Andexanet Alfa for Specific Anticoagulation Reversal in Patients with Acute Bleeding during Treatment with Edoxaban

Background Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban. Methods Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients. Results Thirty-six patients (mean age: 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 patients (80.6%). In the efficacy population (n = 28), median antifactor Xa activity decreased from 121.1 (interquartile range [IQR]: 70.3–202.4) ng/mL at baseline to 24.0 (IQR: 77.7–83.7) ng/mL at the end of andexanet bolus (median decrease: 68.9%, 95% confidence interval [CI]: 56.1–77.7%). Excellent or good hemostasis at 12 hours was achieved in 78.6% (95% CI: 59.0–91.7%) of patients. Within 30 days, four patients (11.1%) experienced a thrombotic event and four others (11.1%) died. Conclusion In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients.

Abstract 1122‐000165: Endovascular Intervention for a Thrombotic Adverse Event During Andexanet Alfa Infusion

Introduction : Andexanet alfa is the only specific reversal agent for factor Xa inhibitors and received FDA approval in 2018. Here we report an early infusion adverse event in a patient with acute intraventricular hemorrhage (IVH) that received Andexanet alfa, with an unfavorable outcome. Methods : A 73‐year‐old male presented to our emergency department (ED) after he developed sudden onset of severe headache without other associated neurological symptoms. An outpatient brain MRI showed IVH, that remained stable in size (2.4 cm3) on a follow‐up head CT performed in our ED. CT angiogram showed a 60% stenosis of the left supraclinoid internal carotid artery. The patient was taking apixaban 5 mg twice daily for atrial fibrillation (last dose 5.5 hours prior to presentation). Results : The anticoagulation was reversed with Andexanet alfa, 400 mg bolus given at 18:30, followed by 480 mg infusion over 2 hours started at 19:00 (12 hours from last apixaban dose). At 19:00, he developed left middle cerebral artery (MCA) ischemic stroke symptoms (global aphasia) that resolved with head‐of‐the‐bed flattening. CT perfusion demonstrated left ICA territory mismatch (342 ml) and 76 ml core. Shortly after CT perfusion, the patient developed a persistent complete left MCA stroke syndrome with NIH stroke scale (NIHSS) score 23. Decision was made to perform emergent cerebral angiogram which demonstrated a large, fresh thrombus in the left cervical ICA. Thrombectomy was successful with TICI score 2B. Patient’s neurological status initially improved. However, despite this intervention, patient developed a large territory infarct. As neurologic status remained poor, family withdrew care and patient died. Conclusions : ANNEXA‐A and ANNEXA‐R were parallel trials of Andexanet alfa for factor Xa inhibitor reversal that demonstrated a transient increase in prothrombotic factors post Andexanet alfa infusion. Neither of these phase 3 trials nor the previous phase 2 trials reported a clinical thrombotic event very early during the infusion. The ANNEXA‐4 trial (Phase 3) enrolled subjects with active major bleeding on a factor Xa inhibitor and 10% developed a thrombotic event during the 30‐day follow‐up period. 41% of the thrombotic complications were acute ischemic stroke (AIS), 35% (5 patients) experienced an AIS in the first six days post‐administration and the earliest reported thrombotic event occurred day 1 post infusion. Our case report illustrates an early cerebrovascular thrombotic event with dismal outcome despite timely and effective mechanical reperfusion therapy, which could be due to vessel re‐obstruction in setting of a hypercoagulable state. We aim to make vascular neurologists, neurointensivists and neurosurgeons aware of this possible occurrence when reversing patients with factor Xa‐related intracranial hemorrhages.

Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor–Related Atraumatic Intracerebral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care

Background and Purpose: It is unestablished whether andexanet alfa, compared with guideline-based usual care including prothrombin complex concentrates, is associated with reduced hematoma expansion (HE) and mortality in patients with factor-Xa inhibitor–related intracerebral hemorrhage (ICH). We compared the occurrence of HE and clinical outcomes in patients treated either with andexanet alfa or with usual care during the acute phase of factor-Xa inhibitor–related ICH. Methods: Data were extracted from the multicenter, prospective, single-arm ANNEXA-4 trial (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) and a multicenter observational cohort study, RETRACE-II (German-Wide Multicenter Analysis of Oral Anticoagulant-Associated Intracerebral Hemorrhage - Part Two). HE was based on computed tomography scans performed within 36 hours from baseline imaging. Inverse probability of treatment weighting was performed to adjust for baseline comorbidities and ICH severity. Patients presenting with atraumatic ICH while receiving apixaban or rivaroxaban within 18 hours of admission were included. Patients with secondary ICH or not fulfilling the inclusion criteria for the ANNEXA-4 trial were excluded. We compared ANNEXA-4 patients, who received andexanet alfa for hemostatic treatment, with RETRACE-II patients who were treated with usual care, primarily administration of prothrombin complex concentrates. Primary outcome was rate of HE defined as relative increase of ≥35%. Secondary outcomes comprised mean absolute change in hematoma volume, as well as in-hospital mortality and functional outcome. Results: Overall, 182 patients with factor-Xa inhibitor–related ICH (85 receiving andexanet alfa versus 97 receiving usual care) were selected for analysis. There were no relevant differences regarding demographic or clinical characteristics between both groups. HE occurred in 11 of 80 (14%) andexanet alfa patients compared with 21 of 67 (36%) usual care patients (adjusted relative risk, 0.40 [95% CI, 0.20–0.78]; P =0.005), with a reduction in mean overall hematoma volume change of 7 mL. There were no statistically significant differences among in-hospital mortality or functional outcomes. Sensitivity analysis including only usual care patients receiving prothrombin complex concentrates demonstrated consistent results. Conclusions: As compared with usual care, andexanet alfa was associated with a lower rate of HE in atraumatic factor-Xa inhibitor–related ICH, however, without translating into significantly improved clinical outcomes. A comparative trial is needed to confirm the benefit on limiting HE and to explore clinical outcomes across patient subgroups and by time to treatment.