A major research gap: The use of anticoagulants in cirrhosis

Abstract

none. none. MS and JCGP conception, writing of the paper and revision of the literature Trial registration number: not available. Data availability statement: data sharing is not applicable to this review article as no new data were created or analysed in this study. The relationship between anticoagulation and cirrhosis has markedly changed during the last decades. For many years, this relationship was one of strict and mutual avoidance because the low platelet count and high INR levels usually found in patients with cirrhosis were interpreted to cause a spontaneous anticoagulated state and a high risk of bleeding (portal hypertension and non-portal hypertension-related). Moreover, potentially major bleeding in frail patients at risk of minor trauma or easy fallings has probably refrained from prescribing anticoagulants without worries. Thus, anticoagulants were considered highly dangerous and, in general, contraindicated. However, several studies show that patients with cirrhosis are not naturally anticoagulated. Still, they are more prone to develop prothrombotic events (among those, thrombosis of the portal venous system), leading to an interest in these agents as potentially therapeutic in cirrhosis. Although this has allowed the more liberal use of anticoagulants in patients with cirrhosis who have developed thrombotic events, it has not yet culminated in establishing anticoagulants as a cornerstone of treating these patients. This article will briefly review the preclinical and clinical data supporting anticoagulation in cirrhosis. We will also discuss the past and current challenges in assessing the safety and efficacy of anticoagulants in these patients and identify what is still needed to define the proper role of anticoagulants in managing patients with cirrhosis. Several studies have evaluated the effects of different types and doses of anticoagulants (heparin, vitamin K antagonists and direct oral anticoagulants) in different murine models of cirrhosis Table 1. These studies have shown beneficial effects, reducing liver fibrosis, hepatic stellate cell activation, liver function, portal hypertension, and survival 1Zhang R. Huang X. Jiang Y. Wang J. Chen S. Effects of Anticoagulants on Experimental Models of Established Chronic Liver Diseases: A Systematic Review and Meta-Analysis.Can J Gastroenterol Hepatol. 2020; (2020 Dec 11) (PMID: 33381477; PMCID: PMC7749775)8887574https://doi.org/10.1155/2020/8887574Crossref Scopus (6) Google Scholar. Moreover, according to studies conducted on mice fed high-fat diets, dabigatran, a direct thrombin inhibitor, appears to have a protective effect against hepatic fibrin deposition, inflammation, and hepatocellular damage 2Kopec A.K. Abrahams S.R. Thornton S. Palumbo J.S. Mullins E.S. Divanovic S. et al.Thrombin promotes diet-induced obesity through fibrin-driven inflammation.J Clin Invest. 2017 Aug 1; 127 (Epub 2017 Jul 24. PMID: 28737512; PMCID: PMC5531415): 3152-3166https://doi.org/10.1172/JCI92744Crossref PubMed Scopus (76) Google Scholar. In addition, dabigatran has also been associated with a reduction in high-fat diet-induced weight gain 3Kopec A.K. Joshi N. Towery K.L. Kassel K.M. Sullivan B.P. Flick M.J. Luyendyk J.P. Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice.J Pharmacol Exp Ther. 2014 Nov; 351 (Epub 2014 Aug 19. PMID: 25138021; PMCID: PMC4201275): 288-297https://doi.org/10.1124/jpet.114.218545Crossref PubMed Scopus (43) Google Scholar.Table 1Author & yearDesignAnimal typeNumberModel of liver damageTreatment groupsOutcomeDurationKassel et al. 2012NAC57BL/6NAWestern diet (40% kcal from milk fat), NAFLDVehicle pumps and argatroban pumpsAntifibrotic effect23 weeksLi et al. 2006NASprague-Dawley rats52CCl4/porcine serum, hepatic fibrosisNormal control, CCl4, porcine serum, CCl4 + LAAH, and porcine serum + LAAHLiver function tests and area of collagens10 weeksLee et al. 2011NASprague-Dawley rats241% DMN, hepatic fibrosisControl, DMN, DMN + LH, and DMN + LHPAntifibrotic effect4 weeksVilaseca et al. 2017Randomized controlled studyWistar rats, Sprague-Dawley ratsNACCl4/TAA, cirrhosisRivaroxaban and vehicleAntifibrotic effects, HSC activation, and portal pressure18 weeksCerini et al. 2016Randomized controlled studyWistar rats and Sprague-Dawley ratsNACCl4/TAA, cirrhosisEnoxaparin and vehicleAntifibrotic effect and inflammation response15 weeksFortea et al. 2018NASprague-Dawley ratsNACCl4, cirrhosisSaline, CCl4 + Saline, and CCl4 + enoxaparinSurvival, liver function tests, antifibrotic effect, and inflammation response12 weeksAssy et al. 2007NASprague-Dawley rats28TAA, hepatic cirrhosisControls, aspirin, and enoxaparinSurvival, liver function tests, and antifibrotic effect fibrosis5 weeksLi et al. 2017Randomized controlled studySprague-Dawley rats45TAA, hepatic fibrosisTAA, TAA + low-dose aspirin, TAA + high-dose aspirin, and TAA + enoxaparinLiver function tests and antifibrotic effect4 weeksYan et al. 2017Randomized controlled studyC57BL/6NACCl4, cirrhosisDifferent groups of enzymatically depolymerized heparins and salineLiver function tests, antifibrotic effect, and inflammation response8 weeksAbdel-Salam et al. 2005Randomized controlled studySprague-Dawley rats48Bile duct ligated (BDL), cholestatic liver injurySham, BDL, BDL + UFH, BDL + nadroparin, BDL + tinzaparin, and BDL + enoxaparinLiver function tests3 weeksAbe et al. 2007NAWistar ratsNACCl4, hepatic fibrosisCCl4 and CCl4 + dalteparinAntifibrotic effect7 weeksLee et al. 2019NASprague-Dawley rats24TAA, hepatic fibrosisSaline and dabigatran etexilateLiver function tests, antifibrotic effect, fibrin deposition, intrahepatic angiogenesis, and portal hypertension12 weeksMahmoud et al. 2019Randomized controlled studyAlbino rats24CCl4, hepatic fibrosisControl group, CCl4, and CCl4 + rivaroxabanLiver function tests, antifibrotic effect, and inflammation response6 weeksMahmoud et al. 2019Randomized controlled studyAlbino rats56CCl4, hepatic fibrosisNormal control, fibrosis control, dabigatran-treated, and clopidogrel-treated groupLiver function tests, antifibrotic effect, and inflammation response6 weeksLegend: ATIII, antithrombin III; BDL, bile duct ligated; CDAA, choline-deficient, L-amino acid-defined; CCl4, carbon tetrachloride; CSAA, choline-sufficient l-amino acid; HF/HC, high-fat high-calorie; L-amino acid-defined; DMN, dimethylnitrosamine; LAAH, low anticoagulant activity heparin; LH, low molecular weight heparin; LHP, low molecular weight heparinepluronic nanogel; NAFLD, nonalcoholic fatty liver disease; TAA, thioacetamide; UFH, unfractionated heparin. Open table in a new tab Legend: ATIII, antithrombin III; BDL, bile duct ligated; CDAA, choline-deficient, L-amino acid-defined; CCl4, carbon tetrachloride; CSAA, choline-sufficient l-amino acid; HF/HC, high-fat high-calorie; L-amino acid-defined; DMN, dimethylnitrosamine; LAAH, low anticoagulant activity heparin; LH, low molecular weight heparin; LHP, low molecular weight heparinepluronic nanogel; NAFLD, nonalcoholic fatty liver disease; TAA, thioacetamide; UFH, unfractionated heparin. Such impressive effects would have made to assume a fast translation to clinical practice. However, frequently, the robust efficacy of different strategies observed in animal models is not confirmed in humans; therefore, establishing the efficacy of anticoagulants in patients with cirrhosis is mandatory. Randomised clinical trials are the most robust way to demonstrate the effectiveness and safety of new treatments, and this approach has been used for establishing the indication of anticoagulants in several other clinical situations, mainly from the cardiovascular or osteoarticular domains 4Carnicelli A.P. Hong H. Connolly S.J. Eikelboom J. Giugliano R.P. Morrow D.A. et al.COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) Investigators. Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex.Circulation. 2022 Feb 22; 145 (PMID: 34985309; PMCID: PMC8800560)e640Google Scholar,5O'Toole R.V. Stein D.M. O'Hara N.N. Frey K.P. Taylor T.J. Scharfstein D.O. et al.Major Extremity Trauma Research Consortium (METRC)Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture.N Engl J Med. 2023 Jan 19; 388 (PMID: 36652352): 203-213https://doi.org/10.1056/NEJMoa2205973Crossref Scopus (11) Google Scholar. In these studies, thousands of patients were included to evaluate the efficacy and safety of anticoagulants. Positive results from these studies have led to the approval of several anticoagulants for everyday clinical situations, including atrial fibrillation 4Carnicelli A.P. Hong H. Connolly S.J. Eikelboom J. Giugliano R.P. Morrow D.A. et al.COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) Investigators. Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex.Circulation. 2022 Feb 22; 145 (PMID: 34985309; PMCID: PMC8800560)e640Google Scholar and thromboprophylaxis after a fracture 5O'Toole R.V. Stein D.M. O'Hara N.N. Frey K.P. Taylor T.J. Scharfstein D.O. et al.Major Extremity Trauma Research Consortium (METRC)Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture.N Engl J Med. 2023 Jan 19; 388 (PMID: 36652352): 203-213https://doi.org/10.1056/NEJMoa2205973Crossref Scopus (11) Google Scholar, among others. However, patients with chronic liver disorders were usually excluded from these studies due to their higher risk of experiencing severe side effects, including hemorrhagic and hepatic toxicity. Experiencing such side effects could have precluded the approval of using anticoagulants for the above-mentioned clinical indication. The risks associated with developing drugs for niche markets, where the patient population is small, and the risk of side effects may be higher (i.e. use of anticoagulants in patients with cirrhosis), has likely discouraged pharmaceutical companies from investing in such potential indications. Indeed, despite all the solid preclinical evidence, the authors of this manuscript are not aware of any industry-sponsored trial assessing the safety or efficacy of anticoagulants in patients with liver cirrhosis. An additional challenge to performing clinical studies to evaluate the potential utility of anticoagulants in patients with cirrhosis arises from the competition for patient recruitment with industry-sponsored studies with less preclinical rationale than anticoagulants. Therefore, recruiting a sufficient number of patients to the study, which is essential for ensuring that the results are statistically significant and clinically meaningful, would be unlikely. Consequently, some studies were prematurely stopped by a much lower recruitment than expected and could not obtain the calculated sample size (NCT 02271295 and NCT 02643212). Despite all these considerations, we must recognise that clinicians and researchers interested in investigating the role of anticoagulants in patients with cirrhosis have been able to provide some very interesting data in different clinical scenarios: 1) Anticoagulation used in patients with cirrhosis for a specific indication for anticoagulation not related to the liver disease (i.e. atrial fibrillation); 2) anticoagulation in patients with cirrhosis that have developed a thrombotic event, mainly portal vein thrombosis; and 3) anticoagulation to impact the natural history of patients with cirrhosis.1)Anticoagulation for indications not related to liver disease A higher incidence of Atrial Fibrillation (AF) has been observed in patients with liver cirrhosis, regardless of the underlying cause 6Chokesuwattanaskul R. Thongprayoon C. Bathini T. O'Corragain O.A. Sharma K. Preechawat S. et al.Epidemiology of atrial fibrillation in patients with cirrhosis and clinical significance: a meta-analysis.Eur J Gastroenterol Hepatol. 2019 Apr; 31 (PMID: 30451705): 514-519https://doi.org/10.1097/MEG.0000000000001315Crossref Scopus (11) Google Scholar and from 2012 to 2019, there has been a 10% increase in the prescription of anticoagulants for AF in cirrhotic patients, primarily in the use of Direct Oral Anticoagulants (DOACs) 7Simon T.G. Schneeweiss S. Singer D.E. Sreedhara S.K. Lin K.J. Prescribing Trends of Oral Anticoagulants in US Patients With Cirrhosis and Nonvalvular Atrial Fibrillation.J Am Heart Assoc. 2023 Feb 7; 12 (Epub 2023 Jan 10. PMID: 36625307)e026863https://doi.org/10.1161/JAHA.122.026863Crossref Scopus (2) Google Scholar. A recent study analysed a US national database of patients, mainly with Child-Pugh (CP) A cirrhosis, who developed AF 8Serper M. Weinberg E.M. Cohen J.B. Reese P.P. Taddei T.H. Kaplan D.E. Mortality and Hepatic Decompensation in Patients With Cirrhosis and Atrial Fibrillation Treated With Anticoagulation.Hepatology. 2021 Jan; 73 (Epub 2020 Nov 9. PMID: 32267547; PMCID: PMC7541418): 219-232https://doi.org/10.1002/hep.31264Crossref PubMed Scopus (37) Google Scholar. The results showed that DOACs were associated with a lower risk of all-cause mortality than no anticoagulant treatment. A meta-analysis of seven studies involving 19,798 patients with both atrial fibrillation and cirrhosis revealed that anticoagulation treatment did not significantly increase the risk of bleeding compared to no anticoagulation. Furthermore, the use of DOACs was associated with a lower risk of bleeding compared to warfarin 6Chokesuwattanaskul R. Thongprayoon C. Bathini T. O'Corragain O.A. Sharma K. Preechawat S. et al.Epidemiology of atrial fibrillation in patients with cirrhosis and clinical significance: a meta-analysis.Eur J Gastroenterol Hepatol. 2019 Apr; 31 (PMID: 30451705): 514-519https://doi.org/10.1097/MEG.0000000000001315Crossref Scopus (11) Google Scholar. However, it is worth noting that most of the available data are based on retrospective analyses and that most studies included only a minimal number of patients with decompensated cirrhosis.2)Anticoagulation indicated for PVT Data about the impact of portal vein thrombosis (PVT) on decompensation and mortality in patients with cirrhosis come from cohort studies, mostly retrospective 8Serper M. Weinberg E.M. Cohen J.B. Reese P.P. Taddei T.H. Kaplan D.E. Mortality and Hepatic Decompensation in Patients With Cirrhosis and Atrial Fibrillation Treated With Anticoagulation.Hepatology. 2021 Jan; 73 (Epub 2020 Nov 9. 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C. - in portal Hepatol. 2022 Apr; (Epub 2021 Dec J Hepatol. 2022 PMID: PubMed Scopus Google Scholar, G. et Liver Vein and in Patients With Liver 2020 by the for the of Liver 2021 Jan; 73 (Epub 2021 Jan PMID: PubMed Scopus Google Scholar the use of anticoagulation in patients with cirrhosis and PVT who are current or potential liver transplant in where the more than of the or to the is that we will have any anticoagulation no treatment in this clinical However, in the most studies, the of or thrombosis not of patients during treatment. these there is a for the use of more therapeutic such as intrahepatic compared to anticoagulation in patients with cirrhosis and portal vein thrombosis (PVT) who are for liver potential area for controlled trials would be the of anticoagulation no treatment in patients with thrombosis less than of the portal vein or intrahepatic would the treatment approach for this patient the natural history of PVT, the number needed to to from which would impact would likely be very Consequently, the to develop such studies will these very to the are in the of is the only observed in patients portal vein or are there effects of anticoagulants those with data are S. G. F. N. M. A. M. et and Effects of Anticoagulants in Patients With Cirrhosis and Vein Gastroenterol Hepatol. 2018 Jul; (Epub 2017 Oct PMID: PubMed Scopus Google Scholar, M. Riva N. F. K. et of Splanchnic Vein Thrombosis in Gastroenterol. 2018 Aug (PMID: PMCID: PubMed Scopus Google Scholar, E. C. M. M. R. S. et portal vein thrombosis and liver decompensation in patients with 2012 Nov; (Epub 2012 Jul PMID: PubMed Scopus Google Scholar, A. L. F. T. G. et anticoagulation survival through portal vein in patients with cirrhosis and portal vein patient data meta-analysis of of anticoagulation in the natural history of patients with cirrhosis. The of anticoagulation in reducing portal hypertension and liver fibrosis from preclinical models of cirrhosis, with data in some retrospective studies an effect of and in portal and survival in patients with cirrhosis. This to that portal and survival be the to the efficacy of anticoagulants. assessing the impact of anticoagulants on these researchers could the clinical of this in this patient population and clinicians in the most treatment In that a investigating the role of doses of low molecular weight no treatment showed a significant in the risk of decompensation and death during in the of patients E. C. M. M. R. S. et portal vein thrombosis and liver decompensation in patients with 2012 Nov; (Epub 2012 Jul PMID: PubMed Scopus Google Scholar. A recent including cohort studies of patients with cirrhosis and PVT, a in mortality compared to no regardless of the of PVT, a beneficial effect of anticoagulants effect on PVT E. C. M. M. R. S. et portal vein thrombosis and liver decompensation in patients with 2012 Nov; (Epub 2012 Jul PMID: PubMed Scopus Google Scholar. However, as this with studies S. G. F. N. M. A. M. et and Effects of Anticoagulants in Patients With Cirrhosis and Vein Gastroenterol Hepatol. 2018 Jul; (Epub 2017 Oct PMID: PubMed Scopus Google Scholar, M. Riva N. F. K. et of Splanchnic Vein Thrombosis in Gastroenterol. 2018 Aug (PMID: PMCID: PubMed Scopus Google Scholar in which the was only or more was The study conducted by et al. a of anticoagulants their to PVT that both warfarin and DOACs were associated with lower incidence of hepatic and mortality in patients with cirrhosis and atrial fibrillation 8Serper M. Weinberg E.M. Cohen J.B. Reese P.P. Taddei T.H. Kaplan D.E. Mortality and Hepatic Decompensation in Patients With Cirrhosis and Atrial Fibrillation Treated With Anticoagulation.Hepatology. 2021 Jan; 73 (Epub 2020 Nov 9. PMID: 32267547; PMCID: PMC7541418): 219-232https://doi.org/10.1002/hep.31264Crossref PubMed Scopus (37) Google Scholar. supporting this beneficial effect of anticoagulants from the results A. F. J. J. M. E. et survival and decompensation in cirrhotic patients with liver Scholar of a in patients with cirrhosis and liver this study to the calculated sample but a for survival of clinical was found in the the effect was statistically significant the of Child-Pugh was current not from the of the that anticoagulants could be a for patients with cirrhosis of the of However, this is probably to clinical We despite all the also will other that may the of anticoagulants in treating patients with cirrhosis. These studies must also be able to other efficacy and safety of the different types of the of and which of patients with cirrhosis would is still a way to in investigating the role of anticoagulants in patients with cirrhosis.

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