Please select the eligibility criteria that correspond to the clinical trial below.
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
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.


Options:
A: Inclusion Criteria:

1. Aged 18 years or over
2. Clinical diagnosis of acute ischaemic stroke
3. AF, confirmed by any of:

   1. 12-lead ECG recording
   2. Inpatient ECG telemetry
   3. Other prolonged ECG monitoring technique (e.g. Holter monitor)
   4. Known diagnosis of atrial fibrillation verified by medical records (e.g. primary care records, letter from secondary care)
4. Eligibility to commence DOAC in accordance with approved prescribing recommendations confirmed by treating physician
5. Uncertainty on the part of the treating physician regarding early versus standard initiation of DOAC.

Exclusion Criteria:

1. Contraindication to anticoagulation:

   1. Coagulopathy or current or recent anticoagulation with vitamin K antagonist (VKA) leading to INR ≥1.7 at randomisation.
   2. Thrombocytopenia (platelets \< 75 x 10⁹/L)
   3. Other coagulopathy or bleeding tendency (based on clinical history or laboratory parameters) judged to contraindicate anticoagulation by treating clinician
2. Contraindication to early anticoagulation

   1. Known presence of haemorrhagic transformation with parenchymal haematoma occupying \>30% of the infarct volume and exerting significant mass effect (i.e. PH2) (NB: HI1, HI2 and PH1 are not considered contraindications)
   2. Presence of clinically significant intracranial haemorrhage unrelated to qualifying infarct
   3. Any other contraindication to early anticoagulation as judged by the treating clinician
3. Contraindication to use of DOAC:

   1. Known allergy or intolerance to both Factor Xa inhibitor and direct thrombin inhibitor
   2. Definite indication for VKA treatment e.g. mechanical heart valve, valvular AF, antiphospholipid syndrome
   3. Severe renal impairment with creatinine clearance (Cockcroft \& Gault formula) \<15 mL/min (i.e. 14 mL/min or less)
   4. Liver function tests ALT \> 2x ULN
   5. Cirrhotic patients with Child Pugh score equating to grade B or C
   6. Patient is taking medication with significant interaction with DOAC, including:

      * Azole antifungals (e.g. ketoconazole, itraconazole)
      * HIV protease inhibitors (e.g. ritonavir)
      * Strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort)
      * Dronedarone
4. Pregnant or breastfeeding women
5. Presence on acute brain imaging of non-stroke pathology judged likely to explain clinical presentation (e.g. mass lesion, encephalitis)
6. Inability for patient to be followed up within 90 days of trial entry
7. Patient or representative refusal to consent to study procedures, including the site informing GP and healthcare professional responsible for anticoagulation care of participants
8. Any other reason that the PI considers would make the patient unsuitable to enter OPTIMAS.

Note that current DOAC treatment is NOT an exclusion criterion, as long as the treating physician considers it appropriate to restart (or continue) according to the timings specified in the OPTIMAS trial protocol. Continuation of the DOAC would be recorded as a start time of zero hours.
B: Inclusion Criteria:

1. Male or female patients
2. Must be \>18 years of age
3. Must have TIA or ischemic stroke (NIHSS score \<9 - see section 2.7 for further clarification)
4. Symptom onset is \< 72 hours prior to enrollment or Study therapy must initiated within 48 hours of symptom onset (in case where onset time cannot be established, it will be considered to be the time when the patient was lst know to be well
5. Informed consent must be obtained from either the patient or substitute decision maker (according to local REB policy) prior to any study related procedures being performed
6. All patients will have a MRI including DWI prior to randomization
7. DWI lesion volume must be \<25ml
8. Patients without DWI lesions, but a clinical history considered consistent with TIA, determined by the attending physician, can be included

Exclusion Criteria:

1. Patients with stroke mimics - such as seizures, migraine etc
2. Patients with contraindications to MRI including metallic implants
3. Patients with any past sensitivity to gadolinium contrast media will be eligible, but will not undergo PWI or contrast enhanced MRA (both optional sequences)
4. Patients with renal failure defined as Glomerular Filtration Rate (GFR) \< 30 ml/min
5. Patients deemed, as attending stroke physician, to have any ongoing bleeding risks or unsuitable for dabigatran therapy
6. Patients with MRI demonstrated additional pathology including arteriovenous malformations, intracranial aneurysms, tumors or abscess, which potentially increase the rise of bleed. Individuals with small incidental leasions, at low risk of bleed such as meningiomas may be included at the discretion of the investigator.
7. Patients with an acute DWI lesion volume of \>25 ml (DWI volume to be estimated using the ABC/2 technique 110)\*\*
8. Age \<18 years
9. Pregnant or breast feeding women.
10. Severe dysphagia necessitating naso-gastric (NG) feeding (dabigatran can not be delivered via NG tube)
11. Planned thrombolysis or endovascular intervention for the index event
12. Thrombolysis for ischemic stroke within the preceding 7 days
13. Planned carotid endarterectomy/carotid artery stent within 30 days Note: Carotid Investigations will be completed prior to enrolment. Patients with symptomatic stenoses and a planned carotid procedure will be excluded.
14. Any history of spontaneous intracranial bleeding
15. Clear indication for anticoagulation, including atrial fibrillation, mechanical cardiac valves, deep venous thrombosis, pulmonary embolism or known hypercoagulable state
16. Co-morbid illness with expected life expectancy of \<90 days
C: Inclusion Criteria:

* Males and females ≥ 18 yrs with atrial fibrillation (AF) and one or more of the following risk factors for stroke:
* Age ≥ 75, previous stroke
* transient ischemic attack (TIA) or Systemic Embolism (SE)
* Symptomatic congestive heart failure or left ventricular dysfunction with left ventricular ejection fraction (LVEF) ≤ 40%
* Diabetes mellitus or hypertension requiring pharmacological treatment
D: 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

Answer: D