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Hamostaseologie 2020; 40(02): 201-213
DOI: 10.1055/a-1113-0557
Review Article
Georg Thieme Verlag KG Stuttgart · New York

How Do I Reverse Oral and Parenteral Anticoagulants?

Wie Reversiere ich die Wirkung von Oralen und Parenteralen Antikoagulanzien?
Jürgen Koscielny
1   Charité, Universitätsmedizin Berlin, Gerinnungsambulanz mit Hämophiliezentrum im Ambulanten, Gesundheitszentrum (AGZ), Berlin, Germany
,
Edita Rutkauskaite
1   Charité, Universitätsmedizin Berlin, Gerinnungsambulanz mit Hämophiliezentrum im Ambulanten, Gesundheitszentrum (AGZ), Berlin, Germany
,
Christoph Sucker
2   Gerinnungszentrum Berlin Dr. Sucker, Berlin, Germany
,
Christian von Heymann
3   Klinik für Anästhesie, Intensivmedizin, Notfallmedizin und Schmerztherapie, Vivantes Klinikum, Im Friedrichshain, Berlin, Germany
› Author Affiliations
Further Information

Publication History

09 December 2019

09 February 2020

Publication Date:
26 May 2020 (online)

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Abstract

An understanding of reversal strategies alone is important to safely and effectively care for patients in cases of bleeding or invasive procedures. The recent diversification in the number of licensed anticoagulants makes an understanding of drug-specific reversal strategies essential. Intravenous or oral vitamin K can reverse the effect of vitamin K antagonists (VKAs) within 12 to 48 hours and is indicated for any bleeding or an international normalized ratio >10 or 4.5 to 10 in patients with additional risk factors for bleeding. Furthermore, an additional administration of prothrombin complex concentrate (PCC) may be necessary in cases of major bleeding related to VKA. Protamine (chloride or sulfate) fully reverses the effect of unfractionated heparin and partially in low-molecular-weight heparin. Idarucizumab has been approved for dabigatran reversal, whereas andexanet alfa is approved for the reversal of some oral factor Xa inhibitors (apixaban, rivaroxaban). PCC seems to enhance the haemostatic potential for the reversal of the effect of FXa-inhibitors. So far, there are promising but only limited data on the efficacy of this approach available. Each reversal strategy needs an adequate management beyond the hemostatic treatment (volume replacement, stabilization of homeostasis, e.g., pH and temperature, resumption of anticoagulation after successful treatment of bleeding, etc.) that is crucial for the successful management of acute bleedings, urgent high-risk surgery, thrombolytic therapies or thrombectomies as well as overdosing of anticoagulants.

Zusammenfassung

Das Verständnis für spezifische Reversierungsstrategien antikoagulierter Patienten ist wichtig, um einen Patienten sicher und effektiv bei Blutungen oder invasiven Prozeduren behandeln zu können. Auf Grund der Vielzahl von Antikoagulanzien ist das Wissen um spezifische Reversierungsstrategien essentiell. Intravenös oder oral verabreichtes Vitamin K kann die Wirkung von Vitamin-K-Antagonisten (VKA) innerhalb von 12 bis 48 Stunden reversieren und ist bei jeder Blutung, bei einer international normalized ratio (INR) > 10 oder einer INR von 4,5 bis 10 und weitere Risikofaktoren für Blutungen, indiziert. Zusätzlich kann eine Gabe von Prothrombin-Komplex-Konzentraten (PPSB) bei großen Blutungen unter VKA erforderlich werden. Protamin(-chlorid oder -sulfat) heben die Wirkung von unfraktioniertem Heparin (UFH) vollständig und niedermolekularem Heparin (NMH) partiell auf. Idarucizumab ist zugelassen für die Reversierung von Dabigatran, während Andexanet alfa für die Reversierung einiger oraler Faktor Xa Inhibitoren (Rivaroxaban, Apixaban) bedingt zugelassen ist. PPSB scheint eine Erhöhung des hämostatischen Potenzials zu bewirken, welches einen der Reversierung der FXa-Inhibitoren ähnlichen Effekt aufweist. Zur Effektivität dieser Therapie sind bislang viel versprechende, aber insgesamt nur wenige Daten vorhanden. Jede Reversierungsstrategie benötigt ein über die Aufhebung der Antikoagulation hinausgehendes Management (Volumenersatz, Aufrechterhaltung der Homöostase, z.B. pH, Temperatur, Wiederbeginn der Antikoagulation nach erfolgreicher Therapie der Blutung, etc.), welches für die erfolgreiche Behandlung akuter Blutungen, dringender Operationen mit hohem Risiko, avisierter Thrombolysen oder Thrombektomien sowie Antikoagulanzienüberdosierungen unerlässlich ist.

Keywords

oral and parenteral anticoagulants - reversal strategy - vitamin K antagonist

Schlüsselwörter

Orale und parenterale Antikoagulanzien - Reversierung - Vitamin K Antagonist
 

  • References

  • 1 Stahmann MA, Hübner CF, Link KP. Studies on the hemorrhagic sweet clover disease identification and synthesis of the hemorrhagic agent. J Biol Chem 1941; 138 (02) 513-527
    CrossrefPubMedGoogle Scholar
  • 2 Czuprynska J, Patel JP, Arya R. Current challenges and future prospects in oral anticoagulant therapy. Br J Haematol 2017; 178 (06) 838-851
    CrossrefPubMedGoogle Scholar
  • 3 Makris M, Van Veen JJ, Tait CR, Mumford AD, Laffan M. ; British Committee for Standards in Haematology. Guideline on the management of bleeding in patients on antithrombotic agents. Br J Haematol 2013; 160 (01) 35-46
    CrossrefPubMedGoogle Scholar
  • 4 Hunt BJ, Allard S, Keeling D, Norfolk D, Stanworth SJ, Pendry K. ; British Committee for Standards in Haematology. A practical guideline for the haematological management of major haemorrhage. Br J Haematol 2015; 170 (06) 788-803
    CrossrefPubMedGoogle Scholar
  • 5 Koscielny J, Rutkauskaite E. Bleedings under NOAC (non vitamin-K dependent oral anticoagulants). Evidence and practical management [in German]. Hamostaseologie 2015; 35 (Suppl. 01) S43-S53
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Frontera JA, Lewin III JJ, Rabinstein AA. , et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016; 24 (01) 6-46
    CrossrefPubMedGoogle Scholar
  • 7 Albaladejo P, Samama CM, Sié P. , et al; GIHP-NACO Study Group. Management of severe bleeding in patients treated with direct oral anticoagulants: an observational registry analysis. Anesthesiology 2017; 127 (01) 111-120
    CrossrefPubMedGoogle Scholar
  • 8 Koscielny J, Rosenthal C, von Heymann C. Bleeding management under direct oral anticoagulants (DOAC) [in German]. Dtsch Med Wochenschr 2018; 143 (24) 1734-1738
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Eikelboom JW, Kozek-Langenecker S, Exadaktylos A. , et al. Emergency care of patients receiving non-vitamin K antagonist oral anticoagulants. Br J Anaesth 2018; 120 (04) 645-656
    CrossrefPubMedGoogle Scholar
  • 10 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
    CrossrefPubMedGoogle Scholar
  • 11 Douketis JD, Spyropoulos AC, Duncan J. , et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med 2019; 179 (11) 1469-1478
    CrossrefPubMedGoogle Scholar
  • 12 Douxfils J, Ageno W, Samama C-M. , et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018; 16 (02) 209-219
    CrossrefPubMedGoogle Scholar
  • 13 Keeling D, Tait RC, Watson H. ; British Committee of Standards for Haematology. Perioperative management of anticoagulation and antiplatelet therapy. Br J Haematol 2016; 175: 602-613
    CrossrefPubMedGoogle Scholar
  • 14 Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108 (02) 217-224
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Körber MK, Langer E, Ziemer S, Perzborn E, Gericke C, Heymann Cv. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost 2014; 20 (07) 735-740
    CrossrefPubMedGoogle Scholar
  • 16 Godier A, Miclot A, Le Bonniec B, Durand M, Lecompte T, Samama CM. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Eur J Anaesthesiol 2011; 28: 1-9
    PubMedGoogle Scholar
  • 17 Steffel J, Verhamme P, Potpara TS. , et al; ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: executive summary. Europace 2018; 20 (08) 1231-1242
    CrossrefPubMedGoogle Scholar
  • 18 Godier A, Dincq AS, Martin AC. , et al. Predictors of pre-procedural concentrations of direct oral anticoagulants: a prospective multicentre study. Eur Heart J 2017; 38 (31) 2431-2439
    CrossrefPubMedGoogle Scholar
  • 19 Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H. ; Beriplex P/N Anticoagulation Reversal Study Group. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008; 6 (04) 622-631
    CrossrefPubMedGoogle Scholar
  • 20 Wang X, Mondal S, Wang J. , et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs 2014; 14 (02) 147-154
    CrossrefPubMedGoogle Scholar
  • 21 Sajkov D, Gallus A. Accidental rivaroxaban overdose in a patient with pulmonary embolism: some lessons for managing new oral anticoagulants. Clin Med Insights Case Rep 2015; 8: 57-59
    PubMedGoogle Scholar
  • 22 Jourdi G, Delrue M, Stepanian A. , et al. Potential usefulness of activated charcoal (DOAC remove®) for dRVVT testing in patients receiving direct oral anticoagulants. Thromb Res 2019; 184: 86-91
    CrossrefPubMedGoogle Scholar
  • 23 Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med 2006; 144 (09) 673-684
    CrossrefPubMedGoogle Scholar
  • 24 Kitchen S, Gray E, Mackie I, Baglin T, Makris M. ; BCSH Committee. Measurement of non-coumarin anticoagulants and their effects on tests of haemostasis: guidance from the British Committee for Standards in Haematology. Br J Haematol 2014; 166 (06) 830-841
    CrossrefPubMedGoogle Scholar
  • 25 Guy S, Kitchen S, Maclean R, Van Veen JJ. Limitation of the activated partial thromboplastin time as a monitoring method of the direct thrombin inhibitor argatroban. Int J Lab Hematol 2015; 37 (06) 834-843
    CrossrefPubMedGoogle Scholar
  • 26 Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014; 64 (11) 1128-1139
    CrossrefPubMedGoogle Scholar
  • 27 Spyropoulos AC, Al-Badri A, Sherwood MW, Douketis JD. To measure or not to measure direct oral anticoagulants before surgery or invasive procedures: comment. J Thromb Haemost 2016; 14 (12) 2556-2559
    CrossrefPubMedGoogle Scholar
  • 28 Gosselin RC, Adcock DM, Bates SM. , et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 2018; 118 (03) 437-450
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Funk DM. Coagulation assays and anticoagulant monitoring. Hematology (Am Soc Hematol Educ Program) 2012; 2012 (01) 460-465
    CrossrefPubMedGoogle Scholar
  • 30 Patriquin C, Crowther M. Treatment of warfarin-associated coagulopathy with vitamin K. Expert Rev Hematol 2011; 4 (06) 657-665 , quiz 666–667
    CrossrefPubMedGoogle Scholar
  • 31 Brekelmans MPA, Ginkel KV, Daams JG, Hutten BA, Middeldorp S, Coppens M. Benefits and harms of 4-factor prothrombin complex concentrate for reversal of vitamin K antagonist associated bleeding: a systematic review and meta-analysis. J Thromb Thrombolysis 2017; 44 (01) 118-129
    CrossrefPubMedGoogle Scholar
  • 32 Hunt BJ, Levi M. Urgent reversal of vitamin K antagonists. BMJ 2018; 360: j5424
    PubMedGoogle Scholar
  • 33 Schiele F, van Ryn J, Canada K. , et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121 (18) 3554-3562
    CrossrefPubMedGoogle Scholar
  • 34 Pollack Jr CV, Reilly PA, van Ryn J. , et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med 2017; 377 (05) 431-441
    CrossrefPubMedGoogle Scholar
  • 35 Khadzhynov D, Wagner F, Formella S. , et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013; 109 (04) 596-605
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Ondexxya. Available at: https://www.ema.europa.eu/en/documents/product-information/ondexxya-epar-product-information_de.pdf . Accessed June 30, 2019
    PubMed
  • 37 Connolly SJ, Milling Jr TJ, Eikelboom JW. , et al; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; 375 (12) 1131-1141
    CrossrefPubMedGoogle Scholar
  • 38 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
    CrossrefPubMedGoogle Scholar
  • 39 Majeed A, Ågren A, Holmström M. , et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 2017; 130 (15) 1706-1712
    CrossrefPubMedGoogle Scholar
  • 40 Zahir H, Brown KS, Vandell AG. , et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 2015; 131 (01) 82-90
    CrossrefPubMedGoogle Scholar
  • 41 Piran S, Khatib R, Schulman S. , et al. Management of direct factor Xa inhibitor-related major bleeding with prothrombin complex concentrate: a meta-analysis. Blood Adv 2019; 3 (02) 158-167
    CrossrefPubMedGoogle Scholar
  • 42 Schulman S, Gross PL, Ritchie B. , et al; Study Investigators. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemost 2018; 118 (05) 842-851
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Juergens CP, Semsarian C, Keech AC, Beller EM, Harris PJ. Hemorrhagic complications of intravenous heparin use. Am J Cardiol 1997; 80 (02) 150-154
    CrossrefPubMedGoogle Scholar
  • 44 Kortchinsky T, Vigué B, Samama CM. Reversal for heparins and new anticoagulant treatments [in French]. Ann Fr Anesth Reanim 2013; 32 (01) 37-49
    CrossrefPubMedGoogle Scholar
  • 45 Koster A, Börgermann J, Gummert J, Rudloff M, Zittermann A, Schirmer U. Protamine overdose and its impact on coagulation, bleeding, and transfusions after cardiopulmonary bypass: results of a randomized double-blind controlled pilot study. Clin Appl Thromb Hemost 2014; 20 (03) 290-295
    CrossrefPubMedGoogle Scholar
  • 46 Meesters MI, Veerhoek D, de Lange F. , et al. Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial. Thromb Haemost 2016; 116 (02) 251-261
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Crowther MA, Berry LR, Monagle PT, Chan AK. Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol 2002; 116 (01) 178-186
    CrossrefPubMedGoogle Scholar
  • 48 Schroeder M, Hogwood J, Gray E, Mulloy B, Hackett AM, Johansen KB. Protamine neutralisation of low molecular weight heparins and their oligosaccharide components. Anal Bioanal Chem 2011; 399 (02) 763-771
    CrossrefPubMedGoogle Scholar
  • 49 Desmurs-Clavel H, Huchon C, Chatard B, Negrier C, Dargaud Y. Reversal of the inhibitory effect of fondaparinux on thrombin generation by rFVIIa, aPCC and PCC. Thromb Res 2009; 123 (05) 796-798
    CrossrefPubMedGoogle Scholar
  • 50 Bijsterveld NR, Moons AH, Boekholdt SM. , et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106 (20) 2550-2554
    CrossrefPubMedGoogle Scholar
  • 51 Huvers F, Slappendel R, Benraad B, van Hellemondt G, van Kraaij M. Treatment of postoperative bleeding after fondaparinux with rFVIIa and tranexamic acid. Neth J Med 2005; 63 (05) 184-186
    PubMedGoogle Scholar
  • 52 Danaparoid Sodium. Eur Pharmacop 2006
    PubMed
  • 53 Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20 (03) 318-329
    CrossrefPubMedGoogle Scholar
  • 54 Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 2008; 99 (05) 830-839
    Article in Thieme ConnectPubMedGoogle Scholar
  • 55 Beyer JT, Lind SE, Fisher S. , et al. Evaluation of intravenous direct thrombin inhibitor monitoring tests: correlation with plasma concentrations and clinical outcomes in hospitalized patients. J Thromb Thrombol 2019; 49 (02) 259-267
    PubMedGoogle Scholar
  • 56 Sié P, Samama CM, Godier A. , et al; Working Group on Perioperative Haemostasis; French Study Group on Thrombosis and Haemostasis. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis. Arch Cardiovasc Dis 2011; 104 (12) 669-676
    CrossrefPubMedGoogle Scholar
  • 57 Douketis JD, Spyropoulos AC, Spencer FA. , et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e326S-e350S
    CrossrefPubMedGoogle Scholar
  • 58 Lincoff AM, Mehran R, Povsic TJ. , et al; REGULATE-PCI Investigators. Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial. Lancet 2016; 387 (10016): 349-356
    CrossrefPubMedGoogle Scholar
  • 59 Levy JH, Douketis J, Weitz JI. Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol 2018; 15 (05) 273-281
    CrossrefPubMedGoogle Scholar
  • 60 Lu G, DeGuzman FR, Hollenbach SJ. , et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19 (04) 446-451
    CrossrefPubMedGoogle Scholar
  • 61 Kuramatsu JB, Gerner ST, Schellinger PD. , et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 2015; 313 (08) 824-836
    CrossrefPubMedGoogle Scholar
  • 62 Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?. Thromb Haemost 2014; 111 (02) 189-198
    Article in Thieme ConnectPubMedGoogle Scholar
  • 63 Piran S, Khatib R, Schulman S. , et al. Management of direct factor Xa inhibitor-related major bleeding with prothrombin complex concentrate: a meta-analysis. Blood Adv 2019; 3 (02) 158-167
    CrossrefPubMedGoogle Scholar
  • 64 Grottke O, Levy JH. Prothrombin complex concentrates in trauma and perioperative bleeding. Anesthesiology 2015; 122 (04) 923-931
    CrossrefPubMedGoogle Scholar
  • 65 Katsanos AH, Schellinger PD, Köhrmann M. , et al. Fatal oral anticoagulant-related intracranial hemorrhage: a systematic review and meta-analysis. Eur J Neurol 2018; 25 (10) 1299-1302
    CrossrefPubMedGoogle Scholar
  • 66 Lai A, Davidson N, Galloway SW, Thachil J. Perioperative management of patients on new oral anticoagulants. Br J Surg 2014; 101 (07) 742-749
    CrossrefPubMedGoogle Scholar
  • 67 Li YG, Lip GYH. Anticoagulation resumption after intracerebral hemorrhage. Curr Atheroscler Rep 2018; 20 (07) 32-34
    CrossrefPubMedGoogle Scholar