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Drug Safety

, Volume 38, Issue 8, pp 711–720 | Cite as

Hepatotoxicity of New Oral Anticoagulants (NOACs)

  • Evangelia Liakoni
  • Alexandra E. Rätz Bravo
  • Stephan Krähenbühl
Review Article

Abstract

Case reports and analyses of clinical studies and of pharmacovigilance data suggest that new oral anticoagulants (NOACs) are associated with a small risk for hepatotoxicity. The objective of this publication is to summarize the current data about this subject, with a special emphasis on pharmacovigilance data in the World Health Organization (WHO) Global Individual Case Safety Reports (ICSR) database and on potential mechanisms of hepatotoxicity. For that, all available case reports as well as published analyses of clinical studies were obtained with a detailed search in PubMed. In addition, pharmacovigilance data from VigiBase®, the WHO Global ICRS database, were extracted and analyzed. The data show that liver injury associated with NOACs was reported in clinical studies and in pharmacovigilance databases. Several case reports described potentially life-threatening hepatotoxicity in patients treated with rivaroxaban or dabigatran. For rivaroxaban, most affected patients were symptomatic and liver injury was most often hepatocellular or mixed. The frequency was between 0.1 and 1 % in clinical studies and was by trend lower than for comparators (mostly enoxaparin or warfarin). Comparing the pharmacovigilance reports for the individual NOACs, more hepatic adverse events were reported for rivaroxaban than for dabigatran or apixaban. With the exception of edoxaban, for which only few reports are available, patients with acute liver failure have been reported for every NOAC, but most patients had concomitant drugs or diseases. So far, there are no clear mechanisms explaining the hepatotoxicity of these drugs. We conclude that hepatotoxicity appears to be associated with all NOACs currently on the market. Hepatotoxicity associated with NOACs is idiosyncratic; it appears at therapeutic doses, is rare and the mechanism is not related to the pharmacological action of these drugs. Prescribers should inform patients about possible symptoms of hepatotoxicity and stop these drugs in patients presenting with severe liver injury.

Keywords

Liver Injury Dabigatran Rivaroxaban Apixaban Acute Liver Failure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Compliance with ethical standards

Funding

No sources of funding were used to assist in the preparation of this study.

Conflicts of interest

Evangelia Liakoni and Alexandra Rätz Bravo have no conflicts of interest that are directly relevant to the content of this study. Stephan Krähenbühl has given talks about the pharmacology and safety of NOACs that were financially supported by Bayer and by Pfizer.

References

  1. 1.
    Dager WE, Vondracek TG, McIntosh BA, Nutescu EA. Ximelagatran: an oral direct thrombin inhibitor. Ann Pharmacother. 2004;38(11):1881–97.PubMedCrossRefGoogle Scholar
  2. 2.
    Eriksson BI, Bergqvist D, Kalebo P, Dahl OE, Lindbratt S, Bylock A, et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet. 2002;360(9344):1441–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med. 2003;349(18):1703–12.PubMedCrossRefGoogle Scholar
  4. 4.
    Lee WM, Larrey D, Olsson R, Lewis JH, Keisu M, Auclert L, et al. Hepatic findings in long-term clinical trials of ximelagatran. Drug Saf. 2005;28(4):351–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Kenne K, Skanberg I, Glinghammar B, Berson A, Pessayre D, Flinois JP, et al. Prediction of drug-induced liver injury in humans by using in vitro methods: the case of ximelagatran. Toxicol In Vitro. 2008;22(3):730–46.PubMedCrossRefGoogle Scholar
  6. 6.
    Kindmark A, Jawaid A, Harbron CG, Barratt BJ, Bengtsson OF, Andersson TB, et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J. 2008;8(3):186–95.PubMedCrossRefGoogle Scholar
  7. 7.
    Andersson U, Lindberg J, Wang S, Balasubramanian R, Marcusson-Stahl M, Hannula M, et al. A systems biology approach to understanding elevated serum alanine transaminase levels in a clinical trial with ximelagatran. Biomarkers. 2009;14(8):572–86.PubMedCrossRefGoogle Scholar
  8. 8.
    Leil TA, Feng Y, Zhang L, Paccaly A, Mohan P, Pfister M. Quantification of apixaban’s therapeutic utility in prevention of venous thromboembolism: selection of phase III trial dose. Clin Pharmacol Ther. 2010;88(3):375–82.PubMedCrossRefGoogle Scholar
  9. 9.
    Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Suzuki A, Andrade RJ, Bjornsson E, Lucena MI, Lee WM, Yuen NA, et al. Drugs associated with hepatotoxicity and their reporting frequency of liver adverse events in VigiBase: unified list based on international collaborative work. Drug Saf. 2010;33(6):503–22.PubMedCrossRefGoogle Scholar
  11. 11.
    Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11(2):272–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806–15.PubMedCrossRefGoogle Scholar
  13. 13.
    Fontana RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology. 2014;146(4):914–28.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’er I, Floratos A, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009;41(7):816–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Wuillemin N, Terracciano L, Beltraminelli H, Schlapbach C, Fontana S, Krahenbuhl S, et al. T cells infiltrate the liver and kill hepatocytes in HLA-B(*)57:01-associated floxacillin-induced liver injury. Am J Pathol. 2014;184(6):1677–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568–79.PubMedCrossRefGoogle Scholar
  17. 17.
    Singer JB, Lewitzky S, Leroy E, Yang F, Zhao X, Klickstein L, et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet. 2010;42(8):711–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Krahenbuhl S, Brandner S, Kleinle S, Liechti S, Straumann D. Mitochondrial diseases represent a risk factor for valproate-induced fulminant liver failure. Liver. 2000;20(4):346–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Stewart JD, Horvath R, Baruffini E, Ferrero I, Bulst S, Watkins PB, et al. Polymerase gamma gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology. 2010;52(5):1791–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Knapp AC, Todesco L, Beier K, Terracciano L, Sagesser H, Reichen J, et al. Toxicity of valproic acid in mice with decreased plasma and tissue carnitine stores. J Pharmacol Exp Ther. 2008;324(2):568–75.PubMedCrossRefGoogle Scholar
  21. 21.
    Felser A, Stoller A, Morand R, Schnell D, Donzelli M, Terracciano L, et al. Hepatic toxicity of dronedarone in mice: role of mitochondrial beta-oxidation. Toxicology. 2014;2(323):1–9.CrossRefGoogle Scholar
  22. 22.
    Shaw PJ, Ganey PE, Roth RA. Idiosyncratic drug-induced liver injury and the role of inflammatory stress with an emphasis on an animal model of trovafloxacin hepatotoxicity. Toxicol Sci. 2010;118(1):7–18.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Eypasch E, Lefering R, Kum CK, Troidl H. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ. 1995;311(7005):619–20 (Clinical research ed).PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Watkins PB, Desai M, Berkowitz SD, Peters G, Horsmans Y, Larrey D, et al. Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug Saf. 2011;34(3):243–52.PubMedCrossRefGoogle Scholar
  25. 25.
    Bjornsson E. Drug-induced liver injury: Hy’s rule revisited. Clin Pharmacol Ther. 2006;79(6):521–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Zimmerman HJ. The spectrum of hepatotoxicity. Perspect Biol Med. 1968;12(1):135–61.PubMedCrossRefGoogle Scholar
  27. 27.
    Caldeira D, Barra M, Santos AT, de Abreu D, Pinto FJ, Ferreira JJ, et al. Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis. Heart. 2014;100(7):550–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Mahan CE. Practical aspects of treatment with target specific anticoagulants: initiation, payment and current market, transitions, and venous thromboembolism treatment. J Thromb Thrombolysis. 2015;39(3):295–303.PubMedCrossRefGoogle Scholar
  29. 29.
    Barrett P, Vuppalanchi R, Masuoka H, Chalasani N. Severe drug-induced skin and liver injury from rivaroxaban. Dig Dis Sci. 2015;60(6):1856–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Fulcrand J, Lerooy A, Giraud J, Cailliau A, Delrot C, Petitpain N, et al. [Cytolysis in an elderly patient treated with dabigatran etexilate]. Therapie. 2013;68(5):332–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Lambert A, Cordeanu M, Gaertner S, Nouri S, Alt M, Stephan D. Rivaroxaban-induced liver injury: results from a venous thromboembolism registry. Int J Cardiol. 2015;1(191):265–6.CrossRefGoogle Scholar
  32. 32.
    Liakoni E, Ratz Bravo AE, Terracciano L, Heim M, Krahenbuhl S. Symptomatic hepatocellular liver injury with hyperbilirubinemia in two patients treated with rivaroxaban. JAMA Intern Med. 2014;174(10):1683–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Raschi E, Poluzzi E, Koci A, Salvo F, Pariente A, Biselli M, Moretti U, Moore N, De Ponti F. Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system. Br J Clin Pharmacol. 2015. doi: 10.1111/bcp.12611 PubMedGoogle Scholar
  34. 34.
    Rochwerg B, Xenodemetropoulos T, Crowther M, Spyropoulos A. Dabigatran-induced acute hepatitis. Clin Appl Thromb Hemost. 2012;18(5):549–50.PubMedCrossRefGoogle Scholar
  35. 35.
    Russmann S, Niedrig DF, Budmiger M, Schmidt C, Stieger B, Hurlimann S, et al. Rivaroxaban postmarketing risk of liver injury. J Hepatol. 2014;61(2):293–300.PubMedCrossRefGoogle Scholar
  36. 36.
    Pichler WJ, Naisbitt DJ, Park BK. Immune pathomechanism of drug hypersensitivity reactions. J Allergy Clin Immunol. 2011;127(3 Suppl):S74–81.PubMedCrossRefGoogle Scholar
  37. 37.
    Thong BY, Mirakian R, Castells M, Pichler W, Romano A, Bonadonna P, et al. A world allergy organization international survey on diagnostic procedures and therapies in drug allergy/hypersensitivity. World Allergy Organ J. 2011;4(12):257–70.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Ratanasavanh D, Beaune P, Morel F, Flinois JP, Guengerich FP, Guillouzo A. Intralobular distribution and quantitation of cytochrome P-450 enzymes in human liver as a function of age. Hepatology (Baltimore, Md). 1991;13(6):1142–51.CrossRefGoogle Scholar
  39. 39.
    Gong IY, Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol. 2013;29(7 Suppl):S24–33.PubMedCrossRefGoogle Scholar
  40. 40.
    Harder S, Graff J. Novel oral anticoagulants: clinical pharmacology, indications and practical considerations. Eur J Clin Pharmacol. 2013;69(9):1617–33.PubMedCrossRefGoogle Scholar
  41. 41.
    Waldhauser KM, Torok M, Ha HR, Thomet U, Konrad D, Brecht K, et al. Hepatocellular toxicity and pharmacological effect of amiodarone and amiodarone derivatives. J Pharmacol Exp Ther. 2006;319(3):1413–23.PubMedCrossRefGoogle Scholar
  42. 42.
    Zahno A, Brecht K, Morand R, Maseneni S, Torok M, Lindinger PW, et al. The role of CYP3A4 in amiodarone-associated toxicity on HepG2 cells. Biochem Pharmacol. 2011;81(3):432–41.PubMedCrossRefGoogle Scholar
  43. 43.
    Keisu M, Andersson TB. Drug-induced liver injury in humans: the case of ximelagatran. Handb Exp Pharmacol. 2010;196:407–18.PubMedCrossRefGoogle Scholar
  44. 44.
    Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology (Baltimore, Md). 2008;47(6):2003–9.CrossRefGoogle Scholar
  45. 45.
    Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost. 2010;103(3):572–85.PubMedCrossRefGoogle Scholar
  46. 46.
    Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J. 2013;11(1):10.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Evangelia Liakoni
    • 1
  • Alexandra E. Rätz Bravo
    • 1
    • 2
  • Stephan Krähenbühl
    • 1
  1. 1.Clinical Pharmacology and ToxicologyUniversity HospitalBaselSwitzerland
  2. 2.Regional Pharmacovigilance CenterUniversity Hospital BaselBaselSwitzerland

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