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Abstract

Objective

Currently, there is limited evidence regarding the use of direct oral anticoagulants (DOACs) for patients with liver cirrhosis (LC). We performed a meta-analysis to compare the efficacy and safety of DOACs versus warfarin in this population.

Methods

We searched PubMed, Cochrane Library, Web of Science, Embase and Scopus databases from inception to August 2024. Clinical studies comparing the use of DOACs with warfarin in cirrhotic patients were included. Hazard ratios (HRs) with 95% CIs were estimated by either fixed or random effects models. Primary efficacy outcomes were ischemic stroke/thromboembolism (IS/TE) and all-cause death, the primary safety outcomes were the bleeding risks.

Results

Sixteen studies were included (16 829 individuals). DOACs had similar benefits in preventing IS/TE (HR = 0.87, 95% CI: 0.69-1.10), but DOACs were significantly associated with reduced risk of all-cause death (HR = 0.87, 95% CI: 0.79-0.97). On the other hand, we observed significantly reduced risks of any bleeding (HR = 0.60; 95%CI: 0.37-0.95), major bleeding (HR = 0.72; 95%CI: 0.63-0.82), intracranial hemorrhage (ICH) (HR = 0.47; 95%CI: 0.30-0.73), and gastrointestinal bleeding (GIB) (HR = 0.72, 95% CI: 0.60-0.87) in patients receiving DOACs. Results were consistent in cirrhotic patients with AF. Furthermore, DOACs reduced the incidence of major bleeding (HR = 0.65, 95%CI: 0.55-0.78) and ICH (HR = 0.17, 95%CI: 0.04-0.76) in patients with moderate to severe cirrhosis.

Conclusion

Our study demonstrates that DOACs, compared with warfarin, exerted comparable efficacy and better safety and may represent a safer alternative to warfarin in cirrhotic patients.

Keywords

liver cirrhosis direct oral anticoagulants warfarin meta-analysis

Introduction

Patients with cirrhosis are at a higher risk of both bleeding and thrombosis due to an imbalance between pro- and anticoagulant homeostasis.^1,2 Studies have confirmed that patients with cirrhosis are prone to experience thrombosis in the portal as well as systemic circulation venous,³ which was linked to the altered hemostatic balance, in particular, an increase in thrombin generation as well as a decrease in coagulation factors except for factor VIII.^4-6 Recent investigations indicated that patients with LC had a higher risk of stroke or venous thromboembolism (VTE) than those without LC.^7-10 Additionally, atrial fibrillation (AF) is more common in patients with cirrhosis.^11-14 A previous study reported higher risks of stroke and ICH in cirrhotic patients with AF than patients with AF alone.⁷ Furthermore, available research shows that hypercoagulability may promote hepatic decompensation and the development of fibrosis,¹⁵ whereas prophylactic anticoagulation appears to improve clinical outcomes in patients with cirrhosis by delaying the occurrence of hepatic decompensation.¹⁶ Therefore, patients with cirrhosis may have AF in addition to other risk factors for thromboembolic events and treatment with anticoagulants should be considered.

Vitamin K antagonists (VKAs) are currently considered the standard of care for stroke prevention in AF, and they also serve as the standard treatment for VTE prevention in patients with cirrhosis.⁶ VKAs, particularly warfarin, have been used for the management and prophylaxis of thrombosis in LC.^7,17 Despite the proven efficacy, its narrow therapeutic index and dose adjustment requirements limited the use of warfarin. However, direct oral anticoagulants (DOACs) could have specific advantages in patients with LC. DOACs did not require frequent monitoring than VKAs and lower potential for food-drug and drug-drug interactions.¹⁸ Research has shown that DOACs had similar efficacy to warfarin for the treatment of acute VTE or stroke in AF, often accompanied by lower bleeding rates.^19-22 In addition, several studies suggest that DOACs showed similar efficacy and safety compared to warfarin in patients with liver disease.^23-27 Accordingly, DOACs have gradually developed as an alternative to warfarin in clinical practice, including in patients with liver disease.²⁸ However, few data on the safety and efficacy of DOACs in cirrhotic patients because patients with cirrhosis have routinely been excluded from randomized clinical trials (RCTs) of DOACs. Although several studies have revealed that DOACs could remarkably decrease bleeding rates in cirrhotic patients compared to warfarin,^29-31 which is limited by its small sample. As a result, concerns regarding the use of DOACs in cirrhotic patients were raised, and there remains a paucity of consensus regarding the choice of anticoagulants in patients with LC. Therefore, we conducted this meta-analysis to assess the safety and efficacy of DOACs versus warfarin in cirrhotic patients.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines,³² and preregistered in PROSPERO (registration number: CRD42018102664).

Search Strategy

We searched the potential studies through Web of Science, PubMed, Cochrane Library, Embase, and Scopus through August 31, 2024 for articles using the search keywords “novel oral anticoagulant,” “new oral anticoagulant,” “direct oral anticoagulant, “ “non-vitamin K antagonist,” “Oral Factor Xa Inhibitor,” “factor Xa inhibitors,” “edoxaban,” “rivaroxaban,” “dabigatran,” “apixaban,” “DOAC,” “NOAC,” “vitamin K antagonist,” “VKAs,” “warfarin,” “liver cirrhosis,” “cirrhotic,” “chronic liver disease” combined by the Boolean “AND/OR”.

Eligibility Criteria

The following inclusion criteria were used to select articles: (1) patients with cirrhosis were prescribed DOACs or warfarin; (2) included studies comparing the efficacy and safety outcomes of DOACs and warfarin; (3) primary efficacy outcomes included the incidence of IS/TE and all-cause death, whereas the primary safety outcomes included a safety composite of any bleeding, major bleeding, GIB and ICH; (4) studies were RCTs or observational design studies.

The exclusion criteria were: (1) studies with insufficient data or study details; (2) certain publications, including reviews, meeting abstracts, and case reports.

Data Extraction and Quality Assessment

Two authors extracted available information independently (C.CW and H.J.). Extraction from literature: study title, year, first author's name and publication time, geographical location, duration of follow-up, population number, demographic and characteristic data of cirrhotic patients, and Child-Pugh classification. In addition, the risk of bias was assessed using the Newcastle–Ottawa scale (NOS) for the observational studies. We regarded the NOS score of ≥7 as a high-quality.³³ The detailed quality assessment of each study is provided in Table S1.

Statistical Analysis

RevMan5.4 and stata15 software were used to analyze data. In this study, heterogeneity was examined by the I² statistic. When I² values <50% and P>.1, a fixed-effects model was chosen to pool effect sizes; otherwise, the random effect model was utilized. Hazard ratios (HRs) with 95% CIs were estimated by either fixed or random effects models. Sensitivity analysis was further conducted by sequentially deleting each study and reanalyzing all outcomes. Publication bias was evaluated by funnel plots and Egger's test.

Results

In the preliminary retrieval, we identified 1494 eligible articles by searching electronic databases. After removing duplicates and no relevant articles, we screened the titles, abstracts, and full-text screening. Finally, sixteen eligible studies^{12,13,23,34-46} were included in our meta-analysis (Figure 1).

Figure 1.

The flow chart of the literature search and screening process.

Baseline Characteristics

The baseline clinical characteristics of the individual studies are illustrated in Table 1. Sixteen observational cohort studies were included in the analysis, including fifteen retrospective cohort studies and one prospective cohort study.³⁵ Among these, nine studies were from the USA, two were from Korea, two were from Canada, with the others were from Italy, Taiwan and New Zealand, respectively. Six studies only involved cirrhosis, and ten studies included cirrhotic patients with AF. This study involved 16 829 cirrhosis patients, with 8861 (52.7%) receiving DOACs and 7968 (47.3%) receiving warfarin. Most patients were male, average age ranged from 46 to 79. Regarding the Child-Pugh score, most cirrhotic patients in this study had mild or moderate status. In five studies,^{37,40,41,45,46} patients were classified further into the moderate cirrhosis and severe cirrhosis groups, and data on the use of DOACs in comparison to warfarin were analyzed in this population.

Table 1.

Basic Characteristics of the Included Studies.

Study	Region	Design	Patients	Age (years)(D/W)	Male (%)(D/W)	Follow-up(Years)	Indication	DOACs, Type	MELD Score (D/W)	Child–Pugh Class (%) (D/W)	NOSScore
Nagaoki 2018	USA	R	20/30	D:69 ± 5.25 W:67 ± 14.75	65/56.7%	0.5	PVT	E (100%)	D:11 ± 4.56 W:13 ± 6.76	Class A 61.4/39.1 Class B 19.3/48.2 Class C 5.3/6.4	8
Pastori 2018	Italy	P	52/77	78.9 ± 7.5	60.5	D:1.54 ± 1 W:2.8 ± 1.84	AF	NA	NA	NA	7
Goriacko 2018	USA	R	75/158	D:66 ± 10.58 W:65 ± 10.29	57.3/59.5	NA	AF	A (14.7%) D (46.7%) R (38.6%)	D:12 ± 12.54 W:13 ± 5.24	Class A 64/35.4 Class B 34.7/58.9 Class C 1.3/5.7	7
Lee HF 2019	Taiwan	R	1438/990	D:72.80 ± 11.05 W:72.41 ± 11.21	63.65/63.70	D:1.13 W:1.3	AF	A (11.9%) D (37.2%) R (50.9%)	NA	NA	7
Lee SR 2019	Korean	R	446/322	D:69.5 ± 9.3 W:66.9 ± 11.3	58.9/67.7	1.2	AF	A, D E, R	NA	NA	7
Davis 2020	USA	R	57/110	D:64.4 ± 10.64 W:59.35 ± 11.27	56.1/62.7	0.25	DVT, PE, PVT, AF	A (52.6%) D (1.8%) R (45.6%)	D:11 ± 4.56 W:13 ± 6.76	Class A 61.4/39.1 Class B 19.3/48.2 Class C 5.3/6.4	7
Serper 2020	USA	R	201/614	D:64 ± 7.7 W:64.6 ± 7.5	99.5/98.2	4.6	AF	NA	D:10.6 ± 3.6 W:10.7 ± 4.1	Class A 91.5/69.9 Class B 8.5/29.5 Class C 0/0.65	6
Jones 2020	USA	R	42/37	D:71.9 ± 6.2 W:70.3 ± 7.5	97.6/100	D:1.37 ± 1.18 W：4.53 ± 4.5	DVT, PE, PVT, AF, VTE	A (52.6%) D (1.8%) R (45.6%)	D:9.4 ± 4.3 W:16.3 ± 7.1	Class A 81/43.2 Class B 19/51.4 Class C 0/5.4	7
Coons 2021	USA	R	44/41	D:67.2 ± 9 W:63.6 ± 10.5	52.3/75.6	1	DVT, PE, PVT, AF	A, D, R	D:15.1 ± 6.9 W:17.7 ± 7.68	Class A 27.3/36.6 Class B 54.5/41.5 Class C 18.2/21.9	7
Oldham 2021	USA	R	69/32	D:61 ± 14 W:67 ± 14	72/69	D: 1.18 W:1.79	AF, VTE	A (83%) D (3%) R (14%)	D: 15 ± 5 W: 19 ± 5	Class B 86/94 Class C 14/6	8
Douros 2022	Canada	R	246/130	D:71.9 ± 10.2 W:71.7 ± 8.9	57.3/53.1	0.5	AF	A,R	NA	NA	8
Munevar 2022	New Zealand	R	48/52	NA	68.8/67.3	NA	AF, ST	D (100%)	NA	NA	8
Yoo SY 2022	Korean	R	128/110	D:70.4 W:65.2	80.5/75.5	D: 3.3 W:7.3	AF	A (29.7%) E (18.7%) D (13.3%) R (38.3%)	NA	Class A 78.1/71.8 Class B 21.9/28.2	8
Lawal 2023	USA	R	1399/1541	NA	NA	0.57 ± 1.02	AF	A, D, E, R	NA	NA	8
Douros 2024	Canada	R	1811/872	NA	NA	D: 4 W: 3	AF	A, D, E, R	NA	NA	8
Simon 2024	USA	R	2785/2852	NA	NA	1	AF	A	NA	NA	8

DOACs direct oral anticoagulants; D DOACs group, W warfarin group, DVT deep vein thrombosis, PE pulmonary embolism, PVT portal vein thrombosis, AF Atrial fibrillation, ST systemic embolism, A apixaban, E edoxaban, D dabigatran, R rivaroxaban, MELD, model for end-stage liver disease, NA not applicable, Data are mean ± SD.

Efficacy Outcomes

IS/TE

Eleven studies reported IS/TE. As shown in Figure 2A, our results indicated that there was no statistical difference in IS/TE between DOACs and warfarin groups (HR = 0.87, 95% CI: 0.69-1.10).

Figure 2.

The efficacy outcomes of DOACs and warfarin in cirrhotic patients. (A) IS/TE; (B) all-cause death.

All-Cause Death

Nine studies reported all-cause death. As illustrated in Figure 2B, the results showed a slightly significant difference in all-cause death between patients taking DOACs and warfarin (HR = 0.87, 95% CI: 0.79-0.97).

Safety Outcomes

Any Bleeding

Eight studies reported any bleeding data. As presented in Figure 3A, DOAC users had a 40% lower risk of any bleeding than warfarin users (HR = 0.60, 95% CI: 0.37-0.95).

Figure 3.

The safety outcomes of DOACs and warfarin in cirrhotic patients. (A) any bleeding; (B) major bleeding; (C) ICH; (D) GIB.

Major Bleeding

Thirteen studies reported major bleeding. As shown in Figure 3B, DOAC users experienced a lower risk of major bleeding compared with warfarin users (HR = 0.72, 95% CI: 0.63-0.82).

ICH

Eight studies reported the incidence of ICH. As depicted in Figure 3C, the use of DOACs resulted in a lower risk of ICH than warfarin users (HR = 0.47, 95% CI: 0.30-0.73).

GIB

Twelve studies reported gastrointestinal bleeding. The risk of GIB was lower in patients receiving DOACs compared with patients receiving warfarin (HR = 0.72, 95% CI: 0.60-0.87) (Figure 3D).

Subgroup Analyses

Subgroup Analyses of Patients with LC and AF

Subgroup analyses were conducted to assess whether the comparative efficacy and safety of DOACs versus warfarin were consistent in cirrhotic patients with AF. As shown in Figure 4A, our results showed that patients receiving DOACs did not experience a significant reduction in IS/TE (HR = 0.88, 95% CI: 0.67-1.15). On the other hand, DOACs experienced a significant reduction in all-cause death (HR = 0.87, 95% CI: 0.79-0.97) (Figure 4B). Additionally, in terms of safety, our results demonstrated a significant reduction in the risks of any bleeding (HR = 0.40, 95% CI: 0.20-0.79), major bleeding (HR = 0.72, 95% CI: 0.63-0.82), ICH (HR = 0.48, 95% CI: 0.31-0.75), and GIB (HR = 0.68, 95% CI: 0.56-0.82) in DOACs group compared with warfarin (Figure 4C–F).

Figure 4.

Comparing the efficacy and safety of DOACs with warfarin in patients with cirrhosis and AF. (A) IS/TE; (B) all-cause death; (C) any bleeding; (D) major bleeding; (E) ICH; (F) GIB.

Subgroup Analysis of Cirrhotic Patients with Moderate to Severe Status

A more detailed analysis was also performed in patients with moderate to severe cirrhosis (Child-Pugh B and C). Our results revealed no significant variation in the risk of IS/TE (HR = 1.43, 95% CI: 0.78-2.60) and GIB (HR = 0.75, 95% CI: 0.49-1.15) between these two groups (Figure 5A and D). Furthermore, DOAC users had decreased risks of major bleeding (HR = 0.65, 95% CI: 0.55-0.78) and ICH (HR = 0.17, 95% CI: 0.04-0.76) than warfarin users (Figure 5B and C).

Figure 5.

Comparing the efficacy and safety of DOACs with warfarin in moderate-severe cirrhosis patients. (A) IS/TE; (B) major bleeding; (C) ICH; (D) GIB.

Sensitivity Analysis and Publication Bias

The sensitivity analysis revealed that none of the studies significantly altered the results except all-cause death and any bleeding (sensitivity analysis in Supplementary Figure 1 corresponding to Figure 2A and B and Figure 3A–D), suggesting that the meta-analysis results of major safety outcomes were robust. Egger's test and funnel plots indicated no significant publication bias (Funnel plot in supplementary Figure 2 corresponding to Figure 2A and B and Figure 3A–D).

Discussion

In our current study, our results revealed that in comparison with warfarin, DOACs had significantly lower rates of all-cause death, any bleeding, major bleeding, ICH and GIB in cirrhotic patients, but there was no significant difference in the risks of IS/TE. Similar findings were also observed in cirrhotic patients with AF. Moreover, we found that DOACs were associated with lower risks of major bleeding and ICH than warfarin among moderate-severe cirrhosis patients. In summary, our study provides evidence that DOACs may be a safer alternative to warfarin for cirrhotic patients.

Cirrhosis patients are at a higher risk of bleeding and thrombosis.^31,47 Besides, individuals with esophageal and gastric varices and thrombocytopenia are prone to gastrointestinal bleeding.⁴⁸ Therefore, anticoagulant therapy in cirrhotic patients is challenging. Warfarin is commonly used in cirrhotic patients for prophylaxis and treatment of thrombosis.^49,50 However, warfarin is considered burdensome for many patients due to the frequent monitoring and dietary restrictions, which influence its efficacy.⁵¹ In contrast, DOACs do not require routine monitoring or dose adjustment, making them a favorable alternative. However, data on the use of DOAC in cirrhosis patients remains scanty as they are generally excluded from RCT studies. Additionally, most DOACs require hepatic metabolism, hence liver dysfunction may increase drug levels and bleeding risks. Hence, DOACs represent a challenge in cirrhotic patients. Nonetheless, with the clinical use of DOACs, accumulating evidence shows that DOACs appear to be a promising alternative in cirrhotic patients in terms of efficacy and safety.

Previous meta-analyses revealed that DOACs had similar efficacy to warfarin but a lower bleeding risk in patients with LC,^29,52-54 while these analyses are constrained by a small sample size or a limited number of studies. A current meta-analysis of nine studies demonstrated that, in terms of safety, DOACs could reduce any bleeding, GIB, ICH, and all-cause death but not reduce the risk of major bleeding in cirrhotic patients compared to warfarin.⁵⁵ Compared with the aforesaid study, we conducted a more recent and comprehensive analysis with updated data to evaluate the use of DOACs in cirrhotic patients using anticoagulants for various reasons and provide new insights into the advantages of DOACs over warfarin. Our results revealed that DOACs achieved lower risks of bleeding events versus warfarin. DOACs decreased the risk of any bleeding by 40%, major bleeding by 28%, ICH by 53%, and GIB by 28%. One possible explanation of these differences in safety outcomes is that the slower onset and offset of anticoagulant activity of warfarin, in addition to its longer half-life, may result in an elevated risk of bleeding events relative to DOACs, which exert anticoagulant effects rapidly by acting on coagulation factors.^56,57 Additionally, although significant differences existed in the risks of all-cause death and any bleeding, sensitivity analysis showed that the results had significant change after excluding several studies. Such discrepancy may be attributed to several factors, such as study design, regions, cirrhosis severity, type and dosages of DOACs. Notably, the majority of the meta-analysis results were robust in sensitivity analysis, including IS/TE, major bleeding, ICH and GIB. In addition, Egger's test and funnel plots indicated that these results had no publication bias. Taken together, DOACs have comparable or even better clinical benefits in efficacy outcomes and superior safety in cirrhotic patients compared with warfarin.

Cirrhotic patients with AF are prone to thrombotic complications and necessitate anticoagulant therapy. However, the efficacy and safety outcomes of anticoagulant therapy in cirrhotic patients with AF remain controversial. Kuo and colleagues found that warfarin could decrease the incidence of stroke in LC and AF patients and obtain better clinical net benefits compared with the non-anticoagulant therapy group.⁷ Yet, another study reported that warfarin failed to produce a significant reduction in the incidence of ischemic stroke in individuals with cirrhosis and AF; instead, it increased the incidence of hemorrhagic complications.⁵⁸ A recent study using MarketScan claims data shows that DOAC use has increased substantially and surpassed warfarin in patients with cirrhosis and AF⁵⁹; nevertheless, more than half of patients remain untreated, underscoring the need for optimal treatment. Therefore, the optimal management of such patients remains uncertain. Previous meta-analyses comparing DOACs with warfarin found that DOACs have similar efficacy with lower bleeding risk.^29,60,61 However, these studies may be limited by small sample sizes. In contrast, we performed an updated meta-analysis and more comprehensively compared different clinical outcomes between DOACs and warfarin in patients with cirrhosis and AF compared to previous studies. Our results revealed that DOACs significantly lowered the risks of all-cause death and bleeding events, including any bleeding, major bleeding, and ICH, as well as GIB, but no significant differences in rates of IS/TE. Our meta-analysis expanded the results of prior research to a comprehensive comparison of the effects and safety of DOACs with warfarin. Taken together, our results further reveal that DOACs may be slightly more effective and safer in individuals with cirrhosis and AF.

In many past studies, clinical data on the effect of DOACs has primarily concentrated on mild-moderate liver cirrhosis, but the role of DOACs in advanced liver cirrhosis patients has not been well-studied. Currently, DOACs are safe in Child-Pugh class A and B liver cirrhosis (except rivaroxaban), and in the Child-Pugh C class are contraindicated.^62,63 Additionally, anticoagulated cirrhotic patients who have esophageal varices are at an increased risk of bleeding.⁴⁸ Despite several studies assessing the effect of DOACs in cirrhotic patients based on Child-Pugh classifications or liver cirrhosis severity, included patients were those with mild-moderate cirrhosis, designated as Child-Pugh A or B.^39,53,64 However, a recent study concluded that the safe use of DOACs in advanced cirrhosis patients may be feasible.⁶⁵ Another study including 101 patients with cirrhosis⁴¹ suggested that DOACs were recommended for Child-Pugh B or C patients based on safety, efficacy, and convenience. However, due to the limited data and the greater proportion of compensated cirrhosis patients in these studies, the effect of DOACs could not be extrapolated to patients with advanced cirrhosis. One prior meta-analysis revealed that DOACs only improved major bleeding in advanced cirrhosis when compared to warfarin.⁶⁰ However, this study assessed the efficacy and safety of DOACs versus warfarin using only two studies. In contrast, our results of subgroup analysis including five studies revealed that DOACs had lower rates of major bleeding and ICH than warfarin. In line with our study, a registry-based cohort analysis shows that DOACs had a statistically significant reduction in ICH and GIB compared to warfarin in patients with Child-Pugh Class C cirrhosis.⁶⁶ In general, our study demonstrated that DOACs may represent a relatively safer therapy for moderate to severe cirrhosis patients. However, this result required cautious interpretation due to the inclusion of only five studies.

In this study, our results of subgroup analysis indicated that DOACs have equal efficacy to warfarin and superior safety in cirrhotic patients with AF or moderate-severe status. Collectively, DOACs are generally favored over warfarin in terms of safety outcomes in cirrhotic patients.

Limitations

Our study has several limitations. First, the studies included in our research were retrospective studies. Further, we did not investigate the type or dose of DOACs for cirrhosis patients because of the scarcity of studies. Prospective studies or RCTs are required to ascertain the potential benefits of DOACs. In addition, although we have demonstrated that DOAC users achieved a reduced incidence of major bleeding and ICH versus warfarin and showed similar efficacy outcomes in moderate to severe cirrhosis patients, further studies are required to underpin our results since only five retrospective studies were included. Above all, this study reinforced the current limited available evidence, demonstrating that DOACs exerted comparable efficacy and superior safety profile relative to warfarin in this patient population, including moderate-severe cirrhosis.

Conclusion

Taken together, our study demonstrated that DOACs exerted comparable efficacy and superior safety than warfarin in the treatment of cirrhosis or combined with AF, even in advanced cirrhosis. However, this study still has the abovementioned limitations. In the future, larger RCTs and prospective studies are necessary to confirm its efficacy and safety.

Supplemental Material

sj-docx-1-cat-10.1177_10760296241301402 - Supplemental material for Comparison of the Efficacy and Safety of Direct Oral Anticoagulants and Warfarin in Cirrhotic Patients: A Systematic Review and Meta-Analysis

Supplemental material, sj-docx-1-cat-10.1177_10760296241301402 for Comparison of the Efficacy and Safety of Direct Oral Anticoagulants and Warfarin in Cirrhotic Patients: A Systematic Review and Meta-Analysis by Chunwei Cheng, Juan Hua and Liang Xiong in Clinical and Applied Thrombosis/Hemostasis

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the The Doctoral Research Initiation Fund of Jiangxi University of Technology (2024),

ORCID iD

Liang Xiong

Supplemental Material

Supplemental material for this article is available online.

References

Tripodi

Primignani

Mannucci

, et al. Changing concepts of cirrhotic coagulopathy. Am J Gastroenterol. 2017;112(2):274-281.

O’Leary

Greenberg

Patton

, et al. AGA clinical practice update: Coagulation in cirrhosis. Gastroenterology. 2019;157(1):34-43.e31.

Violi

Loffredo

Pastori

. Anticoagulation in patients with advanced liver disease: An open issue. Intern Emerg Med. 2021;16(1):61-71.

Tripodi

Primignani

Chantarangkul

, et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology. 2009;137(6):2105-2111.

Lisman

Porte

. Rebalanced hemostasis in patients with liver disease: Evidence and clinical consequences. Blood. 2010;116(6):878-885.

Pereira Portela

Gautier

Zermatten

, et al. Direct oral anticoagulants in cirrhosis: Rationale and current evidence. JHEP Rep. 2024;6(8):101116.

Kuo

Chao

Liu

, et al.

Liver cirrhosis in patients with atrial fibrillation: Would oral anticoagulation have a net clinical benefit for stroke prevention?

J Am Heart Assoc. 2017;6(6):e005307.

Xiong

Huang

, et al. Cirrhosis and risk of stroke: A systematic review and meta-analysis. Atherosclerosis. 2018;275(1):296-303.

Zhang

Yoshida

, et al. Ischemic stroke in liver cirrhosis: Epidemiology, risk factors, and in-hospital outcomes. Eur J Gastroenterol Hepatol. 2018;30(2):233-240.

10.

Søgaard

Horváth-Puhó

Montomoli

, et al. Cirrhosis is associated with an increased 30-day mortality after venous thromboembolism. Clin Transl Gastroenterol. 2015;6(7):e97.

11.

Gundling

Schmidtler

Zelihic

, et al. Frequency of cardiac arrhythmia in patients with liver cirrhoses and evaluation of associated factors. Z Gastroenterol. 2012;50(11):1149-1155.

12.

Serper

Weinberg

Cohen

, et al. Mortality and hepatic decompensation in patients with cirrhosis and atrial fibrillation treated with anticoagulation. Hepatology. 2021;73(1):219-232.

13.

Lee

Choi

, et al. Direct oral anticoagulants in patients with atrial fibrillation and liver disease. J Am Coll Cardiol. 2019;73(25):3295-3308.

14.

Chokesuwattanaskul

Thongprayoon

Bathini

, et al. Epidemiology of atrial fibrillation in patients with cirrhosis and clinical significance: A meta-analysis. Eur J Gastroenterol Hepatol. 2019;31(4):514-519.

15.

Stine

Shah

Cornella

, et al. Portal vein thrombosis, mortality and hepatic decompensation in patients with cirrhosis: A meta-analysis. World J Hepatol. 2015;7(27):2774-2780.

16.

Villa

Cammà

Marietta

, et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology. 2012;143(5):1253-1260.e1254.

17.

Chun

Choe

Lee

, et al. Treatment of direct oral anticoagulants in patients with liver cirrhosis and portal vein thrombosis. Clin Mol Hepatol. 2021;27(4):535-552.

18.

Ruff

Giugliano

Braunwald

, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962.

19.

Kearon

Akl

Ornelas

, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.

20.

January

Wann

Calkins

, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the heart rhythm society. J Am Coll Cardiol. 2019;74(1):104-132.

21.

Büller

Prins

Lensin

, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297.

22.

Becattini

Agnelli

. Acute treatment of venous thromboembolism. Blood. 2020;135(5):305-316.

23.

Douros

Cui

Platt

, et al. Effectiveness and safety of direct oral anticoagulants among patients with non-valvular atrial fibrillation and liver disease: A multinational cohort study. Thromb Res. 2024;237(1):71-78.

24.

Lawal

Aronow

Hume

, et al. Venous thromboembolism, chronic liver disease and anticoagulant choice: Effectiveness and safety of direct oral anticoagulants versus warfarin. Res Pract Thromb Haemost. 2024;8(1):102293.

25.

Costache

Dragomirică

Gheorghe

, et al. Oral anticoagulation in patients with chronic liver disease. Medicina (Kaunas). 2023;59(2):346.

26.

Wang

Kuo

, et al. Efficacy and safety of non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients with impaired liver function: A retrospective cohort study. J Am Heart Assoc. 2018;7(15):e009263.

27.

De Maria

Galante

Fasoli

, et al.

When and how to use direct oral anticoagulants in patients with advanced chronic liver disease?

Curr Opin Pharmacol. 2021;60(1):111-116.

28.

Qamar

Antman

Ruff

, et al. Edoxaban versus warfarin in patients with atrial fibrillation and history of liver disease. J Am Coll Cardiol. 2019;74(2):179-189.

29.

Chokesuwattanaskul

Thongprayoon

Bathini

, et al. Efficacy and safety of anticoagulation for atrial fibrillation in patients with cirrhosis: A systematic review and meta-analysis. Dig Liver Dis. 2019;51(4):489-495.

30.

Zhu

Zhou

, et al. Non-vitamin K antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and liver disease: A meta-analysis and systematic review. Am J Cardiovasc Drugs. 2020;20(2):139-147.

31.

Hoolwerf

Kraaijpoel

Büller

, et al. Direct oral anticoagulants in patients with liver cirrhosis: A systematic review. Thromb Res. 2018;170(10):102-108.

32.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Br Med J. 2021;372(3):n71.

33.

Stratakis

Rock

La Merrill

, et al. Prenatal exposure to persistent organic pollutants and childhood obesity: A systematic review and meta-analysis of human studies. Obes Rev. 2022;23(Suppl 1):e13383.

34.

Nagaoki

Aikata

Daijyo

, et al. Efficacy and safety of edoxaban for treatment of portal vein thrombosis following danaparoid sodium in patients with liver cirrhosis. Hepatol Res. 2018;48(1):51-58.

35.

Pastori

Lip

GYH

Farcomeni

, et al. Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants. Int J Cardiol. 2018;264(1):58-63.

36.

Goriacko

Veltri

. Safety of direct oral anticoagulants vs warfarin in patients with chronic liver disease and atrial fibrillation. Eur J Haematol. 2018;100(5):488-493.

37.

Lee

Chan

Chang

, et al. Effectiveness and safety of non-vitamin K antagonist oral anticoagulant and warfarin in cirrhotic patients with nonvalvular atrial fibrillation. J Am Heart Assoc. 2019;8(5):e011112.

38.

Davis

Joseph

Nisly

SA.

Direct oral anticoagulants and warfarin in patients with cirrhosis: A comparison of outcomes. J Thromb Thrombolysis. 2020;50(2):457-461.

39.

Jones

Pham

Aguilar

, et al. Retrospective review on the safety and efficacy of direct oral anticoagulants compared with warfarin in patients with cirrhosis. Fed Pract. 2020;37(10):479-485.

40.

Coons

Staubes

Casey

, et al. Direct oral anticoagulants versus warfarin for treatment of thrombosis or atrial fibrillation in patients with cirrhosis: A retrospective cohort study. Ann Pharmacother. 2022;56(5):533-540.

41.

Oldham

Palkimas

Hedrick

. Safety and efficacy of direct oral anticoagulants in patients with moderate to severe cirrhosis. Ann Pharmacother. 2022;56(7):782-790.

42.

Douros

Cui

Platt

, et al. Utilization and long-term persistence of direct oral anticoagulants among patients with nonvalvular atrial fibrillation and liver disease. Br J Clin Pharmacol. 2022;88(3):994-1009.

43.

Munevar Aquite

Hayes

Beyene

, et al. Bleeding risk of oral anticoagulants in liver cirrhosis. N Z Med J. 2022;135(1563):52-61.

44.

Yoo

Kim

Nam

, et al. Safety of direct oral anticoagulants compared to warfarin in cirrhotic patients with atrial fibrillation. Korean J Intern Med. 2022;37(3):555-566.

45.

Simon

Singer

Zhang

, et al. Comparative effectiveness and safety of apixaban, rivaroxaban, and warfarin in patients with cirrhosis and atrial fibrillation : A nationwide cohort study. Ann Intern Med. 2024;177(8):1028-1038.

46.

Lawal

Aronow

Shobayo

, et al. Comparative effectiveness and safety of direct oral anticoagulants and warfarin in patients with atrial fibrillation and chronic liver disease: A nationwide cohort study. Circulation. 2023;147(10):782-794.

47.

Flores

Trivedi

Robson

, et al. Hemostasis, bleeding and thrombosis in liver disease. J Transl Sci. 2017;3(3):1-7.

48.

Sasso

Rockey

. Anticoagulation therapy in patients with liver cirrhosis is associated with an increased risk of variceal hemorrhage. Am J Med. 2019;132(6):758-766.

49.

Konstantinides

Meyer

Becattini

, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European respiratory society (ERS). Eur Heart J. 2020;41(4):543-603.

50.

Pastori

Menichelli

Gingis

, et al. Tailored practical management of patients with atrial fibrillation: A risk factor-based approach. Front Cardiovasc Med. 2019;6(3):17.

51.

Suárez Fernández

Castilla-Guerra

Cantero Hinojosa

, et al. Satisfaction with oral anticoagulants in patients with atrial fibrillation. Patient Prefer Adherence. 2018;12(2):267-274.

52.

Lapumnuaypol

DiMaria

Chiasakul

. Safety of direct oral anticoagulants in patients with cirrhosis: A systematic review and meta-analysis. QJM: Int J Med. 2019;112(8):605-610.

53.

Nisly

Mihm

Gillette

, et al. Safety of direct oral anticoagulants in patients with mild to moderate cirrhosis: A systematic review and meta-analysis. J Thromb Thrombolysis. 2021;52(3):817-827.

54.

Violi

Vestri

Menichelli

, et al. Direct oral anticoagulants in patients with atrial fibrillation and advanced liver disease: An exploratory meta-analysis. Hepatol Commun. 2020;4(7):1034-1040.

55.

Zhao

Zhu

Yang

, et al. Safety of direct oral anticoagulants in patients with liver disease: A systematic review and meta-analysis. Acta Clin Belg: Int J Clin Lab Med. 2023;78(3):234-244.

56.

Abraham

Castillo

. Novel anticoagulants: Bleeding risk and management strategies. Curr Opin Gastroenterol. 2013;29(6):676-683.

57.

Baron

Kamath

McBane

. New anticoagulant and antiplatelet agents: A primer for the gastroenterologist. Clin Gastroenterol Hepatol. 2014;12(2):187-195.

58.

Choi

Kim

Shim

, et al. Risks versus benefits of anticoagulation for atrial fibrillation in cirrhotic patients. J Cardiovasc Pharmacol. 2017;70(4):255-262.

59.

Simon

Schneeweiss

Singer

, et al. Prescribing trends of oral anticoagulants in US patients with cirrhosis and nonvalvular atrial fibrillation. J Am Heart Assoc. 2023;12(3):e026863.

60.

Han

, et al. Direct oral anticoagulants versus vitamin K antagonists in cirrhotic patients with atrial fibrillation: Update of systematic review and meta-analysis. Am J Cardiovasc Drugs. 2023;23(6):683-694.

61.

Lee

Z-Y

Suah

B-H

Teo

, et al. Comparison of the efficacy and safety of direct oral anticoagulants an d vitamin K antagonists in patients with atrial fibrillation and conco mitant liver cirrhosis: A systematic review and meta-analysis. Am J Cardiovasc Drugs: Drugs Devices Intervent. 2022;22(2):157-165.

62.

Kubitza

Roth

Becka

, et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol. 2013;76(1):89-98.

63.

Corrigendum to: 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European association of cardio-thoracic surgery (EACTS). Eur Heart J. 2021;42(5):546-547.

64.

Hum

Shatzel

Jou

, et al. The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis. Eur J Haematol. 2017;98(4):393-397.

65.

Jarboe

Dadlani

Bandikatla

, et al. Drug use evaluation of direct oral anticoagulants (DOACs) in patients with advanced cirrhosis. Cureus. 2022;14(4):e24029.

66.

Ayoub

Faris

Chumbe

, et al. Safety of DOACs in patients with child-pugh class C cirrhosis and atrial fibrillation. JGH Open. 2024;8(5):e13074.

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