Direct oral anticoagulants versus no anticoagulation for the prevention of stroke in survivors of intracerebral haemorrhage with atrial fibrillation (PRESTIGE-AF): a multicentre, open-label, randomised, phase 3 trial.
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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, PRESTIGE-AF Consortium
Аннотация
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: European Commission.