1932

Abstract

The target-specific oral anticoagulants are a class of agents that inhibit factor Xa or thrombin. They are effective and safe compared to warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are comparable to low-molecular-weight heparin for thromboprophylaxis after hip or knee arthroplasty. For other indications, however, such as the prevention of stroke in patients with mechanical heart valves, initial studies have been unfavorable for the newer agents, leaving warfarin the anticoagulant of choice. Further studies are needed before the target-specific anticoagulants can be recommended for patients with cancer-associated thrombosis or heparin-induced thrombocytopenia. Concerns also persist about difficulties with the laboratory assessment of anticoagulant effect and the lack of a specific reversal agent. For these reasons, we anticipate that the vitamin K antagonists will continue to be important anticoagulants for years to come.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-051113-024633
2015-01-14
2024-10-06
Loading full text...

Full text loading...

/deliver/fulltext/med/66/1/annurev-med-051113-024633.html?itemId=/content/journals/10.1146/annurev-med-051113-024633&mimeType=html&fmt=ahah

Literature Cited

  1. Diener HC, Eikelboom J, Granger CB, Hacke W. 1.  2012. The king is dead (warfarin): direct thrombin and factor Xa inhibitors: the next Diadochian War?. Int. J. Stroke 7:139–41 [Google Scholar]
  2. Landefeld CS, Beyth RJ. 2.  1993. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am. J. Med. 95:315–28 [Google Scholar]
  3. Ageno W, Gallus AS, Wittkowsky A. 3.  et al. 2012. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141:e44S–88S [Google Scholar]
  4. Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. 4.  2008. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am. J. Hematol. 83:137–43 [Google Scholar]
  5. Yeh CH, Fredenburgh JC, Weitz JI. 5.  2012. Oral direct factor Xa inhibitors. Circ. Res. 111:1069–78 [Google Scholar]
  6. Nar H.6.  2012. The role of structural information in the discovery of direct thrombin and factor Xa inhibitors. Trends Pharmacol. Sci. 33:279–88 [Google Scholar]
  7. You JJ, Singer DE, Howard PA. 7.  et al. 2012. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141:e531S–75S [Google Scholar]
  8. Patel MR, Mahaffey KW, Garg J. 8.  et al. 2011. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365:883–91 [Google Scholar]
  9. Granger CB, Alexander JH, McMurray JJ. 9.  et al. 2011. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365:981–92 [Google Scholar]
  10. Giugliano RP, Ruff CT, Braunwald E. 10.  et al. 2013. Edoxaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 369:2093–104 [Google Scholar]
  11. Connolly SJ, Ezekowitz MD, Yusuf S. 11.  et al. 2009. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361:1139–51 [Google Scholar]
  12. Wallentin L, Yusuf S, Ezekowitz MD. 12.  et al. 2010. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 376:975–83 [Google Scholar]
  13. January CT, Wann LS, Alpert JS. 13.  et al. 2014. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J. Am. Coll. Cardiol. 64e1–76 [Google Scholar]
  14. Falck-Ytter Y, Francis CW, Johanson NA. 14.  et al. 2012. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141:e278S–325S [Google Scholar]
  15. Eriksson BI, Dahl OE, Huo MH. 15.  et al. 2011. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb. Haemost. 105:721–29 [Google Scholar]
  16. Turpie AG, Lassen MR, Eriksson BI. 16.  et al. 2011. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb. Haemost. 105:444–53 [Google Scholar]
  17. Lassen MR, Gallus A, Raskob GE. 17.  et al. 2010. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N. Engl. J. Med. 363:2487–98 [Google Scholar]
  18. Lassen MR, Raskob GE, Gallus A. 18.  et al. 2010. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 375:807–15 [Google Scholar]
  19. Raskob G, Cohen AT, Eriksson BI. 19.  et al. 2010. Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study. Thromb. Haemost. 104:642–49 [Google Scholar]
  20. Goldhaber SZ, Leizorovicz A, Kakkar AK. 20.  et al. 2011. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N. Engl. J. Med. 365:2167–77 [Google Scholar]
  21. Cohen AT, Spiro TE, Buller HR. 21.  et al. 2013. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N. Engl. J. Med. 368:513–23 [Google Scholar]
  22. Bauersachs R, Berkowitz SD, Brenner B. 22.  et al. 2010. Oral rivaroxaban for symptomatic venous thromboembolism. N. Engl. J. Med. 363:2499–510 [Google Scholar]
  23. Buller HR, Prins MH, Lensin AW. 23.  et al. 2012. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N. Engl. J. Med. 366:1287–97 [Google Scholar]
  24. Schulman S, Kearon C, Kakkar AK. 24.  et al. 2009. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N. Engl. J. Med. 361:2342–52 [Google Scholar]
  25. Agnelli G, Buller HR, Cohen A. 25.  et al. 2013. Oral apixaban for the treatment of acute venous thromboembolism. N. Engl. J. Med. 369:799–808 [Google Scholar]
  26. Buller HR, Decousus H, Grosso MA. 26.  et al. 2013. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N. Engl. J. Med. 369:1406–15 [Google Scholar]
  27. Kearon C, Akl EA, Comerota AJ. 27.  et al. 2012. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141:e419S–94S [Google Scholar]
  28. Schulman S, Kearon C, Kakkar AK. 28.  et al. 2013. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N. Engl. J. Med. 368:709–18 [Google Scholar]
  29. Agnelli G, Buller HR, Cohen A. 29.  et al. 2013. Apixaban for extended treatment of venous thromboembolism. N. Engl. J. Med. 368:699–708 [Google Scholar]
  30. Mehta SR, Granger CB, Eikelboom JW. 30.  et al. 2007. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J. Am. Coll. Cardiol. 50:1742–51 [Google Scholar]
  31. Olson ST, Swanson R, Raub-Segall E. 31.  et al. 2004. Accelerating ability of synthetic oligosaccharides on antithrombin inhibition of proteinases of the clotting and fibrinolytic systems: comparison with heparin and low-molecular-weight heparin. Thromb. Haemost. 92:929–39 [Google Scholar]
  32. Yau JW, Stafford AR, Liao P. 32.  et al. 2011. Mechanism of catheter thrombosis: comparison of the antithrombotic activities of fondaparinux, enoxaparin, and heparin in vitro and in vivo. Blood 118:6667–74 [Google Scholar]
  33. Cannegieter SC, Rosendaal FR, Briet E. 33.  1994. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 89:635–41 [Google Scholar]
  34. Eikelboom JW, Connolly SJ, Brueckmann M. 34.  et al. 2013. Dabigatran versus warfarin in patients with mechanical heart valves. N. Engl. J. Med. 369:1206–14 [Google Scholar]
  35. Hylek EM.35.  2013. Dabigatran and mechanical heart valves—not as easy as we hoped. N. Engl. J. Med. 369:1264–66 [Google Scholar]
  36. Lee AYY, Peterson EA. 36.  2013. Treatment of cancer-associated thrombosis. Blood 122:2310–17 [Google Scholar]
  37. Carrier M, Khorana AA, Zwicker J. 37.  et al. 2013. Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J. Thromb. Haemost. 11:1760–65 [Google Scholar]
  38. Levine MN, Gu C, Liebman HA. 38.  et al. 2012. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J. Thromb. Haemost. 10:807–14 [Google Scholar]
  39. Malik Q, Crevecoeur LR. 39.  2013. Use of novel oral anticoagulants for treatment of venous thromboembolism (VTE) in patients with malignancy: meta-analysis of randomized controlled trials. Blood 122:1150 (Abstr.) [Google Scholar]
  40. Lyman GH, Khorana AA, Kuderer NM. 40.  et al. 2013. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J. Clin. Oncol. 31:2189–204 [Google Scholar]
  41. Farge D, Debourdeau P, Beckers M. 41.  et al. 2013. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J. Thromb. Haemost. 11:56–70 [Google Scholar]
  42. Linkins L-A, Dans AL, Moores LK. 42.  et al. 2012. Treatment and prevention of heparin-induced thrombocytopenia: treatment of HIT: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141:e495S–e530S [Google Scholar]
  43. Krauel K, Hackbarth C, Fürll B, Greinacher A. 43.  2012. Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies. Blood 119:1248–55 [Google Scholar]
  44. Hirsh J, Heddle N, Kelton JG. 44.  2004. Treatment of heparin-induced thrombocytopenia: a critical review. Arch. Int. Med. 164:361–69 [Google Scholar]
  45. Sardar P, Chatterjee S, Herzog E. 45.  et al. 2014. Novel oral anticoagulants in patients with renal insufficiency: a meta-analysis of randomized trials. Can. J. Cardiol. 30888–97 [Google Scholar]
  46. Kedar R, Melamed N, Matlow J. 46.  et al. 2013. The transfer of dabigatran and rivaroxaban across a dually perfused isolated human placental cotyledon—implications for therapy in pregnancy. Blood 122:1142 (Abstr.) [Google Scholar]
  47. 47. Rivaroxaban [package insert] Titusville, NJ: Janssen Pharmaceuticals 2014.
  48. 48. Dabigatran [package insert] Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2014.
  49. 49. Apixaban [package insert] Princeton, NJ: Bristol-Myers Squibb; 2014.
  50. Graff J, Harder S. 50.  2013. Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment. Clin. Pharmacokinet. 52:243–54 [Google Scholar]
  51. Martinelli I, Bucciarelli P, Artoni A. 51.  et al. 2013. Anticoagulant treatment with rivaroxaban in severe protein S deficiency. Pediatrics 132:e1435–39 [Google Scholar]
  52. van Ryn J, Stangier J, Haertter S. 52.  et al. 2010. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb. Haemost. 103:1116–27 [Google Scholar]
  53. Asmis LM, Alberio L, Angelillo-Scherrer A. 53.  et al. 2012. Rivaroxaban: quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb. Res. 129:492–98 [Google Scholar]
  54. Douxfils J, Chatelain C, Chatelain B. 54.  et al. 2013. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb. Haemost. 110:283–94 [Google Scholar]
  55. Reilly PA, Lehr T, Haertter S. 55.  et al. 2014. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J. Am. Coll. Cardiol. 63:321–28 [Google Scholar]
  56. Siegal DM, Garcia DA, Crowther MA. 56.  2014. How I treat target-specific oral anticoagulant-associated bleeding. Blood 123:1152–58 [Google Scholar]
  57. Dickneite G, Hoffman M. 57.  2014. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): What is the evidence?. Thromb. Haemost. 111:189–98 [Google Scholar]
  58. Dager WE, Gosselin RC, Roberts AJ. 58.  2013. Reversing dabigatran in life-threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit. Care Med. 41:e42–e46 [Google Scholar]
  59. Maurice-Szamburski A, Graillon T, Bruder N. 59.  2014. Favorable outcome after a subdural hematoma treated with Feiba in a 77-year-old patient treated by rivaroxaban. J. Neurosurg. Anesthesiol. 26:183 [Google Scholar]
  60. Harinstein LM, Morgan JW, Russo N. 60.  2013. Treatment of dabigatran-associated bleeding: case report and review of the literature. J. Pharm. Pract. 26:264–69 [Google Scholar]
  61. Schiele F, van Ryn J, Canada K. 61.  et al. 2013. A specific antidote for dabigatran: functional and structural characterization. Blood 121:3554–62 [Google Scholar]
  62. van Ryn J, Litzenburger T, Gan G. 62.  et al. 2013. Evaluation of a specific antidote to dabigatran: in vitro properties, pharmacokinetics and reversal of dabigatran etexilate-induced bleeding in rats. J. Am. Coll. Cardiol. 61:E1825 (Abstr.) [Google Scholar]
  63. Lu G, DeGuzman FR, Hollenbach SJ. 63.  et al. 2013. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat. Med. 19:446–51 [Google Scholar]
  64. Vandana M, Michael K, Genmin L. 64.  et al. 2013. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (prt064445), an antidote for FXa inhibitors. Blood 122:3636 (Abstr.) [Google Scholar]
  65. Harrington AR, Armstrong EP, Nolan PE, Malone DC. 65.  2013. Cost-effectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation. Stroke 44:1676–81 [Google Scholar]
  66. Kasmeridis C, Apostolakis S, Ehlers L. 66.  et al. 2013. Cost effectiveness of treatments for stroke prevention in atrial fibrillation: focus on the novel oral anticoagulants. Pharmacoeconomics 31:971–80 [Google Scholar]
  67. Coyle D, Coyle K, Cameron C. 67.  et al. 2013. Cost-effectiveness of new oral anticoagulants compared with warfarin in preventing stroke and other cardiovascular events in patients with atrial fibrillation. Value Health 16:498–506 [Google Scholar]
  68. Bauer KA.68.  2013. Pros and cons of new oral anticoagulants. Hematol. Am. Soc. Hematol. Educ. Program 2013:464–70 [Google Scholar]
/content/journals/10.1146/annurev-med-051113-024633
Loading
/content/journals/10.1146/annurev-med-051113-024633
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error