Please select the eligibility criteria that correspond to the clinical trial below.
Title: Avoiding Anticoagulation After IntraCerebral Haemorrhage
Brief Summary: Randomised controlled trials (RCTs) demonstrate a substantial benefit from oral anticoagulant drugs for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation (AF). However, these RCTs excluded patients with prior intracerebral haemorrhage (ICH). Therefore, guidelines are unable to recommend whether oral anticoagulant drugs, in particular non-vitamin K antagonist (called direct OAC) - can be used for patients with AF after an intracerebral haemorrhage.

Roughly 30% of adults with ICH have AF but in 2017 it remains unclear whether they should start oral anticoagulant drugs, be treated with left atrial appendage closure (LAAC) or avoid anticoagulation and LAAC.


Options:
A: Inclusion criteria

* Adult (older than 18 years old, no upper age limit)
* with a history of paroxysmal, persistent or long-standing non-valvular atrial fibrillation (documented on an electrocardiogram)
* and a CHA2DS2VASc score of 2 or more who have an indication for long-term anticoagulation
* who suffered from a spontaneous intracerebral haemorrhage (while being treated with oral anticoagulants or not) documented with brain CT or MRI
* more than 14 days before randomization (no upper delay limit)
* for whom there is a clinical equipoise regarding the choice of the best preventive strategy to avoid future vascular events.

Exclusion criteria for all treatment groups

* Pre-randomisation modified Rankin score of 4 or 5
* Conditions other than atrial fibrillation for which the patient requires long term anticoagulation (for example prosthetic mechanical heart valve)
* Serious bleeding events within the 6 months before randomisation (except for intracerebral haemorrhage)
* Life expectancy of less than 1 year
* Pregnancy or breastfeeding

Exclusion criteria related to the LAAC only

* Contraindications due to local, anatomical reasons (such as thrombus in the left atrial appendage, infection with a risk of endocarditis)
* Patients older than 85 years
* CHA2DS2VASc score of 2 or 3
* Patient or attending physician are unwilling to undergo/perform intervention for LAAC

Exclusion criteria related to the Direct OAC only

* Chronic renal insufficiency (clearance of creatinine by Cockcroft method \< 30ml/min)
* Body weight lower than 50 kg
* Allergy to apixaban
* Coexisting conditions predisposing to head trauma (e.g. gait disturbances, uncontrolled seizures disorders)
* Patient or attending physician are unwilling to use of Direct OAC
B: 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.
C: Inclusion Criteria:

1. Written informed consent provided
2. Age ≥45 years, at the time of signing the informed consent
3. Previous intracranial hemorrhage (symptomatic, spontaneous and non-traumatic non-lobar intraparenchymal or intraventricular hemorrhage, and symptomatic spontaneous or non-penetrating traumatic subdural hemorrhages) on or off antithrombotic therapy
4. Documented atrial fibrillation (paroxysmal, persistent, permanent)
5. CHA2DS2-VASc score ≥2

Exclusion Criteria:

1. Recent intracranial hemorrhage (within 14 days)
2. Secondary macrovascular, neoplastic or infectious causes of intracranial hemorrhage (except for antithrombotic treatment or non-penetrating traumatic subdural hemorrhages)
3. Isolated subarachnoid hemorrhage (convexity or basal); subarachnoid blood tracking onto convexity secondary to an intraventricular hemorrhage or as part of a multicompartment bleed in cases of traumatic subdural hemorrhages are eligible
4. Need for ongoing oral anticoagulant therapy for indication other than AF (e.g. mechanical heart valve, venous thromboembolic disease)
5. Need for ongoing antiplatelet therapy for indication where edoxaban would not be a suitable substitute
6. Plans for left atrial appendage occlusion
7. Estimated creatinine clearance (CrCl) \< 15 mL/min
8. Platelet count less than 100,000mm3 at enrollment or other bleeding diathesis
9. Persistent, uncontrolled hypertension (systolic BP averaging \>150 mmHg)
10. Chronic use of NSAID
11. Clinically significant active bleeding, including gastrointestinal bleeding
12. Lesions or conditions at increased risk of clinically significant bleeding, e.g. active peptic ulcer disease with recent bleeding, patients with spontaneous or acquired impairment of hemostasis
13. Antiphospholipid antibody syndrome
14. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk
15. Known hypersensitivity to edoxaban
16. Estimated inability to adhere to study procedures
17. Pregnancy or breastfeeding
18. Estimated life expectancy \< 6 months at the time of enrollment
19. Close affiliation with the investigational site; e.g. a close relative for the investigator, dependent person (e.g., employee or student of the investigational site)
20. Lobar intraparenchymal hemorrhage

    * Post menopausal female subjects must be amenorrheic for ≥12 months prior to screening or ≥6 weeks post-surgical bilateral oophorectomy (with or without hysterectomy) prior to screening. Women of childbearing potential must have negative serum pregnancy test within 7 days prior to randomization or urine pregnancy testing within 24 hours of randomization. Heterosexually active women of childbearing potential must use highly effective methods of contraception for 32 days after discontinuation (duration of study drug plus 30 days duration of one ovulatory cycle).
D: Inclusion Criteria:

1. history of significant bleeding (i.e. bleeding which required intervention or hospitalization), even in the absence of anticoagulation treatment at the time of the bleeding event, or
2. a cardioembolic event, which occurred on anticoagulation, or
3. a high risk profile of the patient, defined as a CHA2DS2-VASc score ≥ 3 and a HAS-BLED score ≥ 2

Exclusion Criteria:

1. thrombus in the LA or LAA;
2. mechanical valve prosthesis;
3. mitral stenosis;
4. previous LAA ligation during cardiac surgery;
5. life expectancy less than 2 years;
6. comorbidities other than AF, which present an indication for anticoagulation;
7. patent foramen ovale with atrial septal aneurysm
8. mobile plaque in the aorta;
9. symptomatic atherosclerosis of the carotid artery;
10. pericardial effusion greater than 10 mm;
11. clinically significant bleeding within the 30 days prior to the scheduled procedure;
12. stroke or other cardioembolic event within the 30 days prior to the scheduled procedure;
13. acute coronary syndrome within the 90 days prior to the scheduled procedure,
14. gravidity,
15. significant valvular disease,
16. creatinine clearance less than 30 ml/min

Answer: A