First Clear Win for Factor XIa Inhibitors in Stroke

The factor XIa inhibitor, asundexian (Bayer), has finally achieved the holy grail of reducing thrombotic events without increasing bleeding.

In the OCEANIC-STROKE trial, conducted in patients with noncardioembolic ischemic stroke or high-risk transient ischemic attack (TIA) treated with antiplatelet therapy, asundexian 50 mg given orally significantly reduced the occurrence of recurrent ischemic stroke, without causing increased bleeding.

The reduction in recurrent stroke, including disabling or fatal events, was evident early and persisted throughout the treatment period, with a consistent effect across all subgroups.

There was no increase in any type of bleeding, including major, minor, or intracranial bleeding.

“This is a major achievement to separate the bleeding from the stroke reduction. It’s a complete shift in the paradigm. We haven’t seen this before with antithrombotics,” lead study investigator, Mike Sharma, MD, professor of medicine, McMaster University, and senior scientist at the Population Health Research Institute, both in Hamilton, Ontario, Canada, told Medscape Medical News.

“Generally, interfering with blood clotting will cause some bleeding, but because of where factor XI is in the coagulation cascade, the hypothesis was that clinical efficacy could be dissociated from safety — that it could be possible to prevent recurrent strokes without causing bleeding. And we have showed that very nicely in this trial,” he said.

Sharma presented the results of the OCEANIC-STROKE trial on February 5 at the International Stroke Conference (ISC) 2026.

A New Antithrombotic Approach

Patients who have had a recent stroke or high-risk TIA remain at substantial risk for recurrence, yet options for secondary stroke prevention are limited. While cardioembolic stroke can be effectively treated with anticoagulation, the majority of strokes — which are noncardioembolic — are typically managed long term with single antiplatelet therapy, most commonly aspirin or clopidogrel.

Under the trial protocol, patients received either single or dual antiplatelet therapy, with 66% initially treated with dual therapy. The efficacy of asundexian was similar regardless of whether patients were treated with single or dual antiplatelet therapy.

Dual antiplatelet therapy can be used for a short initial period, but it is not typically continued long term because of the risk for bleeding. As a result, many patients remain at high risk for recurrence.

Factor XIa inhibitors represent a novel antithrombotic approach that is believed to carry a lower risk for bleeding.

“While we’re all obviously concerned about major bleeding which can result in hospitalization, transfusion, or even disability and death, minor bleeding also causes fear and anxiety for patients and often leads them to stop their medications. So we were very pleasantly surprised that in this trial there was a significant reduction in stroke without an increase in any type of bleeding — even minor bleeding,” said Sharma.

The O CEANIC-STROKE trial was conducted to investigate whether adding a factor XIa inhibitor to antiplatelet therapy could reduce the risk for recurrent stroke without causing an increase in bleeding.

The trial included 12,300 patients who were within 72 hours of a noncardioembolic stroke (95%) or high-risk TIA (5%), managed with single or dual antiplatelet therapy. They were randomly assigned to receive asundexian 50 mg administered orally once daily or placebo.

‘Impressive’ Reduction in Recurrence

In addition to the primary endpoint of recurrent ischemic stroke, secondary efficacy endpoints were also reduced with asundexian, including ischemic and hemorrhagic stroke, cardiovascular death/myocardial infarction (MI)/stroke, all-cause mortality/MI/stroke, and disabling/fatal stroke.

The primary safety outcome was major bleeding as defined by the International Society on Thrombosis and Haemostasis, which was similar between groups, occurring in 1.9% of patients receiving asundexian and 1.7% of those receiving placebo (HR, 1.10; 95% CI, 0.85-1.44).

All other safety endpoints and bleeding types were also comparable between the two groups.

Sharma described the reduction in recurrent ischemic stroke with asundexian as “impressive,” highlighting an absolute risk reduction of 1.9% at 1 year. This translated into a hazard ratio of 0.74 (95% CI, 0.65-0.84; P < .001) and a number needed to treat of 53 to prevent one recurrent stroke at 1 year, which fell to about 44 with longer-term follow-up.

“That is very pleasing for a secondary preventive therapy and is about double the effect seen with statins for secondary prevention in stroke,” he noted.

Sharma’s presentation was interrupted by applause from the audience when he revealed the efficacy and safety results.

Elaborating on the findings, he pointed out that the positive effect on stroke reduction continued for as long as the drug was continued and noted that the risk for bleeding with asundexian did not increase over time and, in fact, actually decreased as time went on.

He said follow-up now extends out to 18 months to 2 years, and although participant numbers decline over time, there is no indication that the treatment effect wanes. On that basis, he said he believes the drug should be continued for as long as patients remain at risk for stroke, which is a persistent risk.

Sharma described asundexian as “a new mode of treatment, which is an improvement on aspirin or clopidogrel for secondary stroke prevention, especially over the long term.”

“We now have something that works on top of antiplatelets, that very safely reduces the occurrence of stroke substantially, and really doesn’t have the bleeding price to pay that we’ve seen in other trials with antithrombotics,” he said.

Sharma added that the results were strong and consistent, with benefits seen across all groups and no safety signal, making him confident the drug will be widely adopted once it’s approved.

Two Failures and a Win

Previous trials of factor XIa inhibitors in patients with atrial fibrillation (AF) or acute coronary syndrome (ACS) have failed to demonstrate a clear benefit for this new class of agents.

Addressing this, Sharma said those populations represent different diseases with different underlying mechanisms and standards of care, which may explain the divergent results.

“I think what we have learned is that what drives blood clotting in AF/ACS is different from what causes strokes in noncardioembolic situations,” he said.

He noted that in the AF trial, asundexian was used as monotherapy and compared with a direct oral anticoagulant (DOAC), highly potent antithrombotic agents.

In contrast, in the stroke trial, asundexian was added to background antiplatelet therapy, with placebo as the comparator, reflecting the fact that DOACs are not used in noncardioembolic stroke.

“I think in AF/ACS it is difficult to find added benefit on top of very effective therapies already used. Whereas in noncardioembolic stroke, there are fewer secondary preventative treatment options, and so we were able to show a benefit of this new class of agent,” Sharma said.

‘A Major Achievement’

Commenting on the trial results for Medscape Medical News, Joseph Broderick, MD, director of the UC Gardner Neuroscience Institute at the University of Cincinnati in Cincinnati, said the reduction in recurrent stroke without increasing bleeding was a major achievement.

“We have been trying to use DOAC-type drugs in these stroke patients without a clear cardiac source, but the trials have not shown net benefit because of an increased bleeding risk, so this is obviously a great step forward.”

He said the drug’s lack of success in patients with stroke and AF likely reflected the fact that it was tested against DOACs, whereas in patients with noncardioembolic stroke — who are not treated with DOACs because of bleeding risk — the approach worked.

Broderick also noted that the absolution reduction of stroke of almost 2% at 1 year was impressive and would be added on top of the 1% seen with an antiplatelet drug.

“So yes I think this study will eventually change practice,” he said.

However, he cautioned that asundexian, like other factor XIa inhibitors, has not yet been approved, and the FDA may require two positive trials for a new agent. Cost will also be an important consideration, he added, noting that new medications are typically expensive.

This study was sponsored by Bayer AG. Sharma reported consulting for Bayer, Regeneron, and Anthos; research funding for the current study from Bayer paid to his institution; and research funding from BMS and Janssen.