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Semin Liver Dis 2019; 39(02): 195-208
DOI: 10.1055/s-0039-1679934
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Direct-Acting Oral Anticoagulants (DOACs) in Cirrhosis and Cirrhosis-Associated Portal Vein Thrombosis

Ethan M. Weinberg   *
1   Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
,
Julia Palecki   *
1   Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
,
K. Rajender Reddy
1   Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
› Author Affiliations
Further Information

Publication History

Publication Date:
12 April 2019 (online)

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Abstract

Direct-acting oral anticoagulants (DOACs) have provided benefit in patients requiring anticoagulation for certain diseases by decreasing the burden of subcutaneous injections and the requirement for frequent monitoring through regular blood tests, to ensure adequacy of the therapeutic doses. Studies have demonstrated DOACs to be as safe, and in some instance safer, compared with traditional anticoagulants in the general population. However, the studies evaluating DOACs excluded patients with cirrhosis, a condition associated with an increased risk of developing portal vein thrombosis (PVT). Warfarin or low-molecular weight heparin are the standard-of-care treatment for acute PVT in cirrhosis, although there is enthusiasm in a paradigm shift switching to DOACs for the treatment of acute PVT in cirrhosis, particularly since the release of DOAC antidotes. This article reviews the current Food and Drug Administration-approved DOACs, hepatic metabolism of DOACs, pharmacokinetics of DOACs in patients with cirrhosis, safety of DOACs (including bleeding, hepatotoxicity, and pregnancy), current treatment guidelines for PVT in cirrhosis, and studies evaluating the use of DOACs in cirrhosis and for the treatment of PVT in cirrhosis. The potential use of DOACs for PVT primary prophylaxis in at-risk patients with cirrhosis and the possible antifibrotic effects of DOACs are also discussed.

Keywords

portal vein thrombosis - cirrhosis - anticoagulation - DOAC - NOAC

* Co-First Authors.


 

  • References

  • 1 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (02) 147-156
    CrossrefPubMedGoogle Scholar
  • 2 Sarin SK, Philips CA, Kamath PS. , et al. Toward a comprehensive new classification of portal vein thrombosis in patients with cirrhosis. Gastroenterology 2016; 151 (04) 574-577.e3
    CrossrefPubMedGoogle Scholar
  • 3 Kumar A, Sharma P, Arora A. Review article: portal vein obstruction--epidemiology, pathogenesis, natural history, prognosis and treatment. Aliment Pharmacol Ther 2015; 41 (03) 276-292
    CrossrefPubMedGoogle Scholar
  • 4 Runyon BA. ; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology 2013; 57 (04) 1651-1653
    CrossrefPubMedGoogle Scholar
  • 5 Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2017; 65 (01) 310-335
    CrossrefPubMedGoogle Scholar
  • 6 Nery F, Chevret S, Condat B. , et al; Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology 2015; 61 (02) 660-667
    CrossrefPubMedGoogle Scholar
  • 7 Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther 2010; 31 (03) 366-374
    CrossrefPubMedGoogle Scholar
  • 8 Amitrano L, Guardascione MA, Brancaccio V. , et al. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 2004; 40 (05) 736-741
    CrossrefPubMedGoogle Scholar
  • 9 Qi X, De Stefano V, Wang J. , et al. Prevalence of inherited antithrombin, protein C, and protein S deficiencies in portal vein system thrombosis and Budd-Chiari syndrome: a systematic review and meta-analysis of observational studies. J Gastroenterol Hepatol 2013; 28 (03) 432-442
    CrossrefPubMedGoogle Scholar
  • 10 Zocco MA, Di Stasio E, De Cristofaro R. , et al. Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development. J Hepatol 2009; 51 (04) 682-689
    CrossrefPubMedGoogle Scholar
  • 11 Girleanu I, Stanciu C, Cojocariu C, Boiculese L, Singeap AM, Trifan A. Natural course of nonmalignant partial portal vein thrombosis in cirrhotic patients. Saudi J Gastroenterol 2014; 20 (05) 288-292
    CrossrefPubMedGoogle Scholar
  • 12 Luca A, Caruso S, Milazzo M. , et al. Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis. Radiology 2012; 265 (01) 124-132
    CrossrefPubMedGoogle Scholar
  • 13 DeLeve LD, Valla DC, Garcia-Tsao G. ; American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology 2009; 49 (05) 1729-1764
    CrossrefPubMedGoogle Scholar
  • 14 Garcia-Pagán JC, Buscarini E, Janssen HLA. , et al; European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu. EASL Clinical Practice Guidelines: vascular diseases of the liver. J Hepatol 2016; 64 (01) 179-202
    CrossrefPubMedGoogle Scholar
  • 15 Loffredo L, Pastori D, Farcomeni A, Violi F. Effects of anticoagulants in patients with cirrhosis and portal vein thrombosis: a systematic review and meta-analysis. Gastroenterology 2017; 153 (02) 480-487.e1
    CrossrefPubMedGoogle Scholar
  • 16 Yerdel MA, Gunson B, Mirza D. , et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation 2000; 69 (09) 1873-1881
    CrossrefPubMedGoogle Scholar
  • 17 Kim SJ, Kim DG, Park JH. , et al. Clinical analysis of living donor liver transplantation in patients with portal vein thrombosis. Clin Transplant 2011; 25 (01) 111-118
    CrossrefPubMedGoogle Scholar
  • 18 D'Amico G, Tarantino G, Spaggiari M. , et al. Multiple ways to manage portal thrombosis during liver transplantation: surgical techniques and outcomes. Transplant Proc 2013; 45 (07) 2692-2699
    CrossrefPubMedGoogle Scholar
  • 19 Gao PJ, Gao J, Li Z, Hu ZP, Leng XS, Zhu JY. Liver transplantation in adults with portal vein thrombosis: data from the China Liver Transplant Registry. Clin Res Hepatol Gastroenterol 2016; 40 (03) 327-332
    CrossrefPubMedGoogle Scholar
  • 20 Wu H, Nguyen GC. Liver cirrhosis is associated with venous thromboembolism among hospitalized patients in a nationwide US study. Clin Gastroenterol Hepatol 2010; 8 (09) 800-805
    CrossrefPubMedGoogle Scholar
  • 21 Ali M, Ananthakrishnan AN, McGinley EL, Saeian K. Deep vein thrombosis and pulmonary embolism in hospitalized patients with cirrhosis: a nationwide analysis. Dig Dis Sci 2011; 56 (07) 2152-2159
    CrossrefPubMedGoogle Scholar
  • 22 Saleh T, Matta F, Alali F, Stein PD. Venous thromboembolism with chronic liver disease. Am J Med 2011; 124 (01) 64-68
    CrossrefPubMedGoogle Scholar
  • 23 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 (07) 1524-1528 , quiz 1680
    CrossrefPubMedGoogle Scholar
  • 24 Anthony Lizarraga W, Dalia S, Reinert SE, Schiffman FJ. Venous thrombosis in patients with chronic liver disease. Blood Coagul Fibrinolysis 2010; 21 (05) 431-435
    CrossrefPubMedGoogle Scholar
  • 25 Gulley D, Teal E, Suvannasankha A, Chalasani N, Liangpunsakul S. Deep vein thrombosis and pulmonary embolism in cirrhosis patients. Dig Dis Sci 2008; 53 (11) 3012-3017
    CrossrefPubMedGoogle Scholar
  • 26 Walsh KA, Lewis DA, Clifford TM. , et al. Risk factors for venous thromboembolism in patients with chronic liver disease. Ann Pharmacother 2013; 47 (03) 333-339
    CrossrefPubMedGoogle Scholar
  • 27 Dabbagh O, Oza A, Prakash S, Sunna R, Saettele TM. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest 2010; 137 (05) 1145-1149
    CrossrefPubMedGoogle Scholar
  • 28 Søgaard KK, Horváth-Puhó E, Montomoli J, Vilstrup H, Sørensen HT. Cirrhosis is associated with an increased 30-day mortality after venous thromboembolism. Clin Transl Gastroenterol 2015; 6 (June): e97
    CrossrefPubMedGoogle Scholar
  • 29 Kremers RMW, Kleinegris M-C, Ninivaggi M. , et al. Decreased prothrombin conversion and reduced thrombin inactivation explain rebalanced thrombin generation in liver cirrhosis. PLoS One 2017; 12 (05) e0177020
    CrossrefPubMedGoogle Scholar
  • 30 Marra F, DeFranco R, Grappone C. , et al. Expression of the thrombin receptor in human liver: up-regulation during acute and chronic injury. Hepatology 1998; 27 (02) 462-471
    CrossrefPubMedGoogle Scholar
  • 31 Marra F, Grandaliano G, Valente AJ, Abboud HE. Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury. Hepatology 1995; 22 (03) 780-787
    PubMedGoogle Scholar
  • 32 Bogatkevich GS, Ludwicka-Bradley A, Nietert PJ, Akter T, van Ryn J, Silver RM. Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease. Arthritis Rheum 2011; 63 (05) 1416-1425
    CrossrefPubMedGoogle Scholar
  • 33 Kassel KM, Sullivan BP, Cui W, Copple BL, Luyendyk JP. Therapeutic administration of the direct thrombin inhibitor argatroban reduces hepatic inflammation in mice with established fatty liver disease. Am J Pathol 2012; 181 (04) 1287-1295
    CrossrefPubMedGoogle Scholar
  • 34 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 (02) 288-297
    CrossrefPubMedGoogle Scholar
  • 35 Mehta H, Mashiko S, Goulet P-O. , et al. Dabigatran aggravates topoisomerase I peptide-loaded dendritic cells-induced lung and skin fibrosis. Clin Exp Rheumatol 2017; 35 (04) (Suppl. 106) 35-39
    PubMedGoogle Scholar
  • 36 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 (02) 286-294
    CrossrefPubMedGoogle Scholar
  • 37 Assy N, Hussein O, Khalil A. , et al. The beneficial effect of aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of cirrhosis. Dig Dis Sci 2007; 52 (05) 1187-1193
    CrossrefPubMedGoogle Scholar
  • 38 Cerini F, Vilaseca M, Lafoz E. , et al. Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol 2016; 64 (04) 834-842
    CrossrefPubMedGoogle Scholar
  • 39 Fortea JI, Zipprich A, Fernandez-Mena C. , et al. Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis. Liver Int 2018; 38 (01) 102-112
    PubMedGoogle Scholar
  • 40 Vilaseca M, García-Calderó H, Lafoz E. , et al. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology 2017; 65 (06) 2031-2044
    CrossrefPubMedGoogle Scholar
  • 41 Oken OF, Yildirim AO, Gulcek M. , et al. The effect of prophylactic dose of a low molecular weight heparin on skin wound healing of rats. Acta Cir Bras 2009; 24 (06) 471-475
    CrossrefPubMedGoogle Scholar
  • 42 Ferlitsch M, Reiberger T, Hoke M. , et al. von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. Hepatology 2012; 56 (04) 1439-1447
    CrossrefPubMedGoogle Scholar
  • 43 Prasanna KS, Goel A, Amirtharaj GJ. , et al. Plasma von Willebrand factor levels predict in-hospital survival in patients with acute-on-chronic liver failure. Indian J Gastroenterol 2016; 35 (06) 432-440
    CrossrefPubMedGoogle Scholar
  • 44 Joshi N, Kopec AK, Ray JL. , et al. Von Willebrand factor deficiency reduces liver fibrosis in mice. Toxicol Appl Pharmacol 2017; 328: 54-59
    CrossrefPubMedGoogle Scholar
  • 45 Geys L, Bauters D, Roose E. , et al. ADAMTS13 deficiency promotes microthrombosis in a murine model of diet-induced liver steatosis. Thromb Haemost 2017; 117 (01) 19-26
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Lancellotti S, Basso M, Veca V. , et al. Presence of portal vein thrombosis in liver cirrhosis is strongly associated with low levels of ADAMTS-13: a pilot study. Intern Emerg Med 2016; 11 (07) 959-967
    CrossrefPubMedGoogle Scholar
  • 47 Villa E, Cammà C, Marietta M. , et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143 (05) 1253-1260.e4
    CrossrefPubMedGoogle Scholar
  • 48 De Caterina R, Husted S, Wallentin L. , et al; General mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013; 109 (04) 569-579
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Barnes GD, Ageno W, Ansell J, Kaatz S. ; Subcommittee on the Control of Anticoagulation of the International Society on Thrombosis and Haemostasis. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (06) 1154-1156
    CrossrefPubMedGoogle Scholar
  • 50 Cohen AT, Spiro TE, Büller HR. , et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (06) 513-523
    CrossrefPubMedGoogle Scholar
  • 51 Bauersachs R, Berkowitz SD, Brenner B. , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedGoogle Scholar
  • 52 Agnelli G, Buller HR, Cohen A. , et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
    CrossrefPubMedGoogle Scholar
  • 53 Eriksson BI, Dahl OE, Rosencher N. , et al; RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5 (11) 2178-2185
    CrossrefPubMedGoogle Scholar
  • 54 Schulman S, Kearon C, Kakkar AK. , et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (08) 709-718
    CrossrefPubMedGoogle Scholar
  • 55 Connolly SJ, Ezekowitz MD, Yusuf S. , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
    CrossrefPubMedGoogle Scholar
  • 56 Giugliano RP, Ruff CT, Braunwald E. , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
    CrossrefPubMedGoogle Scholar
  • 57 Büller HR, Décousus H, Grosso MA. , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
    CrossrefPubMedGoogle Scholar
  • 58 Cohen AT, Harrington RA, Goldhaber SZ. , et al; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016; 375 (06) 534-544
    CrossrefPubMedGoogle Scholar
  • 59 Weitz JI, Lensing AWA, Prins MH. , et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
    CrossrefPubMedGoogle Scholar
  • 60 Patel MR, Mahaffey KW, Garg J. , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
    CrossrefPubMedGoogle Scholar
  • 61 Büller HR, Prins MH, Lensin AW. , et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
    CrossrefPubMedGoogle Scholar
  • 62 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 (06) 594-604
    CrossrefPubMedGoogle Scholar
  • 63 Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. ; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363 (26) 2487-2498
    CrossrefPubMedGoogle Scholar
  • 64 Goldhaber SZ, Leizorovicz A, Kakkar AK. , et al; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365 (23) 2167-2177
    CrossrefPubMedGoogle Scholar
  • 65 Connolly SJ, Eikelboom J, Joyner C. , et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364 (09) 806-817
    CrossrefPubMedGoogle Scholar
  • 66 Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev 2018; 3: CD008980
    PubMedGoogle Scholar
  • 67 Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database Syst Rev 2015; (06) CD010956
    PubMedGoogle Scholar
  • 68 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 (01) 89-98
    CrossrefPubMedGoogle Scholar
  • 69 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 (04) 243-254
    CrossrefPubMedGoogle Scholar
  • 70 Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor Xa inhibitor. Drugs 2011; 71 (12) 1503-1526
    CrossrefPubMedGoogle Scholar
  • 71 Mendell J, Johnson L, Ridout G, He L, Chen S. An open-label phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics. Eur Heart J 2012; 33 (S1): Abstract 2024
    PubMedGoogle Scholar
  • 72 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: 343-351
    PubMedGoogle Scholar
  • 73 Clinicaltrials NIH. gov. The Effect of Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Betrixaban, an Oral FXa Antagonist. Available at: https://clinicaltrials.gov/ct2/show/NCT03397888 . Accessed September 24, 2018
    PubMedGoogle Scholar
  • 74 De Gottardi A, Seijo S, Plessier A. , et al. O077: use of direct oral anticoagulants (DOACs) in patients with splanchnic vein thrombosis and/or cirrhosis. J Hepatol 2015; 62: S229
    PubMedGoogle Scholar
  • 75 De Gottardi A, Trebicka J, Klinger C. , et al; VALDIG Investigators. Antithrombotic treatment with direct-acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis. Liver Int 2017; 37 (05) 694-699
    CrossrefPubMedGoogle Scholar
  • 76 Hum J, Shatzel JJ, Jou JH, Deloughery TG. The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis. Eur J Haematol 2017; 98 (04) 393-397
    CrossrefPubMedGoogle Scholar
  • 77 Intagliata NM, Henry ZH, Maitland H. , et al. Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation. Dig Dis Sci 2016; 61 (06) 1721-1727
    CrossrefPubMedGoogle Scholar
  • 78 Nagaoki Y, Aikata H, Daijyo K. , et al. Efficacy and safety of edoxaban for treatment of portal vein thrombosis following danaparoid sodium in patients with liver cirrhosis. Hepatol Res 2018; 48 (01) 51-58
    CrossrefPubMedGoogle Scholar
  • 79 Hanafy AS, Abd-Elsalam S, Dawoud MM. Randomized controlled trial of rivaroxaban versus warfarin in the management of acute non-neoplastic portal vein thrombosis. Vascul Pharmacol 2018; S1537-1891(18)30099-5
    PubMedGoogle Scholar
  • 80 Scheiner B, Stammet PR, Pokorny S. , et al. Anticoagulation in non-malignant portal vein thrombosis is safe and improves hepatic function. Wien Klin Wochenschr 2018 Doi: 10.1007/s00508-018-1351-y
    PubMedGoogle Scholar
  • 81 Pastori D, Lip GYH, Farcomeni A. , et al; ATHERO-AF study group. Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants. Int J Cardiol 2018; 264: 58-63
    CrossrefPubMedGoogle Scholar
  • 82 Janczak DT, Mimier MK, McBane RD. , et al. Rivaroxaban and apixaban for initial treatment of acute venous thromboembolism of atypical location. Mayo Clin Proc 2018; 93 (01) 40-47
    CrossrefPubMedGoogle Scholar
  • 83 Intagliata NM, Maitland H, Northup PG, Caldwell SH. Treating thrombosis in cirrhosis patients with new oral agents: ready or not?. Hepatology 2015; 61 (02) 738-739
    CrossrefPubMedGoogle Scholar
  • 84 Lenz K, Dieplinger B, Buder R, Piringer P, Rauch M, Voglmayr M. Successful treatment of partial portal vein thrombosis (PVT) with low dose rivaroxaban. Z Gastroenterol 2014; 52 (10) 1175-1177
    Article in Thieme ConnectPubMedGoogle Scholar
  • 85 Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by nontraditional anticoagulation. Hepatology 2014; 60 (01) 425-426
    CrossrefPubMedGoogle Scholar
  • 86 Qi X, Yoshida EM, Mendez-Sanchez N, Guo X. Rivaroxaban recanalized occlusive superior mesenteric vein thrombosis, but increased the risk of bleeding in a cirrhotic patient. Liver Int 2017; 37 (10) 1574-1575
    CrossrefPubMedGoogle Scholar
  • 87 Yang H, Kim SR, Song MJ. Recurrent acute portal vein thrombosis in liver cirrhosis treated by rivaroxaban. Clin Mol Hepatol 2016; 22 (04) 499-502
    CrossrefPubMedGoogle Scholar
  • 88 Pannach S, Babatz J, Beyer-Westendorf J. Successful treatment of acute portal vein thrombosis with rivaroxaban. Thromb Haemost 2013; 110 (04) 626-627
    Article in Thieme ConnectPubMedGoogle Scholar
  • 89 NIH ClinicalTrials.gov. Multicenter Prospective Randomized Trial of the Effect of Rivaroxaban on Survival and Development of Complications of Portal Hypertension in Patients with Cirrhosis. Available at: https://clinicaltrials.gov/ct2/show/NCT02643212 . Accessed September 24, 2018
    PubMedGoogle Scholar
  • 90 NIH ClinicalTrials.gov. Xarelto Versus no Treatment for the Prevention of Recurrent Thrombosis in Patients With Chronic Portal Vein Thrombosis. Available at: https://clinicaltrials.gov/ct2/show/NCT02555111 . Accessed September 24, 2018
    PubMedGoogle Scholar
  • 91 Ponziani FR, De Candia E, De Cristofaro R, Pompili M. Portal vein thrombosis occurrence in a cirrhotic patient during treatment with rivaroxaban. Liver Int 2017; 37 (08) 1251
    CrossrefPubMedGoogle Scholar
  • 92 Cutts BA, Dasgupta D, Hunt BJ. New directions in the diagnosis and treatment of pulmonary embolism in pregnancy. Am J Obstet Gynecol 2013; 208 (02) 102-108
    CrossrefPubMedGoogle Scholar
  • 93 Bapat P, Kedar R, Lubetsky A. , et al. Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta. Obstet Gynecol 2014; 123 (06) 1256-1261
    CrossrefPubMedGoogle Scholar
  • 94 Bapat P, Pinto LSR, Lubetsky A, Berger H, Koren G. Rivaroxaban transfer across the dually perfused isolated human placental cotyledon. Am J Obstet Gynecol 2015; 213 (05) 710.e1-710.e6
    CrossrefPubMedGoogle Scholar
  • 95 Bapat P, Pinto LSRR, Lubetsky A. , et al. Examining the transplacental passage of apixaban using the dually perfused human placenta. J Thromb Haemost 2016; 14 (07) 1436-1441
    CrossrefPubMedGoogle Scholar
  • 96 Hoeltzenbein M, Beck E, Meixner K, Schaefer C, Kreutz R. Pregnancy outcome after exposure to the novel oral anticoagulant rivaroxaban in women at suspected risk for thromboembolic events: a case series from the German Embryotox Pharmacovigilance Centre. Clin Res Cardiol 2016; 105 (02) 117-126
    CrossrefPubMedGoogle Scholar
  • 97 Beyer-Westendorf J, Michalski F, Tittl L. , et al. Pregnancy outcome in patients exposed to direct oral anticoagulants - and the challenge of event reporting. Thromb Haemost 2016; 116 (04) 651-658
    Article in Thieme ConnectPubMedGoogle Scholar
  • 98 Wang L, He K, Maxwell B. , et al. Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos 2011; 39 (02) 256-264
    CrossrefPubMedGoogle Scholar
  • 99 Wiesen MHJ, Blaich C, Müller C, Streichert T, Pfister R, Michels G. The direct factor Xa inhibitor rivaroxaban passes into human breast milk. Chest 2016; 150 (01) e1-e4
    CrossrefPubMedGoogle Scholar
  • 100 Ruff CT, Giugliano RP, Braunwald E. , et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383 (9921): 955-962
    CrossrefPubMedGoogle Scholar
  • 101 Coleman CI, Peacock WF, Bunz TJ, Alberts MJ. Effectiveness and safety of apixaban, dabigatran, and rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and previous stroke or transient ischemic attack. Stroke 2017; 48 (08) 2142-2149
    CrossrefPubMedGoogle Scholar
  • 102 Lip GYH, Pan X, Kamble S. , et al. Major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin: a “real-world” observational study in the United States. Int J Clin Pract 2016; 70 (09) 752-763
    CrossrefPubMedGoogle Scholar
  • 103 Jacobs V, May HT, Bair TL. , et al. Long-term population-based cerebral ischemic event and cognitive outcomes of direct oral anticoagulants compared with warfarin among long-term anticoagulated patients for atrial fibrillation. Am J Cardiol 2016; 118 (02) 210-214
    CrossrefPubMedGoogle Scholar
  • 104 Abraham NS, Singh S, Alexander GC. , et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ 2015; 350 (02) h1857-h1857
    CrossrefPubMedGoogle Scholar
  • 105 Chang H-Y, Zhou M, Tang W, Alexander GC, Singh S. Risk of gastrointestinal bleeding associated with oral anticoagulants: population based retrospective cohort study. BMJ 2015; 350 (01) h1585-h1585
    CrossrefPubMedGoogle Scholar
  • 106 Cangemi DJ, Krill T, Weideman R, Cipher DJ, Spechler SJ, Feagins LA. A comparison of the rate of gastrointestinal bleeding in patients taking non-vitamin K antagonist oral anticoagulants or warfarin. Am J Gastroenterol 2017; 112 (05) 734-739
    CrossrefPubMedGoogle Scholar
  • 107 Nagata N, Yasunaga H, Matsui H. , et al. Therapeutic endoscopy-related GI bleeding and thromboembolic events in patients using warfarin or direct oral anticoagulants: results from a large nationwide database analysis. Gut 2018; 67 (10) 1805-1812
    CrossrefPubMedGoogle Scholar
  • 108 Reilly PA, Lehr T, Haertter S. , et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
    CrossrefPubMedGoogle Scholar
  • 109 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 (07) 550-556
    CrossrefPubMedGoogle Scholar
  • 110 Raschi E, Poluzzi E, Koci A. , et al. 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; 80 (02) 285-293
    CrossrefPubMedGoogle Scholar
  • 111 Bunchorntavakul C, Reddy KR. Drug hepatotoxicity: newer agents. Clin Liver Dis 2017; 21 (01) 115-134
    CrossrefPubMedGoogle Scholar
  • 112 Anastasia EJ, Rosenstein RS, Bergsman JA, Parra D. Use of apixaban after development of suspected rivaroxaban-induced hepatic steatosis; a case report. Blood Coagul Fibrinolysis 2015; 26 (06) 699-702
    CrossrefPubMedGoogle Scholar
  • 113 Tomaselli GF, Mahaffey KW, Cuker A. , et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017; 70 (24) 3042-3067
    CrossrefPubMedGoogle Scholar
  • 114 Pollack Jr CV, Reilly PA, Eikelboom J. , et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373 (06) 511-520
    CrossrefPubMedGoogle Scholar
  • 115 Pollack Jr CV, Reilly PA, van Ryn J. , et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377 (05) 431-441
    CrossrefPubMedGoogle Scholar
  • 116 Connolly SJ, Milling Jr TJ, Eikelboom JW. , et al; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; 375 (12) 1131-1141
    CrossrefPubMedGoogle Scholar
  • 117 De Gottardi A, Garcia-Pagan JC. ; VALDIG Investigators. The anticoagulant efficacy of rivaroxaban may be attenuated in cirrhotic patients. Liver Int 2017; 37 (08) 1252
    PubMedGoogle Scholar
  • 118 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 (02) e88390
    CrossrefPubMedGoogle Scholar