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Study Summary

Andexanet alfa is an inactive protein that binds and sequesters factor Xa inhibitors (FXaIs). Interim analysis of the ANNEXA-4 Phase 3b/4 single-arm, open label study evaluated efficacy and safety of Andexanet alfa in 132 patients with FXaI-associated life-threatening bleeding and clinical hemostasis at 12 hours post-IV bolus and infusion. Patients with FXaI exposure ≤ 18 hours and acute bleed causing hemodynamic instability, hemoglobin decrease > 2 g/dL, or evidence of critical organ damage (e.g. intracranial hemorrhage) were included. Recent thrombosis, recent administration of blood products, Glasgow coma scale score < 7, ICH volume > 60 cc, life expectancy < 1 month, or upcoming surgery were exclusion criteria. Patients presented primarily with intracerebral hemorrhage (61%) and gastrointestinal bleeding (27%). Andexanet alfa significantly lowered anti-FXa activity levels across subgroups and all FXaIs (see accompanying Hurst’s Central Illustration). “Excellent or good” hemostasis occurred in 83% (109/132). At 30 days, thrombotic events occurred in 24 patients; 27 patients died (11 cardiovascular deaths); 16 patients died after intracerebral hemorrhage.


Study Strengths: This is a “real world” assessment of the safety and efficacy of andexanet alfa as a universal FXaI antidote. Cases and outcomes were independently adjudicated with standardized criteria; an independent core lab reviewed brain imaging.

Study Limitations: The time from presentation to andexanet alfa was 5 ± 3.1 hours; reasons for delay to treatment are not clear. During follow-up, only 57% of patients resumed anticoagulation, which may account for thrombotic events. The follow-up period was relatively short (30 days).

Next Steps/Clinical Perspective: Andexanet alfa appears to be an effective option for universal FXaI reversal in the setting of acute, life-threatening bleeding. Drug approval, accessibility, availability, and cost-effectiveness remain to be seen.

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