Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy.

Abstract

Background and Purpose:

Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH).

Methods:

ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days.

Results:

A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population).

Conclusions:

Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation.

Registration:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.

• Authors: Andrew M Demchuk, Patrick Yue, Elena Zotova, Juliet Nakamya, Lizhen Xu, Truman J Milling Jr, Tomoyuki Ohara, Joshua N Goldstein, Saskia Middeldorp, Peter Verhamme, Jose Luis Lopez-Sendon, Pamela B Conley, John T Curnutte, John W Eikelboom, Mark Crowther, Stuart J Connolly, ANNEXA-4 Investigators
• Journal: Stroke (Stroke) Vol. 52 Issue 6 Pg. 2096-2105 (06 2021) ISSN: 1524-4628 [Electronic] United States
• PMID: 33966491 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Coagulation Factor Inhibitors
• PRT064445
• Pyrazoles
• Pyridones
• Recombinant Proteins
• apixaban
• Rivaroxaban
• Factor Xa

Topics

• Aged
• Aged, 80 and over
• Blood Coagulation Factor Inhibitors (blood)
• Factor Xa (administration & dosage)
• Female
• Hemostasis
• Humans
• Intracranial Hemorrhages (blood, drug therapy)
• Male
• Pyrazoles (administration & dosage)
• Pyridones (administration & dosage)
• Recombinant Proteins (administration & dosage)
• Rivaroxaban (administration & dosage)