LC is a complex process involving multiple cell types: both hepatocytes and sinusoidal lining liver cells such as hepatic stellate cells (HSCs), sinusoidal endothelial cells (SECs), and Kupffer cells (KCs). Upon exposure to inflammatory cytokines, these cells—particularly HSCs—become activated and differentiate into myofibroblasts, leading to the deposition of collagen. This fibrotic process disrupts the normal exchange of nutrients between hepatocytes and the sinusoidal blood flow [12,13]. The ongoing interplay between fibrosis, hepatocyte atrophy, and localized regeneration results in the formation of characteristic cirrhotic nodules [14]. Sinusoidal endothelial cells (SECs), are uniquely characterized by fenestrations that facilitate the exchange of fluids and nutrients between the blood and hepatocytes [14]. Chronic alcohol consumption can lead to the loss of these fenestrations, which contributes to perisinusoidal fibrosis and disrupts normal liver microcirculation [15].

Alcohol-related liver damage is driven by several mechanisms, including the release of pro-inflammatory cytokines (like tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], and interleukin-8 [IL-8]), oxidative stress, lipid peroxidation, and the toxic effects of acetaldehyde. These factors collectively lead to hepatocellular inflammation, apoptosis, and progressive fibrosis [16,17].

A hallmark of alcoholic liver disease (ALD), steatosis, is often accompanied by hepatocellular necrosis and inflammation. Cytokines such as TNF-α, IL-6, and IL-8 are considered to be central mediators of liver injury, contributing to hepatocyte apoptosis, cytotoxic hepatomegaly, and progressive hepatotoxicity [18,19].

Excessive lipid accumulation in hepatocytes occurs when the liver increases the uptake of circulating fatty acids (FAs) or activates de novo lipogenesis, leading to the synthesis of lipids within the liver itself [20,21]. Acetaldehyde plays an essential role in this process. especially by promoting lipolysis in adipose tissue, thereby increasing the influx of free fatty acids (FFAs) to the liver [22]. These FFAs are taken up by hepatocytes through fatty acid transporters, including fatty acid transport proteins (FATPs) and fatty acid translocase (FAT/CD36). Notably, elevated expression of FATP2, FATP5, and FAT/CD36 has been described in liver tissues of ALD mouse models [22].

Acetaldehyde also interferes with the 5′-adenosine monophosphate-activated protein kinase (AMPK) pathway, which normally regulates lipid metabolism by suppressing lipogenic transcription factors [23,24]. Disruption of this pathway leads to the upregulation of sterol regulatory element-binding protein 1c (SREBP-1c) that further activates the expression of key lipogenic enzymes such as acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1) [23,24].

LIPIN1 (a gene encoding a key enzyme in lipid metabolism) also plays a crucial role in hepatic lipid homeostasis, acting as a transcriptional coactivator, as well as functioning as a magnesium-dependent phosphatide phosphatase, promoting the synthesis of triglycerides and phospholipids [25]. Ethanol exposure has been shown to increase LIPIN1 expression via SREBP-1c activation in an AMPK-dependent manner, further contributing to lipid accumulation in hepatocytes [25].

Hepatic lipid disposal primarily involves two key processes: mitochondrial β-oxidation and the export of excess triglycerides via very-low-density lipoproteins (VLDLs) [26]. The RNA splicing factor SFRS10 (serine/arginine-rich splicing factor 10) promotes the generation of the LIPIN1α isoform through exon skipping [26]. However, studies by Yin et al. [27] have shown that ethanol increases microRNA-217 levels, which suppress SIRT1-mediated activation of SFRS10. This results in a shift toward the LIPIN1β isoform, increasing the LIPIN1β/α ratio. As a result, LIPIN1’s function favors lipid biosynthesis over mitochondrial fatty acid (FA) β-oxidation [27].

Peroxisome proliferator-activated receptor alpha (PPARα) is a key transcription factor that regulates genes involved in mitochondrial FA oxidation [28]. Acetaldehyde impairs PPARα function by reducing its DNA-binding capacity [29], leading to downregulation of target genes like carnitine palmitoyltransferase 1 (CPT1), a critical enzyme responsible for transporting fatty acids into mitochondria for β-oxidation [30]. In addition, autophagy plays an important role in clearing ethanol-induced lipid droplet accumulation. However, chronic ethanol exposure impairs autophagy, likely due to acetaldehyde-mediated suppression of AMPK activity [31,32].

Since hepatocellular fat accumulation is the first hallmark of ALD, a deeper understanding of lipid metabolism in hepatocytes is crucial, providing valuable opportunities for early therapeutic interventions in individuals at risk of disease progression [33].

Emerging research shows that chronic alcohol consumption disrupts the integrity of the intestinal barrier, particularly by impairing tight and adherens junctions within the colonic mucosa. This compromise allows the translocation of lipopolysaccharide (LPS), a bacterial endotoxin, into the systemic circulation [34,35]. Acetaldehyde, a key ethanol metabolite, exacerbates this effect by upregulating microRNA-212 in enterocytes and downregulating zona occludens-1 (ZO-1), a critical component of tight junctions [36]. LPS and acetaldehyde activate Kupffer cells—the liver’s resident macrophages—triggering the release of reactive oxygen species (ROS) and chemokines [36]. These mediators promote the recruitment and infiltration of immune cells, including monocytes and bone marrow-derived neutrophils, into the liver [34]. ROS produced by Kupffer cells further activate the toll-like receptor 4 (TLR4)/mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) signaling pathway, amplifying the inflammatory response [37]. In parallel, free fatty acids (FFAs) have also been shown to activate the TLR4/NF-κB pathway in vitro, leading to increased inflammatory mediators such as cyclooxygenase-2 (COX-2) in macrophages [38]. In support of the central role of TLR4 in alcohol-induced liver injury, in vivo studies have demonstrated that TLR4-deficient mice are resistant to ethanol-induced hepatic steatosis [39].

Elevated cytokines—tumor necrosis factor-alpha (TNFα), interleukin-1 beta (IL-1β), and interleukin-8 (IL-8)—are commonly observed in patients with ALD [40]. Exposure to oxidative ethanol metabolites activates the NF-κB signaling pathway, leading to increasing TNFα production in macrophages [17,41], activation of NF-κB in Kupffer cells and, finally, systemic release of pro-inflammatory mediators [42]. Additionally, partial activation of NF-κB signaling can result from the inhibition of SIRT1, a natural antagonist of NF-κB [43]. This pathway mediates reactive oxygen species (ROS)-triggered inflammatory responses via downstream signaling effectors, including intercellular adhesion molecule 1 (ICAM1). ICAM1 facilitates interactions between hepatocytes and neutrophils, thereby promoting neutrophil-driven hepatocyte damage [44].

Patients with alcoholic hepatitis exhibit elevated circulating antibodies targeting hydroxyethyl radical (HER)-protein adducts and lipid peroxidation-derived aldehydes such as malondialdehyde (MDA) [45]. Elevated levels of anti-HER and anti-MDA antibodies are related to activation of peripheral CD4+ T cells. Additionally, oxidative metabolism of ethanol impairs proteasome function in macrophages, leading to defective antigen presentation [46,47]. This disruption compromises the activity of both macrophages and dendritic cells [46]. Furthermore, chronic alcohol consumption reduces the population of F4/80+ macrophages expressing major histocompatibility complex class I (MHC-I) and class II (MHC-II) molecules [48].

Fatty acids increase the sensitivity of hepatocytes to inflammatory signals while simultaneously impairing their response to protective factors like signal transducer and activator of transcription 3 (STAT3) [49,50]. Additionally, ROS produced during ethanol metabolism rapidly increase hepatocyte membrane permeability, leading to excessive accumulation of cytoplasmic iron [51] and intensified lipid peroxidation. This cascade ultimately results in widespread hepatocyte death [51].

The majority of persistent and permanent AF cases are linked to underlying conditions such as hypertension, valvular heart disease, ischemic heart disease, and other structural cardiac abnormalities. However, approximately 15% of AF cases are classified as “lone AF,” occurring in the absence of any obvious underlying heart disease. Early research identified a genetic locus on chromosome 10 (10q22-q24) associated with familial AF exhibiting an autosomal dominant inheritance pattern [90]. Nonetheless, familial AF shows considerable heterogeneity in its presentation [91]. More recent studies have uncovered the genetic complexity underlying familial AF. For example, a mutation in the gene encoding the α subunit of the cardiac IKs channel on chromosome 11 has been reported in a family with persistent AF [92]. This mutation enhances the channel’s function, leading to shortened atrial refractoriness—i.e., the heart’s reduced ability to regain electrical stability between beats—thus predisposing affected individuals to persistent AF [92,93].

The underlying mechanisms of AF in individuals with seemingly healthy hearts remain less well understood. While some overlap exists, pulmonary vein triggers tend to play a more significant role in younger patients with structurally normal hearts who experience brief episodes of paroxysmal AF. In contrast, for patients with structural heart disease and persistent or permanent AF, the presence of an abnormal atrial substrate is likely the dominant factor driving the arrhythmia [94].

AF risk increases significantly after the age of 65, a concern that is amplified by demographic projections estimating the population over 65 will rise from 12% in 2010 to 22% by 2040 [95]. Chronic subclinical inflammation—a persistent, low-grade activation of the immune system that accompanies biological aging across multiple organs—is a shared feature of both AF and advanced age. Inflammation is closely associated with endothelial dysfunction, collagen degradation, increased activity of TGF-β1, and remodeling of the extracellular matrix, all playing critical roles in AF pathogenesis [96].

AF and LC share a deep, cross-organ connection rooted in common underlying disease processes [97]. While cirrhosis affects the liver and AF affects the heart, both are driven by chronic inflammation, fibrosis, and oxidative stress. Indeed, cirrhosis is now recognized as an independent risk factor for new-onset AF, mediated through cirrhotic cardiomyopathy [98].

Alcohol consumption is widespread in Western countries, with nearly half of the American population drinking regularly. The American Heart Association recommends limiting alcohol intake to a maximum of two drinks per day for men and one drink per day for women, preferably consumed with meals [112]. A comprehensive meta-analysis found that moderate alcohol consumption—defined as one drink per day—does not significantly increase the risk of developing AF [112]. However, in the U.S., about 17% of adult drinkers (approximately 37 million people) engage in binge drinking [113]. A recent meta-analysis revealed that each additional daily alcoholic drink raises the risk of AF by nearly 8%, demonstrating a clear linear and dose-dependent relationship [114]. Evidence from the ARIC study further highlights that both the amount and duration of alcohol consumption increase susceptibility to AF [115]; conversely, abstinence is linked to a reduced risk of AF [116].

Prolonged ethanol exposure induces notable changes in cardiac electrophysiology, including lengthened His bundle–ventricle (HV) intervals, widened QRS complexes, and disrupted atrial myocyte action potentials. These alterations increase vulnerability to arrhythmias in both animal and human studies [117]. Equally important, heavy alcohol intake exerts direct toxic, inflammatory, and oxidative damage on the left atrial myocardium. Findings from the Framingham Heart Study (FHS) link alcohol consumption to enlargement of the left atrium and a higher risk of developing AF [118]. Additionally, alcohol affects the left ventricle by promoting remodeling and increasing left ventricular pressure, thereby contributing to diastolic dysfunction [119].

Recent research highlights that a significant reduction in alcohol intake or abstinence effectively reduces AF recurrence in habitual drinkers [116]. This benefit likely results not only from halting alcohol’s direct proarrhythmic effects but also from weight loss, as alcohol is calorie-dense (7 kcal/g). Excessive alcohol consumption can lead to weight gain and hypertension, both of which are recognized triggers for AF onset [120].

The liver is the primary site for the synthesis of multiple coagulation factors, although factor VIII is also produced extrahepatically. All pro- and antifibrinolytic proteins are synthesized in the liver, both by hepatocytes and endothelial cells, which makes fibrinolysis particularly vulnerable to hepatic dysfunction [121]. Patients with cirrhosis frequently exhibit profound disturbances in their hemostatic system, with abnormalities affecting all phases—primary hemostasis, secondary hemostasis, and fibrinolysis. These alterations contribute to a paradoxical increased risk of both bleeding and thrombosis [121].

The increased risk of thrombosis in patients with liver disease is largely due to reduced levels of natural anticoagulants alongside elevated circulating procoagulants. Impaired liver function leads to decreased synthesis of key anticoagulants such as protein C and antithrombin, which significantly contributes to a heightened thrombotic tendency [122]. Additionally, patients with liver disease often experience increased platelet aggregation driven by elevated activity of von Willebrand factor (vWF) and reduced levels of ADAMTS13—a protease that regulates vWF function [123,124]. This imbalance enhances platelet binding to glycoprotein Ib and collagen, increasing the effectiveness of high-molecular-weight vWF multimers in supporting clot formation. Proteases like plasmin and elastase can also degrade vWF in the setting of liver disease, further influencing its multimeric structure, which is normally regulated by ADAMTS13-mediated proteolysis [125].

Since the liver produces almost all coagulation factors (except factor VIII and vWF), their plasma levels decline in liver disease, increasing bleeding risk. Reduced levels of fibrinogen and factors II, V, VII lead to prolonged prothrombin time (PT), while decreased activity of factors II, V, IX, X, XI, and XII results in an extended activated partial thromboplastin time (aPTT) [126,127].

Increased fibrinolysis has also been observed in liver disease, primarily due to elevated levels of tissue plasminogen activator and reduced concentrations of plasmin inhibitor and thrombin-activatable fibrinolysis inhibitor (TAFI) [128]. In patients with compensated cirrhosis, the balance between procoagulant and anticoagulant forces is delicate. However, this fragile equilibrium can be easily disrupted by precipitating factors such as hepatic decompensation, sepsis, fluid shifts, renal impairment, or invasive procedures—potentially tipping the balance toward either thrombosis or bleeding complications [129].

The three major anticoagulant proteins—named protein C, protein S, and antithrombin—are significantly reduced in LC, related to both decreased hepatic synthesis and increased consumption [130]. When a strong thrombotic stimulus is present, thrombin generation can still occur despite the diminished levels of procoagulant factors [131].

Furthermore, in LC, both the number and function of platelets are decreased. However, the elevated levels of von Willebrand factor (vWF) can partially compensate for the defects in primary hemostasis caused by thrombocytopenia and platelet dysfunction, by enhancing platelet adhesion [132]. Some mechanisms have been proposed to explain the increasing vWF levels in liver disease, including endothelial dysfunction, stimulated hepatic synthesis of vWF, and delayed clearance of the factor [133].

Endothelial function plays a crucial role in maintaining hemostatic balance. Therefore, localized endothelial dysfunction can lead to a hypercoagulable state in a specific anatomical region, even in the presence of a systemic prothrombotic environment [134]. Both intrahepatic and extrahepatic endothelial dysfunction contribute to the development of portal hypertension. Within the intrahepatic microcirculation, hypoactive endothelial cells increase vascular resistance, primarily through reduced nitric oxide (NO) production—an early trigger of portal hypertension (PHT) [135,136]. Once established, PHT impacts not only the hepatic vasculature but also the systemic and splanchnic circulations. It promotes arterial vasodilation and the formation of collateral vessels, resulting in increased blood flow through the portal vein, which in turn further exacerbates portal hypertension [136,137].

In contrast to the hypoactive endothelial cells within the liver, endothelial cells in the splanchnic and systemic circulations become hyperactive, leading to excessive NO production [138]. Additionally, sinusoidal endothelial cell dysfunction facilitates hepatic inflammation and plays a key role in modulating liver immune tolerance, acting as a primary mediator of hepatic immune homeostasis [136].

As the liver progressively loses its ability to synthesize coagulation-related proteins, the delicate balance between bleeding and thrombosis becomes increasingly unstable. This paradoxical state predisposes patients with liver failure to both hemorrhagic and thrombotic complications [139,140] (Figure 2).

Vitamin K antagonists (VKAs) have traditionally been the cornerstone of antithrombotic therapy for AF, with the international normalized ratio (INR) serving as the standard measure to monitor their therapeutic effect. More recently, direct-acting oral anticoagulants (DOACs) are preferred for non-valvular AF. However, patients with LC were systematically excluded from the key clinical trials evaluating these agents, primarily due to concerns about impaired hemostasis in these individuals [3,98].

Managing anticoagulation in patients with both AF and LC poses a considerable and noteworthy clinical challenge. LC involves a complex and dynamic imbalance between procoagulant and anticoagulant factors, resulting in a fragile hemostatic equilibrium where both bleeding and thrombotic risks are elevated [125]. This delicate balance is further complicated by thrombocytopenia caused by splenic sequestration, reduced thrombopoietin production, platelet dysfunction, altered drug interaction, impaired synthesis of protein-bound medications, and the presence of gastroesophageal varices [110].

Although routine hemostasis tests, ref. [125] such as prolonged INR, typically indicate a tendency toward impaired clotting, individuals with liver disease paradoxically face a considerable risk of thrombotic events as well [127,152,153]. A large retrospective study using administrative data revealed a significant finding: chronic liver conditions, including viral hepatitis, hepatoma or LC, not only raise the risk of bleeding but also predict a higher likelihood of ischemic cerebrovascular events, strokes, and related complications. As a result, individuals with both AF and liver disease are at a heightened risk of ischemic cerebrovascular events [154,155].

Several studies have identified a link between MASLD and an increased risk of stroke, with stroke risk rising progressively alongside higher fatty liver index values. Therefore, patients with MASLD should receive thorough counseling and close monitoring to evaluate and reduce their stroke risk [155]. Additionally, independent research has shown that MASLD is strongly associated with a greater likelihood of developing atrial fibrillation, a relationship that is especially pronounced in individuals with normal or lower body weights [156,157].

While the CHA₂DS₂-VASc and HAS-BLED scores are foundational tools for guiding anticoagulation decisions in the general population, their utility becomes significantly constrained in patients with cirrhosis, as they fail to capture the unique and dynamic hemostatic profile of liver disease [158].

The CHA₂DS₂-VASc score may underestimate true thromboembolic risk in this cohort because it does not account for the procoagulant imbalance often present in advanced cirrhosis—where reduced production of natural anticoagulants (protein C and S) can paradoxically increase thrombotic potential despite a prolonged INR [159].

Conversely, the HAS-BLED score is inherently flawed in cirrhotic patients. It penalizes patients for an elevated “labile INR,” which in this context reflects baseline synthetic dysfunction rather than anticoagulation control and does not accurately predict bleeding risk [160]. Moreover, HAS-BLED overlooks the most significant source of hemorrhage in these patients—portal hypertension and its sequelae, such as esophageal varices [161]—which require specific endoscopic risk stratification that falls entirely outside the score’s parameters [158,162].

Consequently, over-reliance on these conventional cardiac scores without integrating hepatology-specific factors can lead to either undertreatment of atrial fibrillation due to a perceived prohibitive bleeding risk or inappropriate initiation of anticoagulation in a patient with untreated high-risk varices [163].

Managing anticoagulation in patients with chronic liver conditions poses significant clinical challenges due to their elevated risk of bleeding [164]. This heightened risk stems from impaired hepatic synthetic function, the presence of varices, and thrombocytopenia, all of which are common in progressive liver disease. At the same time, these patients also face an increased risk of thromboembolic events, particularly ischemic stroke [146].

Recent studies indicate that in patients with atrial fibrillation and cirrhosis, the use of direct oral anticoagulants (DOACs) does not significantly reduce bleeding complications compared to vitamin K antagonists (VKAs). Importantly, DOACs are not recommended for individuals with Child–Pugh Class C cirrhosis. Rivaroxaban is contraindicated in patients classified as Child–Pugh B or C [145,165]. However, in patients with milder hepatic damage (Child–Pugh Class A and B), the pharmacokinetic profiles of apixaban and rivaroxaban are generally comparable to those seen in individuals without liver dysfunction [145].

Among the different direct oral anticoagulants (DOACs), hepatic excretion varies significantly: approximately 20% for dabigatran, 65% for rivaroxaban, 50% for edoxaban, and 75% for apixaban. In contrast, warfarin undergoes complete hepatic metabolism, with 100% liver-based clearance (see Table 1). These variations suggest that DOACs, compared to warfarin, may offer more predictable pharmacokinetics in patients with LC [3].

The comparative metabolism and selection criteria for DOACs versus warfarin are summarized in Figure 3. A comprehensive retrospective study of a U.S. national database that examined patients predominantly with class A (Child–Pugh) cirrhosis who developed AF found that the use of DOACs was associated with a diminished all-cause mortality risk, compared to no anticoagulation [144]. Another retrospective cohort study involving 9056 patients with LC and comorbid AF, all with a CHA₂DS₂-VASc score ≥2, evaluated the effectiveness of antithrombotic strategies. Patients were grouped based on treatment: antiplatelet therapy, warfarin, and patients without any anticoagulation [98]. The subgroup of patients with both AF and LC who received no antithrombotic therapy had a considerable higher susceptibility of stroke compared to patients without cirrhosis. Notably, those treated with warfarin showed a statistically significant reduction in ischemic stroke rates, whereas stroke rates in the antiplatelet and no-anticoagulation groups were comparable, indicating limited benefit from antiplatelet therapy in this population [98,166].

The comparative efficacy and safety of DOACs versus warfarin in patients with cirrhosis and AF have been evaluated in numerous meta-analyses of observational data, as summarized in Table 2. However, readers should note that these meta-analyses draw from overlapping primary cohorts—predominantly large Asian administrative databases—which may limit the independence of these analyses and their generalizability to Western populations.

Before initiating OAC in patients with known or suspected liver disease, it is essential to perform a comprehensive workup including liver enzyme tests, platelet count, serum creatinine, and also coagulation profiles. These parameters should be continuously monitored during therapy. In cases of thrombocytopenia (e.g., platelet counts between 50,000 and 70,000/mm³), the initiation of anticoagulation may need to be delayed, depending on the patient’s thrombotic risk [145].

Patients at risk should also undergo evaluation for esophageal varices or other high-risk bleeding lesions before starting OACs, and screening for alcohol misuse should be part of standard care, with cessation support offered as needed [178]. Prior to initiating oral anticoagulant therapy, all patients with liver damage should be assessed for alcohol use and offered appropriate cessation support. It is essential to educate patients on both the potential risks and benefits of anticoagulation therapy and to actively involve them in shared decision-making on its initiation and choice of agent [175].

Patients with recent major bleeding, persistent coagulopathy, or known high-risk hemorrhagic lesions (such as large varices) require individualized anticoagulant strategies [169] (Figure 4). Historically, warfarin has been the default OAC in patients with liver impairment. However, in selected patients with slight hepatic dysfunction (Child–Pugh A), DOACs may be considered without dose adjustment. In more severe hepatic impairment (Child–Pugh C), warfarin is generally preferred, though in cases where warfarin is not viable, cautious use of apixaban, dabigatran, or edoxaban in patients with Child–Pugh B may be considered—with close monitoring and multidisciplinary oversight. Early collaboration between cardiology and hepatology/gastroenterology is key to optimizing OAC use in this complex patient population [179].

If a patient with liver disease experiences major bleeding within two hours of anticoagulant ingestion, administration of activated charcoal is recommended [146,180].

Idarucizumab (Praxbind) is a fully humanized monoclonal antibody fragment specifically designed to reverse the anticoagulant effects of dabigatran, having been approved by both the FDA based on the results of a phase III clinical trial [6].

Reversal agents for other direct oral anticoagulants (DOACs) are also under investigation. These include andexanet alfa, a recombinant modified factor Xa decoy that neutralizes factor Xa inhibitors such as rivaroxaban and apixaban, and ciraparantag, a small synthetic molecule capable of reversing the effects of both factor IIa and Xa inhibitors [181].

In cases of severe thrombocytopenia accompanied by ongoing bleeding, platelet transfusion should be considered. Proton pump inhibitors can be co-administered with somatostatin analogs, such as octreotide, to help reduce portal venous pressure and control bleeding [181].

Additionally, prophylactic antibiotic therapy is recommended to prevent spontaneous bacterial peritonitis (SBP), as studies have demonstrated that short-term antibiotic use in cirrhotic patients with gastrointestinal bleeding not only reduces the incidence of bacterial infections but also improves survival outcomes [169].

Desmopressin, an endothelial stimulant that increases levels of factor VIII and von Willebrand factor, may be used to increase platelet function, particularly in patients with liver disease associated with hepatorenal syndrome [146].

Decisions about anticoagulation must be individualized. An esophagogastroduodenoscopy is recommended at the time of cirrhosis diagnosis to detect high-risk bleeding lesions associated with portal hypertension [182], and in liver transplantation recipients, anticoagulation may be considered to maintain or restore patency of the portal vein, as an unobstructed main portal vein is associated with improved post-transplant survival [183].

In the broader population of patients with both AF and venous thromboembolism (VTE), DOACs have proven effective in reducing the risk of stroke and thrombotic events with an acceptable safety profile [184]. Nonetheless, patients with impaired liver function have largely been omitted from clinical trials evaluating DOACs for stroke and VTE prevention. This omission is significant, as all currently approved DOACs rely to some extent on hepatic metabolism. In the setting of liver dysfunction, this can lead to increased plasma drug concentrations and decreased production of coagulation factors, along with a heightened risk of bleeding [184].

Additionally, several DOACs interact with cytochrome P450 enzymes for their metabolism—enzymes whose activity is often impaired in liver disease [185,186]. Apixaban and rivaroxaban are primarily metabolized via the cytochrome P450 system, making them more susceptible to altered pharmacokinetics in this population. In contrast, dabigatran and edoxaban are less reliant on cytochrome P450 enzymes for metabolism. Liver disease can also reduce biliary excretion of DOACs, and in cases complicated by hepatorenal syndrome or chronic kidney disease, this can be problematic. Furthermore, liver dysfunction affects albumin synthesis. Since some DOACs are highly protein-bound, alterations in albumin levels may increase the proportion of unbound (active) drug, further amplifying bleeding risk [187].

As a result, establishing the most appropriate anticoagulation strategy for both atrial fibrillation and venous thromboembolism patients, in the context of impaired liver function, remains complex and insufficiently defined [145].

Recent studies explore the use of direct oral anticoagulants (DOACs) and conventional antithrombotic drugs—including vitamin K antagonists and heparins—in patients with LC and atrial fibrillation [98]. A large retrospective study conducted on more than 2400 patients with LC and AF, comparing DOAC versus warfarin, concluded that all major digestive bleeding events were significantly lower in the DOAC group [188].

A recent systematic review and meta-analysis of six cohort studies, including 41,954 patients with AF and liver disease treated with DOACs and warfarin, found that anticoagulation therapy was correlated with reduced mortality, with DOACs having a significantly lower risks of major bleeding and gastrointestinal bleeding compared to warfarin [189].

Another recent study conducted by Lee et al. in 2022 concluded that DOACs seem to be associated with greater efficacy and increased safety outcomes in patients with AF and LC, compared to warfarin [171]. Huang ZC et al. showed in a meta-analysis of six studies conducted on 41,859 patients a beneficial effect of DOACs vs. warfarin in patients with liver disease and AF [169].

Cohort studies, including systematic reviews and meta-analyses, indicate that anticoagulation in patients with both LC and AF is associated with a reduced risk of stroke, without a significantly increased risk of bleeding compared to patients without anticoagulation therapy [169,189].

Therefore, DOACs have demonstrated a protective effect against ischemic stroke and systemic embolism in cirrhotic patients with non-valvular atrial fibrillation [180] (Figure 5).

No new data were created.