Reviewer: Dr Mustafa Ferhat Keten

Name of the Study: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention(AXIOM-SSP)

Published Congress: ESC 2022

Link : https://www.escardio.org/The-ESC/Press-Office/Press-releases/Milvexian-shows-potential-to-reduce-the-risk-of-ischaemic-stroke

Background:

Individuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding.

Objective:

Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets.

Methods:

Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2 score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint

Results:

The investigators found that while the rate of the primary efficacy endpoint was numerically lower at the 50 mg and 100 mg twice daily doses, there was no apparent dose-response (placebo 16.6%, 25 mg once daily 16.2%, 25 mg twice daily 18.5%, 50 mg twice daily 14.1%, 100 mg twice daily 14.7%, 200 mg twice daily 16.4%). Milvexian numerically reduced the risk of clinical ischaemic stroke (excluding covert brain infarction) in the intention-to-treat population at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo 5.5%, 25 mg once daily 4.6%, 25 mg twice daily 3.8%, 50 mg twice daily 4.0%, 100 mg twice daily 3.5%, 200 mg twice daily 7.7%).

The incidence of major bleeding was low overall (placebo 0.6%, 25 mg once daily 0.6%, 25 mg twice daily 0.6%, 50 mg twice daily 1.5%, 100 mg twice daily 1.6%, 200 mg twice daily 1.5%). The rate of major bleeding for the milvexian 25 mg once daily and twice daily doses was similar to placebo, while a moderate increase was observed in the milvexian dose arms of 50 mg twice daily and above (the majority of which were gastrointestinal bleeds), with no apparent dose-response. There was no increase in severe bleeding (BARC type 3c or symptomatic intracranial haemorrhage) versus placebo, and there was no fatal bleeding in any arm of the study.

Conclusion:

Milvexian numerically reduced the risk of clinical ischaemic stroke (excluding covert brain infarction) in the intention-to-treat population at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo

Interpretations:

Based on the observed efficacy signal for ischaemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population