What Asundexian’s Approval Means for Secondary Stroke Prevention at the Bedside: Ashkan Shoamanesh, MD

Factor XI has drawn interest as an antithrombotic target because low factor XI levels are associated with a reduced risk of ischemic stroke.¹ Factor XIa inhibition reduces amplification of thrombin generation. In preclinical models, it affects pathologic clotting more than the normal hemostatic response.² Asundexian (Sunharbo; Bayer), an oral small-molecule factor XIa inhibitor, was first evaluated in stroke in the phase 2b PACIFIC-STROKE trial (NCT04304508).

The dose-finding study randomly assigned 1808 patients with acute noncardioembolic ischemic stroke to asundexian 10 mg, 20 mg, or 50 mg, or placebo, on top of antiplatelet therapy. Asundexian did not reduce the composite of MRI-detected covert brain infarcts and recurrent ischemic stroke. It also did not significantly increase major or clinically relevant nonmajor bleeding.³ Reviewers have since concluded that covert infarcts were a poor surrogate end point in these phase 2 trials.⁴

The phase 3 OCEANIC-STROKE trial (NCT05686070) tested the 50-mg dose in 12,327 patients. Asundexian reduced ischemic stroke by 26% compared with placebo, without a higher risk of major bleeding.³ Recently, the FDA approved asundexian in combination with antiplatelet therapy for adults with a recent noncardioembolic ischemic stroke or high-risk TIA.⁵ According to the prescribing information, gastrointestinal bleeding was more common with asundexian than placebo (2.7 vs 2.1 per 100 patient-years). Diarrhea was the most frequent adverse reaction, and the drug is associated with elevated hepatic enzymes.

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“This was a paradigm-changing trial where, for the first time, we’ve been able to demonstrate that you could uncouple pathologic thrombus formation from hemostasis with an antithrombotic agent.”

To discuss the approval's implications for clinical practice, NeurologyLive® spoke with Ashkan Shoamanesh, MD, stroke neurologist, professor of medicine at McMaster University, and senior scientist at the Population Health Research Institute. Shoamanesh, co–principal investigator of the OCEANIC-STROKE trial, explained that the 26% relative reduction in ischemic stroke was achieved on top of optimized lipid-lowering, antihypertensive, antithrombotic, and glycemic therapies. He also discussed how antithrombotic agents for secondary stroke prevention have historically been established first in other cardiovascular conditions.

Shoamanesh further highlighted that strokes occurring on asundexian were less disabling and less lethal than those on placebo, with fewer requiring revascularization. Regarding safety, he noted no overall imbalance in adverse events among more than 12,000 participants, aside from a lower gastrointestinal bleeding signal in exploratory analyses, and no excess of disabling or fatal intracranial bleeding. He also emphasized that treatment benefits were consistent across large artery atherosclerosis, small vessel disease, and cryptogenic stroke, potentially simplifying clinical decision-making without extensive stroke subtyping.

REFERENCES
1. Sharma M, Dong Q, Hirano T, et al. Asundexian for secondary stroke prevention. N Engl J Med. 2026;394(15):1467-1479. doi:10.1056/NEJMoa2513880
2. Bayer’s SUNHARBO (asundexian), 50 mg tablets, the first and only factor XIa inhibitor, approved by the U.S. FDA to reduce the risk of stroke in adults with recent non-cardioembolic ischemic stroke or high-risk transient ischemic attack, in combination with antiplatelet therapy. News release. Bayer. November 9, 2026. Accessed November 10, 2026. https://www.bayer.com/en-us/united-states/news-and-stories/2026/asundexian-fda
3. Shoamanesh A, Mundl H, Smith EE, et al. Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet. 2022;400(10357):997-1007. doi:10.1016/S0140-6736(22)01588-4
4. Palaiodimou L, Theodorou A, Stefanou MI, Tsivgoulis G. FXIa inhibitors and secondary stroke prevention. Curr Opin Neurol. Published online October 27, 2026. doi:10.1097/WCO.0000000000001520
5. FDA approves first factor XIa inhibitor to help prevent stroke in certain adults at high risk. News release. US Food and Drug Administration. November 9, 2026. Accessed November 10, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-factor-xla-inhibitor-help-prevent-stroke-certain-adults-high-risk