APACHE‐AF 2021.

Study characteristics
Methods	Design: randomised controlled PROBE parallel group phase 2 trial Setting: multicentre (16 hospitals) in the Netherlands Dates: 15 January 2015 to 6 July 2020
Participants	Sample size: 101 participants Diagnosis: ICH Inclusion criteria Age ≥ 18 years 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 heparin or low‐ molecular‐weight heparin at a therapeutic dose) ICH occurred between 7 and 90 days before randomisation Diagnosis of paroxysmal or persistent/permanent non‐valvular AF, documented on electrocardiography CHA2DS2‐VASc score ≥ 2 Score on the mRS ≤ 4 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 or haemoglobin level of < 6.2 mmol/L) Ischaemic stroke in the previous 7 days Current alcohol or drug misuse Life expectancy of < 1 year Severe renal insufficiency (a serum creatinine level of > 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) Women of childbearing potential or who were pregnant or breastfeeding Age: median age was 78 years (IQR 73–83) overall; 77 years (74–83) in the intervention group and 79 years (72–83) in the comparator group Sex: 55 (54%) were men overall; 27 (54%) in the intervention group and 28 (55%) in the comparator group
Interventions	Intervention: apixaban oral dose of 5 mg twice daily, or a reduced dose of 2.5 mg twice daily if their creatine clearance was 30 mL/min or less, or if two of three of the following criteria were present: age 80 years or older, bodyweight 60 kg or lower, or serum creatinine 133 μmol/L or greater (50 participants) Comparator: no antithrombotic treatment or oral antiplatelet treatment (acetylsalicylic acid 80 mg once daily; carbasalate calcium 100 mg once daily; clopidogrel 75 mg once daily; or a combination of dipyridamole 200 mg twice daily with either acetylsalicylic acid 80 mg once daily or carbasalate calcium 100 mg once daily) at the discretion of the treating physician. (51 participants; 26 of these received antiplatelet therapy)
Outcomes	Primary outcome Non‐fatal stroke (ischaemic stroke, ICH, or SAH) or vascular death, whichever came first, during follow‐up Secondary outcomes ICH SAH Traumatic intracranial haemorrhage Major extracranial haemorrhage Clinically relevant non‐major bleeding Ischaemic stroke Unclassified stroke Any stroke Myocardial infarction Pulmonary embolism Systemic embolism Vascular death All‐cause death Duration of follow‐up: median 1·9 years (IQR 1·0–3·1), with a total of 222 person‐years
Notes	Declarations of interest: FHBMS reports two grants from the Dutch Heart Foundation (grant 2012T077 for this study; and grant 2019T060 outside the submitted work). DWD reports funding from the Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organisation for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and unrestricted grants from Penumbra, Stryker, Medtronic, Thrombolytic Science, and Cerenovus for research outside the current work, all paid to their institution. JS reports grants to their institution outside the submitted work (H2020 programme). JMC reports research funding from Portola, Boehringer, and Bayer, outside the submitted work. HBvdW reports fees for consultancy from Bayer and LivaNova, all paid to their institution; and grants outside the submitted work (EU Horizon 2020 programme; Dutch Heart foundation; and Stryker, of which the last two are through the CONTRAST consortium). CJMK reports grants from the Dutch Heart Foundation (grant 2012T077; this study), and grants outside the submitted work: The Netherlands Organization for Health Research and Development, ZonMw (grant 015008048); support of the Netherlands Cardiovascular Research Initiative, which is supported by the Dutch Heart Foundation, CVON2015‐01: CONTRAST; and the support of the Brain Foundation Netherlands (HA2015.01.06). All other authors declare no competing interests. Sources of funding: Dutch Heart Foundation (grant 2012T077)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central computerised randomisat ion system. Treatment allocation was stratified by intention to start an antiplatelet agent or not in the avoid group, and subsequently based on proportional minimisation, according to age (≤75 years vs > 75 years) and location of the ICH (lobar vs non‐lobar)
Allocation concealment (selection bias)	Low risk	Prof Bart van der Worp confirmed that allocation was concealed by the randomisation system
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants, their treating physicians, and local investigators were aware of treatment allocation
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome event adjudication was done by LJK and GJER masked to the patient’s identity, treatment allocation, and antithrombotic drug use
Incomplete outcome data (attrition bias) All outcomes	Low risk	None lost to follow‐up
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes were reported