BACKGROUND: 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.
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. No patients died in the placebo group.
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.
| Discipline Area | Score |
|---|---|
| Hospital Doctor/Hospitalists |  |
| Internal Medicine | |
| Cardiology | |
| Hemostasis and Thrombosis | |
| Emergency Medicine |  |
| Neurology | Coming Soon... |
The number of ischemic strokes prevented with AC use was higher than additional ICHs caused. ICH may be associated with more morbidity than some ischemic strokes, so some measure of functional outcomes would have been valuable. This question remains unanswered, and the decision to resume or begin AC use after an ICH should be individualized according to patient preference, bleeding risk, and stroke risk, until further evidence is available.
A great advantage of the PRESTIGE-AF trial is that the number of patients included and analyzed in the study was higher than other studies. PRESTIGE-AF was a very rigorous and well conducted RCT. The findings are important because they can be used to guide clinical practice by performing careful shared decision-making strategies between patients and clinicians and brings up important questions and new opportunities. For example, how to better risk-stratify these vulnerable patients with prior history of major bleeding events like ICH (e.g., patients with microbleeds and features of amyloid angiopathy in the brain). This study may open the door to consider further exploratory research with the novel and “safer” antithrombotic/anticoagulants like FXI inhibitors. These may not necessarily replace DOACs but offer a better safety profile in these subgroups of patients.
Although there is some benefit of anticoagulation with DOACs in preventng ischemic stroke in patients with atrial fibrillation and prior spontaneous intracerebral hemorrhage, the risks of recurrent intracerebral hemorrhage is concerning. Further studies are necessary in this regard.
