ENRICH-AF: A Dosing Clue Emerges After Edoxaban's Miss, With Ashkan Shoamanesh, MD

ENRICH-AF, presented at the European Society of Cardiology (ESC) Congress 2026, is the largest randomized trial yet conducted in patients with atrial fibrillation (AF) and a prior intracranial hemorrhage (ICH), a population historically excluded from landmark AF anticoagulation trials.¹ Ashkan Shoamanesh, MD, of McMaster University, principal investigator of the trial, discussed the results, and a dose-specific signal within them, with HCPLive.

Reconciling ENRICH-AF's Mixed Signal on Stroke and Bleeding

Over an average follow-up of 28 months, edoxaban did not significantly reduce the primary composite endpoint of stroke or systemic embolism compared with no anticoagulation (11.8% vs 12.8%; HR, 0.88; 95% CI, 0.61-1.26; P = .48), while the primary safety outcome, ISTH major bleeding, occurred in 11.6% of patients receiving edoxaban compared with 5.2% receiving no anticoagulation (HR, 2.23; 95% CI, 1.39-3.59; P <.001).¹

Asked how clinicians should reconcile the reductions in ischemic stroke and myocardial infarction (MI) with the nearly 3-fold excess in hemorrhagic stroke, Shoamanesh described a net washout effect: "The myocardial infarction signal that we saw was actually novel and surprising, that there's a 80% reduction in MI as well. However, MI was fairly infrequent,” he said. "What that 40% reduction in ischemic stroke versus that threefold excess in hemorrhagic stroke ends up doing, in an absolute sense, is creating a washout... In all-comers, there was no net benefit that we identified. There was also a twofold excess risk [of ISTH major bleeding], and then concerningly, for fatal bleeding, there was a 4.5 fold excess risk."

Lobar Hemorrhage and a Critical Dose-Response Finding

Regarding which hemorrhage locations drove the excess bleeding risk, Shoamanesh pointed to a specific subgroup identified during the trial: patients with lobar intracerebral hemorrhage or convexity subarachnoid bleeding.

"These are locations of bleeding that typically occurred due to underlying cerebral amyloid angiopathy in this age group," he explained. "Our DSMB, after we had enrolled about two thirds of the population, recommended that this subgroup be excluded because a safety review identified that their rates of recurrent ICH were unacceptably high... 11% of those with edoxaban had a recurrent intracranial hemorrhage within this subgroup versus 1% in those who received non-anticoagulant medical therapy, and the majority of the recurrent ICH on edoxaban were fatal."

By the end of the trial, the annualized rate of recurrent ICH in patients with lobar or convexity hemorrhage was 7.5% with edoxaban versus 3.5% with non-anticoagulant therapy, compared with a much smaller absolute difference in patients with non-lobar ICH (2.5% vs 1.2%).² A separate and, per Shoamanesh, clinically important finding emerged when results were examined by edoxaban dose.

"All of the excess major bleeding was seen in patients who indicated the 60 milligram dose of edoxaban, whereas when we looked at the 30 milligram dose of edoxaban, there was no excess major bleeding. That was a statistically significant interaction for the primary safety endpoint," Shoamanesh said. "And there was a suggestion for the primary efficacy endpoint, where those that were indicated the 30 milligram dose, there was about a 30% risk reduction for the composite of stroke or systemic embolism. What this suggests is that the standard dosing of anticoagulation, particularly with edoxaban, may be too high, and that a lower dose... may actually have been a more favorable dose in this population."

Shoamanesh noted a lower dose, such as the 30 mg dose, or potentially even the 15 mg dose evaluated in the ELDERCARE-AF trial of very elderly Japanese patients ineligible for standard anticoagulation, could prove more favorable in this population.³ The findings raise a question future prospective trials, rather than ENRICH-AF itself, will need to answer directly: whether standard-dose anticoagulation in AF is simply too aggressive for patients with a prior ICH.

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. Okumura K, Akao M, Yoshida T, et al; ELDERCARE-AF Committees and Investigators. Low-dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med. 2020;383:1735-1745. doi:10.1056/NEJMoa2012883