TY - JOUR
T1 - 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
AU - Schreuder, F.H.B.M.
AU - van Nieuwenhuizen, K.M.
AU - Hofmeijer, J.
AU - Vermeer, S.E.
AU - Kerkhoff, H.
AU - Zock, E.
AU - Luijckx, G.J.
AU - Messchendorp, G.P.
AU - van Tuijl, J.
AU - Bienfait, H.P.
AU - Booij, S.J.
AU - van den Wijngaard, I.R.
AU - Remmers, M.J.M.
AU - Schreuder, A.H.C.M.L.
AU - Dippel, D.W.
AU - Staals, J.
AU - Brouwers, P.J.A.M.
AU - Wermer, M.J.H.
AU - Coutinho, J.M.
AU - Kwa, V.I.H.
AU - van Gelder, I.C.
AU - Schutgens, R.E.G.
AU - Zweedijk, B.
AU - Algra, A.
AU - van Dalen, J.W.
AU - Kappelle, L.J.
AU - Rinkel, G.J.E.
AU - van Der Worp, H.B.
AU - Klijn, C.J.M.
AU - APACHE-AF Trial Investigators
N1 - Funding Information:
We thank all participants, their relatives, and caregivers; outcome event adjudicators; and data monitoring committee members. We thank the Dutch Heart Foundation for funding the trial as part of a Clinical Established Investigator grant to CJMK (grant 2012T077). We thank the data safety monitoring board members H Boersma (chair), S A J Chamuleau, and P J Koudstaal; and H M Nathoe for his role in the outcome adjudication committee.
Funding Information:
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.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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 APACHE-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.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. Copyright (C) 2021 Elsevier Ltd. All rights reserved.
AB - 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 APACHE-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.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. Copyright (C) 2021 Elsevier Ltd. All rights reserved.
KW - ANTITHROMBOTIC TREATMENT
KW - INTRACRANIAL HEMORRHAGE
KW - ORAL ANTICOAGULANTS
KW - SECONDARY PREVENTION
KW - STROKE
KW - VASCULAR EVENTS
U2 - 10.1016/S1474-4422(21)00298-2
DO - 10.1016/S1474-4422(21)00298-2
M3 - Article
C2 - 34687635
SN - 1474-4422
VL - 20
SP - 907
EP - 916
JO - Lancet Neurology
JF - Lancet Neurology
IS - 11
ER -