APACHE‐AF.

Trial name or title	Apixaban versus antiplatelet drugs or no antithrombotic drugs after anticoagulation‐associated intracerebral haemorrhage in patients with atrial fibrillation (APACHE‐AF)
Methods	Allocation: randomised Blinding: open‐label (none) Duration: 12 to 30 months Setting: multicentre trial across the Netherlands Dates: September 2014 and currently recruiting
Participants	Inclusion criteria ICH (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) Haemorrhage occurred between 7 and 90 days before randomisation Diagnosis of (paroxysmal) non‐valvular AF, documented on electrocardiography A CHA2DS2‐VASc score ≥ 3 Score on the mRS ≤ 4 Equipoise regarding the optimal medical treatment for the prevention of stroke Age ≥ 18 years Written informed consent by the participant or by a legal representative Exclusion criteria Conditions other than AF for which the participant 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 ICH 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 (participants are eligible thereafter), documented haemorrhagic tendencies, or blood dyscrasias) Current alcohol or drug abuse Life expectancy of < 1 year Severe renal insufficiency (a serum creatinine level of more than 221 μmol per litre or a calculated creatinine clearance of < 15 ml per minute) Alanine aminotransferase or aspartate aminotransferase level > 2 times the upper limit of the normal range or a total bilirubin > 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) Pregnant 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
Interventions	Participants will be randomised into 6 groups apixaban aspirin carbasalate calcium clopidogrel dipyridamole no antithrombotic treatment Each of the groups will run in parallel
Outcomes	Primary outcome measures Number of participants who experience the combination of vascular death or non‐fatal stroke (cerebral infarction, intracerebral haemorrhage, or subarachnoid haemorrhage) Secondary outcome measures: number of participants who experience: vascular death death from any cause all stroke ischaemic stroke intracerebral haemorrhage other major extracranial haemorrhage any intracranial haemorrhage other than ICH systemic embolism myocardial infarction a good functional outcome as assessed with the score on the mRS
Starting date	September 2014
Contact information	Contact: Koen M van Nieuwenhuizen, MD. Tel: +31 88 757 4097; email: k.m.vannieuwenhuizen‐3@umcutrecht.nl Contact: H Bart van der Worp, MD PhD. Tel: +31 88 755 98 99; email: h.b.vanderworp@umcutrecht.nl
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