Inhibition of factor XIa with asundexian reduced recurrent ischaemic stroke and transient ischaemic attack (TIA) without increasing bleeding, analysis has shown.
Ischaemic stroke patients are at an increased risk of having another stroke, and long-term antiplatelet therapy is recommended to reduce recurrence.
It is estimated that more than six per cent of patients with non-cardioembolic ischaemic stroke will have another stroke within a year despite guideline-recommended treatment.
The phase 2 PACIFIC-Stroke trial, presented at the European Society of Cardiology (ESC) Congress 2022, investigated the efficacy, safety and optimal dosage of asundexian for secondary stroke prevention following an acute non-cardioembolic ischaemic stroke.
“This was the first completed randomised trial comparing factor XIa inhibition versus placebo, both on top of antiplatelet therapy, for secondary prevention of non-cardioembolic ischaemic stroke,” said study author, Dr Ashkan Shoamanesh of the Population Health Research Institute, Hamilton, Canada.
“The results of PACIFIC-Stroke indicate that the potential of asundexian to prevent stroke in selected patients should be investigated further.”
He added: “More effective preventive strategies are needed for secondary stroke prevention. Dual pathway inhibition combining an anticoagulant with an antiplatelet agent is hypothetically appealing, but there have been concerns that currently available oral anticoagulants may raise the likelihood of bleeding.
“There is emerging evidence that factor XIa inhibitors, such as asundexian, may prevent thrombosis without increasing bleeding.”
The trial was conducted at 196 sites in 23 countries. A total of 1,808 patients were randomised within 48 hours of non-cardioembolic ischaemic stroke to once daily asundexian 10 mg, 20 mg, 50 mg, or placebo on top of usual antiplatelet therapy.
The average age was 67 years and 34 per cent were women. Participants underwent brain magnetic resonance imaging (MRI) at study entry and after six months, with images independently analysed by two radiologists blinded to treatment allocation. Patients were followed up for six to 12 months.
The primary efficacy outcome was the dose-response effect on the composite of incident MRI-detected covert brain infarcts or recurrent symptomatic ischaemic stroke at six months.
The primary safety outcome was major or clinically-relevant non-major bleeding at 12 months. Secondary exploratory outcomes included ischaemic stroke and the composite of ischaemic stroke and TIA.
There were 362 primary efficacy outcomes at six months, 87 (19.1 per cent) in the placebo group, 86 (18.9 per cent) in the asundexian 10 mg group, 99 (22 per cent) in the 20 mg group and 90 (20.1 per cent) in the 50 mg group.
During the total follow-up, 125 recurrent symptomatic ischaemic strokes or TIA occurred, 38 (8.3 per cent) in the placebo group, 35 (7.7 per cent) in the asundexian 10 mg group, 28 (6.2 per cent) in the 20 mg group and 24 (5.4 per cent) in the 50 mg group.
In a secondary exploratory analysis, recurrent ischaemic stroke or TIA was reduced among patients assigned to asundexian 50 mg compared with placebo, with the largest reduction among those with extracranial or intracranial atherosclerotic plaque.
The primary safety outcome was not significantly increased at 12 months with asundexian, occurring in 2.4 per cent of patients assigned to placebo and 3.9 per cent of those assigned to asundexian.
Dr Shoamanesh said: “The promising results from this phase two trial require validation in an adequately-powered phase three randomised trial before being applied to clinical care for secondary stroke prevention.
“These findings may form the foundation for a phase three study investigating asundexian in addition to antiplatelet therapy in patients with non-cardioembolic ischaemic stroke.”
