Safety of direct oral anticoagulants in patients with liver disease: a systematic review and meta-analysis

Direct oral anticoagulants (DOACs), such as apixaban, edoxaban, rivaroxaban, or dabigatran, are an effective treatment for atrial fibrillation (AF) and deep venous thromboembolism. We hope to evaluate the safety of DOACs versus warfarin/low molecular weight heparin (LMWH) in improving bleeding events in patients with different severity of the liver disease. We systematically searched the Cochrane Library, PubMed, and Embase databases for studies reporting the effects of DOACs in patients with liver cirrhosis. A random-effects model or fixed-effects model was selected to pool risk ratios (RR) and 95% confidence intervals (CI). A total of 18 studies involving 41,447 participants was included in this meta-analysis. Compare with warfarin/ LMWH, the use of DOACs significantly reduced the incidence of all bleeding (RR: 0.76; 95%CI: 0.66 to 0.87), major bleeding (RR: 0.51; 95%CI: 0.28 to 0.91), intracranial hemorrhage (RR: 0.50; 95%CI: 0.31 to 0.81), and gastrointestinal bleeding (RR: 0.76, 95% CI: 0.60 to 0.97), and all-cause death in patients with liver disease (RR: 0.77; 95%CI: 0.62 to 0.95). Similar results were observed in atrial fibrillation patients with liver disease and cirrhosis subgroups. Furthermore, the pooled estimates of the Child-Turcotte-Pugh (CTP) class indicated that DOACs reduced the incidence of all bleeding (RR: 0.61; 95%CI: 0.45 to 0.82), gastrointestinal bleeding (RR 0.55; 95%CI: 0.37 to 0.83), and all-cause death (RR: 0.62; 95%CI: 0.49 to 0.79) in patients with mild to moderate cirrhosis. Our study demonstrates that DOACs significantly reduce the risk of bleeding in patients with liver disease compared with warfarin/LMWH.

直接口服抗凝药（Direct oral anticoagulants, DOACs），如阿哌沙班、依度沙班、利伐沙班或达比加群，是治疗心房颤动（atrial fibrillation, AF）与深静脉血栓栓塞症的有效手段。本研究旨在评估相较于华法林/低分子肝素（low molecular weight heparin, LMWH），DOACs在不同严重程度肝病患者中改善出血事件的安全性。我们系统检索了考克兰图书馆、PubMed及Embase数据库，筛选关于DOACs用于肝硬化患者的相关研究。采用随机效应模型或固定效应模型合并风险比（risk ratios, RR）与95%置信区间（confidence intervals, CI）。本荟萃分析共纳入18项研究，涉及41447名受试者。相较于华法林/LMWH，DOACs的使用可显著降低所有出血事件（RR=0.76；95%CI：0.66~0.87）、大出血事件（RR=0.51；95%CI：0.28~0.91）、颅内出血（RR=0.50；95%CI：0.31~0.81）与胃肠道出血（RR=0.76；95%CI：0.60~0.97）的发生率，同时降低肝病患者的全因死亡风险（RR=0.77；95%CI：0.62~0.95）。在合并肝病的房颤患者及肝硬化亚组中也观察到了相似结果。此外，针对Child-Turcotte-Pugh（CTP）分级的合并分析显示，在轻中度肝硬化患者中，DOACs可降低所有出血事件（RR=0.61；95%CI：0.45~0.82）、胃肠道出血（RR=0.55；95%CI：0.37~0.83）与全因死亡（RR=0.62；95%CI：0.49~0.79）的发生率。本研究表明，相较于华法林/LMWH，DOACs可显著降低肝病患者的出血风险。