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.

Keywords: andexanet alfa; direct factor Xa inhibitor reversal; intracranial hemorrhage.

Figure 1.

Flow chart. ANNEXA-4 indicates Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors; and anti-FXa, anti-factor Xa activity. *Patients not evaluable due to administrative reasons were excluded: n=1 for the spontaneous intracranial hemorrhage (ICrH) population; n=2 for the traumatic ICrH population.

Figure 2.

Subgroup analysis of patients achieving excellent or good hemostasis 12 h after andexanet treatment. Spontaneous (A) and traumatic (B) ICrH populations reported separately. *Evaluable patients. In A, 1 patient from the efficacy cohort of 99 patients was not evaluable. In B, 2 patients from the efficacy cohort of 72 patients were not evaluable. Sizes of squares indicate relative numbers of patients. ICH indicates intracerebral hemorrhage; ICrH, intracranial hemorrhage; IVH, intraventricular hemorrhage; SAH, subarachnoid hemorrhage; and SDH, subdural hemorrhage.