For survivors of intracerebral haemorrhage (ICH) with atrial fibrillation (AF), the use of direct oral anticoagulants (DOACs) works to prevent ischaemic stroke events, but this benefit appears to be offset by major bleeding side effects, as shown in the PRESTIGE-AF trial.

Analysis of data from 319 patients indicated a very high rate of ischaemic strokes?the first co-primary endpoint?in those who were not anticoagulated but a strong protection against such events in those who received DOACS, reported lead investigator Dr Roland Veltkamp from Imperial College of London, London, UK, during a late-breaking session at ISC 2025. 

Over a median follow-up of 1.43 years, a first ischaemic stroke occurred in 20 patients in the no-anticoagulation arm as opposed to only one in the DOAC arm (unadjusted hazard ratio [HR], 0.05, 95 percent confidence interval [CI], 0.01?0.36; p<0.001). [ISC 2025, abstract LB37]

On the downside, DOACs did not demonstrate noninferiority vs no anticoagulation in terms of the second co-primary endpoint of ICH recurrence, according to Veltkamp.

A substantially higher number of patients in the DOAC arm than in the no-anticoagulation arm experienced a first recurrent ICH: 11 as opposed to only one (unadjusted HR, 10.9, 95 percent CI, 1.95?60.72; p=0.961).

“Assignment to DOAC was associated with an absolute reduction in the event rate of all ischaemic strokes by 7.77 per 100 patient-years and an absolute increase in the event rate of recurrent ICH by 4.18 per 100 patient-years,” Veltkamp noted. “These event rates resulted in a number needed to treat to prevent one ischaemic stroke per year of 13 and a number needed to harm to cause one more ICH per year of 24.”

Balancing act

Veltkamp acknowledged that managing stroke risk in ICH survivors with AF presents a classic “caught between a rock and a hard place” scenario, wherein the protective benefit obtained with DOACs comes with a simultaneous increase in the risk of ICH recurrence.

“However, of course, we have to take into account secondary endpoints. And most of the efficacy endpoints were in favour of oral anticoagulation,” he said.

For example, the event rate for cardiovascular mortality in the present cohort was 2.92 per 100 patient-years in the DOAC arm vs 5.73 per 100 patient-years in the no coagulation arm (unadjusted HR, 0.51, 95 percent CI, 0.21?1.27), while that for all stroke and systemic embolism was 5.83 vs 11.06 per 100 patient-years, respectively (unadjusted event rate ratio, 0.53, 95 percent CI, 0.27?0.99).

Although Veltkamp noted that the CIs were wide, with the effect estimates not adjusted for multiplicity, he asserted that the balance between the opposing risks of ischaemic events and recurrent ICH in ICH survivors with AF “is more tilted towards anticoagulation at this point in time.”

As for the optimal DOAC to use, the investigator mentioned that the outcomes did not differ among patients who received apixaban, dabigatran, edoxaban, or rivaroxaban.

A significant step

PRESTIGE-AF is a significant step towards determining the best therapy for patients with AF who have survived ICH, Veltkamp said. “Data from ongoing phase III trials?ENRICH-AF, being run globally, and ASPIRE, being run mainly in the US?are awaited to further clarify the net benefit of DOACs.”

He also pointed to the potential of medical or mechanical interventions, such as left atrial appendage occlusion, as a safer alternative for select patients, which should be established in ongoing trials (STROKECLOSE, A3ICH, CLEARANCE).

Ultimately, Veltkamp and colleagues aim to establish predictive criteria for personalized selection of suitable or unsuitable patients for DOAC therapy using clinical, imaging, and genetic biomarkers.

PRESTIGE-AF details

PRESTIGE-AF was an open-label, phase III trial conducted across six European countries. It included 319 adult patients (35 percent female, 95.9 percent White) with AF, enrolled between 14 days and 12 months after their index spontaneous ICH, and had an indication for anticoagulation therapy.

The patients had traditional risk factors, with 19.4 percent having had an ischaemic stroke and 4.3 percent had another intracerebral haemorrhage. Blood pressure at enrolment and subsequent visits was well controlled, and the median interval between index ICH and enrolment was 48 days. ICH was lobar in 29.8 percent of the patients and nonlobar in 70.2 percent. The median ICH volume was 4.0 ml.

Of the patients, 158 were randomly allocated to the DOAC arm (median age 78 years) and 161 to the no-anticoagulation arm. In the DOAC arm, 53.8 percent received apixaban, 20.9 percent dabigatran, 18.4 percent edoxaban, and 5.7 percent rivaroxaban. In the no-anticoagulation arm, 30 percent received acetylsalicylic acid and 2 percent clopidogrel. None of the patients were lost to follow-up.

DOAC was discontinued in 16 patients and initiated in 19, representing a treatment crossover of 10.3 percent, which Veltkamp said was in line with expectations. Deaths occurred in 16 patients in the DOAC arm and in 21 in the no-anticoagulation arm.

There were 11 patients who received left atrial appendage occlusion, but the sensitivity analysis showed no effect of this, and there was no meaningful subgroup analysis for co-primary endpoints possible because of the low number of outcome events, as Veltkamp pointed out. Post hoc analysis showed no apparent difference in the incidence of recurrent ICH between patients with lobar and those with nonlobar ICH.

*Clinical Trials of Investigational Medicinal Products