaching Hospital
Study officials:
affiliation: Dept. of Neurology, Inselspital Bern
name: Urs Fischer, Prof. MD
role: PRINCIPAL_INVESTIGATOR
References: