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Abstract：
While direct oral anticoagulants (DOACs) are increasingly used in patients with liver disease, safety data especially in advanced chronic liver disease (ACLD) are limited.
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.
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.
Anticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.
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.
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.
Anticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.
摘要：
虽然直接口服抗凝剂（DOAC）越来越多地用于肝病患者，安全性数据,尤其是晚期慢性肝病(ACLD)的安全性数据有限.
回顾性纳入2010年1月至2020年9月期间接受DOAC治疗（ACLD：n=104；血管性肝病：n=29）或维生素K拮抗剂（VKA）/低分子量肝素（LMWH；ACLD：n=45；血管：n=13）的肝病患者。记录侵入性程序和出血事件。在35/28名DOAC患者的亚组中测量了校准的抗Xa峰水平和血栓调节蛋白修饰的凝血酶生成测定(TM-TGA)。
在接受DOAC的患者中，55（41.3％）患有晚期肝功能障碍（Child-Pugh期[CPS]B/C），66（49.6％）患有代偿失调。总的来说,在60例患者中进行了205例手术，在7例（11.7％）患者中发生了与手术相关的出血。此外,38例(28.6%)患者经历了自发性(15例轻微，23个主要）出血，中位随访时间为10.5个月（IQR：4.0-27.8个月）。ACLD患者的自发性出血在CPS-B/C中更为常见（12个月时：36.9％vsCPS-A：15.9％，子分布危险比[SHR]：3.23[95%CI：1.59-6.58]，P<.001),主要出血(12个月时：22.0%vs5.0%，SHR：5.82[95%CI：2.00-16.90]，P<.001)。重要的是,CPS（调整后的SHR：4.12[91%CI：1.82-9.37]，P<.001),但不是肝细胞癌或静脉曲张的存在，在DOAC治疗期间与大出血独立相关。此外,经历出血的ACLD患者总生存期较差（12个月时：88.9%vs无出血的95.0%；P<.001）。CPS-B/C患者的依多沙班抗Xa峰值水平较高(345[95%CI:169-395]vsCPS-A:137[95%CI:96-248]ng/mL,P=0.048)，并与较低的TM-TGA相关。重要的是,自发性出血率与VKA/LMWH患者相当.
晚期肝病患者应谨慎使用包括DOAC在内的抗凝剂，因为自发性出血事件发生率显著。
回顾性纳入2010年1月至2020年9月期间接受DOAC治疗（ACLD：n=104；血管性肝病：n=29）或维生素K拮抗剂（VKA）/低分子量肝素（LMWH；ACLD：n=45；血管：n=13）的肝病患者。记录侵入性程序和出血事件。在35/28名DOAC患者的亚组中测量了校准的抗Xa峰水平和血栓调节蛋白修饰的凝血酶生成测定(TM-TGA)。
在接受DOAC的患者中，55（41.3％）患有晚期肝功能障碍（Child-Pugh期[CPS]B/C），66（49.6％）患有代偿失调。总的来说,在60例患者中进行了205例手术，在7例（11.7％）患者中发生了与手术相关的出血。此外,38例(28.6%)患者经历了自发性(15例轻微，23个主要）出血，中位随访时间为10.5个月（IQR：4.0-27.8个月）。ACLD患者的自发性出血在CPS-B/C中更为常见（12个月时：36.9％vsCPS-A：15.9％，子分布危险比[SHR]：3.23[95%CI：1.59-6.58]，P<.001),主要出血(12个月时：22.0%vs5.0%，SHR：5.82[95%CI：2.00-16.90]，P<.001)。重要的是,CPS（调整后的SHR：4.12[91%CI：1.82-9.37]，P<.001),但不是肝细胞癌或静脉曲张的存在，在DOAC治疗期间与大出血独立相关。此外,经历出血的ACLD患者总生存期较差（12个月时：88.9%vs无出血的95.0%；P<.001）。CPS-B/C患者的依多沙班抗Xa峰值水平较高(345[95%CI:169-395]vsCPS-A:137[95%CI:96-248]ng/mL,P=0.048)，并与较低的TM-TGA相关。重要的是,自发性出血率与VKA/LMWH患者相当.
晚期肝病患者应谨慎使用包括DOAC在内的抗凝剂，因为自发性出血事件发生率显著。
