2015_Anticoagulant Therapy in Patients with Cirrhosis

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Anticoagulant Therapy in Patients with Cirrhosis Nicolas M. Intagliata, MD1

Patrick G. Northup, MD1

1 Division of Gastroenterology and Hepatology, University of Virginia

Health System, University of Virginia, Charlottesville, Virginia

Address for correspondence Patrick G. Northup, MD, Division of Gastroenterology and Hepatology, University of Virginia, PO Box 800708, Charlottesville, VA 22908 (e-mail: [email protected]).

Abstract

Keywords

► liver disease ► deep venous thrombosis ► thrombosis ► warfarin ► heparin

Recent studies have greatly expanded our understanding of the coagulopathy of cirrhosis. It is clear that cirrhosis patients are at a risk of both bleeding and thrombosis. While prediction of these events remains challenging, cirrhosis patients are not protected from the development of venous and arterial thrombosis. In fact, studies show that hypercoagulability may promote hepatic decompensation and development of fibrosis. Anticoagulation for thrombosis is now becoming a common prospect in many clinical situations. Our understanding of the efficacy and safety of commonly used therapeutics is only beginning to emerge and the risks and benefits remain unclear in this unique population. In this review, we discuss the role of anticoagulation in the treatment and prevention peripheral and splanchnic thrombosis in patients with cirrhosis, as well as examine the potential role of anticoagulants in altering the progression of chronic liver disease.

In recent years the paradigm of hemostasis and thrombosis in patients with cirrhosis has evolved significantly.1,2 The risk for patients with cirrhosis developing venous thromboembolism (VTE) and portal vein thrombosis (PVT) is now better understood.3–7 Patients with cirrhosis are not protected from development of thrombosis via “autoanticoagulation.” Rather, as cirrhosis and portal hypertension progress the coagulation system is rebalanced with compensatory changes in both anti and procoagulant directions.8–10 This rebalanced state is more sensitive to perturbations manifested by bleeding or inappropriate thrombosis. Conventional coagulation parameters, such as quantitative platelet count or prothrombin time, are inadequate to predict bleeding or clotting risk in cirrhosis. Investigators using in vitro analysis with thrombin generation assay (TGA) have even observed a tendency toward a hypercoagulable state in advanced cirrhosis.9–13 As evidence continues to expand in this field the myth of autoanticoagulation in cirrhosis is fading. Consequently, patients with cirrhosis are now more commonly diagnosed with thrombosis and considered for anticoagulant therapy. Evidence is accumulating that prevention14–17 and treatment18–21 of thrombosis with anticoagulants is safe and effective in cirrhosis patients. While low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) remain the

most extensively studied therapeutics in this population, newer direct acting oral anticoagulants (DOAC) against factor Xa and thrombin, respectively, have expanded a previously sparse therapeutic armamentarium.22–24 Unfortunately, cirrhosis patients are excluded from pharmaceutical trials ipso facto due to the presence of liver disease. Accordingly, clinicians are left to extrapolate clinical trial data to fit to the cirrhosis patient with thrombosis. Current evidence indicates that with careful patient selection cirrhosis patients can safely tolerate anticoagulation for prevention or therapy of VTE or PVT. However, support from large prospective clinical trials are desperately lacking in this population. Instead, we rely on the anecdotal experience and smaller prospective and retrospective studies to direct current care. Herein, we review the current literature pertaining to anticoagulant therapy to treat and prevent thrombosis in cirrhosis patients and review mechanisms underlying the potential benefits of anticoagulant therapy in prevention of fibrogenesis and hepatic decompensation.

published online June 6, 2015

Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

Issue Theme Hemostatic Dysfunction in Liver Diseases; Guest Editors: Ton Lisman, PhD, and Hau C. Kwaan, MD, FRCP.

Anticoagulant Therapeutics Anticoagulant medications for treatment of thrombosis vary considerably in delivery method, mechanism, efficacy, and

DOI http://dx.doi.org/ 10.1055/s-0035-1550436. ISSN 0094-6176.

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Semin Thromb Hemost 2015;41:514–519.

approved indication (►Table 1). Heparins (e.g., unfractionated heparin, LMWH, fondaparinux) and VKA, such as warfarin, are the most widely used agents. LMWH and VKA are the most extensively studied therapeutic agents in patients with cirrhosis. DOAC that directly inhibit factor Xa (apixaban, rivaroxaban, and endoxaban) or factor IIa (dabigatran) are now increasingly used in medical or surgical patients for a range of indications. Reports of success in cirrhosis patients are emerging, but robust clinical safety data are lacking.23,24 LMWH (e.g., enoxaparin) acts via binding to antithrombin (AT) to inhibit factor Xa. The advantages for use in cirrhosis patients include documented safety and efficacy in a small number of studies and the ability to use in the outpatient setting without the need for routine monitoring. Notably, studies have shown that using available antifactor Xa assays to monitor the anticoagulant effect of LMWH in cirrhosis patients is misleading especially in advanced liver disease, likely secondary to concurrent AT deficiency.25–28 In fact, these studies nicely illustrate dangers inherent in a priori application of validated measurements and therapeutic strategies based on experience from traditional medical patients to patients with cirrhosis. At this time, there are no recommendations to routinely monitor LMWH in cirrhosis patients, although some investigators have used TGA to demonstrate anticoagulant efficacy.26–28 A clear disadvantage to LMWH is patient discomfort with repeated subcutaneous injections leading to noncompliance. Renal insufficiency, quite common in cirrhosis, is also a potential contraindication for use of LMWH. Therefore, clinicians often opt for long-term therapy with VKA due to lower associated costs and the more desirable oral delivery method. VKA act to decrease vitamin K-dependent procoagulant proteins factors II, VII, IX, X, and

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anticoagulant proteins C and S. These medications have been used routinely for many years in patients without cirrhosis and remain the mainstay for anticoagulant therapy in multiple disease processes. Major advantages of VKA include low cost, oral administration, and ability to reverse effect with vitamin K and/or exogenous replacement of coagulation factors. However, VKAs require routine monitoring and adjustment with international normalized ratio (INR), diet adherence, and have a very narrow therapeutic window. The reliance on INR for monitoring makes VKAs particularly undesirable in cirrhosis patients who often have inherent elevation of INR due to deficient synthesis of coagulation factors. Several studies have clearly demonstrated that INR does not predict bleeding or risk of clotting in cirrhosis and interlaboratory variation is very common.29–32 While a poor predictor of bleeding in cirrhosis, INR is incorporated into the model for end-stage liver disease (MELD) to predict survival and used frequently by clinicians in caring for cirrhosis patients.33 The utility of INR for prognostication in liver disease often belies its inadequacies as an actual measure of bleeding risk. Responding to this dilemma investigators have sought to establish recalibrated INR using plasma from cirrhosis patients, so termed the “INRliver.”34,35 While shown to be relatively safe in small studies, anticoagulation with VKA in cirrhosis present unfavorable challenges in respect to monitoring therapeutic effect and directly alters MELD for transplant eligible patients. DOAC used in treatment and prophylaxis for thrombosis is garnering increasing interest. Available DOAC in the United States include direct factor Xa inhibitors (apixaban, rivoraxaban, and endoxaban) and direct factor IIa inhibitor (dabigatran). DOAC have relative contraindications in

Table 1 Anticoagulant therapeutics for thrombosis studied in cirrhosis Anticoagulant

Mechanism of action

Intravenous or subcutaneous administration Unfractionated heparin

Potentiates antithrombin, inactivating FXa, thrombin

LMWH

Potentiates antithrombin, inactivating FXa, thrombin

Enoxaparin Dalteparin Nadroparin Oral administration Vitamin K antagonist

Inhibits vitamin K epoxide reductase complex, reducing synthesis of FII, VII, IX, X, protein C þ S

Warfarin Factor Xa inhibitors

Directly inhibit FXa

Rivaroxaban Apixaban Endoxaban Thrombin inhibitor

Directly inhibits thrombin

Dabigatran Aspirin

Irreversibly inhibits platelet aggregation via inhibition of cyclooxygenase

Abbreviation: LMWH, low-molecular-weight heparin. Seminars in Thrombosis & Hemostasis

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Anticoagulant Therapy in Patients with Cirrhosis

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decompensated cirrhosis based primarily on in vitro data as cirrhosis patients were excluded from clinical trials. As such, these medications are not extensively studied in this population and potential issues with use in advanced cirrhosis are now reported by investigators.27,36–38 Beyond the unresolved issues regarding dosing, efficacy, and bleeding risk, one recent report39 suggests rivaroxaban may cause direct hepatic injury. However, a large systematic review40 convincingly disputes this. The advantages of DOAC, mainly the ease of administration without a need to monitor effect, are clearly desired by patients and clinicians alike when compared with conventional therapy.41 Disadvantages of DOAC include expense, limited safety data in cirrhosis patients, and perceived lack of “reversal agent.”22 Recent in vitro data indicates that larger clinical studies are now needed to demonstrate efficacy and safety of these medications in cirrhosis patients before they can be routinely recommended.28,42

Nonsplanchnic Venous Thrombosis in Cirrhosis Patients Primary Prevention Patients with cirrhosis are at a risk to develop peripheral nonsplanchnic deep venous thrombosis and pulmonary emboli (VTE).4,6,43–45 Due to entrenched perceptions of “autoanticoagulation,” clinicians historically avoided medical thromboprophylaxis in hospitalized cirrhosis patients.45,46 Several retrospective studies have now specifically examined the safety and efficacy of thromboprophylaxis in hospitalized cirrhosis patients.14,15,17,47 Bechman et al evaluated hospitalized cirrhosis patients receiving prophylactic LMWH and found a bleeding complication rate of 6.7%.15 In a larger, retrospective, single center cohort of hospitalized cirrhosis patients receiving either unfractionated heparin or LMWH for thromboprophylaxis low rates of gastrointestinal bleeding were found (2.5%). However, VTE still occurred in a small percentage of patients despite exposure to thromboprophylaxis at standard doses.17 In well-compensated surgical cirrhosis patients undergoing partial hepatectomy for hepatocellular carcinoma, bleeding rates in patients exposed to medical thromboprophylaxis (LMWH) were similar to controls (3.18 vs. 1.38%, respectively, p ¼ 0.38).14 Another retrospective study evaluating patients with “chronic liver disease,” found that minor rates of hemorrhage were significantly higher in patients receiving medical thromboprophylaxis compared with those who did not.47 Notably in this study rates of major hemorrhage, quantity of packed red blood cells transfused, and bleeding related mortality were similar between exposed and unexposed cohorts. A systematic review of this topic reveals the heterogeneity of these studies and emphasizes the need for properly powered, prospective trials aimed at establishing safety and efficacy of thromboprophylaxis in this unique population.48 Current guidelines do not address the role of thromboprophylaxis in cirrhosis patients and the overall rarity of an event requires very large cohorts to achieve sufficient statistical power for a clinical trial.49 However, given the compelling evidence that patients with cirrhosis are at risk to develop VTE, clinicians Seminars in Thrombosis & Hemostasis

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should strongly consider application of standard recommendations for primary prevention to hospitalized cirrhosis patients when direct contraindications are absent.22,50,51

Therapy The vast majority of studies investigating therapeutic anticoagulants in cirrhosis patients examine therapy for PVT and not specifically nonsplanchnic VTE. Cirrhosis patients are clearly at risk to develop VTE in the outpatient and inpatient setting.4,6,43,45 While focus on primary prevention is important, no current studies examine the efficacy or safety of anticoagulants for this indication per se in cirrhosis patients. Rather, the majority of studies examining therapeutic anticoagulants have been conducted in patients with splanchnic thrombosis, such as portal vein and/or superior mesenteric vein thrombosis. Clinicians are left to extrapolate therapeutic choice and regimen for VTE in cirrhosis patients from trials and guidelines in medical patients.52 When a clinician is confronted with a cirrhosis patient that develops VTE it seems reasonable to apply similar rationale and treatment paradigms to this situation. However, cirrhosis patients are unique and studies are now needed examining efficacy and safety of not only classic agents such as VKA or LMWH, but newer therapies that are beginning to gain empiric use in cirrhosis patients. Furthermore, as cirrhosis patients can represent a substantially heterogeneous population, it is likely that a “one-size fits all approach” will be inadequate.

Splanchnic Venous Thrombosis in Cirrhosis Patients Primary Prevention Therapy for PVT is a topic of increasing interest and controversy in the hepatology community. Numerous studies have examined the prevalence of PVT in cirrhosis patients finding rates ranging from 2.1 to 16.2%.3,5,18 Currently, it is unclear if the presence of PVT simply represents worsening liver disease or signifies a fundamental link in hepatic decompensation that is benefited by therapeutic prevention or intervention. A recent randomized trial examined the efficacy and safety of prophylaxis for primary prevention of PVT in cirrhosis patients with LMWH (40 IU subcutaneously daily).16 Patients with compensated cirrhosis and no evidence of PVT were randomized to either thromboprophylaxis or no therapy. No patients in the treatment arm developed PVT compared with 16.6% of patients in controls over the 48 weeks (p ¼ 0.025). By the end of the follow-up period 8.8% of the treated group and 27.7% of the control group had developed PVT. In this outpatient setting it appears that LMWH prophylaxis is effective at preventing development of PVT, tolerable and safe. Perhaps more remarkable was the observed significant reduction in hepatic decompensation events in the treatment group with a significantly higher overall survival rate in patients exposed to LMWH. Potential reasons that may explain this observation include decreased microthrombi formation resulting in improved splanchnic blood flow and maintenance of gut enterocyte integrity. These encouraging and provocative findings highlight a

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potential role for anticoagulants beyond therapy for clinically evident thrombi in the splanchnic system. Future studies must corroborate this before routine thromboprophylaxis is widely adopted.

Therapy Most studies in cirrhosis patients with anticoagulants have been conducted in therapy for PVT with LMWH, VKA or a combination of these therapies.5,18–21,53 Development of PVT can often be clinically silent and is usually diagnosed on imaging via ultrasound or cross-sectional modalities, such as computed tomography or magnetic resonance imaging. PVT is classified according to temporal (acute vs. chronic) and spatial characteristics (occluded vs. partial; portal vein only vs. extension into superior mesenteric venous system).54 Studies examining anticoagulation for PVT in cirrhosis patients are small and retrospective with widely varying methodologies making comparisons difficult. The largest study to date evaluated 55 cirrhosis patients with acute PVT treated with LMWH (26 patients), VKA (8 patients) or combination (21 patients).19 Overall, 60% of the treated patients displayed successful recanalization of the portal vein. A shorter time to initiation of therapy (< 2 weeks) was associated with a greater likelihood of success. Similarly, Senzolo et al found a significant association with time to therapy (< 6 months) and successful recanalization of the portal vein in patients treated with LMWH when compared with controls that were not treated.21 In both the studies, low rates of complications from therapy were reported. Anticoagulation with VKA and a platelet count of less than 50  109/L were associated with an increased risk of bleeding.19 DOAC are recently reported in a case report23 and small case series24 to be effective and safe in treatment of PVT in well-compensated patients. In general, evidence indicates that anticoagulation for PVT in carefully selected cirrhosis patients is safe and effective. Patients being considered for anticoagulation should undergo evaluation for esophageal varices before initiation of anticoagulation. While shorter time to therapy is apparently predictive of success, others support a “wait and see” approach to determine if the thrombus will spontaneously resolve.55 Currently, it is not entirely clear if the development of PVT is a cause or effect of hepatic decompensation. Data from the transplant literature supports the notion that PVT is associated with increased mortality and therapy may provide overall benefit.5,53,56 However, a recent large longitudinal cohort study of cirrhosis patients from France suggests that development of PVT may not change overall prognosis of cirrhosis patients, thus questioning the need for anticoagulation therapy with the ensuing risks.57

Beyond Prevention and Treatment of Thrombosis After noting the presence of intrahepatic microvascular thrombi in autopsy specimens of patients with liver disease, Wanless and colleagues hypothesized a role for thrombosis and a hypercoagulable state in generation of fibrosis in the

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liver.58–60 Termed parenchymal extinction, it is thought that microinfarctions from accumulation of thrombosis in terminal hepatic arterioles and portal venules initiate inflammation and sinusoidal injury that result in hepatocyte apoptosis and eventual formation of fibrous tissue in the interceding space. Another mechanism whereby the coagulation system may potentiate fibrogenesis in liver disease is through thrombin-mediated activation of hepatic stellate cells.61 Accordingly, associations with inherited thrombophilic disorders (e.g., factor V Leiden mutation) and more advanced liver disease have been reported.62,63 One study reported that the presence of factor V Leiden mutation was associated with a risk of faster fibrosis progression in a cohort of individuals with hepatitis C.64 Animal models of cirrhosis further implicate the potential role of coagulation in hepatocyte injury and fibrosis. It has been known for some time that thrombin can stimulate hepatic stellate cell proliferation and augment fibrosis production.65 Duplantier et al demonstrated that inhibition of thrombin resulted in a trend toward decreased liver fibrosis in a rat model of cirrhosis.66 A study in mice fed high fat diets to simulate fatty liver disease showed that inhibition of thrombin with dabigatran reduced hepatocellular injury and hepatic fibrin deposition over the course of 3 months.67 Factor Xa, potentially via similar mechanisms to thrombin, may also play a role in pathogenesis of fibrosis.68 Supporting this contention, studies in murine models of cirrhosis69,70 and humans71 have demonstrated that therapy with LMWH potentially reduces fibrogenesis in the liver. Interestingly, a recent large population study in the United States found an association with aspirin use and a decreased risk of fatty liver disease in men.72 The potential relationship of the coagulation system to liver fibrosis provides attractive avenues of therapy that may abrogate fibrogenesis and stall or even reverse the progression to cirrhosis in patients at risk for chronic liver disease. In addition to these several studies in animal models, the exciting results recently reported with LMWH to prevent PVT lend even further support the relationship between liver disease and the coagulation system.16 It is clear from this study that the effects of anticoagulation may extend well beyond the level of VTE and PVT prevention and treatment.

Conclusion The paradigm of bleeding and thrombosis in liver disease has significantly changed over the past 25 years. In the past cirrhosis patients were thought to be in a perpetual hypocoagulable state and protected from thrombosis by virtue of an underproduction of coagulation factors. It is now clear that the situation is more complex and the coagulopathy in cirrhosis is instead rebalanced with significant physiological alterations in both hypo and hypercoagulability directions. Due to these unique properties and profound differences from individuals with a normal functioning liver, anticoagulation in patients with cirrhosis is a very challenging prospect. To date, there are no formal guidelines that direct clinicians in treating cirrhosis patients. As our understanding of the risk and prevalence of thrombosis in this population grows, the Seminars in Thrombosis & Hemostasis

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need for further investigation in this population is quite apparent. Beyond the therapeutic role of anticoagulation, evidence in both animals and humans suggests a potential role of anticoagulants to modify the course of chronic liver disease. These studies are exciting and reveal fundamental mechanisms underlying liver disease pathophysiology and hepatic decompensation. With the development of new anticoagulants and expanding interest in this field, studies are needed in this unique population to better define the role of anticoagulation to prevent and treat thrombosis and to potentially modify disease progression.

15 Bechmann LP, Sichau M, Wichert M, Gerken G, Kröger K, Hilgard P.

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Disclosures None.

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Anticoagulant Therapy in Patients with Cirrhosis