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Review of Direct Oral Anticoagulants and Guide for Effective Drug Utilization

  • Tigran KhachatryanEmail author
  • Christopher Hauschild
  • Jason Hoff
  • Tahmeed Contractor
  • Arthur Khachatryan
  • Huyentran Tran
  • Bert Matsuo
  • Alan Jacobson
  • Anthony Hilliard
Review Article

Abstract

Direct oral anticoagulants (DOACs) have been developed as a viable and in some cases superior alternative to warfarin. These agents have overcome some of the limitations of warfarin, which has a narrow therapeutic window and many food and drug interactions. DOACs have been demonstrated to have a more predictable and reliable pharmacology and, unlike warfarin, do not require frequent monitoring of anticoagulant effect. For these reasons, the use of DOACs is increasing. Despite the many positive attributes of these agents, limitations and contraindications do exist. An understanding of the pharmacology, indications, and contraindications is therefore crucial for effective patient management. We review the available agents to aid in effective drug utilization.

Notes

Compliance with Ethical Standards

Conflict of interest

TK, CH, JH, TC, AK, HT, BM, AJ, and AH have no conflicts of interest that are relevant to the content of this review.

Funding

No sources of funding were used to assist with the preparation of this review.

References

  1. 1.
    Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.Google Scholar
  2. 2.
    Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92.Google Scholar
  3. 3.
    Gibson CM, Halaby R, Korjian S, et al. The safety and efficacy of full- versus reduced-dose betrixaban in the acute medically ill VTE (venous thromboembolism) prevention with extended-duration betrixaban (APEX) trial. Am Heart J. 2017;185:93–100.Google Scholar
  4. 4.
    Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104.Google Scholar
  5. 5.
    Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.Google Scholar
  6. 6.
    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 randomized trials. Lancet. 2014;383(9921):955–62.Google Scholar
  7. 7.
    Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893–962.Google Scholar
  8. 8.
    January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol. 2019.  https://doi.org/10.1016/j.jacc.2019.01.011.Google Scholar
  9. 9.
    Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315–52.Google Scholar
  10. 10.
    Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300–5.Google Scholar
  11. 11.
    Baetz BE, Spinler SA. Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. Pharmacotherapy. 2008;28(11):1354–73.Google Scholar
  12. 12.
    Spinler Sarah. The pharmacology and therapeutic use of dabigatran etexilate. J Clin Pharmacol. 2013;53(1):1–13.Google Scholar
  13. 13.
    Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303.Google Scholar
  14. 14.
    Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2017.Google Scholar
  15. 15.
    Vazquez Sara. Drug–drug interactions in an ear of multiple anticoagulants: a focus on clinically relevant drug interactions. Blood. 2018;132(21):2230–9.Google Scholar
  16. 16.
    “Dabigatran Drug Interaction Potential”. University of Washington. 2014. http://www.depts.washington.edu/anticoag/home/content/dabigatran-drug-interaction-potential. Accessed 9 Feb 2019.
  17. 17.
    Todd Crump “Straight Healthcare”. http://www.straighthealthcare.com. Accessed 10 Feb 2019.
  18. 18.
    Gosselin RC, Adcock DM. The laboratory’s 2015 perspective on direct oral anticoagulant testing. J Thromb Haemost. 2016;14(5):886–93.Google Scholar
  19. 19.
    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(2):209–19.Google Scholar
  20. 20.
    Julia S, James U. Direct oral anticoagulants: a quick guide. Eur Cardiol Rev. 2017;12(1):40–5.Google Scholar
  21. 21.
    Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on expert consensus decision pathways. J Am Coll Cardiol. 2017;70(24):3042–67.Google Scholar
  22. 22.
    Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330–93.Google Scholar
  23. 23.
    Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033–69.Google Scholar
  24. 24.
    “Summery of Product Characteristics”. European Medicines Agency, European Union agencies network. 2018. http://www.ema.europa.eu/en/medicines/human/EPAR/pradaxa#product-information-section%20pr. Accessed 9 Feb 2019.
  25. 25.
    Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–52.Google Scholar
  26. 26.
    Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709–18.Google Scholar
  27. 27.
    Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370(9591):949–56.Google Scholar
  28. 28.
    Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206–14.Google Scholar
  29. 29.
    Fauchier L, Philippart R, Clementy N, et al. How to define valvular atrial fibrillation? Arch Cardiovasc Dis. 2015;108(10):530–9.Google Scholar
  30. 30.
    Di Biase L. Use of direct oral anticoagulants in patients with atrial fibrillation and valvular heart lesions. J Am Heart Assoc. 2016;5(2):e002776.Google Scholar
  31. 31.
    Beasley BN, Unger EF, Temple R. Anticoagulant options—why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med. 2011;364(19):1788–90.Google Scholar
  32. 32.
    Moore TJ, Cohen MR, Mattison DR. Dabigatran, bleeding, and the regulators. BMJ. 2014;23(349):g4517.Google Scholar
  33. 33.
    Safouris A, Triantafyllou N, Parissis J, Tsivgoulis G. The case for dosing dabigatran: how tailoring dose to patient renal function, weight and age could improve the benefit–risk ratio. Ther Adv Neurol Disord. 2015;8(6):245–54.Google Scholar
  34. 34.
    January CT, Wann LS, Alpert JS, et al. 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. 2014;64(21):e1–76.Google Scholar
  35. 35.
    Schulman S, Carrier M, Lee AY, et al. Perioperative management of dabigatran a prospective cohort study. Circulation. 2015;132(3):167–73.Google Scholar
  36. 36.
    Healey JS, Eikelboom J, Douketis J, et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial. Circulation. 2012;126(3):343–8.Google Scholar
  37. 37.
    Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol. 2017;69(7):871–98.Google Scholar
  38. 38.
    Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med. 2017;377(5):431–41.Google Scholar
  39. 39.
    Stacy ZA, Call WB, Hartmann AP, Peters GL, Richter SK. Edoxaban: a comprehensive review of the pharmacology and clinical data for the management of atrial fibrillation and venous thromboembolism. Cardiol Ther. 2016;5(1):1–18.Google Scholar
  40. 40.
    Andexxa (andexant alfa) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals Inc; 2018.Google Scholar
  41. 41.
    Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with Factor Xa inhibitors. N Engl J Med. 2016;375(12):1131–41.Google Scholar
  42. 42.
    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):2413–24.Google Scholar
  43. 43.
    Connors JM. Antidote for Factor Xa anticoagulants. N Engl J Med. 2015;373(25):2471–2.Google Scholar
  44. 44.
    Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37(1):74–81.Google Scholar
  45. 45.
    Frost C, Wang J, Nepal S, et al. Apixaban, an oral, direct Factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol. 2013;75(2):476–87.Google Scholar
  46. 46.
    “Apixaban Drug Interaction Potential”. University of Washington. 2014. http://www.depts.washington.edu/anticoag/home/content/apixaban-drug-interaction-potential. Accessed 10 Feb 2019.
  47. 47.
    Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2017.Google Scholar
  48. 48.
    Cabral KP. Pharmacology of the new target-specific oral anticoagulants. J Thromb Thrombolysis. 2013;36(2):133–40.Google Scholar
  49. 49.
    Martin A, Stewart R. Safety and efficacy of apixaban in the treatment of atrial fibrillation. Clin Med Insights Cardiol. 2012;6:103–9.Google Scholar
  50. 50.
    Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.Google Scholar
  51. 51.
    Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699–708.Google Scholar
  52. 52.
    Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375(9717):807–15.Google Scholar
  53. 53.
    Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487–98.Google Scholar
  54. 54.
    Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–17.Google Scholar
  55. 55.
    Avezum A, Lopes RD, Schulte PJ, et al. Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the ARISTOTLE trial. Circulation. 2015;132(8):624–32.Google Scholar
  56. 56.
    Lassen MR, Davidson BL, Gallus A, et al. The efficacy and safety of apixaban, an oral, direct Factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost. 2007;5(12):2368–75.Google Scholar
  57. 57.
    Frost C, Nepal S, Wang J, et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a Factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013;76(5):776–86.Google Scholar
  58. 58.
    Stanton BE, Barasch NS, Tellor KB. Comparison of the safety and effectiveness of apixaban versus warfarin in patients with severe renal impairment. Pharmacotherapy. 2017;37(4):412–9.Google Scholar
  59. 59.
    Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc; 2019.Google Scholar
  60. 60.
    Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412–21.Google Scholar
  61. 61.
    EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–510.Google Scholar
  62. 62.
    EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287–97.Google Scholar
  63. 63.
    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.Google Scholar
  64. 64.
    Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765–75.Google Scholar
  65. 65.
    Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31–9.Google Scholar
  66. 66.
    Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776–86.Google Scholar
  67. 67.
    Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319–30.Google Scholar
  68. 68.
    Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation. 2006;114(22):2374–81.Google Scholar
  69. 69.
    Savaysa (edoxaban) [prescribing information]. Parsippany, NJ: Daiichi Sankyo; 2016.Google Scholar
  70. 70.
    Lip GY, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J. 2014;35(28):1844–55.Google Scholar
  71. 71.
    Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15.Google Scholar
  72. 72.
    Carnicelli AP, De Caterina R, Halperin JL, et al. Edoxaban for the prevention of thromboembolism in patients with atrial fibrillation and bioprosthetic valves. Circulation. 2017;135(13):1273–5.Google Scholar
  73. 73.
    Bohula EA, Giugliano RP, Ruff CT, et al. Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial. Circulation. 2016;134(1):24–36.Google Scholar
  74. 74.
    Weitz JI, Connolly SJ, Patel I, et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral Factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost. 2010;104(3):633–41.Google Scholar
  75. 75.
    Bevyxxa (betrixaban) [prescribing information]. South San Francisco, CA: Portola Pharmaceuticals Inc; 2017.Google Scholar
  76. 76.
    Chan NC, Bhagirath V, Eikelboom JW. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015;11:343–51.Google Scholar
  77. 77.
    Turpie AG, Bauer KA, Davidson BL, et al. A randomized evaluation of betrixaban, an oral Factor Xa inhibitor, for prevention of thromboembolic events after total knee. Thromb Haemost. 2009;101(1):68–76.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Tigran Khachatryan
    • 1
    Email author
  • Christopher Hauschild
    • 1
  • Jason Hoff
    • 1
  • Tahmeed Contractor
    • 1
  • Arthur Khachatryan
    • 2
  • Huyentran Tran
    • 1
  • Bert Matsuo
    • 1
  • Alan Jacobson
    • 3
  • Anthony Hilliard
    • 1
  1. 1.International Heart InstituteLoma Linda University Medical CenterLoma LindaUSA
  2. 2.Reno School of MedicineUniversity of NevadaRenoUSA
  3. 3.Department of CardiologyVA Loma Linda Health Care SystemsLoma LindaUSA

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