Transitioning Between Anticoagulants

Chapter

Abstract

There has been rapid growth in the development of anticoagulant drugs. Unfortunately, an “ideal” anticoagulant—one that is rapid-acting and fully reversible, does not require monitoring, and can be used in patients with end-stage renal disease and moderate-severe liver dysfunction—is not available to date. Currently, the differences in the pharmacokinetic and pharmacodynamic properties of each agent allow for a unique, individualized anticoagulation plan for different patients with different underlying indications for anticoagulation therapy. Because of the multiple options for both parenteral and oral anticoagulation available, transitioning between anticoagulants is becoming increasingly common both in the inpatient and outpatient settings. Given the absence of prospective randomized data comparing different strategies for transition between anticoagulants, suggested strategies are largely extrapolated from pharmacokinetic data, as well as from expert opinions. Despite limited data, better understanding on how to safely implement a transition from one anticoagulant drug to another is of utmost importance to minimize the risk of recurrent thromboembolic events and hemorrhagic complications during such periods of transition between different drugs.

Keywords

Transition therapy Anticoagulation bridging Anticoagulation therapy Pharmacology Direct oral anticoagulants Vitamin K antagonists Warfarin Heparin Low-molecular-weight heparins Fondaparinux Apixaban Edoxaban Rivaroxaban Dabigatran Direct thrombin inhibitors Argatroban Bivalirudin Hirudins 

References

  1. 1.
    Hirsh J, Raschke R. Heparin and low-molecular-weight heparin. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:188S–203S.CrossRefGoogle Scholar
  2. 2.
    Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins: a meta-analysis. Arch Intern Med. 1995;155:601–7.CrossRefGoogle Scholar
  3. 3.
    Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med. 1996;100:269–77.CrossRefGoogle Scholar
  4. 4.
    Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334:677–81.CrossRefGoogle Scholar
  5. 5.
    Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasma Study Group. N Engl J Med. 1996;334:682–7.CrossRefGoogle Scholar
  6. 6.
    Weitz JI, Hirsh J, Samama MM. New anticoagulant drugs. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:265S–86S.CrossRefGoogle Scholar
  7. 7.
    Buller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140:867–73.CrossRefGoogle Scholar
  8. 8.
    The MATISSE Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349:1695–702.CrossRefGoogle Scholar
  9. 9.
    Harenberg J. Development of idraparinux and idrabiotaparinux for anticoagulant therapy. Thromb Haemost. 2009;102:811–5.CrossRefGoogle Scholar
  10. 10.
    Büller HR, Gallus AS, Zpillion G, et al. Enoxaparin followed by once-weekly idrabiotaparinux versus enoxaparin plus warfarin for patients with acute symptomatic pulmonary embolism: a randomised, double-blind, double-dummy, non-inferiority trial. Lancet. 2012;379:123–9.CrossRefGoogle Scholar
  11. 11.
    The EQUINOX Investigators. Efficacy and safety of once weekly idrabiotaparinux in the treatment of patient with symptomatic deep venous thrombosis. J Thromb Haemost. 2011;9:92–9.CrossRefGoogle Scholar
  12. 12.
    Hirsh J, Heddle N, Kelton JG. Treatment of heparin-induced thrombocytopenia: a critical review. Arch Intern Med. 2004;164:361–9.CrossRefGoogle Scholar
  13. 13.
    Joseph L, Casanegra AI, Dhariwal M, et al. Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia. J Thromb Haemost. 2014;12:1044–55.CrossRefGoogle Scholar
  14. 14.
    Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.CrossRefGoogle Scholar
  15. 15.
    Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.CrossRefGoogle Scholar
  16. 16.
    Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.CrossRefGoogle Scholar
  17. 17.
    Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–104.CrossRefGoogle Scholar
  18. 18.
    Schulman S, Kearon K, Kakkar AJ, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–52.CrossRefGoogle Scholar
  19. 19.
    The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–510.CrossRefGoogle Scholar
  20. 20.
    The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–97.CrossRefGoogle Scholar
  21. 21.
    Agnelli G, Büller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699–708.CrossRefGoogle Scholar
  22. 22.
    Agnelli G, Büller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799–808.CrossRefGoogle Scholar
  23. 23.
    The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–15.CrossRefGoogle Scholar
  24. 24.
    Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017;376(13):1211–22.  https://doi.org/10.1056/NEJMoa1700518.CrossRefPubMedGoogle Scholar
  25. 25.
    Weitz JI, Eikelboom JW, Samama MM. New antithrombotic drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e120S–51S.CrossRefGoogle Scholar
  26. 26.
    Abildgaard U. Highly purified antithrombin III with heparin cofactor activity prepared by disc electrophoresis. Scand J Clin Lab Invest. 1968;21:89–91.CrossRefGoogle Scholar
  27. 27.
    Rosenberg R, Lam L. Correlation between structure and function of heparin. Proc Natl Acad Sci U S A. 1979;76:1218–22.CrossRefGoogle Scholar
  28. 28.
    Lindahl U, Backstrom G, Hook M, et al. Structure of the antithrombin-binding site of heparin. Proc Natl Acad Sci U S A. 1979;76:3198–202.CrossRefGoogle Scholar
  29. 29.
    Rosenberg R, Bauer K. The heparin-antithrombin system: a natural anticoagulant mechanism. 3rd ed. Philadelphia, PA: Lippincott; 1994.Google Scholar
  30. 30.
    Casu B, Oreste P, Torri G, et al. The structure of heparin oligosaccharide fragments with high anti-(factor Xa) activity containing the minimal antithrombin III-binding sequence. Biochem J. 1981;97:599–609.CrossRefGoogle Scholar
  31. 31.
    Choay J, Lormeau J, Petitou M, et al. Structural studies on a biologically active hexasaccharide obtained from heparin. Ann N Y Acad Sci. 1981;370:644–9.CrossRefGoogle Scholar
  32. 32.
    Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (6th Edition). Chest. 2001;119:64S–94S.CrossRefGoogle Scholar
  33. 33.
    Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(Suppl):e24S–43S.CrossRefGoogle Scholar
  34. 34.
    Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncologia. 2013;31:2189–204.CrossRefGoogle Scholar
  35. 35.
    Carrier M, Cameron C, Delluc A, et al. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res. 2014;134:1214–9.CrossRefGoogle Scholar
  36. 36.
    Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: chest guideline and expert panel report. Chest. 2016;149:315–52.CrossRefGoogle Scholar
  37. 37.
    Choay J, Petitou M, Lormeau JC, et al. Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem Biophys Res Commun. 1983;116:492–9.CrossRefGoogle Scholar
  38. 38.
    Thunberg L, Bäckström G, Lindahl U. Further characterization of the antithrombin-binding sequence in heparin. Carbohydr Res. 1982;100:393–410.CrossRefGoogle Scholar
  39. 39.
    Choay J. Biologic studies on chemically synthesized pentasaccharide and tetrasaccharide fragments. Semin Thromb Hemost. 1985;11:81–5.CrossRefGoogle Scholar
  40. 40.
    Toschi V, Lettino M, Gallo R, et al. Biochemistry and biology of hirudin. Coron Artery Dis. 1996;7:420–8.CrossRefGoogle Scholar
  41. 41.
    Wallis RB. Hirudins: from leeches to man. Semin Thromb Hemost. 1996;22:185–96.CrossRefGoogle Scholar
  42. 42.
    Fox I, Dawson A, Loynds P, et al. Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans. Thromb Haemost. 1993;69:157–63.PubMedGoogle Scholar
  43. 43.
    Robson R. The use of bivalirudin in patients with renal impairment. J Invasive Cardiol. 2000;12(Suppl F):33F–6F.PubMedGoogle Scholar
  44. 44.
    Hursting MJ, Alford KL, Becker JC, et al. Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor. Semin Thromb Hemost. 1997;23:503–16.CrossRefGoogle Scholar
  45. 45.
    Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy. 2000;20:318–29.CrossRefGoogle Scholar
  46. 46.
    Stenflo J, Fernlund P, Egan W, Roepstorff P. Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U S A. 1974;71:2730–3.CrossRefGoogle Scholar
  47. 47.
    Nelsestuen GL, Zytkovicz TH, Howard JB. The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin. J Biol Chem. 1974;249:6347–50.PubMedGoogle Scholar
  48. 48.
    Whitlon DS, Sadowski JA, Suttie JW. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry. 1978;17:1371–7.CrossRefGoogle Scholar
  49. 49.
    Friedman PA, Rosenberg RD, Hauschka PV, Fitz-James A. A spectrum of partially carboxylated prothrombins in the plasmas of coumarin-treated patients. Biochim Biophys Acta. 1977;494:271–6.CrossRefGoogle Scholar
  50. 50.
    Malhotra OP, Nesheim ME, Mann KG. The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins. J Biol Chem. 1985;260:279–87.PubMedGoogle Scholar
  51. 51.
    Choonara IA, Malia RG, Haynes BP, et al. The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin. Br J Clin Pharmacol. 1988;25:1–7.CrossRefGoogle Scholar
  52. 52.
    Wessler S, Gitel SN. Warfarin. From bedside to bench. N Engl J Med. 1984;311:645–52.CrossRefGoogle Scholar
  53. 53.
    Zivelin A, Rao LV, Rapaport SI. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors. J Clin Invest. 1993;92:2131–40.CrossRefGoogle Scholar
  54. 54.
    Breckenridge AM. Oral anticoagulant drugs: pharmacokinetic aspects. Semin Hematol. 1978;15:19–26.PubMedGoogle Scholar
  55. 55.
    Kelly JG, O’Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet. 1979;4:1–15.CrossRefGoogle Scholar
  56. 56.
    Nutescu EA, Chuatrisom I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011;31:326–43.CrossRefGoogle Scholar
  57. 57.
    Nutescu EA, Shapiro NL, Chevalier A. New anticoagulant agents: direct thrombin inhibitors. Cardiol Clin. 2008;26:169–87. v–vi.CrossRefGoogle Scholar
  58. 58.
    Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64:292–303.CrossRefGoogle Scholar
  59. 59.
    Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(Suppl):e44S–88S.CrossRefGoogle Scholar
  60. 60.
    Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47:285–95.CrossRefGoogle Scholar
  61. 61.
    Stangier J, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49:259–68.CrossRefGoogle Scholar
  62. 62.
    Jiang X, Crain EJ, Luettgen JM, et al. Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost. 2009;101:780–2.PubMedGoogle Scholar
  63. 63.
    Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37:74–81.CrossRefGoogle Scholar
  64. 64.
    Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61:873–80.CrossRefGoogle Scholar
  65. 65.
    Mueck W, Becka M, Kubitza D, et al. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor—in healthy subjects. Int J Clin Pharmacol Ther. 2007;45:335–44.CrossRefGoogle Scholar
  66. 66.
    Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50:743–53.CrossRefGoogle Scholar
  67. 67.
    Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010;376:975–83.CrossRefGoogle Scholar
  68. 68.
    Warkentin TE, Greinacher A, Craven S, et al. Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation. Thromb Haemost. 2005;94:958–64.PubMedGoogle Scholar
  69. 69.
    Bartholomew JR, Hursting MJ. Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: an analysis of outcomes in patients with elevated international normalized ratio (INR). J Thromb Thrombolysis. 2005;19:183–8.CrossRefGoogle Scholar
  70. 70.
    Argatroban. Highlights of prescribing information. Revised 05/2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022485s009lbl.pdf.
  71. 71.
    Watson H, Davidson S, Keeling D. Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol. 2012;159:528–40.PubMedGoogle Scholar
  72. 72.
    Arpino PA, Demirjian Z, Van Cott EM. Use of the chromogenic factor X assay to predict the international normalized ratio in patients transitioning from argatroban to warfarin. Pharmacotherapy. 2005;25:157–64.CrossRefGoogle Scholar
  73. 73.
    Bartholomew J. Transition to an oral anticoagulant in patients with heparin-induced thrombocytopenia. Chest. 2005;127:27S–34S.CrossRefGoogle Scholar
  74. 74.
    Hursting MJ, Lewis BE, Macfarlane DE. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost. 2005;11:279–87.CrossRefGoogle Scholar
  75. 75.
    Kinkins L-A, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(Suppl):e495S–530S.CrossRefGoogle Scholar
  76. 76.
    Pradaxa. Highlights of prescribing information. Revised 11/2015. http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf.
  77. 77.
    Eliquis. Highlights of prescribing information. Revised 07/2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202155s012lbl.pdf.
  78. 78.
    Xarelto. Highlights of prescribing information. Revised 05/2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202439s017lbl.pdf.
  79. 79.
    Savaysa. Highlights of prescribing information. Revised 09/2016. https://hemonc.org/w/images/9/96/Edoxaban.pdf.
  80. 80.
    Shatzel JJ, Crapster-Pregont M, Seloughery TG. Non-vitamin K antagonist oral anticoagulants for heparin-induced thrombocytopenia. A systematic review of 54 reported cases. Thromb Haemost. 2016;116:397–400.CrossRefGoogle Scholar
  81. 81.
    Baruch L, Sherman O. Potential inaccuracy of point-of-care INR in dabigatran-treated patients. Ann Pharmacother. 2011;45(7–8):e40.PubMedGoogle Scholar
  82. 82.
    Samama MM, Martinoli JL, LeFlem L, et al. Assessment of laboratory assays to measure rivaroxaban: an oral, direct factor Xa inhibitor. Thromb Haemost. 2010;103:815–25.CrossRefGoogle Scholar
  83. 83.
    Moore KT, Byra W, Vaidyanathan S, et al. Switching from rivaroxaban to warfarin: an open-label pharmacodynamic study in healthy subjects. Br J Clin Pharmacol. 2014;79:907–17.CrossRefGoogle Scholar
  84. 84.
    Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015;17:1467–507.CrossRefGoogle Scholar
  85. 85.
    Ruff CT, Giugliano RP, Braunwald E, Mercuri M, Curt V, Betcher J, et al. Transition of patients from blinded study drug to open-label anticoagulation: the ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol. 2014;64:576–84.CrossRefGoogle Scholar
  86. 86.
    Granger C, Alexander JH, Hanna M, Wang J, Mohan P, Lawrence J, et al. Events after discontinuation of randomized treatment at the end of the ARISTOTLE trial. Eur Heart J. 2012;33(Suppl):685–6. (Abstract).Google Scholar
  87. 87.
    Granger CB, Lopes RD, Hanna M, Ansell J, Hylek EM, Alexander JH, et al. Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Am Heart J. 2015;169:25–30.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Cardiovascular Medicine, Section of Vascular MedicineCleveland ClinicClevelandUSA

Personalised recommendations