The ELAN trial


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

Please find more information on www.clinicaltrials.gov

Aim of the study

The ELAN trial aims to estimate the net benefit of early versus late (current standard practice) initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke related to atrial fibrillation.

Background

Figure 1: Acute embolic stroke due to M3-occlusion with diffusion-perfusion mismatch on MRI due to newly detected atrial fibrillation on ECG in a 63-year-old-patient.

When to start anticoagulation in patients with an acute ischaemic stroke and atrial fibrillation is a relevant unanswered question in clinical practice. Figure 1 shows an acute embolic stroke due to atrial fibrillation on MRI. It was shown that DOACs are highly effective for secondary stroke prevention in these patients, but DOACs were never initiated <7 days after stroke onset in recent trials.

Outcome

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

Secondary outcomes are: mRS and compliance at 30 ± 3 days after randomisation as well as mRS, NIHSS, major bleeding, recurrent ischaemic stroke, systemic embolism, all-cause mortality, bleeding, myocardial infarction, vascular death, major cardiovascular events, silent brain lesion and favourable outcome (mRS) at 90 ± 7 days after randomisation.

Trial design

The trial is an international, multicentre, randomised-controlled, two-arm, assessor-blinded trial lasting four years.

Please check the key inclusion and exclusion criteria below.

   

  • Age ≥18 years
  • Acute ischemic stroke
  • Atrial fibrillation (permanent, persistent, or paroxysmal spontaneous)
  • Agreement of treating physician to prescribe direct oral anticoagulants (DOACs)

   

  • Atrial fibrillation due to reversible causes
  • Valvular disease, Mechanical heart valves, Mitral stenosis, Aortic dissection
  • Atrial fibrillation (AF) and conditions other than AF that require therapeutic anticoagulation or heparin, Dual antiplatelet therapy
  • Serious bleeding, Parenchymal haemorrhage, Severe comorbid condition, Renal insufficiency, Tumour, Cerebral vasculitis, Endocarditis
  • Pregnant or lactating women
  • Contradiction to direct oral anticoagulants (DOACs)

We will start the recruitment in October 2017 with currently approximately 80 sites in Switzerland and European countries (https://www.elan-trial.ch/participating-sites/).

Treatment/Control Groups

Figure 2: Trial schedule; DOAC, direct oral anticoagulants; Tel., telephone; h, hours; d, days.

In total 2000 patients, with the experimental arm (early treatment; 1000) and control arm (late treatment, 1000). Patients in the early treatment and the late treatment (control arm) will receive DOACs for prevention of stroke and systemic embolism in patients with atrial fibrillation. The initiation of DOACs will vary depending on lesion size as shown in Figure 2.

Patients with early treatment will receive DOACs within 48 hours after symptom onset (minor and moderate ischaemic stroke) or at day 6 + 1 day after symptom onset (major ischaemic stroke).

Patients with late treatment (which represents the current standard practice in the clinics) will receive DOACs as follows: 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).

All DOACs with marketing authorization in Switzerland and the EU for prevention of stroke and systemic embolism in patients with atrial fibrillation can potentially be used in this trial, i.e the following and potential generics with the dose (as indicated in the product sheets):

  • Rivaroxaban (Xarelto®), 20 mg 1x / day
  • Dabigatran (Pradaxa®), 150 mg 2x / day
  • Apixaban (Eliquis®), 5 mg 2x / day
  • Edoxaban (Lixiana®), 60 mg 1x / day

ELAN stroke size classification

Minor

lesion is ≤1.5 cm in anterior or posterior circulation

Moderate

lesion is in a cortical superficial branch of the middle cerebral artery (MCA), in the MCA deep branch, in the internal border zone territories, in a cortical superficial branch of posterior cerebral artery, in a cortical superficial branch of the anterior cerebral artery

Major

anterior: lesion involves the complete territory of MCA, posterior cerebral artery, or anterior cerebral artery, in two cortical superficial branches of MCA, in a cortical superficial branch of MCA associated to the MCA deep branch, or in >1 artery territory (e.g. MCA associated to anterior cerebral artery territories posterior: lesion is ≥1.5 cm in the brainstem or Cerebellum

cave: multiple minor tiny spots (embolic shower) = minor stroke

cave: two minor lesions = moderate stroke (the sum of the lesions)

cave: two moderate lesions = major stroke

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Steering committee

Prof. Dr. med. Urs Fischer

University Hospital Bern

Prof. Dr. med. Jesse Dawson

University Hospital Glasgow

Prof. Dr. med. Daniel Strbian

University Hospital Helsinki

Dr. med. Maurizio Paciaroni

University Hospital Perugia

Prof. Dr. med. Götz Thomalla

University Clinics Hamburg-Eppendorf

Prof. Dr. med. Georg Ntaios, PhD

University of Thessaly

Prof. Dr. med. Leo Bonati

University Hospital Basel

Prof. Dr. med. Patrik Michel

University Hospital Lausanne

Prof. Dr. med. Krassen Nedeltchev

Cantonal Hospital Aarau

PD Dr. med. Sven Trelle

CTU Bern, University Bern

Prof. Dr. med. Franz Fazekas

University Clinics Graz

Dr. Else Charlotte Sandset

Oslo University Hospital – Ullevål

Financing

The Swiss National Science Foundation has approved a grant over CHF 678 000 in September 2016. In addition funds were granted from the Swiss Heart Foundation (CHF 200 000).

Impact

This pragmatic investigator-initiated international trial will add evidence to the best time of starting DOAC after ischaemic stroke in patients with atrial fibrillation. If earlier initiation of DOACs in patients with ischaemic stroke related to atrial fibrillation is shown to be safe and efficacious, this could have a major impact on better treatment adherence, length of hospital stay and patient outcome.

 

Endorsement

The ELAN Trial is endorsed by the Stroke Alliance For Europe