• SchreuderFloris H B MFHBMDepartment of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands., Koen M van Nieuwenhuizen, Jeannette Hofmeijer, Sarah E Vermeer, Henk Kerkhoff, Elles Zock, Gert-Jan Luijckx, Gert P Messchendorp, Julia van Tuijl, H Paul Bienfait, Suzanne J Booij, Ido R van den Wijngaard, RemmersMichel J MMJMDepartment of Neurology, Amphia, Breda, Netherlands., SchreuderAntonia H C M LAHCMLDepartment of Neurology, Zuyderland, Heerlen, Netherlands., Diederik W Dippel, Julie Staals, BrouwersPaul J A MPJAMDepartment of Neurology, Medisch Spectrum Twente, Enschede, Netherlands., WermerMarieke J HMJHDepartment of Neurology, Leiden University Medical Center, Leiden, Netherlands., Jonathan M Coutinho, KwaVincent I HVIHDepartment of Neurology, OLVG, Amsterdam, Netherlands., Isabelle C van Gelder, SchutgensRoger E GREGVan Creveldkliniek, University Medical Center Utrecht, Utrecht, Netherlands., Berber Zweedijk, Ale Algra, Jan Willem van Dalen, Jaap KappelleLLDepartment of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands., RinkelGabriel J EGJEDepartment of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands., H Bart van der Worp, KlijnCatharina J MCJMDepartment of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands; Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrech, and APACHE-AF Trial Investigators.
• Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands.
• Lancet Neurol. 2021 Nov 1; 20 (11): 907-916.

BackgroundIn patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial.MethodsAPACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7-90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2·5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites.FindingsBetween Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73-83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21-74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1·9 years (IQR 1·0-3·1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12·6% [95% CI 6·7-21·5]) and in 12 (24%) allocated to avoid anticoagulation (11·9% [95% CI 6·2-20·8]; adjusted hazard ratio 1·05 [95% CI 0·48-2·31]; p=0·90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation.InterpretationPatients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous.FundingDutch Heart Foundation (grant 2012T077).Copyright © 2021 Elsevier Ltd. All rights reserved.

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