DOACs for ICH survivors with atrial fibrillation? Stroke protection comes at a cost

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 open-label, phase III PRESTIGE-AF trial.

The incidence of ischaemic stroke, the first co-primary endpoint, was notably high among patients who did not receive an anticoagulant, whereas DOAC therapy provided significant protection, 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, Veltkamp said.

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 preventing stroke in the subpopulation of ICH survivors with AF can be complex. Prescribing DOACs to prevent the formation of blood clots may be risky, as the patients are already at risk of sustaining another brain bleed, he said. The risk increase appears to be two- to three-fold higher among patients who survived lobar vs nonlobar ICH.

Indeed, the data on the co-primary endpoints of PRESTIGE-AF presents a classic “caught between a rock and a hard place” scenario, wherein the stroke protection obtained with DOACs comes with a simultaneous increase in the risk of ICH recurrence, Veltkamp pointed out.

“However, of course, we have to take into account secondary efficacy endpoints. And most of these 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 said the outcomes did not differ among patients who received apixaban, dabigatran, edoxaban, or rivaroxaban.

Shared decision-making

The 2019 American Heart Association focused update for AF management advocates for individualized anticoagulation decisions based on a thorough discussion of stroke and bleeding risk, as well as of patients’ values and preferences. [Circulation 2019;140:e125-e151]

For patients, quality of life (QoL) appears to be central to this decision-making. In a substudy of the PRESTIGE-AF trial, the overarching theme from interviews with 12 patients (mean age 76.2 years, 75 percent male) was ‘Living my life as normal’. It underscored the importance of maintaining an acceptable lifestyle post-ICH when deciding if they would be willing to take oral anticoagulant therapy to prevent AF-related stroke. [Eur J Cardiovasc Nurs 2025;doi:10.1093/eurjcn/zvae177]

Nevertheless, few patients reported being actively involved in clinical decision-making, and most simply trusted their physicians to make the appropriate clinical decision. Of those who sustained an ICH while on oral anticoagulants, most agreed with their physician’s advice to restart therapy post-ICH and only one disagreed.

While patients largely relied on their physicians, informal carers (typically a partner) often provided support as advisors. Yet, both patients and their carers demonstrated a varied and often limited understanding of AF, oral anticoagulation, and stroke.

In light of the findings of this substudy, the authors, led by Dr Elena Ivany from the University of Liverpool in Liverpool, UK, stressed the need for healthcare professionals to better understand what matters to patients who are eligible for stroke prevention in AF post-ICH. “This knowledge can be used to facilitate effective shared decision-making in practice that incorporates discussion of patient values regarding the risks and benefits of long-term oral anticoagulation.”

Ivany and colleagues also urged healthcare professionals involved in formal and informal education of patients to consider involving informal carers in any discussions about proposed treatments or therapies, “where appropriate and where the patient wishes this.”

PRESTIGE-AF population in focus

Conducted across 75 stroke centres in six European countries, PRESTIGE-AF included 319 adult patients (35 percent female, 95.9 percent White) with AF, enrolled between 14 days and a year after their index spontaneous ICH, and had an indication for anticoagulation therapy. The enrolment was carried out between May 2019 and November 2023.

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.

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, which was a key exclusion criterion in PRESTIGE-AF. But Veltkamp noted that the inclusion of these patients had no effect on sensitivity analysis. He mentioned that they encountered a slower than expected recruitment and had to adjust the participant goal from 654 to 312, revising the power calculations accordingly.

Post hoc analysis showed no apparent difference in the incidence of recurrent ICH between patients with lobar and those with nonlobar ICH.

A step closer, but not there yet

PRESTIGE-AF is a significant step towards determining the best therapy for patients with AF who have survived ICH, according to Veltkamp. Global data from the ENRICH-AF and US-focused data from the ASPIRE phase III trials are awaited to further clarify the net benefit of DOACs.

Beyond DOACs, Veltkamp also highlighted alternative strategies, such as left atrial appendage occlusion, as potentially safer options for specific patients. These interventions are currently being evaluated in ongoing trials including STROKECLOSE, A3ICH, and CLEARANCE.

Moving forward, Veltkamp and colleagues are striving to develop criteria to accurately identify patients who will or will not benefit from DOAC therapy by using clinical, imaging, and genetic biomarkers.