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

2021 ◽  
Author(s):  
Spencer Davis ◽  
Stephanie Chauv ◽  
Abby W. Hickman ◽  
Dave S. Collingridge ◽  
Sara Kjerengtroen ◽  
...  
Keyword(s):  
Intracranial Hemorrhage ◽  
Prothrombin Complex Concentrate ◽  
Low Dose ◽  
Factor Xa ◽  
High Dose ◽  
Factor Xa Inhibitor

Evaluation of the Use of Low-Dose 4-Factor Prothrombin Complex Concentrate in the Reversal of Direct Oral Anticoagulants in Bleeding Patients

2018 ◽  
Vol 35 (9) ◽  
pp. 903-908 ◽  
Author(s):  
Teresa A. Allison ◽  
Pei Jen Lin ◽  
Jennifer A. Gass ◽  
Kenneth Chong ◽  
Samuel J. Prater ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Prothrombin Complex Concentrate ◽  
Low Dose ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Final Analysis ◽  
Factor Xa Inhibitor ◽  
Direct Factor

Objective: This study investigated the percentage of patients who achieved hemostasis with 4-factor prothrombin complex concentrate (4-factor PCC) 35 U/kg. The primary end point was to determine the effect of 4-factor PCC 35 U/kg on bleeding progression, assessed using computed tomography. Methods: This was a retrospective, observational, single-center study conducted in patients with a major bleed admitted to a level 1 trauma center from May 1, 2013, to June 15, 2015, who received 4-factor PCC 35 U/kg for reversal of a direct factor Xa inhibitor taken prior to admission. Results: Thirty-three patients were included in the study, with 31 patients in the final analysis. The mean (standard deviation) age was 73 (14.8) years; 54.5% of patients were female. Of the 33 patients, 13 presented with a traumatic brain injury, 9 with an aneurysmal subarachnoid hemorrhage, 8 with an intracerebral hemorrhage, 1 with a gastrointestinal bleed, 1 with a hematoma with active extravasation, and 1 with an intra-abdominal bleed. The most frequently used direct factor Xa inhibitor was rivaroxaban (81.8%). Overall, 83.8% of patients achieved hemostasis with 4-factor PCC 35 U/kg. Progression of hemorrhage was observed in 4 patients on repeat computed tomography scan and 1 patient had continued surgical bleeding. No thromboembolic events were reported. Conclusions: Low-dose, 4-factor PCC 35 U/kg appeared to produce hemostasis in a majority of the patients. This may be an effective dosing regimen for anticoagulant reversal of factor Xa inhibitors in clinically bleeding patients.

Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates

2013 ◽  
Vol 110 (07) ◽  
pp. 162-172 ◽  
Author(s):  
András Gruber ◽  
Hanna Tinel ◽  
Ulla Marzec ◽  
Ulf Buetehorn ◽  
Anja Buchmueller ◽  
...  
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Factor Xa ◽  
Factor Vii ◽  
High Dose ◽  
Factor Xa Inhibitor ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Haemostatic Agents ◽  
Life Threatening ◽  
Anaesthetised Rats

SummaryRivaroxaban is an oral, direct factor Xa inhibitor for the management of thromboembolic disorders. Despite its short half-life, the ability to reverse rivaroxaban anticoagulation could be beneficial in life-threatening emergencies. The potential of prothrombin complex concentrate (PCC; Beriplex®), activated PCC (aPCC; FEIBA®) or recombinant activated factor VII (rFVIIa; NovoSeven®) to reverse rivaroxaban in rats and baboons was investigated. Anaesthetised rats pre-treated with intravenous rivaroxaban (2 mg/kg) received intravenous rFVIIa (100/400 μg/kg), PCC (25/50 U/kg) or aPCC (50/100 U/kg) after initiation of bleeding. Clotting times and bleeding times (BTs) were recorded. Rivaroxaban was administered as an intravenous 0.6 mg/kg bolus followed by continuous 0.6 mg/kg/hour infusion in baboons. Animals received intravenous aPCC 50 U/kg (2 U/kg/minute) or rFVIIa 210 μg/kg. BT and clotting parameters were measured. In rats pre-treated with high-dose rivaroxaban, PCC 50 U/kg, aPCC 100 U/kg and rFVIIa 400 μg/kg significantly reduced BT vs rivaroxaban alone (5.4 ± 1.4-fold to 1.5 ± 0.4-fold [p<0.05]; 3.0 ± 0.4-fold to 1.4 ± 0.1-fold [p<0.001]; and 3.5 ± 0.7-fold to 1.7 ± 0.2-fold [p<0.01] vs baseline, respectively). In baboons pre-infused with rivaroxaban and then given aPCC, BT increased by 2.0 ± 0.2-fold and aPCC returned BT to baseline for the duration of its infusion. rFVIIa reduced BT from 2.5 ± 0.3-fold over baseline to 1.7 ± 0.3-fold over baseline. Prolongation of prothrombin time was reduced by PCC, aPCC and rFVIIa in both species. Rivaroxaban reduced thrombin-antithrombin levels; application of PCC and aPCC, but not rFVIIa, increased these levels. In conclusion, PCC, aPCC or rFVIIa have the potential to reverse the anticoagulant and anti-haemostatic effects of rivaroxaban.

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 Use and outcomes of prothrombin complex concentrate for factor Xa inhibitor-associated bleeding

2021 ◽  
Vol 198 ◽  
pp. 132-134
Author(s):  
Annabel K. Frank ◽  
Previn Ganesan ◽  
Ashley Thompson ◽  
Margaret C. Fang
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Factor Xa ◽  
Factor Xa Inhibitor

Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

2012 ◽  
Vol 107 (02) ◽  
pp. 253-259 ◽  
Author(s):  
Toshio Fukuda ◽  
Yuko Honda ◽  
Chikako Kamisato ◽  
Toshiro Shibano ◽  
Yoshiyuki Morishima
Keyword(s):  
Venous Thrombosis ◽  
Prothrombin Complex Concentrate ◽  
Bleeding Time ◽  
Factor Viia ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Thrombosis Model ◽  
Haemostatic Agents

SummaryEdoxaban, an oral, direct factor Xa inhibitor, has a similar or low incidence of bleeding events compared with other anticoagulants in clinical trials. Therefore, agents to reverse the anticoagulant effects of edoxaban could be desirable in emergency situations. In this study, the reversal effects of haemostatic agents were determined on prothrombin time (PT) prolongation in vitro and bleeding time prolongation in vivo by edoxaban. PT using human plasma was measured in the presence of edoxaban at therapeutic and excess concentrations with the haemostatic agents, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa). In rats, rFVIIa and Feiba was given during intensive anticoagulation with edoxaban. The haemostatic effect was evaluated in a model of planta template bleeding and a potential prothrombotic effect was evaluated in a venous thrombosis model. PPSB-HT, Feiba, and rFVIIa concentration-dependently shortened PT prolonged by edoxaban. Among these, rFVIIa and Feiba showed potent activities in reversing the PT prolongation by edoxaban. rFVIIa (1 and 3 mg/kg, i.v.) and Feiba (100 U/kg, i.v.) significantly reversed edoxaban (1 mg/kg/h)-induced prolongation of bleeding time in rats. In a rat venous thrombosis model, no potentiation of thrombus formation was observed when the highest dose (3 mg/kg) of rFVIIa was added to edoxaban (0.3 and 1 mg/kg/h) compared with the control. The present study indicated that rFVIIa, Feiba, and PPSB-HT have the potential to be reversal agents for edoxaban.

scholarly journals Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Reversal of Factor Xa-Associated Intracranial Hemorrhage

Stroke ◽  
2021 ◽  
Author(s):  
Andrew Micieli ◽  
Andrew M. Demchuk ◽  
Harindra C. Wijeysundera
Keyword(s):  
Cost Effectiveness ◽  
Life Expectancy ◽  
Incremental Cost ◽  
Intracranial Hemorrhage ◽  
Prothrombin Complex Concentrate ◽  
Factor Xa ◽  
Incremental Cost Effectiveness Ratio ◽  
Cost Effectiveness Ratio ◽  
Lifetime Horizon ◽  
Life Years

Background and Purpose: Andexanet was approved by the Food and Drug Administration in 2018 for reversal of life-threatening or uncontrolled bleeding associated with factor Xa anticoagulation; however, the cost-effectiveness of Andexanet compared with standard of care (ie, prothrombin complex concentrate, PCC) in patients with factor Xa–associated intracranial hemorrhage (ICrH) is unknown. Methods: Cost-effectiveness analysis using a Markov cohort decision analytic model with a lifetime horizon was completed to determine the costs and benefits of Andexanet compared with PCC for reversal of factor Xa–associated ICrH. The population of interest was patients living in Canada on chronic factor Xa inhibitors for prevention of ischemic stroke in nonvalvular atrial fibrillation or the prevention/treatment of venous thromboembolism, presenting with an ICrH. Outcomes of interest were life expectancy (measured in years), quality-adjusted life years (QALY), costs (reported in 2020 Canadian dollars), and the incremental cost-effectiveness ratio. Results: An overall reduction in fatal ICrH and increase in thromboembolic events was associated with Andexanet compared with PCC. Andexanet had the highest discounted life expectancy of 2.53 years and a discounted QALY of 1.55. PCC had a discounted life expectancy of 2.09 years and a discounted QALY of 1.28. The average discounted lifetime costs were $237 177 Canadian dollars for Andexanet and $177 871 Canadian dollars for PCC. The strategy of Andexanet had an incremental cost-effectiveness ratio was $219 652 per QALY gained compared with the comparator of PCC. The probabilistic sensitivity analyses demonstrated that Andexanet (at its current cost) was cost-effective in 19% of simulations using a willingness-to-pay threshold of $50 000/QALY and 33% of simulations at $150 000/QALY. A 1-way sensitivity analysis found that for the incremental cost-effectiveness ratio to be <$150 000/QALY gained, Andexanet high or standard dosing would require a price reduction to <$24 000 Canadian (at current baseline efficacy). Conclusions: Based on available evidence, Andexanet represents low value for reversal of factor Xa–associated ICrH; however, there is substantial uncertainty reflecting the currently available data. Further comparative evidence and costing data will become available in the future with randomized trials of Andexanet versus PCC.

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