Veltkamp Roland, Korompoki Eleni, Harvey Kirsten H, Harvey Emily R, Fießler Cornelia, Malzahn Uwe, Rücker Viktoria, Montaner Joan, Caso Valeria, Sibon Igor, Ringleb Peter, Halse Omid, Hügen Klemens, Ullmann Sabine, Schuhmann Carolin, Todd Gabriele Putz, Haas Kirsten, Palà Elena, Debette Stéphanie, Lachaize Morgane, D'Aoust Tim, Enzinger Christian, Ropele Stefan, Fandler-Höfler Simon, Haidegger Melanie, Wang Yanzhong, Wafa Hatem A, Cancelloni Virginia, Mosconi Maria Giulia, Lip Gregory Y H, Lane Deirdre A, Haefeli Walter E, Foerster Kathrin I, Wurmbach Viktoria S, Nielsen Peter Brønnum, Hajjar Karim, Müller Patrick, Poli Sven, Purrucker Jan, Laible Mona, D'Anna Lucio, Silva Yolanda, de Torres Chacon Reyes, Martínez-Sánchez Patricia, Boulanger Marion, Norrving Bo, Paré Guillaume, Wachter Rolf, Ntaios George, Wolfe Charles D A, Heuschmann Peter U
Department of Brain Sciences, Imperial College London, London, UK; Department of Neurology, Alfried-Krupp Krankenhaus, Essen, Germany; Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
Department of Brain Sciences, Imperial College London, London, UK; Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece.
Lancet. 2025 Mar 15;405(10482):927-936. doi: 10.1016/S0140-6736(25)00333-2. Epub 2025 Feb 26.
Direct oral anticoagulants (DOACs) reduce the rate of thromboembolism in patients with atrial fibrillation but the benefits and risks in survivors of intracerebral haemorrhage are uncertain. We aimed to determine whether DOACs reduce the risk of ischaemic stroke without substantially increasing the risk of recurrent intracerebral haemorrhage.
PRESTIGE-AF is a multicentre, open-label, randomised, phase 3 trial conducted at 75 hospitals in six European countries. Eligible patients were aged 18 years or older with spontaneous intracerebral haemorrhage, atrial fibrillation, an indication for anticoagulation, and a score of 4 or less on the modified Rankin Scale. Patients were randomly assigned (1:1) to a DOAC or no anticoagulation, stratified by intracerebral haemorrhage location and sex. Only the events adjudication committee was masked to treatment allocation. The coprimary endpoints were first ischaemic stroke and first recurrent intracerebral haemorrhage. Hierarchical testing for superiority and non-inferiority, respectively, was performed in the intention-to-treat population. The margin to establish non-inferiority regarding intracerebral haemorrhage was less than 1·735. The safety analysis was done in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03996772, and is complete.
Between May 31, 2019, and Nov 30, 2023, 319 participants were enrolled and 158 were randomly assigned to the DOAC group and 161 to the no anticoagulant group. Patients' median age was 79 years (IQR 73-83). 113 (35%) of 319 patients were female and 206 (65%) were male. Median follow-up was 1·4 years (IQR 0·7-2·3). First ischaemic stroke occurred less frequently in the DOAC group than in the no anticoagulant group (hazard ratio [HR] 0·05 [95% CI 0·01-0·36]; log-rank p<0·0001). The rate of all ischaemic stroke events was 0·83 (95% CI 0·14-2·57) per 100 patient-years in the DOAC group versus 8·60 (5·43-12·80) per 100 patient-years in the no anticoagulant group. For first recurrent intracerebral haemorrhage, the DOAC group did not meet the prespecified HR for the non-inferiority margin of less than 1·735 (HR 10·89 [90% CI 1·95-60·72]; p=0·96). The event rate of all intracerebral haemorrhage was 5·00 (95% CI 2·68-8·39) per 100 patient-years in the DOAC group versus 0·82 (0·14-2·53) per 100 patient years in the no anticoagulant group. Serious adverse events occurred in 70 (44%) of 158 patients in the DOAC group and 89 (55%) of 161 patients in the no anticoagulant group. 16 (10%) patients in the DOAC group and 21 (13%) patients in the no anticoagulant group died.
DOACs effectively prevent ischaemic strokes in survivors of intracerebral haemorrhage with atrial fibrillation but a part of this benefit is offset by a substantially increased risk of recurrent intracerebral haemorrhage. To optimise stroke prevention in these vulnerable patients, further evidence from ongoing trials and a meta-analysis of randomised data is needed, as well as the evaluation of safer medical or mechanical alternatives for selected patients.
European Commission.
直接口服抗凝剂（DOACs）可降低心房颤动患者的血栓栓塞发生率，但对于脑出血幸存者的益处和风险尚不确定。我们旨在确定DOACs是否能降低缺血性卒中风险，同时又不会大幅增加复发性脑出血风险。
PRESTIGE-AF是一项在欧洲六个国家的75家医院进行的多中心、开放标签、随机3期试验。符合条件的患者年龄在18岁及以上，有自发性脑出血、心房颤动、抗凝指征，且改良Rankin量表评分≤4分。患者按1:1随机分配至DOAC组或不进行抗凝治疗组，按脑出血部位和性别分层。只有事件判定委员会对治疗分配不知情。共同主要终点是首次缺血性卒中和首次复发性脑出血。在意向性治疗人群中分别进行优效性和非劣效性的分层检验。确定脑出血非劣效性的界值<1.735。在接受意向性治疗的人群中进行安全性分析。该试验已在ClinicalTrials.gov注册，注册号为NCT03996772，现已完成。
2019年5月31日至2023年11月30日期间，共纳入319名参与者，其中158名被随机分配至DOAC组，161名被分配至不进行抗凝治疗组。患者的中位年龄为79岁（四分位间距73 - 83岁）。319例患者中113例（35%）为女性，206例（65%）为男性。中位随访时间为1.4年（四分位间距0.7 - 2.3年）。DOAC组首次缺血性卒中的发生率低于不进行抗凝治疗组（风险比[HR] 0.05 [95%置信区间0.01 - 0.36]；对数秩检验p<0.0001）。DOAC组每100患者年的所有缺血性卒中事件发生率为0.83（95%置信区间0.14 - 2.57），而不进行抗凝治疗组为8.60（5.43 - 12.80）。对于首次复发性脑出血，DOAC组未达到预先设定的非劣效性界值HR<1.735（HR 10.89 [90%置信区间1.9 — 60.72]；p = 0.96）。DOAC组每100患者年的所有脑出血事件发生率为5.00（95%置信区间2.68 - 8.39），而不进行抗凝治疗组为0.82（0.14 - 2.53）。DOAC组158例患者中有70例（44%）发生严重不良事件，不进行抗凝治疗组161例患者中有89例（55%）发生严重不良事件。DOAC组16例（10%）患者死亡，不进行抗凝治疗组21例（13%）患者死亡。
DOACs可有效预防伴有心房颤动的脑出血幸存者发生缺血性卒中，但部分益处被复发性脑出血风险大幅增加所抵消。为了优化这些脆弱患者的卒中预防，需要正在进行的试验的进一步证据以及对随机数据的荟萃分析，同时还需要对选定患者评估更安全的药物或机械替代方案。
欧盟委员会
