rivaroxaban and Liver-Cirrhosis

Until recently, it was widely accepted that patients with cirrhosis have a bleeding tendency related to the changes in the hemostatic system that occur as a consequence of the disease. However, it has now been well established that patients with cirrhosis are at risk for both bleeding and thrombotic complications. These thrombotic complications include portal vein thrombosis, deep vein thrombosis and pulmonary embolism, and coronary or cerebrovascular infarctions. Antithrombotic drugs to prevent or treat thrombotic complications in patients with cirrhosis have been used only minimally in the past due to the perceived bleeding risk. As the thrombotic complications and the necessity of antithrombotic treatment in these patients are increasingly recognized, the use of antithrombotic drugs in this population is likely increasing. Moreover, given the rising incidence of fatty liver disease and generally longer survival times of patients with chronic liver diseases, it would be reasonable to presume that some of these thrombotic complications may be increasing in incidence over time. In this review, we will outline the indications for antithrombotic treatment in patients with cirrhosis. Furthermore, we will discuss the available antithrombotic drugs and indicate possible applications, advantages, and caveats. Since for many of these drugs very little experience in patients with cirrhosis exists, these data are essential in the design of future clinical and laboratory studies on mechanisms, efficacy, and safety of the various antithrombotic strategies in these patients.

Topics: Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Disease Progression; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Liver Cirrhosis; Morpholines; Platelet Aggregation Inhibitors; Rivaroxaban; Thiophenes; Thrombosis; Vitamin K

Anticoagulation therapy is the main line of treatment for acute portal vein thrombosis (PVT) in the absence of cirrhosis. However, the use of this therapy in cirrhotic PVT is still with doubtful evidence. We aimed to evaluate the efficacy and safety of rivaroxaban compared to warfarin for the management of acute non-neoplastic PVT in Hepatitis C virus (HCV)-related compensated cirrhosis.. Out of 578 patients with chronic HCV infection, 80 patients with acute PVT who had undergone splenectomy due to hypersplenism and 4 patients with acute PVT due to portal pyemia were selected. The patients were randomly assigned (1:1) to the study group (n = 40), in which the patients received rivaroxaban 10 mg/12 h, or the control group (n = 40), in which the patients received warfarin.. In the rivaroxaban group, the resolution of PVT was achieved in 34 patients (85%) within 2.6 ± 0.4 months and delayed, partial recanalization after 6.7 ± 1.2 months (n = 6.15%). Complications such as major bleeding, abnormal liver functions, death, or recurrence did not occur during treatment, and patients in this group showed improved short-term survival rate (20.4 ± 2.2 months) compared to the survival rate in the control group (10.6 ± 1.8 months) in which warfarin achieved complete resolution in 45% of patients. Complications such as severe upper GI tract bleeding (43.3%), hepatic decompensation (22.5%), progression to mesenteric ischemia (12.5%), recurrence (10%), and death (20%) were observed in the control group. The duration until complete resolution of thrombus correlated with age, the extent of the thrombus, creatinine level, and MELD score. The recurrence after complete resolution of thrombus correlated with age, the extent of the thrombus, thrombogenic gene polymorphism, and the use of warfarin.. Rivaroxaban was effective and safe in acute HCV-related non-neoplastic PVT with improved short-term survival rate; ClinicalTrials.gov Identifier: NCT03201367.

Topics: Adult; Anticoagulants; Blood Coagulation; Computed Tomography Angiography; Egypt; Factor Xa Inhibitors; Female; Hemorrhage; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Phlebography; Portal Vein; Recurrence; Rivaroxaban; Time Factors; Treatment Outcome; Ultrasonography, Doppler, Color; Venous Thrombosis; Warfarin

New oral anticoagulants (NOACs) have been becoming prevalent in recent years and are increasingly used in the treatment of port vein thrombosis. The difference of the efficacy and safety between rivaroxaban and dabigatran remains unclear in the treatment of cirrhotic patients with acute portal vein thrombosis (PVT).. This retrospective study included all consecutive cirrhotic patients with acute portal vein thrombosis in our institute from January 2020 to December 2021. The patients received oral anticoagulation with rivaroxaban or dabigatran. The demographic, clinical, and imaging data of patients were collected. The diagnosis of acute PVT was confirmed by imaging examinations. The severity of liver cirrhosis was assessed using Child-Pugh score and Model for End-Stage Liver Disease (MELD) score. Outcomes included recanalization (complete, partial, and persistent occlusion), liver function, bleedings, and survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. The Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs).. A total of 94 patients were included, 52 patients (55%) received rivaroxaban and 42 (45%) with dabigatran. The complete and partial recanalization of PVT was observed in 41 patients. There was no significant difference in complete recanalization, partial recanalization, and persistent occlusion between the two groups. With multivariate analysis, D-dimer (HR 1.165, 95% CI 1.036-1.311, p = 0.011) was independent predictors of complete recanalization. The Child-Pugh score (p = 0.001) was significantly improved in both two groups after anticoagulation, respectively. However, there was no difference between the two groups. The probability of survival was 94%, 95% in the rivaroxaban and dabigatran groups (log-rank p = 0.830). Major bleedings were reported in 3 patients (6%) in rivaroxaban group and 1 patient (2%) in dabigatran group (p = 0.646). Six patients (12%) in rivaroxaban group experienced minor bleeding, and five (12%) from dabigatran group (p = 0.691).. The efficacy and safety were comparable between rivaroxaban and dabigatran in the treatment of cirrhotic patients with acute portal vein thrombosis. And D-dimer can contribute to the prediction of PVT recanalization in cirrhotic patients.

Topics: Administration, Oral; Anticoagulants; Dabigatran; End Stage Liver Disease; Hemorrhage; Humans; Liver Cirrhosis; Portal Vein; Retrospective Studies; Rivaroxaban; Severity of Illness Index; Treatment Outcome; Venous Thrombosis

The safety of dabigatran is poorly studied in patients with liver cirrhosis and has rarely been compared to warfarin in terms of bleeding risks.. We undertook a retrospective cohort study across three tertiary centres in Auckland, New Zealand, between 2008 to 2020. Adults 18 years and over and those with a clinically confirmed diagnosis of cirrhosis were included. Data collected included demographic data and clinical characteristics, baseline medication and comorbidities. The primary outcome measure was the incidence of any bleeding event that resulted in hospital admission.. Overall, 100 patients were included in this study. A total of 52 patients took warfarin, and 48 took dabigatran. Baseline characteristics for both groups were generally similar. The incidence rate of bleeds for patients taking warfarin was 14.4 per 100 person-years (95% CI, 8.8-23.5) compared to 9.1 per 100 person-years (95% CI, 4.5-18.1) for patients taking dabigatran. The incidence rate ratio comparing dabigatran to warfarin was 0.63 (95% CI, 0.23-1.60), p=0.25.. Our study found that patients on dabigatran may have a lower bleeding risk than patients taking warfarin, but this was not statistically significant.

Topics: Administration, Oral; Adolescent; Adult; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Liver Cirrhosis; New Zealand; Retrospective Studies; Rivaroxaban; Stroke; Warfarin

Current guidelines recommend anticoagulation as the mainstay of portal vein thrombosis (PVT) treatment in cirrhosis. However, because of the heterogeneity of PVT, anticoagulation alone does not always achieve satisfactory results. This study aimed to prospectively evaluate an individualized management algorithm using a wait-and-see strategy (i.e., no treatment), anticoagulation, and transjugular intrahepatic portosystemic shunt (TIPS) to treat PVT in cirrhosis.. Between February 2014 and June 2018, 396 consecutive patients with cirrhosis with nonmalignant PVT were prospectively included in a tertiary care center, of which 48 patients (12.1%) were untreated, 63 patients (15.9%) underwent anticoagulation, 88 patients (22.2%) underwent TIPS, and 197 patients (49.8%) received TIPS plus post-TIPS anticoagulation. The decision of treatment option mainly depends on the stage of liver disease (symptomatic portal hypertension or not) and degree and extension of thrombus.. During a median 31.7 months of follow-up period, 312 patients (81.3%) achieved partial (n = 25) or complete (n = 287) recanalization, with 9 (3.1%) having rethrombosis, 64 patients (16.2%) developed major bleeding (anticoagulation-related bleeding in 7 [1.8%]), 88 patients (22.2%) developed overt hepatic encephalopathy, and 100 patients (25.3%) died. In multivariate competing risk regression models, TIPS and anticoagulation were associated with a higher probability of recanalization. Long-term anticoagulation using enoxaparin or rivaroxaban rather than warfarin was associated with a decreased risk of rethrombosis and an improved survival, without increasing the risk of bleeding. However, the presence of complete superior mesenteric vein thrombosis was associated with a lower recanalization rate, increased risk of major bleeding, and poor prognosis.. In patients with cirrhosis with PVT, the individualized treatment algorithm achieves a high-probability recanalization, with low rates of portal hypertensive complications and adverse events.

Topics: Adult; Aged; Algorithms; Anticoagulants; Combined Modality Therapy; Enoxaparin; Female; Hemorrhage; Hepatic Encephalopathy; Humans; Liver Cirrhosis; Male; Middle Aged; Mortality; Portal Vein; Portasystemic Shunt, Transjugular Intrahepatic; Prospective Studies; Recurrence; Rivaroxaban; Severity of Illness Index; Thrombosis; Warfarin; Watchful Waiting

Topics: Anticoagulants; Humans; Liver Cirrhosis; Portal Vein; Rivaroxaban; Warfarin

Direct oral anticoagulants are approved for use in the United States and Europe and are increasingly used in chronic liver disease patients who have or are at risk of thrombotic events. While these drugs are clinically attractive because no monitoring is required, the risks and benefits in patients with hepatic or renal insufficiency who undergo surgery remain unclear. In this report, we describe the perioperative consequences, safety issues, and lessons learned from a patient undergoing an orthotopic liver transplant who was anticoagulated with rivaroxaban due to partial superior mesenteric vein thrombosis.

Topics: Factor Xa Inhibitors; Female; Humans; Liver Cirrhosis; Liver Transplantation; Mesenteric Ischemia; Middle Aged; Rivaroxaban; Treatment Outcome

Background Liver cirrhotic patients with nonvalvular atrial fibrillation have been excluded from randomized clinical studies regarding oral anticoagulants for stroke prevention. Whether non-vitamin K antagonist oral anticoagulants ( NOAC s) are superior to warfarin for these patients remains unclear. Methods and Results This nationwide retrospective cohort study, with data collected from the Taiwan National Health Insurance Research Database, enrolled 2428 liver cirrhotic patients with nonvalvular atrial fibrillation taking apixaban (n=171), dabigatran (n=535), rivaroxaban (n=732), or warfarin (n=990) from June 1, 2012, to December 31, 2016. We used propensity score-based stabilized weights to balance covariates across study groups. Patients were followed until the occurrence of an event or the end date of study. The NOAC group (n=1438) showed risk of ischemic stroke/systemic embolism and intracranial hemorrhage comparable to that of the warfarin group (n=990) after adjustment. The NOAC group showed significantly lower risk of gastrointestinal bleeding (hazard ratio: 0.51 [95% CI, 0.32-0.79]; P=0.0030) and all major bleeding (hazard ratio: 0.51 [95% CI, 0.32-0.74]; P=0.0003) compared with warfarin group. Overall, 90% (n=1290) of patients were taking a low-dose NOAC (apixaban 2.5 mg twice daily, rivaroxaban 10-15 mg daily, or dabigatran 110 mg twice daily). The subgroup analysis indicated that both dabigatran and rivaroxaban showed lower risk of all major bleeding than warfarin. The advantage of lower gastrointestinal and all major bleeding with NOACs over warfarin is contributed by those subgroups with either nonalcoholic or nonadvanced liver cirrhosis. Conclusions NOACs have a risk of thromboembolism comparable to that of warfarin and a lower risk of major bleeding among liver cirrhotic Asian patients with nonvalvular atrial fibrillation. Consequently, thromboprophylaxis with low-dose NOAC s may be considered for such patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Patient Safety; Pyrazoles; Pyridones; Retrospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Taiwan; Thromboembolism; Time Factors; Treatment Outcome; Warfarin

Thrombin activates hepatic stellate cells via protease-activated receptor-1. The role of Factor Xa (FXa) in hepatic fibrosis has not been elucidated. We aimed to evaluate the impact of FXa and thrombin in vitro on stellate cells and their respective inhibition in vivo using a rodent model of hepatic fibrosis.. HSC-LX2 cells were incubated with FXa and/or thrombin in cell culture, stained for αSMA and relative gene expression and gel contraction calculated. C57BL/6 J mice were administered thioacetamide (TAA) for 8 weeks with Rivaroxaban (n = 15) or Dabigatran (n = 15). Control animals received TAA alone (n = 15). Fibrosis was scored and quantified using digital image analysis and hepatic tissue hydroxyproline estimated.. Stellate cells treated with FXa and thrombin demonstrated upregulation of procollagen, TGF-beta, αSMA and significant cell contraction (43.48%+/- 4.12) compared to culturing with FXa or thrombin alone (26.90%+/- 8.90, p = 0.02; 13.1%+/- 9.84, p < 0.001). Mean fibrosis score, percentage area of fibrosis and hepatic hydroxyproline content (2.46 vs 4.08, p = 0.008; 2.02% vs 3.76%, p = 0.012; 276.0 vs 651.3, p = 0.0001) were significantly reduced in mice treated with the FXa inhibitor compared to control mice. FXa inhibition was significantly more effective than thrombin inhibition in reducing percentage area of fibrosis and hepatic hydroxyproline content (2.02% vs 3.70%,p = 0.031; 276.0 vs 413.1,p = 0.001).. FXa promotes stellate cell contractility and activation. Early inhibition of coagulation using a FXa inhibitor significantly reduces TAA induced murine liver fibrosis and may be a viable treatment for liver fibrosis in patients.

Topics: Actins; Animals; Antithrombins; Blood Coagulation; Cell Line; Cell Shape; Dabigatran; Disease Models, Animal; Factor Xa; Factor Xa Inhibitors; Gene Expression; Hepatic Stellate Cells; Humans; Hydroxyproline; Liver Cirrhosis; Male; Mice, Inbred C57BL; Procollagen; Receptor, PAR-1; Rivaroxaban; Thrombin; Transforming Growth Factor beta

A simultaneous decline in pro- and anticoagulant drivers in patients with liver diseases results in a "rebalanced" haemostatic system, even in acutely ill patients. Nevertheless, both bleeding and thrombotic events are common. Here, we explored efficacy of pro- and antihaemostatic strategies in compensated and acutely ill cirrhotics which may be unpredictable given the profound haemostatic changes.. We tested the effects in vitro of the addition of clinically relevant doses of commonly used pro- and antihaemostatic strategies in plasma from healthy individuals (n = 30) and patients with compensated (n = 18) and acutely decompensated cirrhosis (n = 18), and acute-on-chronic liver failure (n = 10). We used thrombin generation tests and fibrin clot permeability assays to assess potency of various approaches.. Fresh frozen plasma and recombinant factor VIIa modestly increased thrombin generation (10%-20%). Prothrombin complex concentrate increased thrombin generation two-fold in controls and 2-4-fold in patients. Clot permeability decreased after addition of fibrinogen concentrate by 51% in controls and by 50%-60% in patients. Low molecular weight heparin decreased thrombin generation by 18% in controls and by 23%-54% in patients. Similarly, dabigatran decreased thrombin generation by 33% in controls and by 47%-100% in patients. In contrast, rivaroxaban decreased thrombin generation by 55% in controls, but only by 11%-38% in patients.. These in vitro data suggest little prohaemostatic effect of fresh frozen plasma and recombinant factor VIIa in acutely ill cirrhotics, whereas prothrombin complex concentrate and fibrinogen concentrate clearly improved haemostasis. Furthermore, our data suggest the requirement for dose adjustments of commonly used anticoagulants in these patients.

Topics: Adult; Aged; Anticoagulants; Benzimidazoles; Blood Coagulation Factors; Blood Coagulation Tests; Dabigatran; Factor VIIa; Female; Hemorrhage; Hemostasis; Humans; Liver Cirrhosis; Male; Middle Aged; Plasma; Recombinant Proteins; Rivaroxaban; Thrombin

Topics: Humans; Liver Cirrhosis; Mesenteric Ischemia; Mesenteric Veins; Portal Vein; Rivaroxaban; Thrombosis; Venous Thrombosis

Topics: Anticoagulants; Atrial Fibrillation; Humans; Liver Cirrhosis; Rivaroxaban

Topics: Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Liver Cirrhosis; Rivaroxaban

RVXB decreases PP in two rat models of cirrhosis. This effect is mostly associated with decreased IHVR, enhanced NO bioavailability, HSC deactivation, and reduced intrahepatic microthrombosis. Our findings suggest that RVXB deserves further evaluation as a potential treatment for cirrhotic PH. (Hepatology 2017;65:2031-2044).

Topics: Administration, Oral; Animals; Anticoagulants; Cells, Cultured; Disease Models, Animal; Endothelium, Vascular; Hepatic Stellate Cells; Hypertension, Portal; Liver Cirrhosis; Male; Oxidative Stress; Portal Pressure; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reference Values; Rivaroxaban; Statistics, Nonparametric; Treatment Outcome; Vascular Resistance

Topics: Humans; Liver Cirrhosis; Liver Diseases; Portal Vein; Rivaroxaban; Thrombosis; Venous Thrombosis

Cirrhosis can occur with the development of portal vein thrombosis (PVT). PVT may aggravate portal hypertension, and it can lead to hepatic decompensation. The international guideline recommends for anticoagulation treatment to be maintained for at least 3 months in all patients with acute PVT. Low-molecular-weight-heparin and changing to warfarin is the usual anticoagulation treatment. However, warfarin therapy is problematic due to a narrow therapeutic window and the requirement for frequent dose adjustment, which has prompted the development of novel oral anticoagulants for overcoming these problems. We report a 63-year-old female who experienced complete resolution of recurrent acute PVT in liver cirrhosis after treatment with rivaroxaban.

Topics: Administration, Oral; Factor Xa Inhibitors; Female; Humans; Liver Cirrhosis; Middle Aged; Portal Vein; Recurrence; Rivaroxaban; Tomography, X-Ray Computed; Venous Thrombosis

Treatment and prevention of thrombotic complications is frequently required in patients with cirrhosis. However anticoagulant therapy is often withheld from these patients, because of the perceived bleeding diathesis. As a result of the limited clinical experience, the anticoagulant of choice for the various indications is still not known.. We evaluated the in vitro effect of clinically approved anticoagulant drugs in plasma from patients with cirrhosis.. Thirty patients with cirrhosis and thirty healthy controls were studied. Thrombin generation assays were performed before and after addition of unfractionated heparin, low molecular weight heparin, fondaparinux, dabigatran, and rivaroxaban, to estimate anticoagulant potencies of these drugs.. Addition of dabigatran led to a much more pronounced reduction in endogenous thrombin potential in patients compared to controls (72.6% reduction in patients vs. 12.8% reduction in controls, P<0.0001). The enhanced effect of dabigatran was proportional to the severity of disease. In contrast, only a slightly increased anticoagulant response to heparin and low molecular weight heparin and even a reduced response to fondaparinux and rivaroxaban was observed in plasma from cirrhotic patients as compared to control plasma.. The anticoagulant potency of clinically approved drugs differs substantially between patients with cirrhosis and healthy individuals. Whereas dabigatran and, to a lesser extent, heparin and low molecular weight heparin are more potent in plasma from patients with cirrhosis, fondaparinux and rivaroxaban showed a decreased anticoagulant effect. These results may imply that in addition to dose adjustments based on altered pharmacokinetics, drug-specific dose adjustments based on altered anticoagulant potency may be required in patients with cirrhosis.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Female; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Liver Cirrhosis; Male; Middle Aged; Morpholines; Polysaccharides; Rivaroxaban; Thiophenes; Thrombin

There is increasing recognition that thrombotic complications may occur in patients with cirrhosis, and literature on antithrombotic treatment in these patients is rapidly emerging. Due to extensive haemostatic changes in patients with cirrhosis, careful monitoring of anticoagulant therapy may be required. Recent data suggest that plasma levels of low molecular weight heparin (LMWH) are substantially underestimated by the anti-activated factor X (anti-Xa) assay in patients with cirrhosis. We studied the in vitro recovery of antithrombin (AT)-dependent and -independent anticoagulant drugs in plasma from 26 patients with cirrhosis and 30 healthy controls and found substantially reduced anti-Xa levels when AT-dependent anticoagulant drugs were added to the plasma of patients with cirrhosis. LMWH (0·2 U/ml) had the poorest recovery in plasma from patients with cirrhosis (0·13 ± 0·06 U/ml, compared to 0·23 ± 0·03 U/ml in controls, P < 0·0001), followed by unfractionated heparin and fondaparinux. In contrast, the recovery of rivaroxaban and dabigatran was identical between patients and controls. These data suggest that the anti-Xa assay cannot be used to monitor AT-dependent anticoagulant drugs in patients with cirrhosis, as it substantially underestimates drug levels. The direct factor Xa and IIa inhibitors, however, may be monitored through the respective anti-Xa and anti-IIa assays in patients with cirrhosis.

Topics: Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Diagnostic Tests, Routine; Drug Monitoring; Factor Xa Inhibitors; False Negative Reactions; Female; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Liver Cirrhosis; Male; Middle Aged; Morpholines; Polysaccharides; Prothrombin; Rivaroxaban; Sensitivity and Specificity; Thiophenes; Thrombophilia