Findings from a large phase 3 trial have indicated that the investigational drug asundexian could slash the risk of recurrent ischaemic stroke in those who have had a stroke or high risk transient ischaemic attack (TIA) – without increasing major or intracranial bleeding, which is a major limitation of current therapies, reports Medical News Today.
The drug, which works by inhibiting Factor XIa, a clotting protein involved in harmful clot formation but less critical for normal bleeding control, could usher in a safer approach to long-term stroke prevention, suggest experts.
Nearly a quarter of all people who have previously had a stroke will have another one, and to reduce this risk, clinicians typically recommend antiplatelet or anticoagulant therapy, in addition to making lifestyle changes.
Blood thinners can be particularly crucial for those with atrial fibrillation, or other high risk cardio-embolic causes, with research suggesting they can reduce stroke risk by 64%.
However, while they are generally safe, they carry an increased risk of bleeding in or around the brain, known as a haemorrhagic stroke.
Now, a study suggests that a new investigational medication could offer protection without the heightened bleeding risk associated with current treatments.
Published in The New England Journal of Medicine, the findings indicate that asundexian reduced the risk of a second stroke by 26% in people who had recently experienced a clot-related stroke or TIA, without increasing bleeding risk.
Long-standing challenge in stroke prevention
Preventing a second stroke remains a major clinical priority. However, current strategies can create a difficult balance, by aiming to reduce clot formation without exposing individuals to dangerous bleeding complications.
Various proteins, or clotting factors, play a role in the formation of blood clots. The process of stopping bleeding, known as haemostasis, involves multiple interlinked steps, so targeting specific proteins may offer a viable option for reducing clot formation without complications.
Asundexian is an oral anticoagulant that inhibits the activity of clotting factor XIa. This protein is mainly involved in the formation of harmful blood clots.
As factor XIa plays a limited role in normal bleeding control, blocking its action may provide a viable option to safely prevent dangerous clots while preserving the body’s ability to stop bleeding after injury.
“Asundexian selectively inhibits factor XIa (FXIa), targeting a component of the coagulation cascade that is increasingly recognised as more important for pathologic thrombosis than for physiologic haemostasis,” senior scientist Ashkan Shoamanesh, MD, co‑principal investigator of the study and Population Health Research Institute (PHRI), told Medical News Today.
“This contrasts with existing anticoagulants, such as factor Xa inhibitors, which interrupt core steps required for both thrombus formation and haemostasis.
“FXI occupies a unique position within the intrinsic pathway, functioning primarily as an amplifier of thrombin generation. In the setting of vascular injury, exposure of abundant tissue factor activates the extrinsic pathway and generates a robust thrombin burst sufficient to achieve haemostasis, with only a limited contribution from FXI.
“In contrast, in pathologic states like atherosclerotic plaque disruption, tissue factor exposure is more modest, and sustained thrombin generation relies more heavily on FXIa-mediated amplification. In this context, FXIa promotes clot propagation and stability, contributing to vaso-occlusive and thromboembolic events.”
Shoamanesh said this biological distinction allows FXIa inhibition to uncouple pathologic thrombosis from haemostasis.
Trial results and what this means
The findings come from the large, international OCEANIC-STROKE Phase 3 trial, which included more than 12 300 participants across 37 countries.
Their average age was 68, with a quarter over 75: 33% were female. Roughly 95% of them had recently experienced a non-cardio-embolic stroke (a stroke not caused by a heart condition), with the remaining experiencing high-risk TIA.
They were randomly assigned to receive either 50mg of asundexian plus standard antiplatelet therapy, or a placebo plus standard therapy.
Over the follow-up period, the researchers observed a 26% reduction in recurrent ischaemic stroke in those taking asundexian. Additionally, fewer people experienced major cardiovascular events, disabling or fatal strokes, no increase in intracranial bleeding, or a rise in serious side effects.
“Ischaemic strokes account for 87% of the roughly 800 000 strokes in the US each year,” said Mike Sharma, MD, MSc, FRCPC, co-principal investigator of the study and a senior scientist at the PHRI.
“Despite guideline-recommended therapy, these patients remain at substantial risk of recurrence, with around one in 10 experiencing another stroke within the first year. In this context, we saw a significant 26% relative reduction in the hazard of ischemic stroke with asundexian. This corresponded to an absolute risk reduction of 1.9% and a number needed to treat of 54 at one year.”
Notably, he added, this represents a meaningful incremental benefit on top of contemporary secondary stroke prevention strategies.
“We also observed a 31% reduction in the risk of disabling or fatal strokes. Importantly, these benefits were achieved without an associated increase in bleeding risk.”
These benefits were consistent regardless of age, sex, stroke severity, or underlying cause.
The researchers suggest that asundexian’s ability to reduce stroke risk without increasing bleeding risk may offer a new paradigm in stroke prevention.
On the key clinical takeaways, Shoamanesh told MNT: “OCEANIC-STROKE demonstrates that meaningful breakthroughs in secondary stroke prevention – with substantial treatment effects – remain achievable on top of existing guideline-recommended therapies.
“Second, FXIa inhibitors represent a novel class of antithrombotic agents capable of reducing stroke risk without increasing bleeding, thereby providing a substantial net clinical benefit.”
He added that for about half a century, the mainstay of secondary stroke prevention had been aspirin monotherapy.
“This represents the first significant improvement for most ischaemic strokes, apart from short term use of dual antiplatelet therapy.”
Similarly, Christopher Yi, MD, board certified vascular surgeon at MemorialCare Orange Coast Medical Centre in California, who was not involved in the study, suggested it may represent a new strategy for secondary prevention after non-cardio-embolic ischaemic stroke or high risk TIA.
“It should not replace aggressive risk-factor control, statins, blood pressure management, smoking cessation, diabetes control, and appropriate antiplatelet therapy,” he said, “but it may eventually become an additional tool for selected high-risk patients.”
Limitations
However, despite the promising results, the study authors caution that asundexian remains investigational and is not yet approved for clinical use. Further evaluation, regulatory review, and real-world data will be necessary before it becomes widely available.
Additionally, although the trial was large and diverse, certain patient groups, such as those with more severe strokes, were less represented, which may limit how broadly the findings apply.
If approved, asundexian could provide a safer long-term option for preventing recurrent strokes, particularly for those at high risk of bleeding or unable to tolerate existing therapies.
“Within the framework of trial eligibility, there was no evidence of heterogeneity in treatment effect according to pre-specified subgroups,” Sharma said.
“For instance, patients benefited similarly irrespective of age, race, sex, index event type (ischaemic stroke versus TIA), history or vascular imaging evidence of atherosclerosis, acute lacunar versus non-lacunar infarction on brain imaging, or ischaemic stroke subtype. We expect the results to apply to the majority of patients with non-cardio-embolic ischaemic stroke.”
Yi also suggested that asundexian was likely to benefit those with recent non-cardio-embolic ischaemic stroke or high risk TIA who remain at elevated risk for recurrence, despite standard antiplatelet therapy.
“This may include patients with atherosclerotic disease, multiple vascular risk factors, or other markers of high recurrent stroke risk,” Yi told Medical News Today. “It would not necessarily apply to patients with cardio-embolic stroke from atrial fibrillation, where established anticoagulation strategies remain the standard of care.”
For now, the findings provide cautious optimism that effective stroke prevention without added bleeding risk may be within reach.
See more from MedicalBrief archives:
AI helps drugmakers slash clinical trial costs and time
GPs prescribing anticoagulants for AF against official safety advice
Clopidogrel and aspirin lower risk of major stroke after TIA