Safety of Direct Oral Anticoagulants in Patients with Cirrhosis: A Systematic Review and Meta-Analysis
Authors: Lapumnuaypol Kamolyut , Chiasakul Thita 
Published: October 2019

Abstract
Introduction: The coagulopathy of cirrhosis is characterized by a complex rebalanced hemostasis which increases the risk of bleeding as well as thrombosis. For the treatment and prevention of thromboembolism, low-molecular weight heparin (LMWH) and vitamin K antagonists, such as warfarin, are generally used in cirrhotic patients. Although efficacious, these agents are inconvenient due to the parenteral route of administration, need for monitoring, and interactions with food or drugs. Direct oral anticoagulants (DOACs) may provide safe and effective alternatives for patients with cirrhosis. However, data concerning their safety profile in this population are limited given that patients with advanced liver diseases were excluded from most clinical trials. To address this, we conducted a systematic review and meta-analysis to evaluate the safety of DOACs compared to warfarin or low-molecular weight heparin (LMWH) in patients with cirrhosis.
Methods: A systematic literature search was performed using MEDLINE and EMBASE from inception up to June 2018. We included prospective and retrospective studies involving adults ≥18 years with cirrhosis of any stage in whom anticoagulants were indicated for any indications. Included studies are required to report the incidence, odds ratio, or hazard ratio of bleeding events in both patients receiving DOACs and patients receiving warfarin or LMWH (controls). Two authors independently searched the literature, screened for eligibility, and extracted the data. Any discrepancies were resolved by reaching consensus. Primary outcome of interest was all-cause bleeding events. Secondary outcome was major bleeding. Data analysis was performed using Review Manager version 5.3. For all-cause bleeding, pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using Mantel-Haenszel method. For major bleeding, effect estimates and standard errors from individual studies were combined by the generic inverse variance method of DerSimonian and Laird. Random-effects model was used in all analyses. Inter-study heterogeneity was evaluated using Cochran's Q test and I2statistics.
Results: A total of 279 articles were identified from MEDLINE and EMBASE, of which 93 were removed because of duplication. After screening by title and abstract, 174 articles were excluded. Full text of 12 articles were reviewed, of which 5 studies (4 observational studies and 1 randomized controlled trial) with a total of 447 patients met eligibility criteria and were included in the final analysis. The indications for anticoagulants included atrial fibrillation, deep venous thrombosis, pulmonary embolism, and portal vein thrombosis. The DOACs used in these studies included dabigatran, rivaroxaban, apixaban, and edoxaban. Heterogeneity among studies was low to moderate. Compared to controls, the use of DOACs in cirrhotic patients did not show any significant difference in all-cause bleeding (RR 0.72; 95% CI, 0.32-1.63; I2=59%, Figure 1). Among 3 studies that reported major bleeding, there was no significant difference in major bleeding between both groups (OR 0.46; 95% CI, 0.10-2.09; I2=42%, Figure 2).
Conclusions: Our study demonstrates that, compared to those who were treated with traditional anticoagulants, cirrhotic patients who were treated with DOACs had no significant increase risk of all-cause bleeding and major bleeding. The use of DOACs in patents with cirrhosis appears to be as safe as traditional anticoagulants. Further randomized controlled studies involving larger numbers of patients are required to explore the efficacy as well as potential beneficial effects of DOACs for each indications in cirrhotic patients.

Disclosures
No relevant conflicts of interest to declare.