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Digestive Diseases and Sciences

, Volume 61, Issue 6, pp 1721–1727 | Cite as

Direct Oral Anticoagulants in Cirrhosis Patients Pose Similar Risks of Bleeding When Compared to Traditional Anticoagulation

  • N. M. IntagliataEmail author
  • Z. H. Henry
  • H. Maitland
  • N. L. Shah
  • C. K. Argo
  • P. G. Northup
  • S. H. Caldwell
Original Article

Abstract

Background and Aims

Direct oral anticoagulants (DOAC) are important new anticoagulant therapies that are not well studied in patients with chronic liver disease. The aim of this study was to compare rates of bleeding in cirrhosis patients treated with DOAC (factor Xa inhibitors: rivaroxaban and apixaban) to those in cirrhosis patients treated with traditional anticoagulation (warfarin and low molecular weight heparin).

Methods

We identified a total of 39 patients with cirrhosis who received anticoagulation therapy over a 3-year period (20 DOAC and 19 traditional anticoagulation) from a research database. Medical records were reviewed to obtain clinical data to compare between the groups.

Results

Clinical characteristics between the two groups were similar. There were three documented bleeding events in the traditional anticoagulation group and four bleeding events in the DOAC group (p = 0.9). There were two major bleeding events in the traditional anticoagulation group and one major bleeding event in the DOAC group. There were no documented reports of drug-induced liver injury during this study period. Among all patients, no significant predictors of bleeding were identified using univariate regression and Cox proportional hazard modeling.

Conclusions

This is the first clinical study evaluating the use of DOAC in patients with cirrhosis. DOAC display similar safety characteristics when compared to traditional anticoagulation in patients with cirrhosis and are potentially attractive agents for anticoagulation therapy. Larger studies are now needed to better understand the safety and efficacy of these agents in cirrhosis.

Keywords

Coagulation Thrombosis Anticoagulation Bleeding Portal vein thrombosis DOAC Cirrhosis Factor Xa inhibitor 

Abbreviations

DOAC

Direct-acting anticoagulants

VTE

Venous thromboembolism

VKA

Vitamin K antagonists

LMWH

Low molecular weight heparin

INR

International normalized ratio

CTP

Child–Turcotte–Pugh

MELD

Model for end-stage liver disease

ICH

Intracranial hemorrhage

PCC

Prothrombin complex concentrates

FFP

Fresh frozen plasma

Notes

Compliance with ethical standards

Conflicts of interest

Z.H., C.A., and H.M. have nothing to disclose. N.I., N.S., and S.C. consulted for Vital Therapies. P.N. is consultant for Janssen Pharmaceuticals.

References

  1. 1.
    Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013;11:1064–1074.CrossRefPubMedGoogle Scholar
  2. 2.
    Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365:147–156.CrossRefPubMedGoogle Scholar
  3. 3.
    Ng KJ, Lee YK, Huang MY, Hsu CY, Su YC. Risks of venous thromboembolism in patients with liver cirrhosis: a nationwide cohort study in Taiwan. J Thromb Haemost. 2015;13:206–213.CrossRefPubMedGoogle Scholar
  4. 4.
    Northup PG, McMahon MM, Ruhl AP, et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol. 2006;101:1524–1528; quiz 1680.CrossRefPubMedGoogle Scholar
  5. 5.
    Sogaard KK, Horvath-Puho E, Gronbaek H, Jepsen P, Vilstrup H, Sorensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case–control study. Am J Gastroenterol. 2009;104:96–101.CrossRefPubMedGoogle Scholar
  6. 6.
    Cerini F, Gonzalez JM, Torres F, et al. Impact of anticoagulation on upper-gastrointestinal bleeding in cirrhosis. A retrospective multicenter study. Hepatology. 2015;62:575–583.CrossRefPubMedGoogle Scholar
  7. 7.
    Senzolo M, Ferronato C, Burra P, Sartori MT. Anticoagulation for portal vein thrombosis in cirrhotic patients should be always considered. Intern Emerg Med. 2009;4:161–162; author reply 163–164.Google Scholar
  8. 8.
    Amitrano L, Guardascione MA, Menchise A, et al. Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis. J Clin Gastroenterol. 2010;44:448–451.PubMedGoogle Scholar
  9. 9.
    Bechmann LP, Sichau M, Wichert M, Gerken G, Kroger K, Hilgard P. Low-molecular-weight heparin in patients with advanced cirrhosis. Liver Int. 2011;31:75–82.CrossRefPubMedGoogle Scholar
  10. 10.
    Delgado MG, Seijo S, Yepes I, et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol. 2012;10:776–783.CrossRefPubMedGoogle Scholar
  11. 11.
    Intagliata NM, Henry ZH, Shah N, Lisman T, Caldwell SH, Northup PG. Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding. Liver Int. 2014;34:26–32.CrossRefPubMedGoogle Scholar
  12. 12.
    Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by nontraditional anticoagulation. Hepatology. 2014;60:425–426.CrossRefPubMedGoogle Scholar
  13. 13.
    Intagliata NM, Maitland H, Northup PG, Caldwell SH. Treating thrombosis in cirrhosis patients with new oral agents: ready or not? Hepatology. 2015;61:738–739.CrossRefPubMedGoogle Scholar
  14. 14.
    Tripodi A, Primignani M, Chantarangkul V, Mannucci PM. Pro-coagulant imbalance in patients with chronic liver disease. J Hepatol. 2010;53:586–587.CrossRefPubMedGoogle Scholar
  15. 15.
    Graff J, Harder S. 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. 2013;52:243–254.CrossRefPubMedGoogle Scholar
  16. 16.
    Morrill AM, Ge D, Willett KC. Dosing of target-specific oral anticoagulants in special populations. Ann Pharmacother. 2015;49:1031–1045.CrossRefPubMedGoogle Scholar
  17. 17.
    Potze W, Arshad F, Adelmeijer J, et al. Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis. PLoS ONE. 2014;9:e88390.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kubitza D, Roth A, Becka M, et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2013;76:89–98.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Mendell J, Johnson L, Chen S. An open-label, phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics and pharmacodynamics. J Clin Pharmacol. 2015;55:1395–1405.CrossRefPubMedGoogle Scholar
  20. 20.
    Stangier J, Stahle H, Rathgen K, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol. 2008;48:1411–1419.CrossRefPubMedGoogle Scholar
  21. 21.
    Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the S, Standardization Committee of the International Society on T, Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–694.CrossRefPubMedGoogle Scholar
  22. 22.
    Tripodi A, Primignani M, Lemma L, Chantarangkul V, Mannucci PM. Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis. J Hepatol. 2013;59:265–270.CrossRefPubMedGoogle Scholar
  23. 23.
    Villa E, Camma C, Marietta M, et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology. 2012;143:1253–1260.CrossRefPubMedGoogle Scholar
  24. 24.
    Prins MH, Bamber L, Cano SJ, et al. Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of pulmonary embolism; results from the EINSTEIN PE trial. Thromb Res. 2015;135:281–288.CrossRefPubMedGoogle Scholar
  25. 25.
    Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124:2450–2458.CrossRefPubMedGoogle Scholar
  26. 26.
    Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799–808.CrossRefPubMedGoogle Scholar
  27. 27.
    Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost. 2014;111:189–198.CrossRefPubMedGoogle Scholar
  28. 28.
    Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511–520.CrossRefPubMedGoogle Scholar
  29. 29.
    Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;371:2413–2424.CrossRefGoogle Scholar
  30. 30.
    Russmann S, Niedrig DF, Budmiger M, et al. Rivaroxaban postmarketing risk of liver injury. J Hepatol. 2014;61:293–300.CrossRefPubMedGoogle Scholar
  31. 31.
    Caldeira D, Barra M, Santos AT, et al. Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis. Heart. 2014;100:550–556.CrossRefPubMedGoogle Scholar
  32. 32.
    Potze W, Arshad F, Adelmeijer J, et al. Routine coagulation assays underestimate levels of antithrombin-dependent drugs but not of direct anticoagulant drugs in plasma from patients with cirrhosis. Br J Haematol. 2013;163:666–673.CrossRefPubMedGoogle Scholar
  33. 33.
    Potze W, Adelmeijer J, Lisman T. Decreased in vitro anticoagulant potency of Rivaroxaban and Apixaban in plasma from patients with cirrhosis. Hepatology. 2015;61:1435–1436.CrossRefPubMedGoogle Scholar
  34. 34.
    Abe W, Ikejima K, Lang T, et al. Low molecular weight heparin prevents hepatic fibrogenesis caused by carbon tetrachloride in the rat. J Hepatol. 2007;46:286–294.CrossRefPubMedGoogle Scholar
  35. 35.
    Kopec AK, Joshi N, Towery KL, et al. Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice. J Pharmacol Exp Ther. 2014;351:288–297.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • N. M. Intagliata
    • 1
    Email author
  • Z. H. Henry
    • 1
  • H. Maitland
    • 2
  • N. L. Shah
    • 1
  • C. K. Argo
    • 1
  • P. G. Northup
    • 1
  • S. H. Caldwell
    • 1
  1. 1.Coagulation in Liver Disease Study Group, Division of Gastroenterology and HepatologyUniversity of Virginia Medical CenterCharlottesvilleUSA
  2. 2.Division of Hematology and OncologyUniversity of Virginia Medical CenterCharlottesvilleUSA

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