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Anticoagulation in Venous Thromboembolism Prophylaxis in Medically Ill Patients: Potential Impact of NOACs

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Abstract

While substantial evidence supports the use of standard-duration injectable anticoagulants for venous thromboembolism (VTE) prophylaxis, consensus is mixed about which agents may be preferred in acutely ill patients with ongoing need of VTE prophylaxis past the first 10-day duration of hospital stay and post-discharge. Non-vitamin K antagonist oral anticoagulants (NOACs) provide Factor Xa inhibition to prevent the thrombin generation essential in thromboembolism development, but evidence for the efficacy and safety of most NOACs is conflicting regarding extended-duration prophylaxis. Enoxaparin, a preferred injectable anticoagulant in standard-duration VTE prophylaxis, has shown an increased risk of major bleeding events when used in extended-duration prophylaxis, which outweighs its benefit. Rivaroxaban has demonstrated efficacy in extended-duration prophylaxis, but both rivaroxaban and apixaban have shown increased risks of major bleeding. Betrixaban remains the only NOAC approved in the USA for extended-duration VTE prophylaxis, and it demonstrates efficacy, with fewer adverse effects than other NOACs. This review evaluates the appropriateness of different NOAC agents compared with current therapies for the extended-duration VTE prophylaxis setting in medically ill populations.

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References

  1. Kumar DR, Hanlin E, Glurich I, Mazza JJ, Yale SH. Virchow’s contribution to the understanding of thrombosis and cellular biology. Clin Med Res. 2010;8(3–4):168–72. https://doi.org/10.3121/cmr.2009.866.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Office of the Surgeon General (US), National Heart, Lung, and Blood Institute. The surgeon general’s call to action to prevent deep vein thrombosis and pulmonary embolism. In: Publications and reports of the surgeon general. Rockville: Office of the Surgeon General (US); 2008.

    Google Scholar 

  3. Lau BD, Haut ER. Practices to prevent venous thromboembolism: a brief review. BMJ Qual Saf. 2014;23(3):187–95. https://doi.org/10.1136/bmjqs-2012-001782.

    Article  PubMed  Google Scholar 

  4. Laryea J, Champagne B. Venous thromboembolism prophylaxis. Clin Colon Rectal Surg. 2013;26(3):153–9. https://doi.org/10.1055/s-0033-1351130.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Adriance SM, Murphy CV. Prophylaxis and treatment of venous thromboembolism in the critically ill. Int J Crit Illn Inj Sci. 2013;3(2):143–51. https://doi.org/10.4103/2229-5151.114274.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Attia J, Ray JG, Cook DJ, Douketis J, Ginsberg JS, Geerts WH. Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med. 2001;161(10):1268–79.

    Article  CAS  PubMed  Google Scholar 

  7. Heit JA, Cohen AT, Anderson FA. Estimated annual number of incident and recurrent, non-fatal and fatal venous thromboembolism (VTE) events in the US. Blood. 2005;106(11):267a.

    Google Scholar 

  8. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38(4 Suppl):S495–501. https://doi.org/10.1016/j.amepre.2009.12.017.

    Article  PubMed  Google Scholar 

  9. Centers for Disease Control and Prevention. Venous thromboembolism (blood clots); 2015. https://www.cdc.gov/ncbddd/dvt/data.html. Accessed 15 Aug 2018.

  10. ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Thromb Haemost. 2014;112(5):843–52. https://doi.org/10.1160/TH14-08-0671.

    Article  Google Scholar 

  11. Qaseem A. Venous thromboembolism prophylaxis in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;155(9):625. https://doi.org/10.7326/0003-4819-155-9-201111010-00011.

    Article  PubMed  Google Scholar 

  12. Leizorovicz A, Mismetti P. Preventing venous thromboembolism in medical patients. Circulation. 2004;110(24 suppl 1):IV-13–9. https://doi.org/10.1161/01.cir.0000150640.98772.af.

    Article  Google Scholar 

  13. Zaane B, Squizzato A, Huijgen R, Zanten AP, Fliers E, Buller HR, et al. Hyperthyroidism as a risk factor for venous thromboembolism: a case–control study. Blood. 2008;112(11):5350.

    Google Scholar 

  14. Davis PJ, Mousa SA, Schechter GP. New interfaces of thyroid hormone actions with blood coagulation and thrombosis. Clin Appl Thromb Hemost. 2018;1:1. https://doi.org/10.1177/1076029618774150.

    Article  CAS  Google Scholar 

  15. Barbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M, et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost. 2010;8(11):2450–7. https://doi.org/10.1111/j.1538-7836.2010.04044.x.

    Article  CAS  PubMed  Google Scholar 

  16. Spyropoulos AC, Anderson FA, FitzGerald G, Decousus H, Pini M, Chong BH, et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest. 2011;140(3):706–14. https://doi.org/10.1378/chest.10-1944.

    Article  PubMed  Google Scholar 

  17. Decousus H, Tapson VF, Bergmann J-F, Chong BH, Froehlich JB, Kakkar AK, et al. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest. 2011;139(1):69–79. https://doi.org/10.1378/chest.09-3081.

    Article  PubMed  Google Scholar 

  18. Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, et al. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018;379(12):1118–27. https://doi.org/10.1056/NEJMoa1805090.

    Article  CAS  PubMed  Google Scholar 

  19. Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e227S–77S. https://doi.org/10.1378/chest.11-2297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ. Executive summary. Chest. 2012;141(2 Suppl):7S–47S. https://doi.org/10.1378/chest.1412S3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pendleton R, Wheeler M, Rodgers G. Venous thromboembolism prevention in the acutely ill medical patient: a review of the literature and focus on special patient populations. Am J Hematol. 2005;79(3):229–37. https://doi.org/10.1002/ajh.20360.

    Article  PubMed  Google Scholar 

  22. Turpie AGG. Thrombosis prophylaxis in the acutely ill medical patient: insights from the prophylaxis in medical patients with enoxaparin (MEDENOX) trial. Am J Cardiol. 2000;86(12 Suppl 2):48–52. https://doi.org/10.1016/s0002-9149(00)01481-8.

    Article  Google Scholar 

  23. Alikhan R, Cohen AT, Combe S, Samama MM, Desjardins L, Eldor A, et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Fibrinolysis. 2003;14(4):341.

    Article  CAS  PubMed  Google Scholar 

  24. Leizorovicz A, Cohen AT, Turpie AGG, Olsson C-G, Vaitkus PT, Goldhaber SZ, et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110(7):874–9. https://doi.org/10.1161/01.CIR.0000138928.83266.24.

    Article  CAS  PubMed  Google Scholar 

  25. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ. 2006;332(7537):325–9. https://doi.org/10.1136/bmj.38733.466748.7C.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hull RD, Schellong SM, Tapson VF, Monreal M, Samama M-M, Nicol P, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010;153(1):8–18. https://doi.org/10.7326/0003-4819-153-1-201007060-00004.

    Article  PubMed  Google Scholar 

  27. Hull RD, Schellong SM, Tapson VF, Monreal M, Samama M-M, Turpie AGG, et al. Extended-duration thromboprophylaxis in acutely ill medical patients with recent reduced mobility: methodology for the EXCLAIM study. J Thromb Thrombolysis. 2006;22(1):31–8. https://doi.org/10.1007/s11239-006-7732-5.

    Article  CAS  PubMed  Google Scholar 

  28. Albertsen IE, Larsen TB, Rasmussen LH, Overvad TF, Lip GYH. Prevention of venous thromboembolism with new oral anticoagulants versus standard pharmacological treatment in acute medically ill patients: a systematic review and meta-analysis. Drugs. 2012;72(13):1755–64. https://doi.org/10.2165/11635630-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  29. Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011;365(23):2167–77.

    Article  CAS  PubMed  Google Scholar 

  30. Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368(6):513–23.

    Article  CAS  PubMed  Google Scholar 

  31. Cohen AT, Spiro TE, Spyropoulos AC, Desanctis YH, Homering M, Büller HR, et al. D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial. J Thromb Haemost. 2014;12(4):479–87. https://doi.org/10.1111/jth.12515.

    Article  CAS  PubMed  Google Scholar 

  32. Betrixaban (Bevyxxa) for VTE prophylaxis in acute medical illness. Med Lett Drugs Ther. 2018;60(1537):4–5.

  33. Fuji T. Anticoagulant therapy for venous thromboembolism prophylaxis in orthopaedic surgery in Japan: the evolving role of NOACs. Curr Orthop Pract. 2016;27(6):666. https://doi.org/10.1097/BCO.0000000000000430.

    Article  Google Scholar 

  34. Chan NC, Hirsh J, Ginsberg JS, Eikelboom JW. Betrixaban (PRT054021): pharmacology, dose selection and clinical studies. Future Cardiol. 2014;10(1):43–52. https://doi.org/10.2217/fca.13.98.

    Article  CAS  PubMed  Google Scholar 

  35. Blann A. Nonvitamin K antagonist oral anticoagulants (NOACs): the tide continues to come in. Vasc Health Risk Manag. 2015;11:489–92. https://doi.org/10.2147/VHRM.S89736.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Palladino M, Merli G, Thomson L. Evaluation of the oral direct factor Xa inhibitor—betrixaban. Expert Opin Investig Drugs. 2013;22(11):1465–72. https://doi.org/10.1517/13543784.2013.825605.

    Article  CAS  PubMed  Google Scholar 

  37. Cohen AT, Harrington R, Goldhaber SZ, Hull R, Gibson CM, Hernandez AF, et al. The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. Am Heart J. 2014;167(3):335–41. https://doi.org/10.1016/j.ahj.2013.11.006.

    Article  PubMed  Google Scholar 

  38. Turpie AGG, Bauer KA, Davidson BL, Fisher WD, Gent M, Huo MH, et al. A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb Haemost. 2009;101(1):68–76. https://doi.org/10.1160/TH08-07-0460.

    Article  CAS  PubMed  Google Scholar 

  39. 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. https://doi.org/10.2147/VHRM.S63060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016;375(6):534–44. https://doi.org/10.1056/NEJMoa1601747.

    Article  CAS  PubMed  Google Scholar 

  41. Ramacciotti E, Hoppensteadt D, Fareed J. Betrixaban for VTE prevention in the medically ill population, the APEX trial: good news for this needy population? Clin Appl Thromb Hemost. 2017;23(7):701–2. https://doi.org/10.1177/1076029616683805.

    Article  PubMed  Google Scholar 

  42. Gibson CM, Nafee T, Yee MK, Chi G, Korjian S, Daaboul Y, et al. Symptomatic event reduction with extended-duration betrixaban in acute medically ill hospitalized patients. Am Heart J. 2018;198:84–90. https://doi.org/10.1016/j.ahj.2017.12.015.

    Article  PubMed  Google Scholar 

  43. Prescribing information for BEVYXXA™ (betrixaban) capsules, for oral use; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208383s000lbl.pdf. Accessed 17 Jan 2019.

  44. Gibson CM, Korjian S, Chi G, Daaboul Y, Jain P, Arbetter D, et al. Comparison of fatal or irreversible events with extended-duration betrixaban versus standard dose enoxaparin in acutely ill medical patients: an APEX Trial Substudy. J Am Heart Assoc. 2017;6(7):e006015. https://doi.org/10.1161/JAHA.117.006015.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Quinlan DJ, Eikelboom JW, Hart RG. Is there a role for betrixaban to prevent stroke in medically ill patients? Circulation. 2017;135(7):656–8. https://doi.org/10.1161/CIRCULATIONAHA.116.026170.

    Article  PubMed  Google Scholar 

  46. Gibson CM, Halaby R, Korjian S, Daaboul Y, Arbetter DF, Yee MK, 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. https://doi.org/10.1016/j.ahj.2016.12.004.

    Article  CAS  PubMed  Google Scholar 

  47. Yee MK, Nafee T, Daaboul Y, Korjian S, AlKhalfan F, Kerneis M, et al. Increased benefit of betrixaban among patients with a history of venous thromboembolism: a post-hoc analysis of the APEX trial. J Thromb Thrombolysis. 2018;45(1):1–8. https://doi.org/10.1007/s11239-017-1583-0.

    Article  CAS  PubMed  Google Scholar 

  48. Chi G, Gibson CM, Hernandez AF, Hull RD, Kazmi SHA, Younes A, et al. Association of anemia with venous thromboembolism in acutely ill hospitalized patients: an APEX trial substudy. Am J Med. 2018;131(8):972 e1–e7. https://doi.org/10.1016/j.amjmed.2018.03.031.

    Article  Google Scholar 

  49. Chi G, Yee MK, Amin AN, Goldhaber SZ, Hernandez AF, Hull RD, et al. Extended-duration betrixaban reduces the risk of rehospitalization associated with venous thromboembolism among acutely ill hospitalized medical patients findings from the APEX Trial (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban Trial). Circulation. 2018;137(1):91–4. https://doi.org/10.1161/Circulationaha.117.031187.

    Article  CAS  PubMed  Google Scholar 

  50. Raskob GE, Spyropoulos AC, Zrubek J, Ageno W, Albers G, Elliott CG, et al. The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Thromb Haemost. 2016;115(6):1240–8. https://doi.org/10.1160/TH15-09-0756.

    Article  PubMed  Google Scholar 

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Correspondence to Shaker A. Mousa.

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T. Knotts and S. A. Mousa have no potential conflicts of interest that might be relevant to the contents of this manuscript.

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Knotts, T.L., Mousa, S.A. Anticoagulation in Venous Thromboembolism Prophylaxis in Medically Ill Patients: Potential Impact of NOACs. Am J Cardiovasc Drugs 19, 365–376 (2019). https://doi.org/10.1007/s40256-019-00329-5

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