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

Ischaemic Stroke Clinical Trial

— ELAN  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03148457
• Other study ID #: 2017-00588
• Status: Completed
• Phase: N/A
• Start date: November 6, 2017
• Est. completion date: May 24, 2023

Study information

• Verified date: July 2023
• Source: Insel Gruppe AG, University Hospital Bern
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 2013
• Est. completion date: May 24, 2023
• Est. primary completion date: December 21, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrial Fibrillation
• Cerebral Infarction
• Ischaemic Stroke
• Ischemia
• Ischemic Stroke
• Stroke

Intervention

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 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).

Locations

Country	Name	City	State
Austria	Krankenhaus der Barmherzigen Brüder Eisenstadt	Eisenstadt
Austria	Medizinische Universität Graz	Graz
Austria	Kepler Universitätsklinikum, Klinik für Neurologie 1	Linz
Austria	Kepler Universitätsklinikum, Klinik für Neurologie 2	Linz
Austria	Universitätsklinikum St. Pölten	St.Pölten
Austria	Universitätsklinikum Tulln	Tulln
Austria	Medizinische Universität Wien	Wien
Belgium	Onze-Lieve-Vrouw Ziekenhuis VZW	Aalst
Belgium	Cliniques Universitaires Saint-Luc	Bruxelles
Belgium	Antwerp University Hospital	Edegem
Belgium	University Hospital Gent	Gent
Belgium	AZ Groeninge	Kortrijk
Belgium	UZ Leuven	Leuven
Belgium	CHC - Saint Joseph	Liège
Belgium	Cliniques de l'Europe - Site Ste-Elisabeth	Uccle
Finland	Helsinki University Hospital	Helsinki
Finland	Siun sote - North Karelia social and health services	Joensuu
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	Neurologische Universitätsklinik Heidelberg	Heidelberg
Germany	Universitätsklinikum Leipzig	Leipzig	Sachsen
Germany	Universitätsklinikum Schleswig-Holstein	Lübeck
Germany	Mannheim University Hospital	Mannheim
Germany	Klinikum der Universität München	München
Germany	Universitäsklinikum Tübingen	Tübingen
Greece	Dept. of Medicine, University of Thessaly	Larissa	Thessaly
India	Narayana Hrudayalaya Bangalore	Bengaluru	Karnataka
India	Amrita Institute of Medical Sciences	Kochi	Kerala
India	Lalitha Super Speciality Hospitals	Kothapeta	Guntur
India	Christian Medical College & Hospital	Ludhiana	Punjab
India	All India Institute Of Medical Sciences	New Delhi	Delhi
India	Government Medical College Thiruvananthapuram	Thiruvananthapuram	Kerala
India	Sree Chitra Tirunal Institute for Medical Sciences and Technology	Trivandrum	Kerala
Ireland	Cork University Hospital	Cork
Ireland	Mater Misericordiae University Hospital	Dublin
Ireland	St. James's Hospital	Dublin
Ireland	St. Vincent's University Hospital	Dublin
Ireland	Tallaght University Hospital	Dublin
Ireland	University Hospital Waterford	Waterford
Israel	Hadassah Medical Center	Jerusalem
Israel	Shaare Zedek Medical Center	Jerusalem
Israel	Sheba Medical Centre	Ramat Gan
Italy	Ospedale Santa Maria della Misericordia	Perugia
Italy	Umberto Policlinico di Roma	Rom
Japan	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
Norway	Ålesund sjukehus	Ålesund
Norway	Vestre Viken Health Trust - Drammen Hospital	Drammen
Norway	Akershus University Hospital	Lørenskog
Norway	Oslo University Hospital, Ullevål	Oslo
Portugal	Coimbra University Hospital	Coimbra
Portugal	Hospital de Egas Moniz	Lisboa
Portugal	Hospital de Santa Maria	Lisbon
Slovakia	Košice Medical University	Košice
Slovakia	Fakultná Nemocnica Trnava	Trnava
Switzerland	Dept. of Neurology, Kantonsspital Aarau	Aarau	Aargau
Switzerland	Kantonsspital Baden	Baden
Switzerland	Dept. of Neurology, Universitätsspital Basel	Basel	Basel Stadt
Switzerland	Dept. of Neurology, Bern University Hospital	Bern
Switzerland	Dept. of Neurology, Kantonsspital Chur	Chur	Graubünden
Switzerland	Dept. of Neurology, Kantonsspital Fribourg	Fribourg
Switzerland	Dept. of Neurology, Universitätsspital Genf	Geneve
Switzerland	Dept. of Neurology, Universitätsspital Lausanne	Lausanne	Waadt
Switzerland	Ospedale Regionale di Lugano (EOC)	Lugano
Switzerland	Dept. of Neurology, Kantonsspital Luzern	Luzern
Switzerland	Kantonsspital Münsterlingen	Münsterlingen
Switzerland	Hôpital neuchâtelois	Neuchâtel
Switzerland	Dept. of Neurology, Hôpital de Zone de Nyon	Nyon	Waadt
Switzerland	Dept. of Neurology, Kantonsspital Sion	Sion	Wallis
Switzerland	Dept. of Neurology, Kantonsspital St.Gallen	St.Gallen
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	Dept. of Neurology, Universitätsspital Zürich	Zurich
Switzerland	Klinik Hirslanden Zürich	Zürich
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	Glan Clwyd Hospital	Rhyl
United Kingdom	University Hospital of North Tees	Stockton-on-Tees
United Kingdom	Royal Stoke University Hospital	Stoke-on-Trent
United Kingdom	St George's University Hospitals NHS Foundation Trust	Tooting	London
United Kingdom	Weston General Hospital	Weston-super-Mare
United Kingdom	Wirral University Teaching Hospital	Wirral

Sponsors (1)

Lead Sponsor	Collaborator
Insel Gruppe AG, University Hospital Bern

Countries where clinical trial is conducted

Austria,  Belgium,  Finland,  Germany,  Greece,  India,  Ireland,  Israel,  Italy,  Japan,  Norway,  Portugal,  Slovakia,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of major bleeding, recurrent ischaemic stroke, systemic embolism and/or vascular death		30 ± 3 days after randomisation
Secondary	Modified Rankin Scale (mRS)		30 days, 90 days after randomisation
Secondary	Major bleeding		30 days, 90 days after randomisation
Secondary	Non-major bleeding		30 days, 90 days after randomisation
Secondary	Recurrence of stroke		30 days, 90 days after randomisation
Secondary	Systemic embolism		30 days, 90 days after randomisation
Secondary	Vascular death		30 days, 90 days after randomisation
Secondary	All-cause mortality		90 days after randomisation
Secondary	Myocardial infarction		90 days after randomisation
Secondary	Major cardiovascular events defined as composite of stroke, myocardial infarct, heart failure or cardiovascular death		90 days after randomisation
Secondary	Silent brain lesions	If CT/MRI is performed in clinical routine	90 days after randomisation
Secondary	Favourable outcome defined as mRS = 2 and shift analysis adjusted to premorbid mRS		90 days after randomisation
Secondary	NIHSS		90 days after randomisation
Secondary	Transient ischemic attack		30 days, 90 days after randomisation
Secondary	Undetermined stroke		30 days, 90 days after randomisation
Secondary	Compliance		30 days after randomisation