Please select the eligibility criteria that correspond to the clinical trial below.
Title: Apixaban Versus Antiplatelet Drugs or no Antithrombotic Drugs After Anticoagulation-associated Intracerebral Haemorrhage in Patients With Atrial Fibrillation: A Randomised Phase II Clinical Trial
Brief Summary: There is a marked lack of evidence on the optimal prevention of ischaemic stroke in patients with atrial fibrillation and a recent intracerebral haemorrhage (ICH) during treatment with oral anticoagulation. These patients are currently treated with vitamin K antagonists, DOACs, antiplatelet drugs, or no antithrombotic treatment, depending on personal and institutional preferences. Treatment with a direct oral anticoagulant like apixaban might be an attractive alternative in terms of a low risk of recurrent ICH, while at the same time being effective for the prevention of ischaemic stroke. This study aims to obtain reliable estimates of the rates of vascular death or non-fatal stroke in patients with atrial fibrillation and a recent anticoagulation-associated intracerebral haemorrhage who are treated with apixaban versus those who are treated with antiplatelet drugs or no antithrombotic drug at all.

This study has a multi-centre, phase II, randomised, open-label clinical trial with blinded outcome assessment design.


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:

1. Adults (≥30 years) with spontaneous primary ICH (i.e. without known underlying structural, macrovascular or other cause (e.g. arteriovenous malformation, tumour) after adequate investigation at the discretion of the local investigator). This will include participants presumed to have cerebral SVD (both hypertensive arteriopathy and cerebral amyloid angiopathy)
2. Clinical team opinion that BP control since the ICH is not adequate AND the measured SBP prior to randomisation is ≥130 mm Hg
3. There is no time limit for recruitment; however, recruitment as soon as is practical after the ICH is encouraged. Recruitment at a later stage is acceptable as long as there is evidence of inadequate BP control AND SBP at randomisation is ≥130 mm Hg
4. Ability and willingness to undertake BP measurements,, either unassisted or with the help of a relative, friend or carer: this can be undertaken in any destination after hospital discharge (e.g. home, rehabilitation unit, nursing or care home)
5. Ability and willingness to attend and complete the study assessments including cognitive screen
6. Ability and willingness to provide informed consent, or with a suitable consultee available and able to participate in the intervention (e.g. with a motivated carer)

Exclusion Criteria:

1. Inability to provide informed consent or lack of suitable consultee (if unable to provide personal consent, lack of suitable consultee)
2. Evidence of a macrovascular or structural cause for ICH (e.g. AVM or tumour)
3. Diagnosis of dementia (DSM IV criteria, or self-reported or documented in medical records)
4. Low Functional status (MRS ≥4) before or after ICH or frailty likely to make participation in 1-year follow-up difficult for the participant
5. Life expectancy \<2 years
6. Taking more than 2 BP-lowering medications (i.e. 3 or more) at the time of consent
7. Consistently good BP control (below 130/80 mm Hg on measures taken as part of routine clinical care) prior to planned recruitment, judged not to require more intensive treatment
8. Known flow-restricting intracranial/extracranial large arterial stenosis
9. Known absence of mobile phone coverage from all network operators and home internet at the participant's home
10. Known sensitivity or contra-indication to BP treatments (e.g. symptomatic postural hypotension) is not an absolute exclusion criterion, but more information must be provided
11. Note that participation in other CTIMP or device trial is NOT an automatic exclusion criterion
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: D