Precision Antithrombotic Therapy After Stroke: Interpreting the OCEANIC-STROKE Results

Secondary stroke prevention remains one of the most pressing challenges in vascular neurology. Although antiplatelet therapy is foundational for patients with non–atrial fibrillation ischemic stroke, recurrent risk persists, and intensifying antithrombotic strategies has historically come at the cost of increased bleeding. Genetic deficiency of factor XI (FXI) has been associated with lower rates of ischemic stroke without a corresponding rise in intracerebral hemorrhage, fueling interest in FXIa inhibition as a way to uncouple pathologic thrombosis from physiologic hemostasis.

OCEANIC-STROKE, a large, placebo-controlled, double-blind, event-driven phase 3 trial (NCT05686070), evaluated the oral FXIa inhibitor asundexian in 12,327 patients randomly assigned within 72 hours of mild to moderate noncardioembolic ischemic stroke or high-risk transient ischemic attack (TIA). Participants received asundexian 50 mg once daily or placebo on top of standard antiplatelet therapy, with stratification by single vs dual antiplatelet use. Eligible patients had evidence of atherosclerotic disease or a nonlacunar infarct, while those requiring anticoagulation or with prior nontraumatic intracranial hemorrhage were excluded. The primary efficacy end point was time to first ischemic stroke, and the primary safety end point was International Society on Thrombosis and Haemostasis major bleeding, positioning the study to directly address whether targeted FXIa inhibition could reduce recurrent ischemic events without increasing serious bleeding risk.

Andrew Russman, DO, medical director of Cleveland Clinic’s Comprehensive Stroke Center and study author of OCEANIC-STROKE, discussed the biologic rationale behind FXIa inhibition, outlined the key efficacy and safety findings presented at the International Stroke Conference 2026, and explained how the durability of benefit beyond 90 days may influence long-term management strategies. He also examined how asundexian could integrate with current antiplatelet regimens and what these findings may signal for the future of precision-guided secondary stroke prevention in broad, real-world populations.

NeurologyLive: For our clinical audience, provide a little bit of background on the hypothesis and rationale behind OCEANIC-STROKE.

Andrew Russman, DO: One of the most exciting areas in stroke and stroke prevention research right now is the development of factor XIa inhibitors. The foundational observation behind this class of drugs is that some individuals are naturally deficient in factor XI. Those individuals tend to have fewer thrombotic events, and importantly, they do not appear to have a dramatically increased risk of bleeding.

That observation led to a very appealing concept. If we could develop a medication that reduces the amount of pathologic clot formation, meaning the clots that cause ischemic stroke and other thrombotic events, without interfering with normal hemostasis and normal healing, then theoretically we could reduce stroke risk without increasing bleeding risk. That is the basic hypothesis that has driven the development of factor XIa inhibitors and ultimately led to the OCEANIC-STROKE study.

For clinicians who may not have been at the meeting, can you walk us through the efficacy and safety results and the major takeaways?

OCEANIC-STROKE was a phase 3, multicenter, international, randomized, placebo-controlled, double-blind, event-driven trial evaluating both the efficacy and safety of asundexian, which is a factor XIa inhibitor. The population studied included patients with noncardioembolic ischemic stroke or high-risk TIA. Importantly, this was in combination with existing standard antiplatelet therapy.

The primary efficacy end point was ischemic stroke, and the primary safety endpoint was major bleeding. The trial enrolled 12,327 patients, which makes it one of the larger contemporary secondary stroke prevention trials. Patients had mild to moderate ischemic stroke or high-risk TIA, and they had to receive the study drug within 72 hours of symptom onset. In addition, they needed to have some history of atherosclerotic disease or a nonlacunar infarct on imaging. Patients could have a lacunar infarct, but there needed to be some identified history of atherosclerosis.

I often describe this as essentially a study of non–atrial fibrillation–associated stroke patients and how we should manage them after hospitalization. Patients were randomized to receive asundexian 50 mg once daily or placebo, on top of standard therapy, which consisted of either single or dual antiplatelet therapy depending on clinical indication.

The trial was positive. Asundexian was associated with a 2.2% absolute risk reduction in ischemic stroke over the study period. That translates into approximately a 26% relative risk reduction compared with standard therapies alone. That is a meaningful reduction in a population where we continue to see substantial residual risk.

From a safety standpoint, which is critically important when we talk about anticoagulant strategies, there was no increase in major bleeding in the asundexian group compared with placebo. That is really central to the promise of factor XIa inhibition. The ability to reduce ischemic events without increasing major bleeding is what differentiates this approach from traditional anticoagulants.

Given the scale of the trial and the population studied, what do you see as the broader clinical significance of these findings?

The development of factor XIa inhibitors truly represents a potential paradigm shift for us. If asundexian receives regulatory approval, and we are hopeful that the FDA process will move forward over the coming months, this could meaningfully change how we approach secondary stroke prevention in non–atrial fibrillation patients.

Currently, when a patient presents with noncardioembolic stroke, we use single or dual antiplatelet therapy based on individual risk profiles. Moving forward, we may be discussing whether adding asundexian is appropriate for many of these patients.

One of the aspects that stood out to me was the breadth of benefit across stroke etiologies. The benefit was not restricted to a single subgroup. It appeared to be present in large vessel disease, small vessel disease, and even in cryptogenic or embolic stroke of undetermined source populations. That suggests this is not a narrowly targeted therapy but rather something broadly applicable within non–atrial fibrillation stroke.

Another very important point is durability. We often focus intensely on the first 90 days after stroke because we know that risk is highest during that period. In this study, there was benefit early on, but about three-quarters of the overall risk reduction actually occurred after 90 days. That tells us that long-term therapy may be particularly impactful. It reinforces the idea that secondary prevention is not just an early window issue but a chronic management strategy.

Some neurologists may wonder whether this reflects something unique to asundexian or a broader class effect of factor XIa inhibition. What are your thoughts?

That is a very important question. At this point, asundexian is the first factor XIa inhibitor with positive phase 3 data in this specific population. There are other agents in development, such as milvexian, which are being studied in somewhat different patient groups.

My suspicion is that this may represent more of a class effect because the mechanism of selectively inhibiting factor XIa and potentially uncoupling thrombosis from hemostasis is intrinsic to the class. However, until we see results from additional phase 3 trials, we cannot definitively say that.

From a clinical standpoint, having multiple agents would be ideal. It would provide flexibility and allow us to tailor therapy to individual patients. But at this stage, asundexian is the agent with robust phase 3 evidence.

As we think about the future of secondary stroke prevention, how can the clinical community continue to evolve and improve care?

I think we are entering an era where precision medicine will play a larger role in stroke prevention. We now have expanding tools in our armamentarium. As we add therapies such as factor XIa inhibitors, the question becomes how to best match therapies to individual patients.

We already know that certain genetic polymorphisms can influence response to P2Y12 inhibitors. We know that cytochrome P450 variability affects how patients metabolize medications. As we learn more about pharmacogenomics and individual metabolic profiles, we may be able to better predict which patients will benefit most from a particular strategy.

The more precise we can be in selecting the right therapy for the right patient, the greater the risk reduction we will achieve. That applies to primary prevention, but especially to secondary prevention, which is where my focus lies. The OCEANIC-STROKE results add an important new tool, and the next step is integrating that tool thoughtfully into individualized care pathways.

Transcript was edited for clarity. Click here for more ISC 2026 coverage.