Clinical Pharmacokinetics

, Volume 52, Issue 4, pp 243–254 | Cite as

Anticoagulant Therapy with the Oral Direct Factor Xa Inhibitors Rivaroxaban, Apixaban and Edoxaban and the Thrombin Inhibitor Dabigatran Etexilate in Patients with Hepatic Impairment

  • Jochen Graff
  • Sebastian HarderEmail author
Review Article


The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. In subjects with moderately impaired liver function (i.e. Child-Pugh classification B), the area under the plasma concentration–time curve (AUC) of rivaroxaban (10 mg single dose) is increased by 2.27-fold, which is paralleled by an increase in FXa inhibition. The AUC of apixaban (5 mg single dose) is increased by 1.09-fold, whereas the AUC of edoxaban (15 mg single dose) is decreased by 4.8 % and the AUC of dabigatran (150 mg single dose) is decreased by 5.6 %. Specific labelling restrictions for rivaroxaban, apixaban and dabigatran regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal clinical trials. Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels >2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Dabigatran is not recommended in patients with elevated liver enzymes (>2× ULN). Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.


Dabigatran Rivaroxaban Hepatic Impairment Apixaban Prothrombin Complex Concentrate 
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.


Acknowledgments and Disclosures

Sebastian Harder has received scientific grants from Merck KGaA and The Medicines Company, and has received honoraria for lectures from Merck KGaA and LEO Pharmaceuticals. No sources of funding were used to prepare this review. The authors have no other conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Deitelzweig SB, Lin J, Lin G. Preventing venous thromboembolism following orthopedic surgery in the United States: impact of special populations on clinical outcomes. Clin Appl Thromb Hemost. 2011;17(6):640–50.PubMedCrossRefGoogle Scholar
  2. 2.
    Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe: the number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98(4):756–64.PubMedGoogle Scholar
  3. 3.
    Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 Suppl):234S–56S.PubMedCrossRefGoogle Scholar
  4. 4.
    Perzborn E, Roehrig S, Straub A, Kubitza D, Mueck W, Laux V. Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol. 2010;30(3):376–81.PubMedCrossRefGoogle Scholar
  5. 5.
    Jimenez D, Yusen RD, Ramacciotti E. Apixaban: an oral direct factor-xa inhibitor. Adv Ther. 2012;29(3):187–201.PubMedCrossRefGoogle Scholar
  6. 6.
    Eisert WG, Hauel N, Stangier J, Wienen W, Clemens A, van Ryn J. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol. 2010;30(10):1885–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Ahrens I, Peter K, Lip GY, Bode C. Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Discov Med. 2012;13(73):445–50.PubMedGoogle Scholar
  8. 8.
    Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor xa inhibitor. Drugs. 2011;71(12):1503–26.PubMedCrossRefGoogle Scholar
  9. 9.
    Harder S. Renal profiles of anticoagulants. J Clin Pharmacol. 2012;52(7):964–75.PubMedCrossRefGoogle Scholar
  10. 10.
    Thachil J. Relevance of clotting tests in liver disease. Postgrad Med J. 2008;84(990):177–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Baczek VL, Chen WT, Kluger J, Coleman CI. Predictors of warfarin use in atrial fibrillation in the United States: a systematic review and meta-analysis. BMC Fam Pract. 2012;13:5.PubMedCrossRefGoogle Scholar
  12. 12.
    Deitelzweig SB, Lin J, Kreilick C, Hussein M, Battleman D. Warfarin therapy in patients with venous thromboembolism: patterns of use and predictors of clinical outcomes. Adv Ther. 2010;27(9):623–33.PubMedCrossRefGoogle Scholar
  13. 13.
    Le Couteur DG, Fraser R, Hilmer S, Rivory LP, McLean AJ. The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance. Clin Pharmacokinet. 2005;44(2):187–200.PubMedCrossRefGoogle Scholar
  14. 14.
    Herrlinger C, Klotz U. Drug metabolism and drug interactions in the elderly. Best Pract Res Clin Gastroenterol. 2001;15(6):897–918.PubMedCrossRefGoogle Scholar
  15. 15.
    Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease: an update. Clin Pharmacokinet. 1995;29(5):370–91.PubMedCrossRefGoogle Scholar
  16. 16.
    Delco F, Tchambaz L, Schlienger R, Drewe J, Krahenbuhl S. Dose adjustment in patients with liver disease. Drug Saf. 2005;28(6):529–45.PubMedCrossRefGoogle Scholar
  17. 17.
    Blaschke TF, Rubin PC. Hepatic first-pass metabolism in liver disease. Clin Pharmacokinet. 1979;4(6):423–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos. 2009;37(5):1056–64.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008;36(2):386–99.PubMedCrossRefGoogle Scholar
  21. 21.
    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(12):1411–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Weinz C, Buetehorn U, Daehler HP, et al. Pharmacokinetics of BAY 59–7939–an oral, direct Factor Xa inhibitor–in rats and dogs. Xenobiotica. 2005;35(9):891–910.PubMedCrossRefGoogle Scholar
  23. 23.
    He K, Luettgen JM, Zhang D, et al. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug Metab Pharmacokinet. 2011;36(3):129–39.PubMedCrossRefGoogle Scholar
  24. 24.
    Reichen J. The role of the sinusoidal endothelium in liver function. News Physiol Sci. 1999;14:117–21.PubMedGoogle Scholar
  25. 25.
    Frye RF, Zgheib NK, Matzke GR, et al. Liver disease selectively modulates cytochrome P450-mediated metabolism. Clin Pharmacol Ther. 2006;80(3):235–45.PubMedCrossRefGoogle Scholar
  26. 26.
    Chalasani N, Gorski JC, Patel NH, Hall SD, Galinsky RE. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts. Hepatology. 2001;34(6):1103–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Elbekai RH, Korashy HM, El-Kadi AO. The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes. Curr Drug Metab. 2004;5(2):157–67.PubMedCrossRefGoogle Scholar
  28. 28.
    Orlando R, Mussap M, Plebani M, et al. Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis. Clin Chem. 2002;48(6 Pt 1):850–8.PubMedGoogle Scholar
  29. 29.
    Amitrano L, Guardascione MA, Brancaccio V, Balzano A. Coagulation disorders in liver disease. Semin Liver Dis. 2002;22(1):83–96.PubMedCrossRefGoogle Scholar
  30. 30.
    Caldwell SH, Hoffman M, Lisman T, et al. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology. 2006;44(4):1039–46.PubMedCrossRefGoogle Scholar
  31. 31.
    Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365(2):147–56.PubMedCrossRefGoogle Scholar
  32. 32.
    Tripodi A, Salerno F, Chantarangkul V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005;41(3):553–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Roberts LN, Patel RK, Arya R. Haemostasis and thrombosis in liver disease. Br J Haematol. 2010;148(4):507–21.PubMedCrossRefGoogle Scholar
  34. 34.
    Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124(1):91–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Cholongitas E, Papatheodoridis GV, Vangeli M, Terreni N, Patch D, Burroughs AK. Systematic review: the model for end-stage liver disease–should it replace Child-Pugh’s classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther. 2005;22(11–12):1079–89.PubMedCrossRefGoogle Scholar
  37. 37.
    FDA. Guidance for industry: pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labelling. 2003. Accessed 15 Jan 2013.
  38. 38.
    EMEA. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. 2005. Accessed 15 Jan 2013.
  39. 39.
    Spray JW, Willett K, Chase D, Sindelar R, Connelly S. Dosage adjustment for hepatic dysfunction based on Child-Pugh scores. Am J Health Syst Pharm 2007; 64(7):692–3.Google Scholar
  40. 40.
    Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59–7939–an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005;3(3):514–21.PubMedCrossRefGoogle Scholar
  41. 41.
    Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59–7939–an oral, direct Factor Xa inhibitor–after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12):873–80.PubMedCrossRefGoogle Scholar
  42. 42.
    Gerotziafas GT, Elalamy I, Depasse F, Perzborn E, Samama MM. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost. 2007;5(4):886–8.PubMedCrossRefGoogle Scholar
  43. 43.
    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.PubMedCrossRefGoogle Scholar
  44. 44.
    Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet. 2009;48(1):1–22.PubMedCrossRefGoogle Scholar
  45. 45.
    Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther. 2011;338(1):372–80.PubMedCrossRefGoogle Scholar
  46. 46.
    Kubitza D, Becka M, Mueck W, Zuehlsdorf M. The effect of extreme age, and gender, on the pharmacology and tolerability of rivaroxaban: an oral, direct Factor Xa inhibitor [abstract]. Blood 2006;108: abstract 905.Google Scholar
  47. 47.
    Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59–7939) in healthy subjects. J Clin Pharmacol. 2007;47(2):218–26.PubMedCrossRefGoogle Scholar
  48. 48.
    Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2010;70(5):703–12.PubMedCrossRefGoogle Scholar
  49. 49.
    Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost. 2011;105(3):444–53.PubMedCrossRefGoogle Scholar
  50. 50.
    Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2012;363(26):2499–510.Google Scholar
  51. 51.
    Buller 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.PubMedCrossRefGoogle Scholar
  52. 52.
    Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.PubMedCrossRefGoogle Scholar
  53. 53.
    Kubitza D, Roth A, Becka M, Alatrach A, Halabi A, Hinrichsen H, 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. Epub 2013 Jan 8. doi: 10.1111/bcp.12054.
  54. 54.
    Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost. 2008;6(5):820–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Frost C, Yu Z, Nepal S, Mosqueda-Garcia R, Shenker A. Apixaban, an oral direct Factor Xa inhibitor: single-dose safety, pharmacokinetics and pharmacodynamics in healthy volunteers [abstract]. J Thromb Haemost 2007;5 (Suppl 1): abstract P-M-665.Google Scholar
  56. 56.
    Frost C, Yu Z, Moore K, et al. Apixaban, an oral direct factor Xa inhibitor: multiple-dose safety, pharmacokinetics, and pharmacodynamics in healthy subjects [abstract]. J Thromb Haemost 2007;5 (Suppl 2): abstract P-M-664.Google Scholar
  57. 57.
    Frost C, Yu Z, Nepal S, et al. Apixaban, a direct Factor Xa inhibitor: single-dose pharmacokinetics and pharmacodynamics of an intravenous formulation [abstract no. 142]. J Clin Pharmacol 2008;48:1132.Google Scholar
  58. 58.
    Wang L, He K, Maxwell B, et al. Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos. 2011;39(2):256–64.PubMedCrossRefGoogle Scholar
  59. 59.
    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.PubMedCrossRefGoogle Scholar
  60. 60.
    Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594–604.PubMedCrossRefGoogle Scholar
  61. 61.
    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.PubMedCrossRefGoogle Scholar
  62. 62.
    Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–17.PubMedCrossRefGoogle Scholar
  63. 63.
    Frost CE YZ, Wang J, Li C, Zeigler C, Schuster A, Ly V, Zhang D, LaCreta F. Single-dose safety and pharmacokinetics of apixaban in subjects with mild or moderate hepatic impairment. Clin Pharmacol Ther 2009; 85 (Suppl.1): S34 (PI-84).Google Scholar
  64. 64.
    Mendell J JL, Ridout G, He L, Chen S. An open-label, phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics [abstract]. Eur Heart J 2012; 33 (Suppl 1): abstract 2024.Google Scholar
  65. 65.
    Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation. 2011;123(13):1436–50.PubMedCrossRefGoogle Scholar
  66. 66.
    Stangier J, Rathgen K, Stahle 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.PubMedCrossRefGoogle Scholar
  67. 67.
    Stangier J, Stahle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008;47(1):47–59.PubMedCrossRefGoogle Scholar
  68. 68.
    Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259–68.PubMedCrossRefGoogle Scholar
  69. 69.
    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.PubMedCrossRefGoogle Scholar
  70. 70.
    Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*): a randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105(4):721–9.PubMedCrossRefGoogle Scholar
  71. 71.
    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.PubMedCrossRefGoogle Scholar
  72. 72.
    Bayer Pharma AG. Xarelto® (rivaroxaban) aummary of product characteristics. 2012. Accessed 31 Jul 2012.
  73. 73.
    Bristol-Myers Squibb PE. Eliquis (apixaban) summary of product characteristics. 2011.®%20(apixaban)%20SmPC.pdf. Accessed 31 Jul 2012.Google Scholar
  74. 74.
    Boehringer Ingelheim IG. Pradaxa (dabigatran etexilate) summary of product characteristics. 2011. Accessed 31 Jul 2012.
  75. 75.
    DAIICHI S. LIXIANA® (edoxaban). Accessed 15 Jan 2013.
  76. 76.
    Boehringer Ingelheim Pharmaceuticals, Inc. Pradaxa (dabigatran etexilate) prescribing information. 2012. Accessed 31 Jul 2012.
  77. 77.
    Janssen Pharmaceuticals, Inc. Xarelto® (rivaroxaban) prescribing information. 2011. Accessed 31 Jul 2012.
  78. 78.
    Wychowski MK, Kouides PA. Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann Pharmacother. 2012;46(4):e10.PubMedCrossRefGoogle Scholar
  79. 79.
    Cano EL, Miyares MA. Clinical challenges in a patient with dabigatran-induced fatal hemorrhage. Am J Geriatr Pharmacother. 2012;10(2):160–3.PubMedCrossRefGoogle Scholar
  80. 80.
    Samama MM, Guinet C. Laboratory assessment of new anticoagulants. Clin Chem Lab Med. 2011;49(5):761–72.PubMedCrossRefGoogle Scholar
  81. 81.
    Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87(Suppl 1):S141–5.PubMedCrossRefGoogle Scholar
  82. 82.
    van Ryn J SP, Kink-Eiband M, Gansser D, Clemens A. Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro [abstract no. 1065]. 51st American Society of Hematology Annual Meeting and Exposition; 5–9 Dec 2009; New Orleans.Google Scholar
  83. 83.
    Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–9.PubMedCrossRefGoogle Scholar
  84. 84.
    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
  85. 85.
    Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011;62:41–57.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-UniversityFrankfurtGermany
  2. 2.Clinical Trial Centre Rhine-Main (KSRM), at the pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-UniversityFrankfurtGermany

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