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Results from the Phase III PRESTIGE-AF trial (NCT03996772) found that treatment with direct oral anticoagulants (DOACs) significantly lowers the risk of ischemic stroke in survivors of intracerebral hemorrhage (ICH) with atrial fibrillation (AF); however, DOACs also cause a substantial increase in the risk of recurrent intracerebral hemorrhage and other major bleeding complications.1,2 The study authors noted these findings demonstrate the importance of conducting a thorough risk-benefit assessment and consideration of safer therapeutic alternatives.
“The PRESTIGE-AF trial is the first completed phase 3 trial of antithrombotic stroke prevention in survivors of (ICH) with (AF) that compared the effects of DOACs versus no anticoagulation,” the study authors wrote. “Participants assigned to DOACs had significantly fewer ischemic strokes than those assigned to no anticoagulation. This benefit was partly offset by a significantly increased risk of recurrent intracerebral hemorrhage and other major bleedings. Nevertheless, trends in favor of DOAC were observed for the prespecified secondary endpoint of all stroke and systemic embolism as well as for cardiovascular and all-cause mortality consistent with previous observations in pilot-phase trials.”1
The investigators noted that prior research indicates survivors of ICH may benefit from the use of oral anticoagulants, such as vitamin K antagonists. They pointed to a large register-based study that found a 45% decrease the risk of mortality among patients administered anticoagulants without causing a significant increase in the risk of recurrent ICH.
“Subsequent pilot-phase, randomized controlled trials using (DOACs), which confer about half the risk of intracranial hemorrhages compared with vitamin K antagonists, and an individual patient data meta-analysis of randomized controlled data reported inconclusive effects of oral anticoagulation on the risk of any stroke, cardiovascular mortality, and hemorrhagic adverse events, but suggested a reduction of ischemic adverse cardiovascular events,” the study authors wrote.1
As such, the researchers sought to determine whether patients with ICH and AF could benefit from an anticoagulant medication regimen.
Trial Design
The multicenter, open-label, randomized, PRESTIGE-AF trial was conducted at 75 hospitals with stroke units in the UK, Germany, Austria, Spain, Italy, and France. Enrollment criteria included being 18 years of age or older with a spontaneous ICH, AF, having an indication for anticoagulation, and a score of four or less on the modified Rankin Scale. Patients were enrolled from 14 days to one year following the index ICH. Exclusion criteria included ICH caused by vascular malformation or trauma and current or planned implantation of a left atrial appendage occlusion device. A total of 319 patients were randomly assigned in a 1:1 ratio to either the DOAC cohort (n = 158) or the no anticoagulant cohort (n = 161).
At a median follow-up of 1.4 years (IQR 0.7–2.3), the first occurrence of ischemic stroke was less frequent in the DOAC cohort compared to the no anticoagulant cohort (hazard ratio [HR] 0.05 [95% CI 0.01–0.36]; log-rank p<0·0001). The ischemic stroke event rate was 0.83 (95% CI 0.14–2.57) per 100 patient-years in the DOAC cohort compared to 8.60 (5.43–12.80) per 100 patient-years in the no anticoagulant cohort. For the first recurrent ICH, patients in the DOAC cohort did not meet the prespecified HR for the non-inferiority margin of under 1.735 (HR 10.89 [90% CI 1.95–60.72]; p=0.96).
The event rate for all ICH was 5.00 (95% CI 2.68–8.39) per 100 patient-years in the DOAC cohort compared to 0.82 (0.14–2.53) per 100 patient years in the no anticoagulant cohort.
In terms of safety, serious adverse events were reported in 44% of patients in the DOAC cohort compared to 55% in the no anticoagulant cohort. Sixteen patients in the DOAC cohort died during the trial compared to 21 patients in the no anticoagulant cohort.
“In conclusion, DOACs are effective in preventing ischemic strokes in survivors of intracerebral hemorrhage with atrial fibrillation,” the study authors wrote. “However, this benefit is partly offset by an increased risk of intracerebral hemorrhage and other major bleeding complications. To further improve stroke prevention in these vulnerable patients, additional evidence is needed from ongoing trials and the COCROACH meta-analysis of randomized data, as well as the evaluation of safer medical or mechanical alternatives for selected patients.”1
References
1. 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. Veltkamp, RolandNaegel, Steffen et al. The Lancet, Volume 0, Issue 0
2. PREvention of STroke in Intracerebral haemorrhaGE Survivors With Atrial Fibrillation (PRESTIGE-AF). ClinicalTrials.gov. Updated January 13, 2025. Accessed February 26, 2025. https://clinicaltrials.gov/study/NCT03996772