AXIOMATIC-SSP
(2024)Objective
Estimate the dose–response effect of the oral factor XIa inhibitor milvexian (25–200 mg twice daily) on preventing ischaemic stroke or covert infarcts without increasing major bleeding, when added to standard dual antiplatelet therapy in patients with acute non-cardioembolic ischaemic stroke or high-risk TIA.
Study Summary
• Symptomatic stroke rates were numerically lower in all groups except for 200 mg BID.
• Major bleeding remained low (1–2%) across all doses, with no fatal bleeding.
• Data informed dose selection for a phase 3 trial.
Intervention
Multinational, phase 2, double-blind, placebo-controlled, dose-finding RCT at 367 sites in 27 countries. N=2366 patients ≥40 years, enrolled within 48h of non-lacunar ischaemic stroke (NIHSS ≤7) or high-risk TIA with atherosclerotic disease. Randomized 1:1:1:1:1:2 to: - Placebo - Milvexian: 25 mg QD, 25/50/100/200 mg BID All groups received aspirin 100 mg x 90 days + clopidogrel 75 mg x 21 days. Primary efficacy: symptomatic ischaemic stroke or covert infarction at 90 days. Primary safety: BARC type 3/5 bleeding.
Inclusion Criteria
• Age ≥40 years
• Acute ischaemic stroke (NIHSS ≤7) or high-risk TIA within 48h
• Evidence of non-occlusive atherosclerosis in a relevant artery
• Premorbid mRS ≤3
Study Design
Arms: 7 arms: - Placebo - Milvexian 25 mg QD - Milvexian 25, 50, 100, or 200 mg BID (Note: 50 and 100 mg QD groups terminated early)
Patients per Arm: Placebo (691); 25 QD (328); 25 BID (318); 50 BID (328); 100 BID (310); 200 BID (351); ~22–18 in early-terminated QD groups
Outcome
- Placebo: 17%
- 25 mg QD: 16%; RR 0.99
- 25 mg BID: 18%; RR 0.99
- 50 mg BID: 14%; RR 0.93
- 100 mg BID: 15%; RR 0.92
- 200 mg BID: 16%; RR 0.91 [oai_citation:0‡AXIOMATIC-SSP.pdf](file-service://file-7riBEgvXRN9a99mgiwMduq)
• Symptomatic stroke alone:
- Placebo: 6%
- All doses except 200 mg BID had lower rates (4–5%)
• Major bleeding (BARC 3/5): 1–2% in all groups
• No fatal bleeding
• Covert infarcts accounted for ~66% of events
• Renal adverse events more common at 200 mg BID
Bottom Line
Milvexian did not demonstrate a clear dose-response benefit for the composite outcome of symptomatic stroke or covert infarcts, but some doses showed a reduction in symptomatic stroke without increasing major bleeding.
Major Points
- Largest phase 2 trial of FXIa inhibition in non-cardioembolic stroke
- No dose-response effect for the primary composite outcome
- Symptomatic stroke was numerically reduced in all but highest dose group
- No increase in intracranial hemorrhage or fatal bleeding across doses
- Major GI bleeding slightly higher with doses ≥50 mg BID
- Findings support moving 25–100 mg BID doses to phase 3 testing
Study Design
- Study Type
- Phase 2, randomised, double-blind, placebo-controlled, dose-finding
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 2366
- Follow-up
- 90 days
- Centers
- 367
- Countries
- Argentina, Austria, Belgium, Brazil, Canada, Chile, Denmark, Finland, France, Germany, Greece, Hungary, Israel, Italy, Japan, Mexico, Norway, Poland, Russia, South Korea, Spain, Sweden, Switzerland, UK, USA, Netherlands, Others
Primary Outcome
Definition: Composite of symptomatic ischemic stroke or new covert brain infarct by day 90
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 17% | 14–16% (no dose-response) | - (varies per dose (e.g., 0.91–1.05)) | NS across all models |
Limitations & Criticisms
- No dose-response for primary efficacy
- MRI-detected covert infarcts may not correlate with clinical benefit
- Potential signal of harm at highest dose (200 mg BID)
- Study underpowered to detect rare safety signals
Citation
Lancet Neurol. 2024 Jan;23(1):46–59. doi:10.1016/S1474-4422(23)00403-9