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Hepatotoxicity of New Oral Anticoagulants (NOACs)

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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.

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References

  1. Dager WE, Vondracek TG, McIntosh BA, Nutescu EA. Ximelagatran: an oral direct thrombin inhibitor. Ann Pharmacother. 2004;38(11):1881–97.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  9. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  11. Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11(2):272–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  13. Fontana RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology. 2014;146(4):914–28.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  25. Bjornsson E. Drug-induced liver injury: Hy’s rule revisited. Clin Pharmacol Ther. 2006;79(6):521–8.

    Article  PubMed  Google Scholar 

  26. Zimmerman HJ. The spectrum of hepatotoxicity. Perspect Biol Med. 1968;12(1):135–61.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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

    PubMed  Google Scholar 

  34. Rochwerg B, Xenodemetropoulos T, Crowther M, Spyropoulos A. Dabigatran-induced acute hepatitis. Clin Appl Thromb Hemost. 2012;18(5):549–50.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  36. Pichler WJ, Naisbitt DJ, Park BK. Immune pathomechanism of drug hypersensitivity reactions. J Allergy Clin Immunol. 2011;127(3 Suppl):S74–81.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  40. Harder S, Graff J. Novel oral anticoagulants: clinical pharmacology, indications and practical considerations. Eur J Clin Pharmacol. 2013;69(9):1617–33.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  43. Keisu M, Andersson TB. Drug-induced liver injury in humans: the case of ximelagatran. Handb Exp Pharmacol. 2010;196:407–18.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Correspondence to Stephan Krähenbühl.

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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.

Additional information

Some data for this work were obtained from the WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden. Data from spontaneous reporting are inhomogeneous as a result of different reporting policies worldwide and are vulnerable to underreporting and reporting bias. The information contained in this work is therefore not homogeneous, at least with respect to origin and also to likelihood that the pharmaceutical product caused the adverse reaction. The conclusions drawn on the basis of these data do not necessarily represent the opinion of the WHO.

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Liakoni, E., Rätz Bravo, A.E. & Krähenbühl, S. Hepatotoxicity of New Oral Anticoagulants (NOACs). Drug Saf 38, 711–720 (2015). https://doi.org/10.1007/s40264-015-0317-5

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