Safety of direct oral anticoagulants (DOACs) in patients with advanced liver disease

Background 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 01/2010-09/2020 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 DOAC patients.

Results Among patients receiving DOAC, 55 (41.3 %) had advanced liver dysfunction (Child-Turcotte-Pugh [CTP] 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 CTP-B/C (at 12 months:36.9 % vs. CTP-A:15.9 %, subdistribution hazard ratio [SHR]: 3.23 [95 %CI: 1.59-6.58], p<0.001), as were major bleedings (at 12 months: 22.0 % vs. 5.0 %, SHR: 5.82 [95 %CI: 2.00-16.90], p<0.001). Importantly, CTP (adjusted SHR: 4.12 [91 %CI: 1.82-9.37], p<0.001), 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 % without bleeding; p<0.001). Edoxaban anti-Xa peak levels were higher in patients with CTP-B/C (345 [95 %CI: 169-395] vs. CTP-A:137 [95 %CI: 96-248]ng/ml, p = 0.048), and were associated with lower TM-TGA. Importantly, spontaneous bleeding rates and procedure-related bleedings were comparable to

VKA/LMWH patients with CTP-B/C being the only factor independently associated with major bleedings.

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

Publikationsverlauf

Artikel online veröffentlicht:
01. September 2021