Stroke Research Center Bern

Clinical Trials

ELAN

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.

main ELAN logo in red

Background

Atrial fibrillation (AF) is the most common cardiac arrhythmia increasing the risk of stroke and systemic thromboembolism and thus mortality and morbidity. Patients with ischaemic stroke and AF are at risk of developing early recurrent strokes with highest risk rates during the first 30 days. 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.

Ethical considerations

When to start oral anticoagulation with DOACs after stroke in patients with atrial fibrillation is a major dilemma for stroke physicians. Delaying treatment initiation may lead to early recurrent ischaemic strokes, whereas early treatment may result in early bleeding complications. Therefore it is unclear whether the prevention of early recurrent strokes outweighs the risk of early bleeding complications. There is clinical equipoise and a randomised controlled trial can answer this clinically relevant question.

Trial procedure

Patients in the experimental arm (early treatment) and the control arm (late treatment) will receive direct oral anticoagulant 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).

Key inclusion- and exclusion criteria

Inclusion criteria

  • Written informed consent according to country specific details
  • Age: ≥18 years
  • Acute ischaemic 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)
  • Conditions other than AF that require anticoagulation, including therapeutical dose of low-molecular-weight heparin or heparin
  • Anticoagulation above the relevant thresholds at ischaemic stroke onset or at hospital admission as follows:
    • Vitamine K antagonist: International Normalized Ratio (INR) ≥ 1.7, or
    • Anti-IIa: thrombin time ≥ 80 seconds and/or anti-IIa ≥ 100 ng/ml and/or aPTT value > 1.5x normal, or
    • Anti-Xa: anti-Xa ≥ 100 ng/ml or ≥ 0.7 U/ml
  • Subject who is contraindicated to DOACs
  • Patients with serious bleeding in the last 6 months or at high risk of bleeding
  • Severe comorbid condition with life expectancy < 6 months
  • Severe renal impairment as described in the summary of medicinal product characteristics for the chosen DOAC
  • Dual antiplatelet therapy (DAPT) at baseline or strong likelihood to be treated with dual antiplatelet therapy during the course of the trial,
    • Please note: transient DAPT is not an exclusion criterion if DAPT is stopped prior to randomisation

Outcomes

Primary outcome measures

  • Composite of major extracranial bleeding, symptomatic intracranial haemorrhage, recurrent ischaemic stroke, systemic embolism, and/or vascular death at 30 ± 3 days after randomisation.

Secondary outcome measures

  • mRS
  • major and non-major bleeding
  • recurrent ischaemic stroke
  • systemic embolism
  • vascular death
  • transient ischaemic attack and undetermined stroke at 30 ± 3 days and 90 ± 7 days after randomisation
  • compliance at 30 ± 3 days after randomisation and NIHSS
  • all-cause mortality
  • myocardial infarction
  • major cardiovascular events
  • silent brain lesion
  • favourable outcome (mRS) at 90 ± 7 days after randomisation.

Contact

Trial Core Team at SRCB