Please select the eligibility criteria that correspond to the clinical trial below.
Title: Start or STop Anticoagulants Randomised Trial (SoSTART) After Spontaneous Intracranial Haemorrhage
Brief Summary: Primary research question: For adults surviving spontaneous (non-traumatic) symptomatic intracranial haemorrhage with persistent/paroxysmal atrial fibrillation/flutter (AF), does starting full treatment dose oral anticoagulation (OAC) result in a beneficial net reduction of all serious vascular events compared with not starting OAC?

Trial design: Investigator-led, multicentre, randomised, open, assessor-masked, parallel group, clinical trial of investigational medicinal product (CTIMP) prescribing strategies. Investigators plan for a pilot phase, followed by a safety phase.


Options:
A: Inclusion Criteria:

* Patient age ≥18 years.
* Spontaneous, primary ICH, of ≥1 day, but not more than 180 days after onset of qualifying ICH, i.e.:

  * No preceding traumatic brain injury, based on history from the patient/witness of spontaneous symptom onset, and brain imaging appearances consistent of spontaneous ICH (i.e. any brain/bone/soft tissue appearances of trauma must have occurred secondary to a spontaneous ICH)
  * No 'secondary' or underlying structural cause (e.g. haemorrhagic transformation of an ischaemic stroke, aneurysm, tumour, arteriovenous malformation, or intracerebral venous thrombosis)
* Patient have indication for antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of ischaemic events, either antiplatelet drugs (for patients with vascular disease), or anticoagulant drug for patients with atrial fibrillation.
* Consent to randomisation from the patient (or personal / legal / professional representative if the patient does not have mental capacity).
* MRI (or CT) is performed before randomisation.

Exclusion Criteria:

* Clear indication for antiplatelet or anticoagulant treatment (e.g. prosthetic heart valves).
* Contraindications to the antithrombotic drug that will be administered.
* Patient is pregnant, breastfeeding, or of childbearing age and not taking contraception.
* For patients examined with MRI: Contraindication for brain MRI
* Malignancy with life expectancy less than 2 years
B: Inclusion Criteria:

1. Patient age ≥18 years
2. Symptomatic intracranial haemorrhage (i.e. intracerebral haemorrhage, non-aneurysmal subarachnoid haemorrhage,intraventricular haemorrhage, or subduralhaemorrhage)

   * Not attributable to a known underlying intracranial aneurysm, arteriovenous malformation, cerebral cavernous malformation, dural arteriovenous fistula, intracranial venous thrombosis
   * Not attributable to known head injury, based on:
   * a history from the patient/witness of spontaneous symptom onset without preceding head trauma (head trauma occurring after symptom onset is permissible)
   * brain imaging appearances consistent with spontaneous intracranial haemorrhage (which may be accompanied by the brain/bone/soft tissue appearances of trauma occurring subsequently)
3. Atrial fibrillation/flutter (persistent or paroxysmal) with a CHA2DS2-VASc score ≥2
4. If included in the brain magnetic resonance imaging (MRI) sub-study, the scan must be done after symptomatic intracranial haemorrhage and before randomisation

Exclusion Criteria:

1. Symptomatic intracranial haemorrhage within the last 24 hours (when the risk of haemorrhage expansion/growth is greatest)
2. Symptomatic intracranial haemorrhage is exclusively due to trauma or haemorrhagic transformation of ischaemic stroke
3. Prosthetic mechanical heart valve or severe (haemodynamically significant) native valve disease
4. Left atrial appendage occlusion for prevention of systemic embolism in AF done in the past, or intended to be performed
5. Intention to start antiplatelet drug(s) if randomised to start full dose OAC
6. Intention to start OAC or parenteral anticoagulation
7. Intention to implement the allocated treatment strategy for \<1 year
8. Patient or their doctor is certain about whether to start or avoid full dose OAC
9. Brain imaging that first diagnosed the intracranial haemorrhage is not available
10. Patient is not registered with a general practitioner
11. Patient is pregnant, breastfeeding, or of childbearing age and not taking contraception
12. Patient and carer unable to understand spoken or written English
13. Contraindications to any of the IMPs, other than recent intracranial haemorrhage
14. Contraindication to MRI (brain MRI sub-study)
15. Life expectancy less than one year
16. Previously randomised in SoSTART
C: Inclusion Criteria:

* Age ≥ 18 years
* Written informed consent obtained from the patient, or for patients who lack the capacity to consent this can be provided by an appropriate representative as defined in protocol
* Non-traumatic spontaneous ICH during the 12 months before enrolment. Patients become eligible 14 days after the date of their ICH.
* Documented evidence of AF (paroxysmal, persistent or permanent)

Exclusion Criteria:

* Fully dependent (mRS \>4)
* Women who are pregnant, breastfeeding, or plan to become pregnant during the Study period
* Women of childbearing potential (WOCBP see section 12.2 for definition) who are unable or unwilling to take measures for effective contraception (4.9)
* Enrolment occurring before 14 days after the date of ICH
* Enrolment occurring longer than 12 months after the date of ICH
* ICH resulting from trauma or vascular malformation
* Another indication for long-term anticoagulation
* Patient has hypertension, which in the opinion of the investigator, is uncontrollable with medication Any contraindication (except intracerebral haemorrhage) to treatment with apixaban, dabigatran, edoxaban, rivaroxaban as per SmPC. Including any of the following:

  * Hypersensitivity to the active principle or any of the excipients
  * Clinically relevant bleeding in progress
  * Liver disease associated with coagulopathy and a clinically relevant bleeding risk
  * Injuries or conditions such as a significant risk of major bleeding
  * Hepatic impairment or liver disease which can have an impact on survival
  * Exclusion of patients with end-stage renal creatinine clearance CrCL, (CrCL \<15 ml / min) or in patients undergoing dialysis
  * Concomitant treatment with other anticoagulants
  * Patients with a history of thrombosis and antiphospholipid antibody syndrome Special warnings and precautions for use for apixaban, dabigatran, edoxaban, rivaroxaban as per SmPC should also be taken into account at randomisation.
* Absolute need for antiplatelet agent (APA) at enrolment, meaning that a patient randomised to receive DOAC who would require an APA is not eligible (single APA is permitted in control group only, at time of randomisation). Presence of a left atrial appendage occlusion device (LAAO) or plan to implant an LAAO
* Presence of any medical, psychological, or psychiatric condition which in the opinion of the Principal or Co-Investigator would cause participation in the Study to be unwise
* Participation in any clinical study with an Investigational Medicinal Product within the past 30 days or 5 half-lives of the study drug (observational studies are permitted)
D: Inclusion Criteria:

* Intracerebral haemorrhage (including including isolated spontaneous intraventricular haemorrhage), documented with CT or MRI, during treatment with anticoagulation (VKA, any direct thrombin inhibitor, any factor Xa inhibitor, or (low molecular weight) heparin at a therapeutic dose).
* The haemorrhage has occurred between 7 and 90 days before randomization.
* Diagnosis of (paroxysmal) non-valvular AF, documented on electrocardiography.
* A CHA2DS2-VASc score ≥ 2.
* Score on the modified Rankin scale (mRS)≤4.
* Equipoise regarding the optimal medical treatment for the prevention of stroke.
* Age ≥ 18 years.
* Written informed consent by the patient or by a legal representative

Exclusion Criteria:

* Conditions other than atrial fibrillation for which the patient requires long-term anticoagulation
* A different clinical indication for the use of an antiplatelet drug even if treated with apixaban, such as clopidogrel for recent coronary stenting.
* Mechanical prosthetic heart valve (biological prosthetic heart valves are allowed) or rheumatic mitral valve disease.
* Serious bleeding event in the previous 6 months, except for intracerebral haemorrhage.
* High risk of bleeding (e.g., active peptic ulcer disease, a platelet count of \<100,000.mL-1 or haemoglobin level of \<6.2 mMol.L-1, ischaemic stroke in the previous 7 days (patients are eligible thereafter), documented haemorrhagic tendencies, or blood dyscrasias).
* Current alcohol or drug abuse.
* Life expectancy of less than 1 year.
* Severe renal insufficiency (a serum creatinine level of more than 221 μmol per liter or a calculated creatinine clearance of \<15 ml per minute).
* Alanine aminotransferase or aspartate aminotransferase level greater than 2 times the upper limit of the normal range or a total bilirubin more than 1.5 times the upper limit of the normal range, unless a benign causative factor (e.g. Gilbert's syndrome) is known or identified.
* Allergy to apixaban.
* Use of strong cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) inhibitors (e.g. systemic azole-antimycotics as ketoconazole or HIV protease inhibitors such as ritonavir).
* Pregnancy or breastfeeding.
* Women of childbearing potential: any woman who has begun menstruation and is not postmenopausal or otherwise permanently unable to conceive. A postmenopausal woman is defined as a woman who is over the age of 45 and has not had a menstrual period for at least 12 months.

Answer: B