Skip to main content
Top
Published in: Digestive Diseases and Sciences 6/2016

01-06-2016 | Original Article

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

Authors: N. M. Intagliata, Z. H. Henry, H. Maitland, N. L. Shah, C. K. Argo, P. G. Northup, S. H. Caldwell

Published in: Digestive Diseases and Sciences | Issue 6/2016

Login to get access

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.
Literature
1.
go back to reference Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013;11:1064–1074.CrossRefPubMed Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013;11:1064–1074.CrossRefPubMed
2.
go back to reference Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365:147–156.CrossRefPubMed Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365:147–156.CrossRefPubMed
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
4.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
6.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
7.
go back to reference 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. 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.
8.
go back to reference 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.PubMed 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.PubMed
9.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
11.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
12.
go back to reference Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by nontraditional anticoagulation. Hepatology. 2014;60:425–426.CrossRefPubMed Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by nontraditional anticoagulation. Hepatology. 2014;60:425–426.CrossRefPubMed
13.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
14.
go back to reference Tripodi A, Primignani M, Chantarangkul V, Mannucci PM. Pro-coagulant imbalance in patients with chronic liver disease. J Hepatol. 2010;53:586–587.CrossRefPubMed Tripodi A, Primignani M, Chantarangkul V, Mannucci PM. Pro-coagulant imbalance in patients with chronic liver disease. J Hepatol. 2010;53:586–587.CrossRefPubMed
15.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
16.
go back to reference Morrill AM, Ge D, Willett KC. Dosing of target-specific oral anticoagulants in special populations. Ann Pharmacother. 2015;49:1031–1045.CrossRefPubMed Morrill AM, Ge D, Willett KC. Dosing of target-specific oral anticoagulants in special populations. Ann Pharmacother. 2015;49:1031–1045.CrossRefPubMed
17.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
18.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
21.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
22.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
23.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
24.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
25.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
26.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
27.
go back to reference Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost. 2014;111:189–198.CrossRefPubMed Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost. 2014;111:189–198.CrossRefPubMed
28.
go back to reference Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511–520.CrossRefPubMed Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373:511–520.CrossRefPubMed
29.
go back to reference 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.CrossRef 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.CrossRef
30.
go back to reference Russmann S, Niedrig DF, Budmiger M, et al. Rivaroxaban postmarketing risk of liver injury. J Hepatol. 2014;61:293–300.CrossRefPubMed Russmann S, Niedrig DF, Budmiger M, et al. Rivaroxaban postmarketing risk of liver injury. J Hepatol. 2014;61:293–300.CrossRefPubMed
31.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
32.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
33.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
34.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
35.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
Metadata
Title
Direct Oral Anticoagulants in Cirrhosis Patients Pose Similar Risks of Bleeding When Compared to Traditional Anticoagulation
Authors
N. M. Intagliata
Z. H. Henry
H. Maitland
N. L. Shah
C. K. Argo
P. G. Northup
S. H. Caldwell
Publication date
01-06-2016
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 6/2016
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-015-4012-2

Other articles of this Issue 6/2016

Digestive Diseases and Sciences 6/2016 Go to the issue