Abstract P3: Andexanet Alfa for Acute Bleeding During Treatment With Edoxaban

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Alexander P Benz ◽  
Lizhen Xu ◽  
John W Eikelboom ◽  
Saskia Middeldorp ◽  
Truman J Milling ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Additional Data ◽  
Thrombotic Event ◽  
Factor Xa ◽  
Acute Bleeding ◽  
Study Enrollment ◽  
Inhibitor Study ◽  
Andexanet Alfa ◽  
Adjudication Committee ◽  
Efficacy Population

Introduction: We previously reported results of a prospective cohort study evaluating andexanet alfa (andexanet) for anticoagulation reversal in patients with acute bleeding on a factor Xa inhibitor. Study enrollment continued to accumulate additional data on patients on edoxaban, which are presented here. Methods: Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a 400 or 800 mg bolus and a 480 or 960 mg 2-hour follow-on infusion of andexanet, depending on edoxaban dosage and time of last dose. The co-primary efficacy outcomes were change in anti-factor Xa activity and the rate of excellent or good hemostasis, 12 hours after andexanet treatment, as determined by an independent adjudication committee. Efficacy was analyzed in patients with confirmed major bleeding and baseline anti-factor Xa activity ≥75 ng/mL. Safety was analyzed in all patients. Results: A total of 36 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 (80.6%) patients. In the efficacy population (n=20), median anti-factor Xa activity decreased from 160.5 (interquartile range [IQR] 106.2-222.2) ng/mL at baseline to 50.9 (IQR 19.9-119.4) ng/mL at the end of bolus (median decrease 69.2%, 95% confidence interval [CI] 25.5-80.2%). Excellent or good hemostasis at 12 hours was achieved in 75.0% (95% CI 50.9-91.3%) of patients overall and in 81.3% (95% CI 54.4-96.0%) of those with intracranial hemorrhage (ICH). Within 30 days, a total of 4 (11.1%) patients experienced at least one thrombotic event and 4 (11.1%) others died. Conclusions: In patients with acute bleeding on edoxaban, andexanet significantly decreased anti-factor Xa activity. Excellent or good hemostasis at 12 hours was observed in 75.0% of patients overall and 81.3% of those with ICH. Thrombotic events occurred at a rate expected in such patients.

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

2022 ◽  
Author(s):  
Alexander P. Benz ◽  
Lizhen Xu ◽  
John W. Eikelboom ◽  
Saskia Middeldorp ◽  
Truman J. Milling ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Thrombotic Event ◽  
Acute Bleeding ◽  
Anticoagulation Reversal ◽  
Limited Experience ◽  
Life Threatening ◽  
Antifactor Xa ◽  
Andexanet Alfa ◽  
Uncontrolled Bleeding ◽  
Efficacy Population

Abstract 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.

Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Charlie J. Nederpelt ◽  
Leon Naar ◽  
Pieta Krijnen ◽  
Saskia le Cessie ◽  
Haytham M. A. Kaafarani ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Prothrombin Complex Concentrate ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Andexanet Alfa

scholarly journals Coagulation Factor Xa (Recombinant), Inactivated-Zhzo (Andexanet Alfa) Hemostatic Outcomes and Thrombotic Event Incidence at an Academic Medical Center

2019 ◽  
Vol 25 ◽  
pp. 107602961989661 ◽  
Author(s):  
Victoria M. Stevens ◽  
Toby Trujillo ◽  
Scott W. Mueller ◽  
Robert MacLaren ◽  
Paul M. Reynolds ◽  
...  
Keyword(s):  
Medical Center ◽  
Academic Medical Center ◽  
Thrombotic Event ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Thromboembolic Events ◽  
Bleeding Events ◽  
Major Bleed ◽  
Academic Medical ◽  
Andexanet Alfa

Andexanet alfa is approved for the reversal of factor Xa inhibitors in patients with major bleeding events. We aimed to review the incidence of effective hemostasis with andexanet alfa in a real-world environment. This retrospective cohort included patients hospitalized for a major bleed that resulted in andexanet alfa administration. The primary outcome was effective hemostasis at 12 hours after andexanet alfa treatment. Thromboembolic events and mortality within 30 days were also assessed. Over a 14-month period, 13 patients received andexanet alfa with a mean age of 69 ± 10 years, 54% male, 69% exposed to apixaban (31% rivaroxaban), and had intracranial (46%) and nonintracranial (54%) bleeding sites. Effective hemostasis was observed in 10 (77%) patients. Four (31%) patients experienced 5 thromboembolic events with a median time to event of 6.5 days (range: 0.5-29). Four thrombotic events occurred during the period in which anticoagulation (prophylaxis or therapeutic) was not restarted. Mortality rate was 15%. Andexanet alfa was effective in obtaining hemostasis in a majority of patients. However, the incidence of thromboembolic events was high and may be attributed to a delay in restarting anticoagulation.

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

2021 ◽  
Vol 1 (S1) ◽  
Author(s):  
Mohammad N Kayyali ◽  
Oana M Dumitrascu
Keyword(s):  
Adverse Event ◽  
Ischemic Stroke ◽  
Ct Perfusion ◽  
Thrombotic Event ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Phase 3 ◽  
Cerebral Angiogram ◽  
Andexanet Alfa

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.

scholarly journals Andexanet Alfa for Acute Major Bleeding Associated With Factor Xa Inhibitors

2017 ◽  
Vol 65 (1) ◽  
pp. 279-280 ◽  
Author(s):  
S.J. Connolly ◽  
T.J. Milling ◽  
J.W. Eikelboom
Keyword(s):  
Major Bleeding ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Andexanet Alfa

scholarly journals Andexanet alfa is an effective reversal agent for factor Xa inhibitors in patients that develop intracranial hemorrhage

2019 ◽  
Vol 5 (2) ◽  
Author(s):  
Joseph Friedli
Keyword(s):  
Clinical Application ◽  
Intracranial Hemorrhage ◽  
Major Bleeding ◽  
Critical Appraisal ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Reversal Agent ◽  
Andexanet Alfa

<p>A critical appraisal and clinical application of Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. <em>N Engl J Med</em>. 2016;375(12):1131-1141. doi: <a href="https://doi.org/10.1056/NEJMoa1607887">10.1056/NEJMoa1607887</a>.</p>

scholarly journals Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage

Stroke ◽  
2021 ◽  
Author(s):  
Andrew M. Demchuk ◽  
Patrick Yue ◽  
Elena Zotova ◽  
Juliet Nakamya ◽  
Lizhen Xu ◽  
...  
Keyword(s):  
Intracranial Hemorrhage ◽  
Factor Xa ◽  
High Rate ◽  
Unique Identifier ◽  
Safety Population ◽  
Traumatic Bleeding ◽  
Fxa Inhibitor ◽  
Hemostatic Efficacy ◽  
Andexanet Alfa ◽  
Efficacy Population

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.

Utilization of 4-Factor Prothrombin Complex Concentrate for Reversal of Oral Factor Xa Inhibitor–Associated Acute Major Bleeding: A Case Series

2020 ◽  
pp. 089719002090701
Author(s):  
Tessa R. Reynolds ◽  
Brian W. Gilbert ◽  
Katherine M. Hall
Keyword(s):  
Major Bleeding ◽  
Prothrombin Complex Concentrate ◽  
Thrombotic Event ◽  
Safety Data ◽  
Case Series ◽  
Factor Xa ◽  
Retrospective Case ◽  
Point Analysis ◽  
Dosing Regimens ◽  
Fxa Inhibitor

Objective: In cases of oral factor Xa (FXa) inhibitor–associated acute major bleeding, several reversal strategies are available. Current guidelines recommend a dose of 50 U/kg if using 4-factor prothrombin complex concentrate (4F-PCC). A paucity of data exists with the use of 4F-PCC for FXa inhibitor reversal for acute major bleeding, specifically the most efficacious dosing regimens and safety data. The purpose of this case series is to describe the utilization of 4F-PCC for reversal of oral FXa inhibitor–associated acute major bleeding. Methods: This retrospective case series included all admitted patients 18 years and older who received 4F-PCC for oral FXa inhibitor–associated major bleeding. Major bleeding was defined using the International Society of Thrombosis and Hemostasis definition for major bleeding in nonsurgical patients. The primary outcome was achievement of hemostasis. Results: A total of 31 patients met inclusion criteria, with 17 receiving rivaroxaban and 14 receiving apixaban. Intracranial hemorrhage was the most common type of bleeding occurring in 15 (55%) patients. The median dose of 4F-PCC was 37 U/kg. Of the patients evaluated in the primary end point analysis, 68% achieved effective hemostasis. Four (12.9%) patients experienced a documented thrombotic event within 7 days of receiving 4F-PCC. Conclusion: The use of 4F-PCC for FXa inhibitor–associated acute major bleeding was effective for the majority of patients. The rate of thrombotic events appears higher compared to previously published studies, although major confounders exist and larger studies are needed to fully evaluate the safety of 4F-PCC for this indication.

scholarly journals Evidence-Based Minireview: Mortality and thrombosis in patients receiving prothrombin complex concentrates or andexanet alfa for the management of direct oral factor Xa inhibitor–associated major bleeding

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 204-208 ◽  
Author(s):  
Miriam Kimpton ◽  
Deborah M. Siegal
Keyword(s):  
Computed Tomography ◽  
Major Bleeding ◽  
Factor Xa ◽  
Evidence Based ◽  
Factor Xa Inhibitor ◽  
Prothrombin Complex Concentrates ◽  
Pharmacological Agents ◽  
Previous Stroke ◽  
Level Of Consciousness ◽  
Andexanet Alfa

Abstract A 77-year-old man with atrial fibrillation and a CHA2DS2Vasc score of 6 for hypertension, age, diabetes, and previous stroke is brought to the emergency department with decreased level of consciousness. He is anticoagulated with rivaroxaban (a direct oral factor Xa inhibitor [FXaI]) and received his last dose about 4 hours before presentation. Urgent computed tomography of the head shows intracerebral hemorrhage. Because of his previous stroke, the patient’s family is concerned about treating the bleed with pharmacological agents that may increase the risk of stroke. What are the risks of thrombosis and mortality related to the use of prothrombin complex concentrates (PCCs) and andexanet alfa for patients with direct oral FXaI-associated major bleeding?

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