Dose-Related Effectiveness of Andexanet Alfa for Reversal of Apixaban Anticoagulation in a Porcine Polytrauma Model

Farahnaz Rayatdoost; Till Braunschweig; Herbert Schöchl; Rolf Rossaint; Oliver Grottke

doi:10.1055/s-0043-1772697

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2024; 124(01): 020-031
DOI: 10.1055/s-0043-1772697

Coagulation and Fibrinolysis

Dose-Related Effectiveness of Andexanet Alfa for Reversal of Apixaban Anticoagulation in a Porcine Polytrauma Model

Farahnaz Rayatdoost

¹Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany

,

Till Braunschweig

²Department of Pathology, RWTH Aachen University Hospital, Aachen, Germany

,

Herbert Schöchl

³Department of Anaesthesiology and Intensive Care Medicine, AUVA Trauma Centre Salzburg, Academic Teaching Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria

,

Rolf Rossaint

¹Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany

,

Oliver Grottke

¹Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany

› Institutsangaben

Abstract

Background Andexanet alfa (andexanet) is a reversal agent for use in patients with life-threatening or uncontrolled bleeding treated with oral factor Xa (FXa) inhibitors. There are limited data on the dose–response relationship of andexanet and FXa inhibitor-related bleeding.

Objective The aim of this study was to assess the dose-related effectiveness of andexanet in reducing blood loss, improving survival, and reversing apixaban anticoagulation in a porcine polytrauma model.

Methods Apixaban was given orally to 40 male pigs for 3 days at a dose of 20 mg/d. On day 3, following bilateral femur fractures and blunt liver injury, animals (n = 8/group) received andexanet (250-mg bolus, 250-mg bolus + 300-mg 2-hour infusion, 500-mg bolus, or 500-mg bolus + 600-mg 2-hour infusion) or vehicle (control). Total blood loss was the primary endpoint. Coagulation parameters were assessed for 300 minutes or until death. Data were analyzed with a mixed-model analysis of variance.

Results Administration of 250-mg bolus + 300-mg infusion, andexanet 500-mg bolus, and 500-mg bolus + 600-mg infusion significantly decreased total blood loss by 37, 58, and 61%, respectively (all p < 0.0001), with 100% survival. Andexanet 250-mg bolus was ineffective in reducing total blood loss (6%) and mortality (63% survival) versus controls. Andexanet 500-mg bolus ± infusion neutralized anti-FXa activity to less than 50 ng/mL. Andexanet neutralization of thrombin generation and thromboelastometry parameters was dose and infusion time dependent.

Conclusion In a porcine polytrauma model with major bleeding on apixaban, andexanet dose dependently decreased anti-FXa activity. Lower anti-FXa levels (<50 ng/mL) with andexanet 500-mg bolus ± infusion were correlated with 60% less blood loss and 100% survival versus controls.

Keywords

anticoagulants - andexanet alfa - antidote - apixaban - polytrauma

Volltext

Referenzen

References
1 Goette A, Merino JL, Ezekowitz MD. et al; ENSURE-AF investigators. Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial. Lancet 2016; 388 (10055): 1995-2003
2 Granger CB, Alexander JH, McMurray JJ. et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
3 Levy JH, Douketis J, Weitz JI. Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol 2018; 15 (05) 273-281
4 Patel MR, Mahaffey KW, Garg J. et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
5 Shoeb M, Fang MC. Assessing bleeding risk in patients taking anticoagulants. J Thromb Thrombolysis 2013; 35 (03) 312-319
6 Yee J, Kaide CG. Emergency reversal of anticoagulation. West J Emerg Med 2019; 20 (05) 770-783
7 Abdulrehman J, Eikelboom JW, Siegal DM. Andexanet alfa for reversal of factor Xa inhibitors: a critical review of the evidence. Future Cardiol 2019; 15 (06) 395-404
8 Sartori M, Cosmi B. Andexanet alfa to reverse the anticoagulant activity of factor Xa inhibitors: a review of design, development and potential place in therapy. J Thromb Thrombolysis 2018; 45 (03) 345-352
9 Spahn DR, Bouillon B, Cerny V. et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care 2019; 23 (01) 98
10 Connolly SJ, Crowther M, Eikelboom JW. et al; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380 (14) 1326-1335
11 Dabi A, Koutrouvelis AP. Reversal strategies for intracranial hemorrhage related to direct oral anticoagulant medications. Crit Care Res Pract 2018; 2018: 4907164
12 Siegal DM, Curnutte JT, Connolly SJ. et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373 (25) 2413-2424
13 Siegal D, Lu G, Leeds JM. et al. Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa. Blood Adv 2017; 1 (21) 1827-1838
14 Grottke O, Braunschweig T, Rossaint R. et al. Transient or extended reversal of apixaban anticoagulation by andexanet alfa is equally effective in a porcine polytrauma model. Br J Anaesth 2019; 123 (02) 186-195
15 Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: a clinical pharmacokinetic and pharmacodynamic review. Clin Pharmacokinet 2019; 58 (10) 1265-1279
16 Grottke O, Braunschweig T, Philippen B. et al. A new model for blunt liver injuries in the swine. Eur Surg Res 2010; 44 (02) 65-73
17 Clark JD, Gebhart GF, Gonder JC, Keeling ME, Kohn DF. Special report: the 1996 guide for the care and use of laboratory animals. ILAR J 1997; 38 (01) 41-48
18 Percie du Sert N, Ahluwalia A, Alam S. et al. Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol 2020; 18 (07) e3000411
19 Grottke O, Honickel M, van Ryn J, ten Cate H, Rossaint R, Spronk HM. Idarucizumab, a specific dabigatran reversal agent, reduces blood loss in a porcine model of trauma with dabigatran anticoagulation. J Am Coll Cardiol 2015; 66 (13) 1518-1519
20 Honickel M, Braunschweig T, van Ryn J. et al. prothrombin complex concentrate is effective in treating the anticoagulant effects of dabigatran in a porcine polytrauma model. Anesthesiology 2015; 123 (06) 1350-1361
21 Honickel M, Maron B, van Ryn J. et al. Therapy with activated prothrombin complex concentrate is effective in reducing dabigatran-associated blood loss in a porcine polytrauma model. Thromb Haemost 2016; 115 (02) 271-284
22 Grottke O, Braunschweig T, Henzler D, Coburn M, Tolba R, Rossaint R. Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury. Crit Care 2010; 14 (02) R62
23 Grottke O, Braunschweig T, Spronk HM. et al. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood 2011; 118 (07) 1943-1951
24 Rayatdoost F, Braunschweig T, Maron B. et al. Reversing rivaroxaban anticoagulation as part of a multimodal hemostatic intervention in a polytrauma animal model. Anesthesiology 2021; 135 (04) 673-685
25 Douxfils J, Ageno W, Samama CM. et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018; 16 (02) 209-219
26 Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI. Subcommittee on Control of Anticoagulation. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14 (03) 623-627
27 Tafur AJ, Clark NP, Spyropoulos AC. et al. Predictors of bleeding in the perioperative anticoagulant use for surgery evaluation study. J Am Heart Assoc 2020; 9 (19) e017316
28 Bai C, Konings J, Ninivaggi M, Lancé M, de Laat B, de Laat-Kremers R. Assessing the individual roles of FII, FV, and FX activity in the thrombin generation process. Front Cardiovasc Med 2022; 9: 1000812
29 Drouet L, Bal Dit Sollier C, Steiner T, Purrucker J. Measuring non-vitamin K antagonist oral anticoagulant levels: When is it appropriate and which methods should be used?. Int J Stroke 2016; 11 (07) 748-758
30 Mujer MTP, Rai MP, Atti V. et al. An update on the reversal of non-vitamin K antagonist oral anticoagulants. Adv Hematol 2020; 2020: 7636104
31 Lu G, Pine P, Leeds JM. et al. Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model. PLoS One 2018; 13 (03) e0195122
32 Seyve L, Richarme C, Polack B, Marlu R. Impact of four direct oral anticoagulants on rotational thromboelastometry (ROTEM). Int J Lab Hematol 2018; 40 (01) 84-93

Zusatzmaterial

Supplementary Material