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

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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 ( IF 46.5 ) Pub Date : 2021-10-20 , DOI: 10.1016/s1474-4422(21)00298-2
Floris H B M Schreuder ₁ , Koen M van Nieuwenhuizen ₂ , Jeannette Hofmeijer ₃ , Sarah E Vermeer ₃ , Henk Kerkhoff ₄ , Elles Zock ₄ , Gert-Jan Luijckx ₅ , Gert P Messchendorp ₅ , Julia van Tuijl ₆ , H Paul Bienfait ₇ , Suzanne J Booij ₈ , Ido R van den Wijngaard ₉ , Michel J M Remmers ₁₀ , Antonia H C M L Schreuder ₁₁ , Diederik W Dippel ₁₂ , Julie Staals ₁₃ , Paul J A M Brouwers ₁₄ , Marieke J H Wermer ₁₅ , Jonathan M Coutinho ₁₆ , Vincent I H Kwa ₁₇ , Isabelle C van Gelder ₁₈ , Roger E G Schutgens ₁₉ , Berber Zweedijk ₂ , Ale Algra ₂₀ , Jan Willem van Dalen ₁ , L Jaap Kappelle ₂ , Gabriel J E Rinkel ₂ , H Bart van der Worp ₂ , Catharina J M Klijn ₂₁ ,

Affiliation

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.
Department of Neurology, Rijnstate Hospital, Arnhem, Netherlands.
Department of Neurology, Albert Schweitzer Hospital, Dordrecht, Netherlands.
Department of Neurology, University Medical Centre Groningen, Groningen, Netherlands.
Department of Neurology, Elisabeth-TweeSteden Hospital, Tilburg, Netherlands.
Department of Neurology, Gelre Hospital, Apeldoorn, Netherlands.
Department of Neurology, Canisius Wilhelmina Hospital, Nijmegen, Netherlands.
Department of Neurology, Haaglanden MC, The Hague, Netherlands; Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
Department of Neurology, Amphia, Breda, Netherlands.
Department of Neurology, Zuyderland, Heerlen, Netherlands.
Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands.
Department of Neurology, Maastricht University Medical Center, Maastricht, Netherlands.
Department of Neurology, Medisch Spectrum Twente, Enschede, Netherlands.
Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
Department of Neurology, Amsterdam UMC location AMC, Amsterdam, Netherlands.
Department of Neurology, OLVG, Amsterdam, Netherlands.
Department of Cardiology, University Medical Centre Groningen, Groningen, Netherlands.
Van Creveldkliniek, 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.
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.

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.

Funding

Dutch Heart Foundation (grant 2012T077).

中文翻译：

荷兰房颤患者抗凝相关脑出血后阿哌沙班与不抗凝 (APACHE-AF)：一项随机、开放标签、2 期试验

背景

在抗凝相关脑出血后幸存的房颤患者中，必须决定是否重新开始或永久避免抗凝是预防卒中复发和其他血管事件的最佳长期策略。在 APACHE-AF 中，我们旨在评估这些患者在接受阿哌沙班治疗与避免抗凝治疗时的非致死性卒中或血管性死亡发生率，为更大的试验设计提供信息。

方法

APACHE-AF 是一项前瞻性、随机、开放标签、2 期试验，在荷兰的 16 家医院进行了隐蔽终点评估。在因房颤接受抗凝治疗时脑出血幸存的患者在出血后 7-90 天有资格入选。参与者也有一个 CHA ₂DS ₂-VASc 评分至少为 2 分，改良 Rankin 量表 (mRS) 评分为 4 分或更低。参与者被随机分配（1:1）接受口服阿哌沙班（5 mg 每天两次或减少剂量 2·5 mg 每天两次）或避免抗凝（可根据主治医师的判断开出口服抗血小板药物）中央计算机化随机化系统，根据参与者开始或停止抗血小板治疗的意图进行分层，随机避免抗凝，并最小化年龄和脑出血部位。主要结果是非致命性卒中或血管性死亡（以先发生者为准）的复合结果，在至少 6 个月的随访期间，使用意向治疗人群中的 Cox 比例风险模型进行分析。APACHE-AF 已在临床试验中注册。

发现

在 2015 年 1 月 15 日至 2020 年 7 月 6 日期间，我们招募了 101 名患者（中位年龄 78 岁 [IQR 73-83]；55 名 [54%] 为男性，46 名 [46%] 为女性；100 名 [99%] 为脑出血后中位数为 46 天（IQR 21-74）的白人和一个 [1%] 是黑人。50 人被分配到阿哌沙班组，51 人被分配到避免抗凝治疗（其中 26 人 [51%] 开始抗血小板治疗）。没有人失访。在 1·9 年（IQR 1·0-3·1；222 人年）的中位随访期间，分配到阿哌沙班组的 13 名 (26%) 参与者发生了非致命性卒中或血管性死亡（年事件发生率为 12 ·6% [95% CI 6·7–21·5]) 和 12 名 (24%) 被分配避免抗凝治疗 (11·9% [95% CI 6·2–20·8]；调整后的风险比为 1· 05 [95% CI 0·48–2·31]；p=0·90)。