DOACs Beneficial in Patients With ICH and Comorbid AF?

LOS ANGELES — Direct oral anticoagulants (DOACs) in patients with a recent intracerebral hemorrhage (ICH) and atrial fibrillation (AF) may have an overall benefit by reducing ischemic stroke, new research suggested.

Results of the PRESTIGE-AF trial showed DOAC treatment in this challenging population led to a large reduction in ischemic stroke, which was partly offset by an increase in ICH. However, there appeared to be a net clinical benefit of DOAC treatment.

“Composite endpoints suggest a quantitative net benefit of DOACs, but a different impact of particular events — ischemic stroke vs ICH — still has to be considered,” said study investigator Roland Veltkamp, MD, Imperial College London, London, England.

He noted that two additional trials investigating the use of DOACs in this population are currently underway, and their results will be combined to provide a clearer understanding of the risks and benefits of this approach.

The PRESTIGE-AF results were presented on February 7 at the International Stroke Conference (ISC) 2025.

An Important, Unmet Need

During his presentation, Veltkamp noted that stroke prevention in ICH survivors is a critical unmet need. He explained that these patients face a heightened risk for recurrent ICH, with annual recurrence rates estimated at 1.3%-7.4%. Notably, the risk is two to three times higher following lobar ICH than following non-lobar ICH.

There is growing evidence suggesting that ICH survivors also have an increased risk for ischemic events, and a particularly vulnerable patient population is the 25% of ICH survivors who have AF, he noted.

“There is a big unresolved dilemma as to whether to treat these patients with oral anticoagulation, which should reduce of future ischemic strokes, but at the same time, there are concerns that this may increase the risk of recurrent ICH,” said Veltkamp.

Observational data and findings from small pilot randomized trials suggest that oral anticoagulation may provide benefit over no anticoagulation for ischemic stroke prevention in this population, without a statistically significant increase in ICH recurrence.

The current PRESTIGE-AF trial was conducted to examine this issue in a larger randomized study.

The phase 3 study was conducted at 75 centers in six European countries and included 319 patients who had experienced spontaneous ICH within the previous 12 months, excluding those within 14 days of the ICH event. The median time to start treatment was 48 days after ICH. Those who were very severely disabled after ICH (modified Rankin Scale, 5) were excluded. Study participants also had AF with an indication for anticoagulation.

Participants were randomly assigned to receive either a DOAC or no oral anticoagulation (control). The choice of DOAC was determined by the local investigator, but a dose approved for stroke prevention in AF was required.

Of the 319 patients included in the intention-to-treat analysis, 158 were assigned to DOAC and 161 were assigned to no anticoagulation. In the DOAC group, 16 patients stopped the treatment, and 19 controls started anticoagulation. Death occurred in 16 DOAC patients and 21 controls, giving a per-protocol analysis population of 266 patients (DOAC, 132; control, 134).

Participants had a median CHA2DS2-VASc score (an indicator of stroke risk) of 4 and a median HAS-BLED score (indicating bleeding risk) of 3. Approximately 30% of patients had lobar ICH and 70% had non-lobar. Median ICH volume was 3-4 mL.

Significant Stroke Reduction

After a median follow-up of 1.43 years, there was a large significant reduction in the first co-primary endpoint of ischemic stroke. There was just one ischemic stroke event in the DOAC group vs 20 in the control group (adjusted hazard ratio, 0.05; 95% CI, 0.01-0.38).

The second co-primary endpoint, first recurrent ICH, was observed in 11 patients in the DOAC group compared with 1 in the control group, resulting in an adjusted hazard ratio of 11.2 (95% CI, 2.01-62.86). The trial aimed to demonstrate the non-inferiority of DOACs to the control group for ICH recurrence, but this criterion was not met.

In terms of secondary outcomes, cardiovascular mortality occurred at a rate of 2.92 per 100 patient-years in the DOAC group vs 5.73 per 100 patient-years in the control group — a nonsignificant difference.

Any major hemorrhage was significantly increased in the DOAC group (8.75 vs 2.01 per 100 patient-years); all stroke and systemic embolism was reduced in the DOAC group (5.83 vs 11.06 per 100 patient-years).

The net clinical benefit endpoint — which included all strokes, systemic embolism, myocardial infarction, cardiovascular mortality, and major bleeding — occurred at a rate of 19.20 per 100 patient-years in the DOAC group compared with 26.52 per 100 patient-years in the control group. While this suggests a potential net clinical benefit with DOACs, the difference was not statistically significant (hazard ratio, 0.69; 95% CI, 0.33-1.40).

Veltkamp reported that these results correspond to a number needed to treat of 13 to prevent one ischemic stroke per year with a DOAC and a number needed to harm of 24 to cause one additional ICH per year.

He noted that the per-protocol analysis yielded a hazard ratio of 7.42 (90% CI, 1.30-42.50) for first recurrent ICH.

Additionally, post hoc analyses indicated that the recurrence rate of ICH did not appear to be higher in patients with a lobar vs non-lobar location of the index ICH.

“Data from other ongoing phase 3 trials (ENRICH-AF and ASPIRE) are awaited to further clarify the net benefit of DOACs in this group of patients including other populations and healthcare systems,” said Veltkamp.

He suggested that alternative medical or mechanical interventions, such as left atrial appendage occlusion, may have a better safety profile for selected patients, but this remains to be established in ongoing trials.

“Our long-term vision is to establish predictive criteria for the personalized selection of suitable or unsuitable patients for DOACs using clinical, imaging, and genetic biomarkers,” he added. Such analyses from the PRESTIGE-AF trial are ongoing.

A Challenging Population

Commenting on the PRESTIGE-AF trial for Medscape Medical News, Lauren Sansing, MD, from Yale University in New Haven, Connecticut, and chair of ISC 2025, noted this patient population poses a significant dilemma.

While Sansing noted that DOACs were associated with a “remarkable reduction” in ischemic stroke, that benefit was partially offset by an increased risk for brain bleeding.

“We need to look more closely at these data and results from further trials yet to report on the impact of these findings on patients’ quality of life,” she said.

“This is the first major randomized trial to have reported on this issue and provides an initial suggestion that perhaps blood thinners could benefit this population, but we’ll need more confirmation from other trials,” Sansing added.

The PRESTIGE-AF trial was funded by a grant from the European Commission. Veltkamp acts as an advisor to AstraZeneca and receives research funding from Bayer, BMS-Pfizer, Boehringer Ingelheim, and Daiichi Sankyo.