Non-vitamin K antagonist oral anticoagulants (NOACs), are direct anticoagulants which inhibit specific coagulation factors and function as anticoagulants. Three NOACs are currently licensed in the United Kingdom: dabigatran, a thrombin inhibitor, and rivaroxaban and apixaban, antagonists of factor Xa. They are set to change the anticoagulant landscape, which was previously ruled by warfarin and heparins. Their advantages including oral formulations, rapid onset and offset of action, predictable pharmacokinetics, no requirement for routine blood monitoring or dose adjustment and very few drug interactions. The increasing use of these drugs means the acute medicine physicians are likely to encounter patients who have been taking them. This article reviews some of the challenging clinical situations in which this may arise.
Levy JH, Spyropoulos AC, Samama CM, et al. Direct Oral Anticoagulants: New Drugs and New Concepts. JACC Cardiovasc Interv. 2014; 7: 1333–1351.
Harder S, Graff J. Novel oral anticoagulants: clinical pharmacology, indications and practical considerations. Eur. J. Clin. Pharmacol.2013; 69: 1617–1633.
Alikhan R, Rayment R, Keeling D, et al. The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran. Emerg Med J. 2014; 31: 163–8.
Kitchen S, Gray E, Mackie I,et al. 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: 830–41.
Baglin T, Hillarp A, Tripodi A, et al. Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: A recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2013 Jan 24. doi: 10.1111/jth.12149. [Epub ahead of print].
Samama MM, Meddahi S, Samama CM. Pharmacology and laboratory testing of the oral Xa inhibitors. Clin Lab Med. 2014; 34: 503–17.
Lindhoff-Last E, Ansell J, Spiro T, et al. Laboratory testing of rivaroxaban in routine clinical practice: when, how, and which assays. Ann Med 2013; 45: 423–9.
Rodgers R, Bagot CN, Lawrence C, et al. Correlating prothrombin time with plasma rivaroxaban level. Br J Haematol. 2013; 163: 685–7.
Becker RC, Yang H, Barrett Y, et al. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban—an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis 2011; 32:183–187.
Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014; 64: 1128–39.
van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116–27.
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014; 383: 955–62.
Majeed A, Hwang HG, Connolly SJ, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128: 2325–32.
Piccini JP, Garg J, Patel MR, et al. ROCKET AF Investigators. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J. 2014; 35: 1873–80.
Garcia D. Target specific oral anticoagulants. Practical considerations. Haematology; 2014; 2014: 367–70.
Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol. 2013; 26:191–202.
Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094–106.
Lambourne MD, Eltringham-Smith LJ, Gataiance S, et al. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J Thromb Haemost 2012; 10: 1830–40.
Perzborn E, Gruber A, Tinel H, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost 2013; 110: 162–72.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: 1573–9.
Marlu R, Hodaj E, Paris A, et al. 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: 217–24.
Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554–62.
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: 446–51.
Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014; 371:2141–2.
Levine M, Goldstein JN. Bleeding complications of targeted oral anticoagulants: what is the risk? Hematology 2014; 2014:504–509.
Atrial Fibrillation: The management of atrial fibrillation. National Institute for Health and Care Excellence (NICE) 2014 www.nice.org.uk/guidance/CG180. Accessed 18th January 2015
Pernod G, Albaladejo P, Godier A, et al. Working Group on Perioperative Haemostasis. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factorXa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013. Arch Cardiovasc Dis. 2013; 106:382–93.
Epple C, Steiner T. Acute stroke in patients on new direct oral anticoagulants: how to manage, how to treat? Expert Opin Pharmacother. 2014; 15: 1991–2001.
Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: Stroke 2007; 38:1655–71.
Pfeilschifter W, Bohmann F, Baumgarten P, et al. Thrombolysis with recombinant tissue plasminogen activator under dabigatran anticoagulation in experimental stroke. Ann Neurol 2012; 71:624–33.
Ploen R, Sun L, Zhou W, et al. Rivaroxaban does not increase hemorrhage after thrombolysis in experimental ischemic stroke. J Cereb Blood Flow Metab 2014; 34: 495–501.
Non-vitamin K antagonist oral anticoagulants (NOACs), are direct anticoagulants which inhibit specific coagulation factors and function as anticoagulants. Three NOACs are currently licensed in the United Kingdom: dabigatran, a thrombin inhibitor, and rivaroxaban and apixaban, antagonists of factor Xa. They are set to change the anticoagulant landscape, which was previously ruled by warfarin and heparins. Their advantages including oral formulations, rapid onset and offset of action, predictable pharmacokinetics, no requirement for routine blood monitoring or dose adjustment and very few drug interactions. The increasing use of these drugs means the acute medicine physicians are likely to encounter patients who have been taking them. This article reviews some of the challenging clinical situations in which this may arise.
Levy JH, Spyropoulos AC, Samama CM, et al. Direct Oral Anticoagulants: New Drugs and New Concepts. JACC Cardiovasc Interv. 2014; 7: 1333–1351.
Harder S, Graff J. Novel oral anticoagulants: clinical pharmacology, indications and practical considerations. Eur. J. Clin. Pharmacol.2013; 69: 1617–1633.
Alikhan R, Rayment R, Keeling D, et al. The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran. Emerg Med J. 2014; 31: 163–8.
Kitchen S, Gray E, Mackie I,et al. 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: 830–41.
Baglin T, Hillarp A, Tripodi A, et al. Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: A recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2013 Jan 24. doi: 10.1111/jth.12149. [Epub ahead of print].
Samama MM, Meddahi S, Samama CM. Pharmacology and laboratory testing of the oral Xa inhibitors. Clin Lab Med. 2014; 34: 503–17.
Lindhoff-Last E, Ansell J, Spiro T, et al. Laboratory testing of rivaroxaban in routine clinical practice: when, how, and which assays. Ann Med 2013; 45: 423–9.
Rodgers R, Bagot CN, Lawrence C, et al. Correlating prothrombin time with plasma rivaroxaban level. Br J Haematol. 2013; 163: 685–7.
Becker RC, Yang H, Barrett Y, et al. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban—an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis 2011; 32:183–187.
Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014; 64: 1128–39.
van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116–27.
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014; 383: 955–62.
Majeed A, Hwang HG, Connolly SJ, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128: 2325–32.
Piccini JP, Garg J, Patel MR, et al. ROCKET AF Investigators. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J. 2014; 35: 1873–80.
Garcia D. Target specific oral anticoagulants. Practical considerations. Haematology; 2014; 2014: 367–70.
Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol. 2013; 26:191–202.
Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094–106.
Lambourne MD, Eltringham-Smith LJ, Gataiance S, et al. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J Thromb Haemost 2012; 10: 1830–40.
Perzborn E, Gruber A, Tinel H, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost 2013; 110: 162–72.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: 1573–9.
Marlu R, Hodaj E, Paris A, et al. 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: 217–24.
Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554–62.
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: 446–51.
Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014; 371:2141–2.
Levine M, Goldstein JN. Bleeding complications of targeted oral anticoagulants: what is the risk? Hematology 2014; 2014:504–509.
Atrial Fibrillation: The management of atrial fibrillation. National Institute for Health and Care Excellence (NICE) 2014 www.nice.org.uk/guidance/CG180. Accessed 18th January 2015
Pernod G, Albaladejo P, Godier A, et al. Working Group on Perioperative Haemostasis. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factorXa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) – March 2013. Arch Cardiovasc Dis. 2013; 106:382–93.
Epple C, Steiner T. Acute stroke in patients on new direct oral anticoagulants: how to manage, how to treat? Expert Opin Pharmacother. 2014; 15: 1991–2001.
Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: Stroke 2007; 38:1655–71.
Pfeilschifter W, Bohmann F, Baumgarten P, et al. Thrombolysis with recombinant tissue plasminogen activator under dabigatran anticoagulation in experimental stroke. Ann Neurol 2012; 71:624–33.
Ploen R, Sun L, Zhou W, et al. Rivaroxaban does not increase hemorrhage after thrombolysis in experimental ischemic stroke. J Cereb Blood Flow Metab 2014; 34: 495–501.
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Department of Emergency
Medicine
Musgrove Park Hospital
Taunton
Problem-Based Review: Non Vitamin K Antagonist Oral Anticoagulants for the Acute Physician
Cite this article as:
Thachil J, Gagg J. Problem-Based Review: Non Vitamin K Antagonist Oral Anticoagulants for the Acute Physician. Acute Med. 2015;14(2):83-9. PMID: 26305087.
Problem-Based Review: Non Vitamin K Antagonist Oral Anticoagulants for the Acute Physician
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