Safety of direct oral anticoagulants in patients with advanced liver disease

Georg Semmler; Katharina Pomej; David J M Bauer; Lorenz Balcar; Benedikt Simbrunner; Teresa Binter; Lukas Hartl; Jeannette Becker; Matthias Pinter; Peter Quehenberger; Michael Trauner; Mattias Mandorfer; Ton Lisman; Thomas Reiberger; Bernhard Scheiner

doi:10.1111/liv.14992

Safety of direct oral anticoagulants in patients with advanced liver disease

Liver Int. 2021 Sep;41(9):2159-2170. doi: 10.1111/liv.14992. Epub 2021 Jul 10.

Authors

Georg Semmler^{1

2}, Katharina Pomej^{1

2}, David J M Bauer^{1

2}, Lorenz Balcar^{1

2}, Benedikt Simbrunner^{1

2

3}, Teresa Binter^{1

2}, Lukas Hartl^{1

2}, Jeannette Becker^{1

2}, Matthias Pinter^{1

2}, Peter Quehenberger⁴, Michael Trauner¹, Mattias Mandorfer^{1

2}, Ton Lisman⁵, Thomas Reiberger^{1

2

3}, Bernhard Scheiner^{1

2}

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
² Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria.
³ Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
⁴ Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
⁵ Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Abstract

Background & aims: While direct oral anticoagulants (DOACs) are increasingly used in patients with liver disease, safety data especially in advanced chronic liver disease (ACLD) are limited.

Methods: Liver disease patients receiving DOAC treatment (ACLD: n = 104; vascular liver disease: n = 29) or vitamin K antagonists (VKA)/low-molecular-weight heparin (LMWH; ACLD: n = 45; vascular: n = 13) between January 2010 and September 2020 were retrospectively included. Invasive procedures and bleeding events were recorded. Calibrated anti-Xa peak levels and thrombomodulin-modified thrombin generation assays (TM-TGAs) were measured in a subgroup of 35/28 DOAC patients.

Results: Among patients receiving DOAC, 55 (41.3%) had advanced liver dysfunction (Child-Pugh-stage [CPS] B/C) and 66 (49.6%) had experienced decompensation. Overall, 205 procedures were performed in 60 patients and procedure-related bleedings occurred in 7 (11.7%) patients. Additionally, 38 (28.6%) patients experienced spontaneous (15 minor, 23 major) bleedings during a median follow-up of 10.5 (IQR: 4.0-27.8) months. Spontaneous bleedings in ACLD patients were more common in CPS-B/C (at 12 months: 36.9% vs CPS-A: 15.9%, subdistribution hazard ratio [SHR]: 3.23 [95% CI: 1.59-6.58], P < .001), as were major bleedings (at 12 months: 22.0% vs 5.0%, SHR: 5.82 [95% CI: 2.00-16.90], P < .001). Importantly, CPS (adjusted SHR: 4.12 [91% CI: 1.82-9.37], P < .001), but not the presence of hepatocellular carcinoma or varices, was independently associated with major bleeding during DOAC treatment. Additionally, ACLD patients experiencing bleeding had worse overall survival (at 12 months: 88.9% vs 95.0% without bleeding; P < .001). Edoxaban anti-Xa peak levels were higher in patients with CPS-B/C (345 [95% CI: 169-395] vs CPS-A: 137 [95% CI: 96-248] ng/mL, P = .048) and were associated with lower TM-TGA. Importantly, spontaneous bleeding rates were comparable to VKA/LMWH patients.

Conclusions: Anticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.

Keywords: ACLD; DOAC; NOAC; bleeding; edoxaban; vascular liver disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Anticoagulants / adverse effects
Heparin, Low-Molecular-Weight*
Humans
Liver Diseases* / complications
Liver Diseases* / drug therapy
Retrospective Studies
Vitamin K

Substances

Anticoagulants
Heparin, Low-Molecular-Weight
Vitamin K