Reversal Of Factor Xa Inhibitors Research Articles

Abstract WP169: Thromboelastography as a Biomarker of Emergent Direct-Acting Oral Anticoagulant Reversal With Prothrombin Complex Concentrates for Intracranial Hemorrhage

Prothrombin complex concentrates (PCCs) are used to emergently reverse direct-acting oral anticoagulant (DOAC) activity. PCCs are recommended as an alternative to recombinant coagulation factor-Xa to reverse anticoagulation activity of apixaban or rivaroxaban. Measuring the degree of anticoagulation reversal in this population is limited. Thromboelastography (TEG) has been used to detect the presence of DOAC plasma levels in patients chronically taking a DOAC but has not been utilized to measure the effect on anticoagulant activity after PCC administration. We aimed to determine whether TEG R-time is useful in detecting the impact of PCC administration on anticoagulation activity in patients with anti-factor Xa-associated intracranial hemorrhage (ICH). We prospectively evaluated the utility of TEG to assess anticoagulation activity after factor Xa inhibitor reversal with 4-factor PCC. Adults with ICH taking apixaban or rivaroxaban were included. Patients were excluded if their last known dose of anticoagulation was >48 hours prior to arrival, had known apixaban or rivaroxaban blood levels <20 ng/mL, or had the following comorbidities: hepatic failure, hereditary disorders of hemostasis, polytrauma, or pregnancy. TEG samples were collected before PCC administration (if available), and 0.5, 12, and 24 hours after PCC administration. Thirty-one patients were enrolled between November 2022 and August 2023. The median PCC dose was 24.5 units/kg (IQR 20.3-26.9 units/kg; n=29). Nine patients received anticoagulation reversal after baseline TEG collection; the remainder received anticoagulation reversal at transferring facilities. Baseline R-time was negatively correlated with time since last dose of DOAC (n=9). A median decrease in R-time of 0.8 minutes after PCC (IQR -1.6 - 0.3; n=8) was found in patients with baseline TEG collection. R-time rebounded by a median of 0.75 minutes (IQR 0.2-2.0; n=8) from 0.5 hours to 12 hours after PCC administration (n=8). TEG R-time, a measure that inversely correlates with the degree of anticoagulant effect, rapidly decreases after PCC in patients taking DOACs that present with acute ICH. TEG R-time rebounds 12 hours after PCC administration. TEG-R time may be a useful biomarker in DOAC reversal with PCC.

Use of Andexanet Alfa for Factor Xa Inhibitor Reversal in US Verified Trauma Centers: A National Survey.

Direct oral factor Xa inhibitors are replacing vitamin K-dependent antagonists as anticoagulation treatment in many clinical scenarios. Trauma centers are noting an increase in patients presenting on these medications. The 2018 Food and Drug Administration approval of andexanet alfa provides an alternative anticoagulation reversal. Barriers may limit utilization of new medications including a lack of grade 1A evidence supporting the use of prothrombin complex concentrate (PCC) versus andexanet alfa and cost. To evaluate barriers of andexanet alfa utilization by trauma surgeons, a 15-question survey was conducted. There was a 9% completion rate (n = 89). The results revealed 23.5% would choose andexanet alfa as first-line treatment in children, and 25.8% as first-line treatment in adults. The majority of respondents, 64.7% and 67.4%, would use PCC preferentially in children and adults, respectively. Respondents indicated that cost burden was an overriding factor (76.3%); 42.4% cited lack of high-level efficacy data of andexanet alfa for reversal of factor Xa inhibitors. Additional double-blinded multi-institutional randomized controlled trials comparing 4F-PCC and andexanet alfa for factor Xa inhibitor reversal are needed to support efficacy especially with the increased cost associated.

A meta-analysis of high-dose versus low-dose 4-factor prothrombin complex concentrate for reversal of factor Xa inhibitor-associated intracerebral hemorrhage

Abstract Background Four-factor prothrombin complex concentrate (4FPCC) are often used off-label for treating factor Xa inhibitor-associated major bleeding, including intracerebral hemorrhage (ICH). In addition to debate over 4FPCC’s effectiveness and safety compared with specific reversal agents, questions regarding the optimal 4FPCC dose remain. Purpose To evaluate the comparative effectiveness of high-dose versus low-dose 4FPCC for management of factor Xa inhibitor-associated ICH. Methods A systematic literature search of electronic databases (PubMed, Embase, and Cochrane) was conducted through January 31, 2023, to identify studies comparing high-dose versus low-dose 4FPCC for reversal of factor Xa inhibitors in individuals with an ICH. The outcomes of interest were hemostatic effectiveness (as defined by the individual study) and thromboembolism. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) individual study comparisons of high- and low-dose 4FPCC were pooled using a random-effects model. Studies were stratified according to whether multivariable adjusted analyses were performed. Results Six studies with a total of 447 individuals (high-dose = 254, low-dose = 193) were included. Definition of high-dose 4FPCC included ≥ 30 IU/kg (n=1), ≥ 35 IU/kg (n=3), and 50 IU/kg (n=2). Definition of low-dose 4FPCC 25 IU/kg (n=2), < 30 IU/kg (n=1), and <35 IU/kg (n=3). The overall pooled proportion of hemostatic effectiveness for 4FPCC was 81.4% (95% CI 77.6 to 84.8%) with no evidence of a difference between those receiving high-dose versus low-dose 4FPCC (OR 1.36, 95% CI 0.57-3.28; Figure). In five studies, the pooled proportion of individuals who developed a thrombosis after receiving 4FPCC was 3.1% (95% CI 0 to 15.7%) with no evidence of a difference in odds between high-dose and low-dose (OR 1.23, 95% CI 0.56 to 2.72). Conclusion Evidence from mostly small single-center retrospective cohort studies suggests that using high-dose 4FPCC for reversal of factor Xa inhibitor-associated ICH is not associated with differences in the odds of hemostatic effectiveness or thrombosis when compared to the low-dose.Figure.Results of Meta-Analysis

Reversal of pre-injury factor-Xa inhibitors with prothrombin complex concentrates in patients following traumatic brain injury

IntroductionThere is substantial debate on the best method to reverse factor Xa-inhibitors in patients following traumatic brain injury (TBI). Prothrombin complex concentrates (PCC) have been used for this indication but their role has been questioned. This study reported failure rates with PCC in patients following TBI and as a secondary objective, compared 4-factor (4 F-PCC) and activated PCC (APCC). Material and methodsConsecutive patients with TBI on factor Xa-inhibitors admitted to one of two trauma centers were retrospectively identified. Patients with penetrating TBI, delays in PCC administration (>6 h), receipt of tranexamic acid, factor VIIa or no follow up CT-scan were excluded. The primary outcome was treatment failure defined as hematoma expansion > 20% from baseline for SDH, EDH or IPH, a new hematoma not present on the initial CT scan or any expansion of a SAH or IVH. Hematoma expansion was further categorized as symptomatic or asymptomatic, designated by a change in the motor GCS score, neurologic exam or change ≥ 3 in NIH Stroke Scale. Multi-variate analysis was performed. ResultsThere were 43 patients with a mean age of 77 ± 13 years with primarily mild TBI (95%) after a ground level fall (79%). The mean dose was 41 ± 12 units/kg. Sixty percent received 4 F-PCC and 40% APCC. The incidence of treatment failure was 28% (12/43). Of the 12 patients with hematoma expansion, only 3 were symptomatic (9.3%). Hematoma expansion with 4 F-PCC and APCC were similar (27% vs. 29%,p = .859). Only sex was associated with hematoma expansion on multivariate analysis [OR (95% CI) = 6.7 (1.1 – 40.9)]. ConclusionPCC was an effective option for factor Xa inhibitor reversal following TBI. The relationship between radiographic expansion and clinical expansion was poor.

Definition of factor Xa inhibitor-related, life-threatening gastrointestinal bleeding and guidance on when to use reversal therapy: A Delphi panel.

To define and contextualize life-threatening gastrointestinal (GI) bleeding in the setting of factor Xa (FXa) inhibitor therapy and to derive a consensus-based, clinically oriented approach to the administration of FXa inhibitor reversal therapy. We convened an expert panel of clinicians representing specialties in emergency medicine, gastroenterology, vascular medicine, and trauma surgery. Consensus was reached among the clinician panelists using the Delphi technique, which consisted of 2 survey questionnaires followed by virtual, real-time consensus-building exercises. Hypovolemia and hemodynamic instability were considered the most important clinical signs of FXa inhibitor-related, life-threatening GI bleeds. Clinician panelists agreed that potentially life-threatening GI bleeding should be determined on the basis of hemodynamic instability, signs of shock, individual patient characteristics, and clinical judgment. Last, the panel agreed that all patients with life-threatening, FXa inhibitor-associated GI bleeding should be considered for FXa inhibitor reversal therapy; the decision to reverse FXa inhibition should be individualized, weighing the risks and benefits of reversal; and when reversal is elected, therapy should be administered within 1h after initial emergency department evaluation, when possible. Consensus-based definitions of life-threatening GI bleeding and approaches to FXa inhibitor reversal centered on hemodynamic instability, signs of shock, individual patient characteristics, and clinical judgment. The results from this Delphi panel may inform clinical decision-making for the treatment of patients experiencing GI bleeding associated with FXa inhibitor use in the emergency department setting.

Andexanet Alfa Should Be Used to Reverse Factor Xa Inhibitors in the Setting of Life-Threatening Bleeding.

Andexanet alfa was approved by the Food and Drug Administration for reversal of factor Xa inhibitors, apixaban and rivaroxaban, in the setting of acute major bleeding. 1 Connolly S.J. Crowther M. Eikelboom J.W. et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019; 380: 1326-1335 Crossref PubMed Scopus (454) Google Scholar ,2 Siegal D.M. Curnutte J.T. Connolly S.J. et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015; 373: 2413-2424 Crossref PubMed Scopus (786) Google Scholar Andexanet alfa and prothrombin complex concentrate have been studied for factor Xa inhibitor reversal. The andexanet alfa is the preferred reversal agent for factor Xa inhibitor bleeds because of its targeted pharmacology for reversal, hemostatic efficacy, mortality outcomes, and its endorsement by numerous guidelines as the preferred agent.

Hemostatic Efficacy and Safety of 4-Factor Prothrombin Complex Concentrate in Doac-Associated Intracranial Hemorrhage

Background: Factor Xa (FXa) inhibitor use has increased over the last decade and though associated rates of major bleeding are lower compared to warfarin, outcomes from intracranial hemorrhage (ICH) are still significant. Targeted FXa inhibitor reversal agent became available in 2018, however use of 4-factor prothrombin complex concentrate (4F-PCC) for FXa inhibitor-associated ICH continues at many institutions. Objective: Evaluate the safety and hemostatic efficacy of 4F-PCC for FXa inhibitor-associated ICH. Methods: Single-center, retrospective study of patients who received 4F-PCC for FXa inhibitor-associated ICH. The primary efficacy endpoint was hemostasis and thrombosis was the main safety endpoint. Secondary endpoints included in-hospital mortality and discharge disposition. Results: 76 patients on apixaban or rivaroxaban were included. Good or excellent hemostasis was achieved in 80.3% of patients. Five patients experienced a thrombotic event. Favorable discharge disposition and lower in-hospital mortality was more likely in patients who achieved excellent hemostasis. Conclusion: 4F-PCC is safe and effective for FXa inhibitor associated ICH.

340: FIXED-DOSE FOUR-FACTOR PCC FOR THE REVERSAL OF FACTOR XA INHIBITOR-ASSOCIATED BLEEDING

Introduction: Four-Factor PCC (4F-PCC) is labeled for the reversal of vitamin K antagonists and may be considered off label for the reversal of factor Xa inhibitors. A fixed-dose strategy of 4F-PCC for the reversal of factor Xa inhibitors has the potential to minimize delay to reversal, avoid confusion during the ordering process, and lead to cost savings. The purpose of this study is to evaluate the safety and efficacy of fixed-dose 4F-PCC for the management of life-threatening bleeds associated with factor Xa inhibitors. Methods: This was a single center retrospective chart review conducted from May 2019 to January 2022. Patients were included if they were 18 years or older, experienced a life-threatening bleed while on a factor Xa inhibitor, and received 4F-PCC at a fixed dose of 2000 units. Exclusion criteria included: reversal for non-emergent surgery, receipt of 4F-PCC at an outside hospital, and/or receipt of an additional reversal agent. The primary outcome was achievement of hemostasis using a hemostatic effectiveness scale described by Sarode et al. Secondary outcomes included incidence of thrombosis within seven days of 4F-PCC administration and mortality. Results: A total of 39 patients received 4F-PCC for the reversal of a factor Xa inhibitor; 26 patients had central nervous system (CNS) bleeding and 13 had a non-CNS bleed. Overall 49% achieved excellent hemostatic effectiveness, 3% achieved good hemostatic effectiveness, 28% achieved poor, and in 20% we were unable to assess hemostatic effectiveness. In the subset of patients with CNS bleeding, 61% had either excellent or good effectiveness, 8% had poor, and 31% were unable to assess. There was one patient who experienced thromboembolism within seven days of reversal. In-hospital mortality was 18%. Conclusions: The results of this study demonstrate that a fixed-dose 4F-PCC dosing strategy for the reversal of factor Xa inhibitors produces reasonable hemostatic effectiveness and is safe. The rates of effectiveness seen in the subset of patients with CNS bleeding are similar to what has previously been reported for a weight-based dosing strategy. Randomized prospective studies are needed comparing 4F-PCC to andexanet alfa, the FDA labeled reversal agent for factor Xa inhibitors.

The use of andexanet alfa and 4-factor prothrombin complex concentrate in intracranial hemorrhage

Objectiveto describe the clinical and safety outcomes between andexanet alfa (AA) and 4-factor prothrombin complex concentrate (4F-PCC) for the reversal of apixaban or rivaroxaban in the setting of an intracranial hemorrhage (ICH). MethodsA retrospective, multicentered descriptive study was conducted in hospitalized patients 18 years of age or older from June 2018 to October 2019 who received AA or 4F-PCC for the reversal of apixaban or rivaroxaban in the setting of ICH. Patients were excluded if they had received 4F-PCC prior to AA after its addition to the institution wide formulary. Other exclusion criteria were history or presence of heparin-induced thrombocytopenia or disseminated intravascular coagulation, estimated hematoma volume of >60 mL, Glasgow Coma Scores <7, or no repeat CT head scan. Information was collected from the electronic medical records. The primary outcome was the achievement of excellent or good hemostatic efficacy upon the repeat computer tomography (CT) scan performed after the infusion of study drugs. Secondary outcomes included disposition, survival to hospital discharge, 30-day readmission, length of hospital stay, length of ICU stay, incidence of thromboembolic events. ResultsA total of 24 patients were included in the study, of which 9 received AA and 15 received 4F-PCC. The achievement of excellent or good hemostatic efficacy upon repeat CT scan occurred in 7 (77.8%) patients in the AA group and in 14 (93.3%) patients in the 4-F PCC group. All patients in the AA group survived to hospital discharge with no 30-day morality and 86.7% patients in the 4F-PCC group. ConclusionThis study suggests that real-world clinical and safety outcomes between andexanet alfa and 4F-PCC for the reversal of factor Xa inhibitors in the setting of ICH are similar to ones reported in clinical trials.

Reversal of apixaban and rivaroxaban with andexanet alfa prior to invasive or surgical procedures.

Outcomes following andexanet alfa reversal of factor Xa inhibitors in patients requiring urgent or emergent invasive procedures are lacking. This study aimed to describe efficacy and safety outcomes following andexanet alfa administration within 24h of an invasive procedure. This single-center, observational, retrospective study included patients who received andexanet alfa within 24h of an invasive or surgical procedure. The primary outcome was hemostatic efficacy graded as excellent, good, or poor using similar definitions to the ANNEXA-4 criteria. Secondary outcomes included hospital discharge disposition, intensive care unit (ICU) and hospital length of stay, 30-day mortality, 30-day thromboischemic event rates, and serum coagulation assay changes pre- and postreversal. Forty-four patients met inclusion criteria; of these, 27 (62.8%) received apixaban and 16 (37.2%) were treated with rivaroxaban prior to admission. The indications for reversal were categorized as intracranial (n=20 [45.5%]) or extracranial (n=24 [54.5%]) sites. Majority of patients required emergent operative procedures (18 [40.9%]), followed by invasive device placement (10 [22.7%]) or arterial embolization (9 [20.5%]). Thirty-eight (86.4%) patients were able to be adequately graded for hemostatic efficacy. Overall, 30 (78.9%) patients achieved excellent or good hemostasis within 24h after periprocedural administration of andexanet alfa (19 [82.6%] apixaban vs. 11 [78.6%] rivaroxaban; 12 [80.0%] intracranial events vs. 18 [78.3%] extracranial events). Discharge disposition was most often to a short- or long-term care facilities (27 [61.4%]). Thirty-day mortality and thromboischemic complications occurred in 15 (34.1%) and 12 (27.3%) patients, respectively. Prothrombin time and antifactor Xa assay results were significantly decreased after andexanet alfa administration (p < 0.05) while thromboelastogram assay values (reaction time, kinetic time, and activated clotting time) showed nonsignificant changes pre- versus postreversal. Andexanet alfa may be used for urgent or emergent reversal of apixaban and rivaroxaban peri-procedurally with promising hemostatic outcomes. Further prospective, comparative clinical research is warranted.

Andexanet-Alfa-Associated Heparin Resistance in the Context of Hemorrhagic Stroke

BackgroundWith a growing number of patients on new oral anticoagulants, interest in reversal agents is rising. Andexanet alfa is used for reversal of factor Xa inhibitors in intracranial hemorrhage.MethodsWe provide a brief review on andexanet-alfa-associated heparin resistance and discuss potentially critical situations from different clinical perspectives.ResultsCase reports point out that andexanet alfa can cause unresponsiveness to heparin, leading to catastrophic events. As a result, regulatory bodies have issued warning notices to avoid heparinization parallel to the use of andexanet alfa.ConclusionsAlthough well known to hematologists, the phenomenon is underrecognized among stroke clinicians. However, patients with intracranial hemorrhage frequently undergo endovascular or surgical interventions that require periprocedural administration of heparin.

Impact of Factor Xa Inhibitor Reversal with Prothrombin Complex Concentrate in Patients with Traumatic Brain Injuries.

Anticoagulant use prior to trauma has been associated with increased incidence of traumatic brain injury (TBI), intracranial hemorrhage (ICH) progression, and mortality. Prothrombin complex concentrates (PCCs) are commonly used as off-label treatments for factor Xa inhibitor-associated life-threatening hemorrhage. At this time, there is no consensus regarding appropriate indication, target dose, or outcomes of PCC administration in patients presenting with traumatic ICH. This study seeks to evaluate the impact of reversal with PCC on hemorrhage progression and outcomes in patients with TBI on preinjury factor Xa inhibitors. This single-center retrospective cohort study included patients ≥ 18years presenting with an acute TBI of any severity on apixaban or rivaroxaban from September 1, 2016, to September 1, 2019. Patients were grouped on the basis of receipt of PCCs for reversal (i.e., reversal or no reversal). Exclusion criteria included spontaneous ICH or known coagulopathy. Propensity score matching was conducted with the following variables: age, Abbreviated Injury Scale (head) score, and Charlson Comorbidity Index score. The primary outcome was hemorrhage stability within 48h. Secondary outcomes included degree of hemorrhage progression, in-hospital mortality, discharge disposition, and incidence of thromboembolic events. Of the 115 patients meeting inclusion criteria, 84 were included in the propensity score matched data set. Baseline characteristics, comorbidities, and TBI severity were similar. The majority of patients in the reversal group (35 [83.3%]) and the no reversal (NR) group (40 [95.2%]) experienced a mild TBI (admission Glasgow Coma Scale score of 14 to 15). In the reversal group, patients received 34.3 units/kg activated PCC, 30.5 units/kg four-factor PCC, or 54.9 units/kg four-factor PCC and activated PCC on average. There was no difference observed in the incidence of hemorrhage progression (10.8% NR vs. 15.0% reversal; p = 0.739) or in median change in ICH volume (0mL NR vs. 1mL reversal; p = 0.2199) between groups. Additionally, reversal did not affect in-hospital mortality (3 [7.1%] NR vs. 4 [9.5%] reversal; p > 0.999). One patient in the reversal group developed a deep vein thrombosis (DVT) during the hospitalization; however, this did not result in a statistically significant difference in the occurrence of DVT (p > 0.999). This study demonstrated that PCC used for the treatment of factor Xa inhibitor-associated ICH related to mild TBI did not significantly impact the incidence or degree of hemorrhage progression, and PCC treatment did not result in increased thromboembolic events.

Comparative hemostatic efficacy of 4F-PCC in patients with intracranial hemorrhage on factor Xa inhibitors versus warfarin

ObjectivePatients experiencing an intracranial hemorrhage (ICH) on oral anticoagulants often require rapid reversal. This study evaluated patients taking factor Xa inhibitors or warfarin that received reversal with 4-factor prothrombin complex concentrate (4F-PCC) for an ICH. The objective of the study was to determine if the efficacy of 4F-PCC for the reversal of factor Xa inhibitors is noninferior to its use in warfarin reversal in patients with ICH. MethodsThis was a retrospective, single center, noninferiority trial. Patients presenting to the emergency department with ICH were divided into two cohorts: those taking factor Xa inhibitors versus those taking warfarin. In each cohort, patients received anticoagulation reversal with weight-based 4F-PCC. The primary endpoint was hemostatic efficacy defined as ≤20% expansion in hematoma volume on repeat computed tomography imaging. A pre-specified noninferiority margin of −10% was selected to evaluate the difference between groups for the primary endpoint. ResultsA total of 221 patients were included in the study (factor Xa inhibitors, n = 87; warfarin, n = 134). Effective hemostasis was achieved in 70 patients (81%) on factor Xa inhibitors compared to 111 patients (83%) on warfarin, (−2.4% difference, [95% confidence interval, −12.87 to 8.12]; p = 0.654). There was no statistically significant difference between groups with regards to the primary outcome; however, the use of 4F-PCC in factor Xa inhibitor reversal was not noninferior when compared to 4F-PCC use for warfarin reversal. Hospital length of stay and discharge disposition were similar between cohorts. ConclusionsThe efficacy of 4F-PCC in reversing factor Xa inhibitor-related ICH compared to warfarin-related ICH was not significantly different between groups; however, these results did not prove noninferiority. Further study is warranted to delineate 4F-PCC's role in reversing factor Xa inhibitors in patients with ICH.

Reversal of factor Xa inhibitors associated intracranial haemorrhage at a tertiary medical centre.

Prior to the approval of andexanet, there were no FDA-approved reversal agents indicated for the treatment of factor Xa inhibitor (FXaI) associated major bleed. Four-factor prothrombin complex concentrate (4F-PCC) has been widely used off-label for FXaI-associated bleeding. The purpose of this study was to compare the effectiveness and safety of andexanet and 4F-PCC for the reversal of FXaI-associated intracranial haemorrhage. The primary end point is in-hospital mortality; secondary endpoints include haemostatic efficacy and safety. This study is a singlecentre, retrospective chart review, including patients admitted between 1 January 2016 and 15 August 2019, who received 4F-PCC or andexanet for the management of FXaI-associated intracranial haemorrhage. Of the 45 patients included in this study, 23 patients were in the andexanet group and 22 were in the 4F-PCC group. At index admission, mean age was 76 years and the majority of patients (64%) were on apixaban with 33% presented with Glasgow Coma Scale 24 (GCS) score less than 12. At hospital discharge, 47% of patients in the andexanet group had died or discharged to hospice compared with 45% in the 4F-PCC group. No thromboembolic events were observed in either group within 5 days after administration of the reversal agent. The results of this study suggest that haemostasis and mortality at discharge during the index hospitalization appears to be similar between groups. Prospective randomized control trials comparing safety and efficacy of andexanet and 4F-PCC are needed.

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.

High-dose versus low-dose 4-factor prothrombin complex concentrate for factor Xa inhibitor reversal in intracranial hemorrhage

Background & purpose4-factor prothrombin complex concentrate (4FPCC) is used off-label for factor Xa (FXa) inhibitor-associated intracranial hemorrhage (ICH). Guideline recommendations provide various 4FPCC dosing regimens for FXa inhibitor reversal in this setting. We evaluated 4FPCC weight-based dosing and outcomes in FXa inhibitor-associated ICH. MethodsWe conducted a multi-center, retrospective, cohort study of ICH patients between July 2017 and February 2020. Patients were greater than 18 years of age, received 4FPCC, and were taking apixaban, rivaroxaban, or edoxaban. Patients were separated into high- (≥35 units/kg) or low-dose (<35 units/kg) 4FPCC groups. The primary outcome was hemostasis achievement. Secondary outcomes included in-hospital mortality, intensive care unit and hospital length of stay, discharge disposition, and thrombotic events. Outcomes were evaluated with binary logistic regression. ResultsOf 390 patients identified, 89 were included with 74 and 15 in the high- vs low-dose groups, respectively. Mean (SD) age was 76.6 (±10.8) years. Most were taking a FXa inhibitor for atrial fibrillation (76.4%) and apixaban was the most common FXa inhibitor (65.2%). Hemostasis achievement was greater in the high- vs low-dose group (89.2% vs 46.7%; OR 11.2; 95% CI 2.4–52.6, P = 0.002). Thrombotic events were 8.2% and 6.7% in the high vs low-dose groups, respectively (OR 0.8; 95% CI 0.08–8.2, P = 0.87). No statistically significant differences were found in secondary outcomes. ConclusionIn patients with FXa inhibitor-associated ICH, high-dose 4FPCC was associated with increased odds of hemostasis achievement. There was no difference in thrombotic events.

Evaluation of anticoagulation re-initiation practices following reversal of factor Xa inhibitors with andexanet alfa or 4F-PCC in patients with major bleeding events

BackgroundBoth andexanet alfa and 4F-PCC reversal strategies have been associated with thrombotic events. It remains unclear whether the risk is associated with the reversal agent or the lack of re-initiation of anticoagulation. ObjectiveThe aim of this study was to describe anticoagulant (AC) re-initiation patterns in patients presenting with major bleeding while on a FXai requiring reversal, and to describe associated post-reversal thrombotic events. MethodsThis was a single-center retrospective cohort study. Patients were included if they received FXai reversal with andexanet alfa or 4F-PCC for major bleeding. ResultsFifty-seven patients met inclusion criteria; of these patients, 34 received andexanet alfa and 23 patients received 4F-PCC. Most patients were prescribed AC for atrial fibrillation. The most common indications for reversal were intracranial hemorrhage 68%, followed by gastrointestinal bleeding 19%. AC was re-initiated at either prophylactic or therapeutic doses in 59% in the andexanet alfa recipients and 65% in the 4F-PCC recipients within 30 days. In those who restarted AC within 30 days, the median time to re-initiate AC was three days [IQR: 1–3]. Thrombotic events occurred in 3% of patients in the andexanet alfa group and 13% in the 4F-PCC group (7% overall rate). None were receiving anticoagulation at the time of the event. ConclusionAnticoagulation was restarted in approximately half of the patients who received a reversal agent for a life-threatening bleed. The thrombotic risk was 7% at the 30 day follow up period. Continuous assessment of bleeding and thrombosis is important for post-reversal management of patients with major bleeding events.

A Retrospective Review of Four-Factor Prothrombin Complex Concentrate for Factor Xa Inhibitor-Related Bleedings

Background: The use of factor Xa inhibitors has grown in popularity; however, the risk of major bleeding events requires for the appropriate reversal agent. The recent approved agent for factor Xa inhibitor reversal, andexanet alfa, has limited clinical efficacy and safety data, and it can be a financial burden on healthcare systems due to its high cost. Four-factor prothrombin complex concentrate (4F-PCC) has been utilized off label in patients with factor Xa inhibitor-related bleedings. Objective: The aim of this study was to assess the safety and efficacy of 4F-PCC in managing factor Xa inhibitor-related bleedings. Methods: This is an observational, retrospective review of 4F-PCC usage in treating factor Xa inhibitor-related bleeds from May 2014 to December 2018 at a single health system. Efficacy was evaluated using the assessment criteria described by Sarode et al. Secondary outcomes analyzed included thromboembolic events, length of stay, mortality, and discharge disposition. Results: Fifty-nine patient charts were reviewed, and 48 patients were included in the study analysis. The administration of 4F-PCC achieved effective hemostasis in 33 patients (68%), and effective hemostasis was achieved in 12 patients (86%) who had intracranial hemorrhage and did not receive any surgical intervention. Thromboembolic events occurred in 4 patients within 30 days from 4F-PCC use. A majority of patients (85.4%) were discharged from the hospital to home or long-term care; 7 patients (14.6%) expired in the hospital. Conclusion: Efficacy was achieved in over half of the patient population in this cohort who received 4F-PCC for factor Xa inhibitor-related bleeding events.

Factor VIII Inhibitor Bypassing Activity (FEIBA) Reversal for Apixaban and Rivaroxaban in Patients With Acute Intracranial and Nonintracranial Hemorrhage.

The clinical use of factor VIII inhibitor bypassing activity (FEIBA) for factor Xa (FXa) inhibitor reversal is derived from small studies with notable variation in patient eligibility for use, dosage regimens, concurrent supportive care, and outcome measures. Consequently, additional effectiveness and safety data are warranted to expand the literature evaluating FEIBA for FXa inhibitor reversal. This study sought to determine the incidence of observed effective hemostasis within 24 hours of post-FEIBA® administration as well as in-hospital and 30-day post-discharge incidences of thromboembolic event (TEE) and mortality between apixaban and rivaroxaban in the intracranial hemorrhage (ICH) and non-ICH populations. This case series evaluated patients between January 1, 2014 through July 1, 2019 who received at least one FEIBA® dose for apixaban or rivaroxaban reversal secondary to acute ICH or non-ICH. Patient demographics, FEIBA® dosages, adjunct treatments, effectiveness, and safety outcomes were retrospectively collected from electronic medical record review. Modified hemostasis outcomes, adapted from criteria previously published by Sarode et al., TEE, and mortality between apixaban and rivaroxaban in the ICH and non-ICH populations were evaluated. Among the 104 patients evaluated, 62 received apixaban and 42 rivaroxaban. Thirty apixaban and 25 rivaroxaban users experienced ICH, whereas 32 apixaban and 17 rivaroxaban users experienced non-ICH. Among the combined ICH and non-ICH populations, effective hemostasis occurred in 89%, TEE in 8%, and mortality in 13%. No statistically significant differences were observed within ICH and non-ICH populations receiving apixaban or rivaroxaban regarding effective hemostasis, TEE, or mortality. The combined ICH and non-ICH overall rates of effective hemostasis, TEE, and mortality were comparable to preexisting studies of FEIBA for factor Xa inhibitor reversal. The limitations inherent to the study design warrant a randomized controlled trial with an active comparator to confirm these observations.

Restart of Anticoagulant Therapy and Risk of Thrombosis, Rebleeding, and Death after Factor Xa Inhibitor Reversal in Major Bleeding Patients.

Background Lack of data on balancing bleeding and thrombosis risk causes uncertainty about restarting anticoagulants after major bleeding. Anticoagulant reversal trials offer prospectively gathered data after major bleeding with well-documented safety events and restarting behavior. Objectives To examine the relationship of restarting anticoagulation with thrombosis, rebleeding, and death. Methods This is a posthoc analysis of a prospective factor Xa inhibitor reversal study at 63 centers in North America and Europe. We compared outcomes of restarted patients with those not restarted using landmark and time-dependent Cox proportional hazards models. Outcomes included thrombotic and bleeding events and death and a composite of all three. Results Of 352 patients enrolled, oral anticoagulation was restarted in 100 (28%) during 30-day follow-up. Thirty-four (9.7%) had thrombotic events, 15 (4.3%) had bleeding events (after day 3), and 49 (14%) died. In the landmark analysis comparing patients restarted within 14 days to those not, restarting was associated with decreased thrombotic events (hazard ratio [HR] = 0.112; 95% confidence interval [CI]: 0.001–0.944; p = 0.043) and increased rebleeding (HR = 8.39; 95% CI: 1.13–62.29; p = 0.037). The time-dependent Cox model showed evidence for a reduction in a composite (thrombotic events, bleeding, and death) attempting to capture net benefit (HR = 0.384; 95% CI: 0.161–0.915; p = 0.031). Conclusion This analysis provides modest evidence that restarting anticoagulation in factor Xa inhibitor-associated major bleeding patients is correlated with reduced risk of thrombotic events and increased risk of rebleeding. There is low-level evidence of net benefit for restarting. A randomized trial of restarting would be appropriate.