Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial
The Lancet Neurology, vol. 20, pp. 907–916
Abstract
BACKGROUND: In 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. METHODS: -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. FINDINGS: Between 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. INTERPRETATION: Patients 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. FUNDING: Dutch Heart Foundation (grant 2012T077).
Authors 29
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Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands
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Affiliation as printed
Department of Neurology, Rijnstate Hospital, Arnhem, Netherlands
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Affiliation as printed
Department of Neurology, Rijnstate Hospital, Arnhem, Netherlands
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Affiliation as printed
Department of Neurology, Albert Schweitzer Hospital, Dordrecht, Netherlands
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Affiliation as printed
Department of Neurology, Albert Schweitzer Hospital, Dordrecht, Netherlands
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University Medical Center Groningen
Affiliation as printed
Department of Neurology, University Medical Centre Groningen, Groningen, Netherlands
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University Medical Center Groningen
Affiliation as printed
Department of Neurology, University Medical Centre Groningen, Groningen, Netherlands
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Elisabeth-TweeSteden Ziekenhuis
Affiliation as printed
Department of Neurology, Elisabeth-TweeSteden Hospital, Tilburg, Netherlands
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Affiliation as printed
Department of Neurology, Gelre Hospital, Apeldoorn, Netherlands
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Canisius-Wilhelmina Ziekenhuis
Affiliation as printed
Department of Neurology, Canisius Wilhelmina Hospital, Nijmegen, Netherlands
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Leiden University Medical Center · Medisch Centrum Haaglanden · Stichting Haaglanden Medisch Centrum
Affiliation as printed
Department of Neurology, Haaglanden MC, The Hague, Netherlands; Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
Department of Neurology, Haaglanden MC, The Hague, Netherlands
Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
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Affiliation as printed
Department of Neurology, Amphia, Breda, Netherlands
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Affiliation as printed
Department of Neurology, Zuyderland, Heerlen, Netherlands
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Affiliation as printed
Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Neurology, Maastricht University Medical Center, Maastricht, Netherlands
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Affiliation as printed
Department of Neurology, Medisch Spectrum Twente, Enschede, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers
Affiliation as printed
Department of Neurology, Amsterdam UMC location AMC, Amsterdam, Netherlands
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Affiliation as printed
Department of Neurology, OLVG, Amsterdam, Netherlands
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University Medical Center Groningen
Affiliation as printed
Department of Cardiology, University Medical Centre Groningen, Groningen, Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Van Creveldkliniek, University Medical Center Utrecht, Utrecht, Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
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Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands
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Catharina J.M. Klijn corresponding
Radboud University Nijmegen · Radboud University Medical Center · University Medical Center Utrecht · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department 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, Utrecht, Netherlands. Electronic address: karin.klijn@radboudumc.nl
Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
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