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AXIOMATIC-SSP: Reducing risk of ischaemic stroke with factor XIa inhibition?

Presented by
Dr Mukul Sharma, McMaster University, Canada
ESC 2022
Late-breaking findings from the phase 2, dose-ranging AXIOMATIC-SSP trial evaluating milvexian for secondary stroke prevention showed that, although dose response was not observed, there appeared to be benefit for symptomatic ischaemic strokes. Overall safety appeared reassuring.

Milvexian is a small molecule inhibitor 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. Because genetic variants known to reduce factor XI levels are associated with reduced risk for ischaemic stroke but are not associated with increased intracranial bleeding, the rationale behind the AXIOMATIC-SSP trial (NCT03766581) was to target factor XI.

In the trial, presented by Dr Mukul Sharma (McMaster University, Canada), participants with a mild-to-moderate acute non-lacunar ischaemic stroke or transient ischaemic attack (TIA) (n=2,366) received dual antiplatelet therapy (75 mg clopidogrel daily for the first 21 days and 100 mg aspirin for 90 days) and were randomised to 1 of 5 doses of milvexian or placebo for 90 days [1]. The primary efficacy endpoint was the composite of ischaemic stroke or incident infarct on brain MRI. Major bleeding was the safety endpoint.

The primary efficacy endpoint was not different between milvexian and placebo. Milvexian was associated with a numerically lower risk for clinical ischaemic stroke 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 (5.5% for placebo; 4.6% for 25 mg once daily; 3.8% for 25 mg twice daily; 4.0% for 50 mg twice daily; 3.5% for 100 mg twice daily; but 7.7% for 200 mg twice daily).

Major bleeding event rates were similar to placebo (0.6%; 95% CI 0.2–1.5) for milvexian 25 mg once daily (0.6%; 95% CI 0.1–2.2)and twice daily (0.6%; 95% CI 0.1–2.3) but was moderately increased in the 50 mg twice daily (1.5%; 95% CI 0.5–3.6), 100 mg twice daily (1.6%; 95% CI 0.5–3.8), and 200 mg twice daily (1.5%; 95% CI 0.5–3.4) arms. Dr Sharma pointed out that “most major bleeding episodes were gastrointestinal and manageable. There was no increase in severe bleeding or symptomatic intracranial haemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.”

  1. Sharma M, et al. AXIOMATIC-SSP: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention. Hot Line Session 5, ESC Congress 2022, Barcelona, Spain, 26–29 August.


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