Beyond Edoxaban: Rethinking Stroke Prevention, With Ashkan Shoamanesh, MD

ENRICH-AF, presented at the European Society of Cardiology (ESC) Congress 2026, found no net benefit from edoxaban among unselected patients with atrial fibrillation (AF) and a prior intracranial hemorrhage (ICH), with excess bleeding offsetting reductions in ischemic events.¹

Ashkan Shoamanesh, MD, of McMaster University, principal investigator of the trial, discussed with HCPLive how clinicians might individualize care in this population going forward.

Not All Intracranial Hemorrhage is the Same

Asked whether prior ICH is too broad a category for clinical decision-making, and whether hemorrhage location or underlying cerebral small vessel disease should factor in instead, Shoamanesh agreed.

"Not all ICH are the same. The natural history and underlying disease that drives subdural hemorrhages is very different than the natural history and underlying disease that drives lobar ICH or convexity bleeds," he said, noting non-lobar ICH is predominantly driven by hypertensive arteriopathy and arteriosclerosis, distinct from the cerebral amyloid angiopathy typically underlying lobar and convexity hemorrhage.

Shoamanesh said a trial powered for a single ICH subtype in isolation would be nearly impossible to conduct. He noted the global initiative behind ENRICH-AF, activating 240 sites and enrolling for years to accumulate its combined study population, illustrates just how difficult recruitment is in this population, with an average enrollment rate of roughly 2 patients per center per year across the broader, lumped strategy the trial ultimately used.²

Balancing Thromboembolic and Bleeding Risk

The trial enrolled patients with high-risk AF, defined by a CHA2DS2-VASc score of ≥ 2, though prior ICH itself did not contribute points toward the score; only an actual history of ischemic stroke or transient ischemic attack did.² The average CHA2DS2-VASc score was 4, and the annualized ischemic stroke rate was approximately 5.5%, reflecting an already high-risk population for ischemic stroke.² Even at higher CHA2DS2-VASc levels, Shoamanesh said stratified analyses showed no clear anticoagulation benefit.

Shoamanesh said stroke risk is unlikely to be the key differentiator for treatment decisions. "I really think that the key discrimination here is on the safety side, not on the ischemic stroke side, and... it's the lower-risk bleeding groups that may have benefit... or a lower dose of an anticoagulant that can have greater safety, but still have some efficacy," he said, adding that factor XI inhibitors, currently being studied for AF more broadly, represent a compelling potential option given their theoretically safer bleeding profile.

On left atrial appendage occlusion (LAAO) as an alternative strategy, Shoamanesh said he now refers patients with lobar or convexity ICH for consideration, prescribing edoxaban 15 mg for those who are not candidates or decline the procedure but have sufficient ischemic stroke risk. He cautioned against assuming LAAO is the default answer, however. "Just assuming that LAAO is the answer is the wrong approach. I think we need an RCT showing that LAAO is the preferred approach in this population," Shoamanesh said, pointing to the CLOSURE-AF trial, testing LAAO in the frailest population studied with the device to date, which was recently stopped for futility. "In the interim, we do our best clinically through guesswork."

What the ASPIRE Trial May Add

On what the ongoing ASPIRE trial, a double-blind comparison of apixaban with aspirin, might add beyond ENRICH-AF, Shoamanesh said he expects dosing, rather than drug choice, to be the key differentiator. He cited prior excess bleeding signals with apixaban in the smaller APACHE-AF trial and the larger PRESTIGE-AF trial as evidence the different DOACs are unlikely to behave differently from edoxaban in this population.³ He described ENRICH-AF's broader lesson as a caution against assuming findings from general AF populations generalize to frail, high-risk subgroups such as ICH survivors, a caution he said extends to LAAO as well as anticoagulation.

Editors’ note: Shoamanesh reports relevant disclosures with AstraZeneca, Bayer AG, Daiichi Sankyo, and others.

References

1. European Society of Cardiology. Safer stroke prevention strategies are needed for patients with atrial fibrillation after intracranial haemorrhage. Published August 29, 2026. Accessed August 30, 2026.

2. Shoamanesh A, et al. ENRICH-AF: edoxaban in intracranial hemorrhage survivors with atrial fibrillation. Presented at: ESC Congress 2026; August 29, 2026; Munich, Germany.

3. Veltkamp R, Korompoki E, Harvey KH, et al. 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. Lancet. 2025;405(10482):927-936. doi:10.1016/S0140-6736(25)00333-2