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 Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: a meta-analysis

2019 ◽  
Vol 3 (2) ◽  
pp. 158-167 ◽  
Author(s):  
Siavash Piran ◽  
Rasha Khatib ◽  
Sam Schulman ◽  
Ammar Majeed ◽  
Anne Holbrook ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Prothrombin Complex Concentrate ◽  
Meta Analysis ◽  
Case Series ◽  
Factor Xa ◽  
The United States ◽  
Effective Management ◽  
Direct Factor ◽  
All Cause Mortality ◽  
Fxa Inhibitor

Abstract A targeted antidote for reversal of direct factor Xa (FXa) inhibitors is now available for clinical use in the United States, but it is costly and has limited availability. In a systematic review, we evaluated the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) as an alternative for managing direct FXa inhibitor–related major bleeding. A systematic literature search was conducted using Medline, Embase, and the Cochrane Register of Controlled Trials up to September 2018. No comparative studies were found. Ten case series with 340 patients who received PCC for direct FXa inhibitor–related major bleeding were included. The pooled proportion of patients with effective management of major bleeding was 0.69 (95% confidence interval [CI], 0.61-0.76) in 2 studies using the International Society on Thrombosis and Haemostasis (ISTH) criteria and 0.77 (95% CI, 0.63-0.92) in 8 studies that did not use the ISTH criteria; all-cause mortality was 0.16 (95% CI, 0.07-0.26), and thromboembolism rate was 0.04 (95% CI, 0.01-0.08). On the basis of evidence with very low certainty from single-arm case series, it is difficult to determine whether 4F-PCC in addition to cessation of direct oral FXa inhibitor is more effective than cessation of direct oral FXa inhibitor alone in patients with direct FXa inhibitor–related major bleeding.

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

2021 ◽  
pp. 106002802110045
Author(s):  
Aleah R. Hunt ◽  
Shawn N. Coffeen ◽  
Dane L. Shiltz ◽  
Calvin Ice ◽  
Jessi Parker
Keyword(s):  
Factor Viii ◽  
Controlled Trial ◽  
Safety Data ◽  
Case Series ◽  
Factor Xa ◽  
Factor Viii Inhibitor ◽  
Post Discharge ◽  
Viii Inhibitor ◽  
Fxa Inhibitor ◽  
Record Review

Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusion and Relevance: 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.

Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study

2018 ◽  
Vol 118 (05) ◽  
pp. 842-851 ◽  
Author(s):  
Peter Gross ◽  
Bruce Ritchie ◽  
Susan Nahirniak ◽  
Yulia Lin ◽  
Lani Lieberman ◽  
...  
Keyword(s):  
Cohort Study ◽  
Major Bleeding ◽  
Prothrombin Complex Concentrate ◽  
Case Series ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Fixed Dose ◽  
Reversal Agent ◽  
Major Bleed ◽  
Post Hoc

AbstractOral factor Xa inhibitors are increasingly used for anticoagulation, but there is no approved reversal agent. Prothrombin complex concentrate (PCC) for the management of Xa-inhibitor–associated bleeding has been described in small case series and one cohort study. Patients on apixaban or rivaroxaban, suffering a major bleed, were treated at nine Canadian hospitals as per existing hospital protocol with a fixed dose of PCC 2,000 units and subsequently recruited for a 30-day follow-up. The treating physician evaluated the haemostatic effectiveness as observed during the first day as good, moderate or poor/none, using an assessment guide. Safety outcomes were thromboembolism or death. We recruited 66 patients with major bleeding who were treated with PCC and who were receiving rivaroxaban (56%) or apixaban (44%). The effectiveness was assessed as good in 65% (95% confidence interval [CI], 53–77), moderate in 20% (95% CI, 10–30) and poor/none in 15% (95% CI, 6–24). For the 36 patients with intracranial haemorrhage, the corresponding ratings were 67, 17 and 17%, and for 16 patients with gastrointestinal bleeding they were 69, 12 and 19%, respectively. There were nine deaths (14%) by 30 days, and five (8%) major thromboembolic events. In a post hoc analysis, according to International Society on Thrombosis and Haemostasis criteria, reversal was effective in 68% and ineffective in 32%. For major bleeding associated with oral Xa inhibitors, PCC may have a beneficial effect. The risk of thromboembolism after reversal of anticoagulation in patients with a prothrombotic background has to be taken into account.

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

A case series of cerebral venous thrombosis as the first manifestation of homocystinuria

2021 ◽  
pp. 239698732110594
Author(s):  
Antonio Ochoa-Ferraro ◽  
Subadra Wanninayake ◽  
Charlotte Dawson ◽  
Adam Gerrard ◽  
Mary Anne Preece ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Effective Treatment ◽  
Cerebral Venous Thrombosis ◽  
Thrombotic Event ◽  
Case Series ◽  
Autosomal Recessive Disorder ◽  
Retrospective Case ◽  
Tertiary Referral Centre ◽  
Physician Awareness ◽  
The Mean

Background Cerebral venous thrombosis (CVT) is an important cause of stroke particularly in younger patients and potentially fatal if diagnosis is delayed. The presentation of symptoms is highly variable and consequently the diagnosis and underlying cause is often delayed or overlooked. Homocystinuria, a rare autosomal recessive disorder is an identified risk factor for CVT. Purpose A timely diagnosis and treatment of the underlying cause of CVT could result in improved outcome and prevent further events. This case series describes the clinical course of six adults presented with unprovoked CVT, in whom the diagnosis of underlying homocystinuria was delayed with adverse consequences. We aim to highlight the importance of recognising homocystinuria as an underlying cause of CVT and offer a practical approach to the diagnosis and management. Methods This is a retrospective case series of a cohort of 30 consecutive patients seen in a UK tertiary referral centre. Result Six out of 30 patients presented with CVT prior to homocystinuria diagnosis. The mean and range of age at the time of the first CVT episode was 22.6 (range 11–31) years. The mean ±SD age at diagnosis of homocystinuria as the underlying cause was 26 ± 4.2 years. The time between first CVT and diagnosis of homocystinuria ranged from 1.6 to 11 years resulting in a delay to introduction of effective treatment and, in some cases, a further large vessels thrombotic event. Conclusion Physician awareness of homocystinuria as an underlying cause for an unprovoked CVT will facilitate timely introduction of effective treatment to prevent a further event.

288Thrombotic events in bleeding patients treated with andexanet alpha: an ANNEXA-4 sub-study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Beyer-Westendorf ◽  
P Yue ◽  
M Crowther ◽  
J W Eikelboom ◽  
C M Gibson ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Median Time ◽  
Major Bleeding ◽  
Oral Anticoagulation ◽  
Thrombotic Event ◽  
Thrombotic Risk ◽  
Number Of Patients ◽  
Fxa Inhibitor ◽  
Deep Vein ◽  
Deep Vein Thromboses

Abstract Background/Introduction Andexanet alfa (“andexanet”) was developed as a specific reversal agent for patients with major bleeding while using factor Xa (FXa) inhibitors. While thrombotic events (TEs) have been reported in patients receiving andexanet, the scope, nature, and timing of these events have not been fully characterized. Purpose The ANNEXA-4 study was a prospective, single-arm, open-label clinical trial that evaluated the safety and efficacy of andexanet in patients with acute major bleeding. In this secondary analysis, the occurrence of TEs was investigated. Methods Patients presenting with acute major bleeding within 18 hours after their last dose of FXa inhibitor were treated with andexanet. Safety outcomes, including TEs (reviewed by an adjudication committee), were evaluated at 30 days. Results Among 352 patients treated with andexanet, 34 (9.7%) experienced one or more TEs (Table). Strokes and deep vein thromboses were the most frequent TE types. Compared to patients with arterial TEs, patients with venous TEs were more likely to have been originally anticoagulated for venous thromboembolism. Median time to first TE was 10.5 days (Figure); time to event was shorter for arterial TEs than for venous TEs. TEs were nonfatal for most patients. Subgroups by age, bleed type, baseline anti-fXa activity, FXa inhibitor dose, and andexanet dose were not associated with the occurrence of TEs. Of the 34 TE patients, 26 (76.4%) had TEs before restart of any (full or prophylactic) anticoagulation; all first TEs occurred in patients not receiving oral anticoagulation. No TEs occurred after resumption of oral anticoagulation (N=100). Table 1. Thrombotic event characteristics Characteristic Result (n/N [%]) TE type   Strokes 14/352 (4.0%)   Deep vein thromboses 13/352 (3.7%)   Myocardial infarctions 7/352 (2.0%)   Pulmonary embolisms 5/352 (1.4%)   Transient ischemic attacks 1/352 (0.3%) Bleed type   Intracranial 23/227 (10.1%)   Gastrointestinal 7/90 (7.8%)   Other 4/35 (11.4%) Arterial TEs   Anticoagulated for AF 17/22 (77.3%)   Anticoagulated for VTE 6/22 (27.3%) Venous TEs   Anticoagulated for AF 11/18 (61.1%)   Anticoagulated for VTE 8/18 (44.4%)   Median time to first TE 10.5 days   Arterial 6 days   Venous 15 days Outcome   Fatal 7/34 (20.6%)   Nonfatal 27/34 (79.4%) AF = atrial fibrillation; n = number of patients with TEs; N = total number of patients for each characteristic; TE = thrombotic event; VTE = venous thromboembolism. Figure 1. Thrombotic Events Over Time Conclusions In patients with FXa inhibitor-associated acute major bleeding treated with andexanet, TEs occurred a rate not unexpected given the high thrombotic risk of the population. No factors predictive of TEs were identified. Resumption of anticoagulation was associated with fewer TEs. Acknowledgement/Funding Study funded by Portola Pharmaceuticals, Inc.

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 Erratum to: Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study

2018 ◽  
Vol 118 (12) ◽  
pp. 2188-2188 ◽  
Author(s):  
Sam Schulman ◽  
Peter Gross ◽  
Bruce Ritchie ◽  
Susan Nahirniak ◽  
Yulia Lin ◽  
...  
Keyword(s):  
Cohort Study ◽  
Prospective Cohort Study ◽  
Major Bleeding ◽  
Prospective Cohort ◽  
Prothrombin Complex Concentrate ◽  
Factor Xa ◽  
Factor Xa Inhibitors

Dual therapy with clopidogrel and rivaroxaban in cats with thromboembolic disease

2021 ◽  
pp. 1098612X2110137
Author(s):  
Sara T Lo ◽  
Ashley L Walker ◽  
Catherine J Georges ◽  
Ronald HL Li ◽  
Joshua A Stern
Keyword(s):  
Adverse Events ◽  
Antithrombotic Therapy ◽  
Case Series ◽  
Factor Xa ◽  
Dual Therapy ◽  
Thromboembolic Disease ◽  
Outpatient Basis ◽  
Retrospective Case ◽  
Very High ◽  
Intracardiac Thrombi

Objectives Feline arterial thromboembolism (ATE), an often devastating outcome, was recently shown to affect 11.3% of cats with hypertrophic cardiomyopathy over 10 years. Current American College of Veterinary Internal Medicine guidelines recommend the use of clopidogrel in cats at risk for ATE, with addition of a factor Xa inhibitor in very high risk or post-ATE cases. To date, no studies have examined the safety or efficacy of this combined antithrombotic therapy. This retrospective case series aimed to assess the frequency and type of adverse events that occurred in cats prescribed dual clopidogrel and rivaroxaban therapy. Secondary aims were to evaluate indications for dual therapy and clinical outcome. Methods The study included 32 cats prescribed clopidogrel (18.75 mg PO q24h) and rivaroxaban (2.5 mg PO q24h) on an outpatient basis over a 5-year period. Results Cats were prescribed dual therapy for at least one of the following: ATE event (n = 18), presence of an intracardiac thrombi (n = 17) or presence of spontaneous echocardiographic contrast (SEC) (n = 16). Five cats experienced adverse effects that could be attributed to medications, a median of 13 days from initiation (epistaxis, hematemesis, hematochezia or hematuria). No cat required hospitalization as a result of these events. Median survival time from onset of therapy was 257 days (interquartile range [IQR] = 38–497) for all cats, 502 days (IQR = 171–663) for ATE cats, 725 days (IQR = 133–856) for cats with an ATE to two or more limbs and 301 days (IQR = 221–431) for cats with only one limb affected. Recurrence rate of ATE while on dual therapy was 16.7%; no cat newly developed an ATE while on dual therapy. Conclusions and relevance Dual antithrombotic therapy with clopidogrel and rivaroxaban resulted in a low reported incidence of adverse events. Cats placed on dual therapy for an ATE event experienced a low rate of recurrence and effective thromboprophylaxis was achieved in cats with intracardiac thrombi or SEC.

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