Safety of direct oral anticoagulants in patients with advanced liver disease

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.

Haemostatic alterations and management of haemostasis in patients with cirrhosis

“…135 However, more recently, experience with DOAC use in patients with Child-Pugh B/C cirrhosis reveals increased bleeding rates in patients with advanced cirrhosis. 136,137 Therefore, caution is required when using DOACs in patients with cirrhosis and further studies are needed.…”

Consensus Statement on Hemostatic Management, Anticoagulation, and Antiplatelet Therapy in Liver Transplantation

“…In patients with Child-Pugh class B, rivaroxaban and edoxaban are contraindicated, while dabigatran and apixaban may be used with caution. In Child-Pugh C patients, direct oral anticoagulants are associated with a high risk of bleeding events 20 and they are contraindicated. 2 Antiplatelet therapies aim to reduce or slow down platelet aggregation, thus precluding thrombus formation.…”

Portal Vein Thrombosis in the Setting of Cirrhosis: A Comprehensive Review

“…Several retrospective studies [ 143 , 144 , 145 , 146 , 147 ] and meta-analyses [ 148 , 149 ] have observed a similar or better safety profile in terms of bleeding complications of DOACs compared to VKAs in cirrhotic patients affected by atrial fibrillation, venous thromboembolism, or PVT. Bleeding definitions differed among these studies, and to control for this bias, Nisly et al conducted a systematic review and meta-analysis considering only studies in which the primary safety outcome was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis.…”