REVIEW

Direct Oral Anticoagulants in Patients with LiverDisease in the Era of Non-Alcoholic Fatty Liver DiseaseGlobal Epidemic: A Narrative Review

Stefano Ballestri . Mariano Capitelli . Maria Cristina Fontana .

Dimitriy Arioli . Elisa Romagnoli . Catia Graziosi . Amedeo Lonardo .

Marco Marietta . Francesco Dentali . Giorgio Cioni

Received: February 24, 2020 / Published online: April 13, 2020� The Author(s) 2020

ABSTRACT

Atrial fibrillation (AF) and venous thromboem-bolism (VTE) are highly prevalent and relevanthealthcare issues. Direct oral anticoagulants(DOACs) are now the first-choice for anticoag-ulant treatment of these conditions displaying abetter efficacy/safety profile than vitamin-Kantagonists, mainly due to significantly reducedrisk of major bleeding, especially of intracranialhaemorrhage. Nonalcoholic fatty liver disease

(NAFLD) is the most common liver disease indeveloped countries showing a continuouslygrowing prevalence. Nonalcoholic steatohep-atitis (NASH), its evolutive form, will be theleading cause for liver transplantation by 2020.NAFLD is independently associated with anincreased risk of abnormalities of cardiac struc-ture and function, including cardiac rhythmdisorders (mainly AF). Moreover, data suggestan increased risk of unprovoked VTE associatedwith NAFLD/NASH. Therefore, a growing num-ber of patients with chronic liver disease (CLD)will be candidate for anticoagulant therapy inthe near future. Cirrhosis of any etiology ischaracterized by an unstable thrombosis/bleed-ing haemostatic balance, making anticoagulanttherapy particularly challenging in this condi-tion. Given that patients with significant activeliver disease and cirrhosis were excluded fromall pivotal randomized controlled trials onDOACs, this comprehensive review aims atcritically discussing real-world evidence,including the latest population studies, regard-ing the use of DOACs in patients withCLD/cirrhosis.

Keywords: Atrial fibrillation; Cardiovasculardisease; Cirrhosis; Direct oral anticoagulants;Fatty liver; Heparin; Liver disease; Stroke;Thrombosis; Warfarin

Enhanced Digital Features To view digital features forthis article go tohttps://doi.org/10.6084/m9.figshare.11993394.

S. Ballestri (&) � M. Capitelli � M. C. Fontana �C. Graziosi � G. CioniInternal Medicine Unit, Pavullo Hospital, AziendaUSL, Modena, Italye-mail: s.ballestri@ausl.mo.it

D. Arioli � E. RomagnoliInternal Medicine and Critical Care Unit, AziendaOspedaliero-Universitaria, Modena, Italy

A. LonardoMetabolic Syndrome Unit, Ospedale Civile diBaggiovara, Azienda Ospedaliero-Universitaria,Modena, Italy

M. MariettaHematology Unit, Azienda Ospedaliero-Universitaria, Modena, Italy

F. DentaliDepartment of Clinical and Experimental Medicine,Insubria University, Varese, Italy

Adv Ther (2020) 37:1910–1932

https://doi.org/10.1007/s12325-020-01307-z

Key Summary Points

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), a globally epidemic condition, isindependently associated with anincreased risk of atrial fibrillation (AF) andunprovoked venous thromboembolism(VTE). Therefore, a growing mole ofpatients with chronic liver disease (CLD)will be a candidate for anticoagulanttherapy in the forthcoming years.

Patients with significant active liverdisease and cirrhosis have been excludedfrom all pivotal randomized controlledtrials (RCTs) on direct oral anticoagulants(DOACs).

Anticoagulant therapy is challenging incirrhotic patients, who exhibit anunstable balance hemostatic betweenthrombosis and bleeding.

Accumulating real world data suggest that,compared to warfarin, DOACs havesimilar efficacy and reduced bleedingcomplications in cirrhotic patients withAF or VTE.

RCTs evaluating efficacy, safety andpossible dose adaptation rules in patientswith cirrhosis are needed.

BACKGROUND

Atrial fibrillation (AF) is the most commoncardiac arrhythmia, with an age-dependentglobal prevalence of 1–3% in the adult popula-tion, exceeding 15% in people aged 80 yearsand over [1, 2]. It is estimated that subjects over65 years affected by AF in Europe will increaseby 89% from 7.6 to 14.4 million within the next40 years, with prevalence rising from 7.8 to9.5% [2]. Moreover, AF is significantly associ-ated with an increased risk of thromboembolic

events [5-times higher risk of stroke], hospital-ization and mortality [1, 2].

Similarly, venous thromboembolism (VTE),including deep vein thrombosis (DVT) andpulmonary embolism (PE), carries a highfinancial burden being the third most frequentacute cardiovascular syndrome after myocardialinfarction and stroke, and ranking high amongthe causes of cardiovascular mortality (more orless 300,000 deaths per year in United Statesand Europe) [3].

Direct oral anticoagulants (DOACs) havebecome the first-line drugs in the treatment ofnon-valvular AF (NVAF) and VTE with provensimilar or better efficacy than vitamin-K antag-onists (VKAs) such as warfarin and significantlyreduced risk of major bleeding, mainlyintracranial haemorrhage (ICH) [3, 4]. However,patients with liver disease and cirrhosis wereexcluded from pivotal randomized controlledtrials (RCTs) of DOACs and evidences in thisparticular setting are limited [5].

Nonalcoholic fatty liver disease (NAFLD),now the most common chronic liver disease(CLD) in developed countries, embraces aspectrum of histopathological conditions rang-ing from simple relatively benign simplesteatosis to nonalcoholic steatohepatitis(NASH), which is associated with progression tofibrosis/cirrhosis and hepatocellular carcinoma[6]. NASH will be the leading cause for livertransplantation by 2020 [7, 8]. NAFLD is inde-pendently associated with an increased risk ofabnormalities of cardiac structure and function,including cardiac rhythm disorders (mainly AF)[9, 10]. Moreover, emergent data suggest NAFLDbeing associated with an increased risk of idio-pathic VTE [11, 12]. Therefore, a growingnumber of patients with advanced fibrosis/cir-rhosis will be candidate for anticoagulant ther-apy in the near future.

Cirrhosis of any etiology carries an increasedrisk of both thrombotic and bleeding compli-cations, making anticoagulant therapy chal-lenging in this condition. Given that patientswith significant active liver disease and cirrhosiswere excluded from trials on DOACs, thisreview aims at critically discussing real-worlddata, including the latest population studies,regarding the use of DOACs in patients with

Adv Ther (2020) 37:1910–1932 1911

CLD/cirrhosis. To this end we searched thePubMed database for publications up to Febru-ary 2020, using pertinent terms and their com-bination: cirrhosis, chronic liver disease, directoral anticoagulants, apixaban, dabigatran,edoxaban, rivaroxaban, venous thromboem-bolism, atrial fibrillation. Clinical trials, obser-vational studies and case series were consideredif relevant to the issue. This article is based onpreviously conducted studies and does notcontain any studies with human participants oranimals performed by any of the authors.

THROMBOEMBOLISM IN LIVERDISEASES

Mechanisms: Hemostatic Balance and itsEvaluation in Cirrhotic Patients

Preserved liver function is essential for the bal-ance between haemostasis and thrombosis.Advanced liver disease of any etiology is typi-cally associated with disorders of coagulationwhich are key in many scores of severity andoutcome of liver disease [13].

Our understanding of the hemostatic bal-ance in liver disease has progressed dramaticallyover the last decades. The prolongation of pro-thrombin time (PT)/international normalizedratio (INR) commonly found in advanced liverdisease was traditionally considered protectivefrom thrombo-embolic events. However, accu-mulating evidence has dismantled the theory of‘‘auto-anticoagulation’’ in cirrhosis showing ahigh risk of VTE in cirrhotic patients, despitePT/INR values [14–16].

In cirrhotic patients, pro-hemorrhagic andprothrombotic drivers co-exist. Pro-hemor-rhagic conditions include: (a) reduced plasmalevels of coagulation factors synthesized by theliver [fibrinogen, factor (F)II, FV, FVII, FIX, FX,FXI, and FXII] reflected by prolonged PT andactivated partial thromboplastin time (aPTT)(b) thrombocytopenia due to splenic sequestra-tion and reduced thrombopoietin synthesis and(c) increased fibrinolysis secondary to elevatedlevels of tissue plasminogen activator, reducedlevels of plasmin inhibitor and thrombin-acti-vatable fibrinolysis inhibitor [17]. Conversely,

pro-thrombotic conditions include: (a) de-creased endogenous anticoagulants synthesizedby the liver: protein C, protein S andantithrombin (AT) (b) increased pro-coagulantendothelial-derived FVIII (c) increased plateletaggregation due to increased endothelial-derived von Willebrand factor (vWF) andreduced ADAMTS13, a natural inhibitor of vWFactivity (d) reduced hepatic synthesis of plas-minogen causing hypo-fibrinolysis [17].

The combination of these pro- and anti-co-agulant factors results in a fragile balance (‘‘re-balanced haemostasis’’) in the stable cirrhoticpatient that can be easily broken by precipitat-ing factors (hepatic decompensation, sepsis,volume status, renal failure or invasive proce-dures) evolving into either thrombosis orbleeding [13, 16] (Fig. 1).

Recognizing the effect of liver disease onthose laboratory tests of coagulation which arecommonly used to monitor the therapeuticeffects of anticoagulants is mandatory toappropriately evaluate and manage anticoagu-lant therapy in cirrhotic patients [18].

Fig. 1 Balance between thrombosis and bleeding in liverdisease. ADAMTS13 ADAM metallopeptidase withthrombospondin type 1 motif 13, PAI plasminogenactivator inhibitor, TAFI thrombin-activatable fibrinolysisinhibitor, TFPI tissue factor pathway inhibitor

1912 Adv Ther (2020) 37:1910–1932

Increased baseline INR/aPTT levels in theabsence of anticoagulants and decreased anti-activated factor X (anti-Xa) levels after unfrac-tionated/low-molecular weight heparin (UFH/LMWH) administration have been found incirrhosis, correlating with the severity of liverdisease [18–20]. Patients with cirrhosis can beunusually sensitive to the anticoagulant effectsof warfarin and this may also be a clue toidentifying latent disease [21].

INR does not appear to be a reliable tool tomonitor haemostasis in cirrhotic patientsbecause it only measures the activity of someprocoagulants factors (FI, FII, FV, FVII and FX),but not that of anticoagulant proteins C/S [13].Specific clotting tests (e.g. thromboelastogra-phy) may overcome the diagnostic limits of INRbut lack validated target levels and are notroutinely used [13, 22]. Similar challenges existin using aPTT test for monitoring UFH therapyas with INR test for VKAs. Indeed, aPTT targetranges are unclear in cirrhotic patients, oftencarrying an aPTT already prolonged at baseline[18–20].

Anti-Xa levels are positively correlated withAT levels, which are reduced in cirrhoticpatients [18, 20, 23, 24]. Therefore, the anti-Xaassay cannot be used to monitor AT-dependentanticoagulant drugs (LMWH/UFH) in patientswith cirrhosis, given that it substantiallyunderestimates drug levels. Conversely, thedirect FXa and thrombin (FIIa) inhibitors can bemonitored through the respective anti-Xa andanti-IIa assays in cirrhotic patients [19].

AF and VTE in Cirrhosis of VariousEtiology

Published studies yielded inconsistent resultsregarding the incidence and prevalence of AF inpatients with liver cirrhosis. In addition, tem-poral trends in risk profiles and clinical out-comes of hospitalized cirrhotic patients withconcomitant AF are still unclear [25]. Patientswith AF and concurrent liver cirrhosis havetypically been excluded from RCTs of oralanticoagulant therapy, both VKAs and DOACs,for stroke prevention; therefore, AF guidelinesare not able to provide specific

recommendation on anticoagulation inpatients with cirrhosis [4]. In a recent nation-wide registry study, the use of warfarin wasassociated with a reduced risk of ischemic strokeand positive net clinical benefit compared tonon-treatment in patients with AF and cirrho-sis, suggesting that thrombo-prophylaxisshould be considered for such patients [26].Conversely, a much smaller study reported thatthe incidence of stroke was similar in AF cir-rhotic patients with and without warfarin use,whereas the incidence of major bleeding eventswas significantly higher in the warfarin group[27]. A recent large retrospective population-based Italian cohort study has shown that AFpatients with concomitant liver disease had anincreased risk of any of the primary study out-comes (stroke, major bleeding and all-causedeath) compared to those without it (medianfollow-up time of 3.8 years); moreover, oralanticoagulation (97% VKAs, 3% DOACs) inpatients with liver disease was associated with asignificant benefit/risk ratio compared to non-treatment [28].

Hospitalized patients with cirrhosis have a0.5–6.3% incidence of newly-diagnosed PE orDVT, similar to those without liver disease [29].Validated risk stratification scores that predictVTE within hospitalized patients, also appear toaccurately predict VTE among hospitalizedpatients with CLD [30]. Interestingly, a recentmeta-analysis has shown that the risk of all VTEevents was higher in patients with cirrhosisthan in controls with an odds ratio (OR) of 1.7[15]. Moreover, patients with cirrhosis and VTEmay have increased mortality over 30 days ascompared to those with VTE without cirrhosis[31, 32]. Nevertheless, prophylactic anticoagu-lation for VTE in hospitalized cirrhotics is sig-nificantly lower than in non-cirrhotics [33].

Aside from DVT/PE, a major issue forpatients affected by CLD is splanchnic veinthrombosis, including mesenteric, portal andhepatic vein thrombosis [32]. Portal veinthrombosis (PVT) is the most common VTEevent in cirrhosis with a prevalence rangingfrom nearly 1% in compensated to 8–25% indecompensated cirrhosis [34, 35]. Mechanisticfactors involved in the development of PVT incirrhotic patients are likely to be multi-factorial.

Adv Ther (2020) 37:1910–1932 1913

Prior VTE, thrombophilia, low portal vein flowvelocity, malignancy, intra-abdominal infec-tion, and recent surgery all increase the risk forPVT [32]. Of note, patients with cirrhosis whodevelop PVT and have no other history ofclotting do not require a hypercoagulableworkup [13]. The clinical presentation is vari-able and stability, regression, or resolutionappear more common than clot progression[36]. Anticoagulation with LMWH appears safeand effective for PVT in cirrhosis [13, 37, 38].

AF and VTE in the NAFLD Spectrum

The epidemiology of liver diseases has signifi-cantly changed over the last years owing toNAFLD continuously growing prevalence inparallel with the decline of chronic hepatitis Cvirus (HCV) thanks to the advent of highly-ef-fective direct-acting antiviral agents [8]. NAFLDis a multi-system disease representing a relevanthealth care issue [39]. Beyond its inherent liver-related morbidity and mortality, NAFLD alsohas a strong mutual, bi-directional relationshipwith type 2 diabetes (T2D)/metabolic syndrome(MetS) [40, 41]. Moreover, it is associated withan increased incidence and prevalence of fataland non-fatal cardiovascular disease (CVD)events, mainly coronary heart disease (CHD),independently of classical cardiovascular riskfactors [42–45]. Interestingly, several observa-tional studies reported an association betweenNAFLD and increased risk of AF in patients withand without T2D, after adjustment for multiplepotential confounders [46]. A recent metanaly-sis showed that NAFLD was independentlyassociated with increased risk of prevalent (OR2.07) and, only in T2D patients, incident [haz-ard ratio (HR) 4.96] AF [47]. Studies investigat-ing whether the reversal of NAFLD will reducethe risk of AF are eagerly awaited. Conversely,longitudinal studies have already proven thatNAFLD reversal/improvement or even its tran-sient remission will reduce the risk of incidentT2D (reviewed in [48]).

Emerging data suggest an associationbetween NAFLD and VTE. One study showed asignificantly higher prevalence of NAFLD inhospitalized patients with unprovoked VTE as

compared to healthy sex/age/body mass index(BMI) matched controls (81% vs 30%), evenafter adjustment for inherited thrombophilia.NAFLD was independently predicted by VTE(OR 1.8) at multivariate analysis [11]. A recentstudy has shown that NASH-related cirrhosis isindependently associated with an increased riskof VTE among hospitalized patients with cir-rhosis after adjustment for confounding factors(OR 2.46) [12]. The risk of PVT is significantlyincreased in patients with NASH-cirrhosis (OR1.55) compared to cirrhosis owing to non-NASHetiologies independently of other risk factors[49] and those aged[60 years, withBMI[30 kg/m2, arterial hypertension and T2Dappear at a particularly high-risk of pre-livertransplant PVT (OR 2.11) [50].

Consistently, some studies provided evi-dence of a pro-coagulant state in NAFLDpatients. An increased activity of some circu-lating coagulation factors (FVIII, FIX, FXI andFXII) has been found in patients of NAFLD,independently of age, gender and BMI [51, 52].NAFLD has independently been associated withincreased plasminogen activator inhibitor-1(PAI-1) in obese patients in a manner related tohistological severity [53]. A procoagulant-im-balance has been observed across the spectrumof NAFLD histological severity progressing fromsimple steatosis to NASH-cirrhosis and resultingfrom increased FVIII (procoagulant) andreduced protein C (anticoagulant) [54]. Thefindings of one study which found thathaemostasis (i.e., platelets, coagulation andfibrinolysis) was rebalanced in NAFLD may havebeen influenced by unusually higher thanexpected FVIII levels in lean controls [55, 56]. Inconclusion the coagulopathy observed acrossthe NAFLD spectrum is an intriguing and as yetincompletely defined area. Therefore, moreresearch is needed in this field.

Potential Role of Coagulation Systemon the Development of the Histogenesisof Cirrhosis and its Complications

Experimental and clinical data suggest an asso-ciation between inflammation, activation of

1914 Adv Ther (2020) 37:1910–1932

coagulation system and development of hepaticfibrosis and portal hypertension in CLD [57].

Histopathological studies on cirrhotic livershave shown that micro-thrombotic occlusion ofsmall intrahepatic veins and sinusoids, sec-ondary to hepatic necroinflammation, fre-quently occurs; this event is followed byprogressive venous obstruction and enhancedfibrogenesis through a process calledparenchymal extinction, which may eventuallylead to liver dysfunction, worsening of portalhypertension and PVT [58–60]. A pathogenicmodel of NASH progression has been proposedbased on lipotoxic necrotic damage, leading todirect inflammatory injury of hepatic veins and,finally, venous obstruction with secondary col-lapse, fibrous septation and cirrhosis [61].

The activation of hepatic stellate cells (HSC)is the key pathogenic mechanism of hepaticfibrogenesis. Experimental animal models sup-port a biological link between coagulation andfibrosis showing that thrombin and FXa canactivate HSC [62, 63] and, conversely, theirinhibition by anticoagulants may prevent orreduce fibrogenesis [57].

Prothrombotic genetic risk factors such as FVLeiden or prothrombin G20210A mutationshave been associated with an increased risk ofclinically relevant liver fibrosis (assessed bytransient elastography) in the general popula-tion [64].

Taken collectively, these observations sug-gest that anticoagulation may represent also aneffective tool to prevent and to treat liverfibrosis and, therefore, portal hypertension.

A milestone small RCT has shown that dailyprophylactic administration of LMWH (enoxa-parin) for 12 months in patients with advancedcompensated cirrhosis [Child-Turcotte-Pugh(CTP) score B7-C10] prevented PVT develop-ment, hepatic decompensation and alsoimproved survival [63]. It was speculated thatthe protective effect of enoxaparin on liverdisease might have been due to an improve-ment in intestinal microcirculation with sec-ondary reduction in bacterial translocation andthus liver inflammation, rather than by merelypreventing PVT [65]. Few other studies onpatients with hepatis B virus (HBV)-related liverfibrosis/cirrhosis or post-liver transplant HCV

recurrence-related fibrosis treated with LMWHor warfarin have also shown improved liverfunction and decreased collagen levels/fibrosis(reviewed in [57]).

Recent data have shown that anticoagulanttherapy (LMWHs or VKAs) in patients with cir-rhosis and PVT is safe and does improve out-come in advanced cirrhosis [38, 66].

While currently available direct-actingantivirals will probably erase the burden ofchronic viral hepatitis, effective antifibroticdrugs for CLD are still lacking [62]. Patients withmetabolic disease (NAFLD/NASH) with indica-tion to anticoagulation are continuously risingand would represent the ideal candidates forfuture studies evaluating the effect of long-termanticoagulation, including DAOCs, on fibroge-nesis and portal hypertension.

DOACS IN ADVANCED CHRONICLIVER DISEASE

Overview on DOACs and Liver Disease

The four DOACs available for clinical useinclude apixaban, rivaroxaban and edoxabanwhich are direct inhibitors of FXa and dabiga-tran which is a direct inhibitor of thrombin(FIIa). DOACS have become the first-choiceanticoagulant drugs in the prevention andtreatment of stroke-systemic embolism and VTEin the great majority of patients, provided thatrenal function is adequate. However, patientswith active liver disease, defined as acute orchronic hepatitis, cirrhosis or elevated alaninetransaminase (ALT) or aspartate transaminase(AST)[ 2 or 3-times the upper limit of normal(ULN) or total bilirubin C 1.5–2 times the ULN,have all been excluded in all the pivotal RCTs ofDOACs [5].

Compared to warfarin, DOACs are less reli-ant on hepatic clearance and have a shorterhalf-life. These pharmacodynamic characteris-tics make them attractive for use also in patientswith liver disease [5, 67]. However, DOACs alsohave hepatorenal body clearance, plasma pro-tein binding and cytochrome P450 metabolism.These pharmacokinetic properties can all beaffected by liver disease to varying degrees,

Adv Ther (2020) 37:1910–1932 1915

suggesting caution in their use in patient withaltered hepatic function [5, 67]. Apixaban andrivaroxaban are principally cleared by the liver(75% and 65% respectively), followed by edox-aban (50%) and lastly by dabigatran (20%),which is mainly eliminated by the kidney.Dabigatran etexilate is the only pro-drug DAOCundergoing the biotransformation to activedrug by ubiquitous esterases; thus, its metabo-lism is not limited to the liver. Some DOACshave a high plasma protein binding capacity(rivaroxaban 95%, apixaban 85%, edoxaban55%, and dabigatran 35%) which can be asso-ciated with increased free drug fraction levelswhen liver albumin synthesis is impaired.Apixaban and rivaroxaban are predominantlymetabolized by cytochrome P450 enzymes,whose activity is reduced by liver disease, whiledabigatran and edoxaban have minimal to nonecytochrome P450 metabolism. Biliary excretionof all DOACs is reduced by liver disease. Finally,also renal clearance of DOACs may be impairedwhen liver disease is either associated withhepatorenal syndrome or other kidney diseasesco-exist.

The CTP scoring system, the prognosticmodel universally used to predict mortality incirrhosis, incorporates five parameters: serumbilirubin, serum albumin, prothrombin time,ascites severity and encephalopathy grade[68, 69]. Based on the sum of these items theindividual patient is categorized into one ofthree CTP classes of growing severity (A, B, or C)which predict survival outcomes. Survival ratesat 1 and 2-year are respectively 95% and 90% forCTP class A patients, while they are 80% and70% for CTP class B and 45% and 38% for classC patients [70].

Therefore, it can be assumed that the risk ofbleeding outweighs the potential benefits ofanticoagulant therapy in cirrhotic CTP class Csubjects, whose 1-year survival rate is less than50% without liver transplantation. In patientswith CTP class B anticoagulation should bebalanced against the presence of portal hyper-tension, oesophageal varices, hypertensive gas-tropathy, thrombocytopenia, coagulopathy,baseline high risk of bleeding, impaired drugmetabolism and impaired renal function.

On these grounds, both drug regulatoryagencies (European Medicines Agency: EMA;Food and Drug Administration: FDA) and cur-rent guidelines recommend all four DOACs inpatients with cirrhosis CTP class A, while con-traindicate their use in patients with liver dis-ease associated with coagulopathy andclinically relevant bleeding risk, including cir-rhosis CTP class C. DOACs are variably recom-mended in CTP class B liver disease [5, 67].Rivaroxaban was contraindicated due to a[twofold increase in drug exposure in thesepatients [71] while dabigatran, apixaban andedoxaban may be used with caution based onlow-grade evidence from few small retrospectivestudies [5, 67]. The U.S. FDA does not recom-mend also Edoxaban in CTP class B [72],although one study found no difference in drugexposure in patients with CTP A and B after asingle low-dose of Edoxaban (15 mg) [73]. TheEuropean society of cardiology (ESC) recom-mends that the prescription and follow-up ofanticoagulant therapy in cirrhotic patientsshould be performed in specialized centres fea-turing a multidisciplinary medical team (in-cluding a hepatologist and an expert ofcoagulation disorders) [67].

Evidence from Real-World Studies

Real-world data on the use of DOACs in patientswith CLD are continuously accumulating. Sev-eral new studies have been published since therelease of the latest guidelines [67] and previousreviews on the use of DOACs in patients withcirrhosis [5, 74–76]. Original studies evaluatingthe use of DOACs vs traditional anticoagulantsin patients with CLD are reported in Table 1[77–89].

The first data came from retrospective caseseries or relatively small-sized cohort studiesshowing that the hemorrhagic risk with DOACswas lower than or similar to warfarin in cir-rhotic patients anticoagulated for various indi-cations. However, the sample size of thesestudies did not usually allow for adequatecomparison of thromboembolic outcomes [74].A seminal retrospective analysis on 39 cirrhoticpatients (approximately 50% in CTP class B)

1916 Adv Ther (2020) 37:1910–1932

Table1

Studiesevaluating

DOACsvs

traditionalanticoagulantsin

patientswithCLD

Autho

r

(reference)

Pop

ulation

characteristics

AC

Indication

stud

y/ctrl,

n

Age

stud

y/ctrl

CTP

stud

y/

ctrl,%

Varices

stud

y/ctrl,

n(%

)

DOACstype

DOACsdo

seAC

duration

stud

y/ctrl

Efficacy

outcom

es

stud

yvs

ctrl,n(%

)

Safety

outcom

es

stud

yvs

ctrl,n

(%)

Intagliata

[77]

USA

,retrospective

cohort,39cirrhoticpts

(DOACs20,w

arfarin/

LMWH

13/6)

AF4/1

VTE4/12

SpVT

12/6

Mean(range)

57(50–

64)/

60(55–

64)

A:45/47

B:55/53

C:0/0

10(50)

/7(41)

Apixaban55%

Rivaroxaban

45%

2.5or

5mgBID

10or

20mgOD

Mean

267/478days

NA

Any

bleeding

rate:

20%vs

16%(ns)

Major

bleeding

rate:5%

vs11%

(ns)

Kun

k[78]

USA

,retrospective

cohort,69cirrhoticpts

(DOACsonly)

AF22

PVT/D

VT

47

Median

(range)73

(44–

92)

A:48

B:38

C:14

36(52)

Apixaban54%

Rivaroxaban

36%

Dabigatran10%

NA

6months

AF:

none

developed

clot

VTE:81%

resolution,

13%

unchanged,6%

progression

Any

bleeding

rate:

16(23)

Major

bleeding

rate:8(12)

Hum

[79]

USA

,retrospective

cohort,45cirrhoticpts

(DOACs27,w

arfarin/

LMWH

15/3)

AF15/9

DVT

12/8

PVT

4/3

Mean(range)

61(26–

90)/

58(34–

80)

A:41/39

B:44/50

C:15/11

4(15) /2(11)

Rivaroxaban

63%

Apixaban47%

15mg

OD

±20

mgload

5mg

BID

±10

mgload

Median

225/317days

Failedefficacy:1(6)

vs1(4)(p

=1.00)

Any

bleeding

rate:

8(30)

vs10

(56)

(p=0.12)

Major

bleeding

rate:1(4)vs

5

(28)

(p=0.03)

DeGottardi

[80]

Europe,retrospective

cohort,36cirrhoticpts

vs58

non-cirrhotic

ctrls(allDOACsonly)

SpVT 27/42

DVT

4/0

AF5/12

Other

0/6

Median

(range)

49.5

(16–

82)/

64.9

(32–

82)

Median

(range)

6(5–8

)

23(64)

/24(41)

Rivaroxaban

83%

Apixaban11%

Dabigatran5%

5to

20mgTDD

2.5to

10mgTDD

110to

220mgTDD

Mean9.6/

13.1

months

NA

Allbleeding

rate:5

(14)

vs9(15.5)

Major

bleeding

rate:1(3)vs

2

(3.5)

Goriacko

[81]

USA

,retrospective

cohort,2

33CLD

pts

(DOACs75,w

arfarin

158)

AF75/158

Median

(IQR)

66(61,

75)/

65(59,

73)

A:64/35

B:35/59

C:1/6

1(1.3)/

11(7)

Dabigatran47%

Rivaroxaban

39%

Apixaban15%

NA

NA

NA

Any

bleeding

rate:

8.4%

vs8.8%

per

year

(ns)

Major

bleeding

rate:3.3%

vs

3.9%

peryear

(ns)

Adv Ther (2020) 37:1910–1932 1917

Table1

continued

Autho

r

(reference)

Pop

ulation

characteristics

AC

Indication

stud

y/ctrl,

n

Age

stud

y/ctrl

CTP

stud

y/

ctrl,%

Varices

stud

y/ctrl,

n(%

)

DOACstype

DOACsdo

seAC

duration

stud

y/ctrl

Efficacy

outcom

es

stud

yvs

ctrl,n(%

)

Safety

outcom

es

stud

yvs

ctrl,n

(%)

Nagaoki

[82]

Japan,

retrospective

cohort,50cirrhoticpts

(DOACs20,w

arfarin

30;IN

Rtarget

1.5–

2)

PVT

20/30

9(53–

74)/67

(24–

83)

A:75/50

B:25/33

C:0/17

16(80)/26

(87)

Edoxaban100%

60mg(20%

)or

30mg(80%

)OD

6/6months

PVT

resolution:

14(70)

vs6(20)

p\

0.001

PVTprogression:

1(5)vs

14(47)

p\

0.001

Any

bleeding

rate:

NA

Major

bleeding

rate:3(15)

vs2

(7)(ns)

Pastori[83]

Italy,retrospectivecohort,

129ptswithadvanced

liver

fibrosis(i.e.F

IB-

4[

3.25)(D

OACs

52,V

KAs77);2201

ctrls(D

OACs981,

VKAs1220)

FIB-4[

3.25:AF

52/77

FIB-4\

3.25:AF

981/1220

Mean±

SD

74.4

±9.3/

78.9

±7.5

NA

NA

Apixaban35%

Rivaroxaban

35%

Dabigatran27%

Edoxaban3%

(pts?

ctrls

n.1033)

Standard

NA

FIB-4

notsignificantly

associated

withCV

eventsneitherin

DOACsor

VKAs

ptsat

MVA

FIB-4

associated

withmajor

bleedingsonlyin

VKAspts(H

R:

3.075,

p=0.001)

Hanafy[84]

Egypt,R

CT,8

0HCV-

relatedcirrhoticCTP

A-B

pts(D

OACs40,

warfarin40)

Acute

PVT

40/40

Mean±

SD

46±

5/

41±

2

A:NA

B:NA

C:0

Grade

C2:

27(68)/

29(73)

Rivaroxaban

100%

10mgevery12

hNA

PVT

resolution:85%

vs45%.S

hort-term

survivalrate:

20.4

±2.2vs

10.6

±1.8months

GIbleeding:0(0)

vs17

(43.3)

Davis[85]

USA

,retrospective

cohort,1

09CLD

pts

(DOACs27,w

arfarin

82)

DVT

9/41

PE10/21

PVT8/20

Median

(IQR)

60(53–

62)/

55(50–

64)

A:41/22

B:59/60

C:0/18

3(11)/17

(21)

Apixaban44.5%

Rivaroxaban

44.5%

Dabigatran11%

NA

NA

Recurrent

VTE:

3(11)

vs10

(12)

at3months(ns)

Major

bleeding

rate:2(7.4)vs

7

(13.4)

(ns)

Adm

ission

fornon-

major

one:1

(3.7)vs

5(6.1)

(ns)

1918 Adv Ther (2020) 37:1910–1932

Table1

continued

Autho

r

(reference)

Pop

ulation

characteristics

AC

Indication

stud

y/ctrl,

n

Age

stud

y/ctrl

CTP

stud

y/

ctrl,%

Varices

stud

y/ctrl,

n(%

)

DOACstype

DOACsdo

seAC

duration

stud

y/ctrl

Efficacy

outcom

es

stud

yvs

ctrl,n(%

)

Safety

outcom

es

stud

yvs

ctrl,n

(%)

Davis[86]

USA

,retrospective

cohort,1

67cirrhotic

pts(D

OACs57,

warfarin110)

DVT 10/32

PE9/18

PVT3/19

AF23/28

Other

10/24

Median

(IQR)

63(58–

72)/

59(52–

67)

A:61.4/

39.1

B:19.3/

48.2

C:5.3/6.4

7(12)/28

(26)

Apixaban52.6%

Rivaroxaban

45.6%

Dabigatran1.8%

NA

NA

Stroke

andrecurrent

embolism

at

90days:1(1.8)vs

0(0)and1(1.8)vs

2(1.8)(bothns)

Major

bleeding

rate

at90

days:3

(5.2)vs

10(9.1)

(ns)

Wang[87]

Taiwan,p

opulation

retrospectivecohort,

633ptswithILF

(DOACs342,

warfarin394)

AF 34

2/394

Mean±

SD

77±

36.9

all

NA

NA

Rivaroxaban

51%

Dabigatran28%

Apixaban19%

Edoxaban2%

NA

NA

Nodifference

inIS

or

SErisk.L

ower

risk

ofdeath(aHR

0.64,0

.49–

0.83)

Nodifference

in

major

orGI

bleeding

Lee

[88]

Korea,p

opulation

retrospectivecohort,

4942

patientswith

significant

active

LD

(DOACs3115,

warfarin1827)from

37,353

total

population

AF3,115/

1,827

Mean±

SD

67.9

±10.2/

68.1

±10.8

NA

NA

Rivaroxaban

43%

Dabigatran27%

Apixaban23%

Edoxaban7%

(totalpopulation)

51%

reduceddose

F-up

15months

Reduced

risk

ofIS

(HR0.445,

0.312–

0.636)

and

composite

outcom

ea(H

R

0.691,

0.577–

0.827)

Lowerriskof

ICH

(HR0.424,

0.241–0.723),

hospitalizationfor

major

bleeding

(HR0.622,

0.442–0.870)

Adv Ther (2020) 37:1910–1932 1919

receiving anticoagulant therapy (20 onDOACs and 19 on traditional anticoagula-tion: warfarin or LMWH) for eithersplanchnic/non-splanchnic VTE or AFshowed no significant difference in the riskof any/major bleeding between the twotreatment groups (4/1 vs 3/19) over a 3-yearperiod. The prevalence of oesophageal vari-ces was high in both groups (50% DOACsand 41% warfarin) [77]. Another retrospec-tive analysis performed at the same Univer-sity Hospital on 69 cirrhotic patients onDOACs for AF or VTE, including several withadvanced liver disease (CTP class A/B/C:33/26/10), reported that all major bleeding(12% of patients) were observed in thosewith CTP class B/C: mainly non-varicealgastrointestinal (GI) bleeding occurring,despite the fact that the majority of patientsdid have oesophageal varices [78]. A retro-spective cohort study conducted on 45 cir-rhotic patients, mostly in CTP class B,treated with anticoagulants (38% rivaroxa-ban, 22% apixaban, 33% warfarin, 7%enoxaparin) for AF stroke prevention or VTE(mainly DVT) found a significantly lowerfrequency of major bleeding (4% vs 28%),mainly due to less ICH (0% vs 17%), inpatients taking DOACs as compared to thosetaking either warfarin or enoxaparin over a3-year follow-up [79].

A retrospective cohort study on 233patients with CLD anticoagulated for AFwith DOACs (n. 75: 15% apixaban, 47%dabigatran, 39% rivaroxaban; mostly CTP A)or warfarin (n. 58; mostly CTP B), showedsimilar all-cause bleeding and major bleed-ing rates between the two treatment groups[81]. A recent single-centre, retrospectivestudy on a population of 109 cirrhoticpatients (59% CTP class B) diagnosed withacute VTE (PE, DVT or PVT) has shown nostatistical difference in recurrent VTE ormajor bleeding events among patients trea-ted with all four DOACs (n. 27) compared tothose with warfarin (n. 82) over a short (3-months) follow-up period; however, theDOACs group did not include CTP class Cpatients [85]. A subsequent study by thesame group, including subjects with AF,T

able1

continued

Autho

r

(reference)

Pop

ulation

characteristics

AC

Indication

stud

y/ctrl,

n

Age

stud

y/ctrl

CTP

stud

y/

ctrl,%

Varices

stud

y/ctrl,

n(%

)

DOACstype

DOACsdo

seAC

duration

stud

y/ctrl

Efficacy

outcom

es

stud

yvs

ctrl,n(%

)

Safety

outcom

es

stud

yvs

ctrl,n

(%)

Lee

[89]

Taiwan,p

opulation

retrospectivecohort,

2428

cirrhoticpts

(DOACs1438,

warfarin990)

AF1,438/

990

Mean±

SD

72.8

±11.1/

72.4

±11.2

NA

NA

Rivaroxaban

51%

Dabigatran37%

Apixaban12%

95%

10–1

5mgOD

89%

110mgBID

69%

2.5mgBID

MeanF-up

1.13/

1.30

years

Com

parablerisk

of

IS/SE

Low

errisk

ofGI

(HR0.51,

0.32–0

.79)

and

all(H

R0.51,

0.32–0

.74)

major

bleeding.

Com

parablerisk

ofIC

H

aSixitems(ischem

icstroke,intracranialh

emorrhage,gastrointestinalbleeding,m

ajor

bleeding,all-causedeath).InternationalSocietyon

Throm

bosis

andHaemostasis

(IST

H)definition

waslargelyadoptedformajor

bleeding

inthe

reported

studies

ACanticoagulation,AFatrialfibrillation,aHRadjusted

hazard

ratio,BID

bisin

die,CLD

chronicliverdisease,CTPChild-Turcotte-Pu

gh,ctrlcontrol,C

Vcardiovascular,DOACsd

irectoralanticoagulants,D

VTdeep

vein

thrombosis,F-up

follow-up,

GIgastrointestinal,H

CVhepatitisCvirus,HRhazard

ratio,ILFim

paired

liverfunction,INRinternationaln

ormalized

ratio,IQRinterquartile

range,IS

ischem

icstroke,L

WMH

low-

molecularweightheparin,MVAmultivariateanalysis,N

Anotavailable,ns

notstatistically

significant,O

Donce

daily,P

Eacutepulmonaryem

bolism,ptspatients,P

VTportalvein

thrombosis,RCTrand

omized

controlled

trial,

SDstandard

deviation,

SEsystem

icem

bolism,S

pVTsplanchn

icvein

thrombosis,

TDD

totaldaily

dose,V

TEvenous

thromboem

bolism,V

KAsvitamin

Kantagonists

1920 Adv Ther (2020) 37:1910–1932

confirmed no statistically significant differencein both recurrent embolism/stroke and majorbleeding at 90 days in cirrhotic patients undereither DOACs or warfarin [86].

Three relatively small sampled studies haveinvestigated the use of DOACs in cirrhoticpatients with prevalent or exclusive indicationto anticoagulant therapy for PVT. A multicentreretrospective study of 94 patients anticoagu-lated with DOACs (83% rivaroxaban, 11%dabigatran and 6% apixaban) mainly for PVT(about 65%) showed a similar over-all adverseevents rate (17% vs 19%) in those with cirrhosis(n. 36, CTP class A–B only) and without it (n.58), including 1 recurrent PVT and 1 majorbleeding (lower GI) in cirrhotic and 2 majorbleeding in non-cirrhotic patients without anyfatal case due to DOACs during follow-up (mean13.1 and 9.6 months, respectively). Patientswith cirrhosis were prescribed more often with areduced dose of all three DOACs not related toan adaptation to kidney dysfunction [80]. Inanother retrospective cohort of 50 cirrhoticpatients (CTP A/B/C 30/15/5) with PVT, treatedinitially for 2 weeks with LMWH and thenswitched to oral anticoagulation, a greater res-olution of PVT at 6 months was found amongpatients on DOAC (edoxaban) as compared tothose on warfarin, without significant differ-ences in the incidence of bleeding, however, itshould be noted that the dose of warfarin was inthe sub-therapeutic range (INR target 1.5 to 2.0)[82]. Finally, a recent RCT on 80 patients withHCV-related compensated cirrhosis with acutePVT showed a higher rate of resolution of PVTand improved short-term survival without anycomplication, including major bleeding, inpatients treated with low-dose rivaroxaban(10 mg every 12 h) as compared to thosereceiving warfarin [84].

A recent post-hoc analysis of a prospectivelarge multicentre study on AF outpatients trea-ted with either VKAs (n.1297) or DOACs(n.1033) has shown that advanced fibrosis,assessed non-invasively by the validated FIB-4score[3.25, was significantly associated withmajor bleeding events in AF patients treatedwith VKAs but not in those on DOACs [83].

Three recent large retrospective Asian popu-lation studies have investigated the use of oral

anticoagulants in patients with liver disease andNVAF. A multicentre Taiwan cohort study basedon electronic medical records, including 6451anticoagulated AF patients over 65-years, hasshown that DOACs were associated with a sig-nificantly reduced risk of death (HR 0.64) butwith no difference in stroke/systemic embolism,major bleeding or GI bleeding as compared towarfarin in 633 patients with impaired liverfunction, defined as ALT or AST[ twofold ortotal bilirubin[1.5-fold ULN [87]. Anotherstudy, using the Korean National Health Insur-ance Service database, reported that, comparedto warfarin, the use of DOACs (43% rivaroxa-ban, 27% dabigatran, 23% apixaban, 7% edox-aban) was associated with lower risk of ischemicstroke, ICH, GI bleeding, major bleeding, all-cause death and composite outcome in a pop-ulation of 37,353 subjects with active liver dis-ease defined by claims for diagnostic codes[International Classification of diseases (ICD)]during a mean 1.2-year follow-up [88]. All 4DOACs showed risk reduction in all six clinicaloutcomes compared with warfarin, except forrivaroxaban which showed comparable hospi-talization rates owing to GI bleeding. In a sub-group of 4942 patients with significant activeliver disease (defined by positive ICD codes forliver cirrhosis, viral hepatitis, or ALT or AST[twofold ULN) a significantly reduced risk forischemic stroke (HR 0.445), ICH (HR 0.424),hospitalization for major bleeding (HR 0.622)and composite outcome (HR 0.691) was con-firmed in those on DOACs (63%) as comparedto those on warfarin (39%). In patients withcirrhosis, no significant difference for efficacyand safety outcome was observed with DOACsuse (n. 446) compared to warfarin (n. 322) [88].Finally, a study on 2428 liver cirrhotic patientswith AF, from the Taiwan National HealthInsurance Research Database, has shown thatthe group taking DOACs (n. 1438; 51%rivaroxaban, 37% dabigatran, 12% apixaban)had a risk of ischemic stroke/systemic embolismand ICH comparable to that of the warfaringroup (n. 990) and significantly lower GI (HR0.51) and all (HR 0.51) major bleeding riskduring a mean 1.2-year follow-up [89]. A sub-group analysis indicated that both dabigatranand rivaroxaban, but not apixaban, showed a

Adv Ther (2020) 37:1910–1932 1921

significant lower risk of all major bleeding thanwarfarin. The authors argue that this finding inthe apixaban group may be due to several

explanations: a higher proportion of standard-dose prescriptions, a small sample size insuffi-cient for statistical significance, increased drug

Fig. 2 Management of anticoagulation in patient withCLD/cirrhosis. a DOACs initiation. AC anticoagulation,CTP Child Turcotte-Pugh, DOACs direct oral anticoag-ulants, EGD esophagogastroduodenoscopy, EVL endo-scopic variceal ligation, INR international normalizedratio, NSBBs non-selective beta-blockers, RWS red wale

signs. *can be used. b Management of bleeding complica-tions. DOACs direct oral anticoagulants, EVL endoscopicvariceal ligation, HRS hepatorenal syndrome, 4F-PCCfour factor-prothrombin complex concentrate, RBC redblood cells, TIPS transjugular intrahepatic portosystemicshunt

1922 Adv Ther (2020) 37:1910–1932

exposure due to higher hepato-biliary clearance.Moreover, the advantage of lower GI and allmajor bleeding with DOACs over warfarin wasobserved only in subjects with either nonalco-holic or non-advanced liver cirrhosis (i.e. with-out complications including ascites, hepaticencephalopathy, spontaneous bacterial peri-tonitis or bleeding oesophageal varices) [89].

In summary, these population studies sug-gest that DOACs have at least comparableeffectiveness and possibly a better safety thanwarfarin in patients with CLD/cirrhosis and AF.However, these results should be interpretedwith caution [90, 91]. The strengths of thesestudies are the large population-based sampleand that propensity score weighting methodswere used to balance covariates between thetwo anticoagulation treatment groups in thetwo largest studies [88, 89]. Nevertheless, theyhave several weaknesses. As observational stud-ies they are prone to confounding by indicationand no adjustment method can fully resolve it[92]. In one study the definition of significantactive liver disease was too broad including aspectrum of conditions ranging from mild ele-vation of aminotransferases to viral hepatitiswith fibrosis of unknown severity and cirrhosisbased on ICD codes. The impact of functionaland prognostic scoring systems of cirrhosis (e.g.CTP) was not assessed [88]. Reduced doses ofDOACs were prescribed from 50–60% [86] to90% [89] of patients. In one study no data wereprovided about DOACs dosage [87]. The qualityof anticoagulation control as reflected by timein therapeutic range (TTR) in the warfarin groupwas not evaluated. Previous data suggest that, inAsian populations, the quality of warfarin anti-coagulation may be suboptimal [93]. Moreover,Asian individuals show pharmacokinetic andpharmacodynamic profiles of DOACs quite dif-ferent from those of Caucasian individuals [94].Therefore, some caution is needed in general-izing the results of these studies to Westernpopulations.

Finally, two previously published metanaly-ses have evaluated the use of warfarin andDOACs in cirrhotic patients including some ofthe above reported studies. The first including19,798 cirrhotic patients with AF from sevencohort studies, two of which comparing DOACs

vs warfarin [81, 83], had two main findings:(a) the use of warfarin was associated with alower risk of stroke compared with no antico-agulation (HR 0.58) without a significantlyincreased bleeding risk (HR 1.45), (b) the use ofDOACs was associated with a lower risk ofbleeding among AF patients with cirrhosis (OR1.93) [95]. The second, including 447 cirrhoticpatients from five studies [77, 79, 81, 82, 84]undergoing anticoagulant therapy (DOACs vswarfarin/LMWH) owing to various indications,found that patients treated with DOACs had nosignificantly increased risk of all-cause bleeding[relative risk (RR) 0.72] and major bleeding (OR0.46) as compared to those who received tradi-tional anticoagulants [96]. Updated meta-anal-yses including the most recent data from largeAsian population studies are eagerly awaited.

In conclusion, real-world data suggest thatDOACs can safely be used in CTP A patients andcautiously in CTP B cirrhotic patients withcomparable efficacy and possibly better safetythan warfarin. Interestingly, Rivaroxaban andEdoxaban have been used in CTP B cirrhoticpatients in some studies without significantadverse events, despite their contraindication inthese patients according to EMA/FDA and FDA,respectively.

Prospective studies and RCTs evaluating theefficacy and safety of DOACs in large subgroupsof patients with compensated (CTP A) anddecompensated (CTP B) cirrhosis are needed toestablish appropriate dose adaptation rulesbased on bleeding/thromboembolic outcomes,aminotransferases/bilirubin cut-offs for DOACsuse, risk factors for serious complications suchas bleeding and, finally, which DOACs are moreeffective and safer in these patients.

A Practical Approach to the Prescriptionof DOACs

Patients with CLD candidate to any type ofanticoagulant treatment including DOACsshould undergo a complete clinical, laboratoryand instrumental examination to assess theseverity/functional prognostic class of liver dis-ease and the burden of thrombotic and haem-orrhagic risk (Fig. 2a).

Adv Ther (2020) 37:1910–1932 1923

Indication to anticoagulation should bebased on currently available general guidelinesfor AF and VTE, given the lack of specificguideline recommendations and evidence fromRCTs in cirrhotic patients [3, 67, 97]. Standardstratification tools such as the CHA2DS2-VAScscore [67] should be used in selecting potentialcandidates for anticoagulation in AF. As far thecomplex scenario of PVT treatment in cirrhoticpatients is concerned, updated clinical practicerecommendations have recently been publishedby the American Society of Gastroenterology(AGA) [13].

All patients should undergo laboratoryexamination to determine hepato-renal func-tion, platelet count and coagulation at baselineand at regular intervals during treatment. CTPscoring should be assessed regularly in patientswith CLD. Screening and counselling for alco-hol misuse should be provided. The decision ofstarting anticoagulation should be fully sharedwith the patients explaining expected benefitsand possible adverse effects. DOACs dosereduction should be applied according to stan-dard rules taking into consideration age, renalfunction, weight and current medications [67].Anticoagulation should be interrupted/reducedin the presence of severe thrombocytopenia(platelet count\50 9 109/L to\ 70 9 109/L),depending on the thrombotic risk of the patient[67, 97]. INR[ 1.8 and/or platelet count\509 109/L has been defined as significant coagu-lopathy in cirrhotic [22, 98]. However, con-ventional coagulation tests show a limited valuein estimating haemostatic competency inpatients with cirrhosis, as reported in Sect.Mechanisms: Haemostatic Balance and itsEvaluation in Patients with Cirrhosis.

Upper endoscopy should be performed in allcirrhotic patients to screen for oesophagealvarices in order to reduce the bleeding riskbefore starting any type of anticoagulant:treatment with either non-selective beta-block-ers or endoscopic variceal ligation (EVL) is rec-ommended based on varices size and risk ofbleeding [76, 99].

As previously stated, DOACs are recom-mended in cirrhotic patients in CTP class Awhile should be prescribed with caution inselected CTP class B cirrhotic patients weighing

the increased risk of bleeding, consideringseverity of portal hypertension, presence ofactive coagulopathy and previous GI bleeding.Warfarin, unlike DOACs, may be used in selec-ted patients with CTP class C; however, giventhe high risk of bleeding and poor prognosis,anticoagulation is generally contraindicated inthese patients.

Cardiologists, hepato-gastroenterologists andhematologists should collaborate to optimizeanticoagulant treatment in patients with CLD:no evidence is available on which DOAC hasthe best efficacy and safety profile in suchpatients. In clinical practice the choice betweendifferent DOACs should consider their phar-macodynamic properties, patient characteristic,data from RCTs and prospective cohort studieson general population and from accumulatingstudies on liver disease patients.

Dabigatran has the lowest hepatic clearanceand binding to albumin, conversely apixabanhas the highest percentage of hepatic metabo-lism but evidence in the general populationsuggest that is associated to the best safetyprofile for GI bleeding [100–102]. Rivaroxabanand partly edoxaban are contraindicated in CTPclass B patients, although in some studies theyhave been used in these patients at variabledosage (Table 1).

Management of Bleeding Complications

The management of bleeding complications inpatients with liver disease should follow thegeneral approach recommended by currentguidelines (Fig. 2b) [67, 103]. The type ofbleeding (non-major, major non-life threaten-ing or life-threatening) and patient/drug char-acteristics (time of last DOAC dose intake,prescribed dosing regimen, renal function,comedications, indication for anticoagulationand underlying thrombotic risk) are key aspectsguiding the strategy for bleeding management.Major bleeding is defined by the associationwith at least one of the following conditions:(a) hemodynamic compromise (b) occurrence atan anatomically critical site (e.g. central ner-vous system, thoracic, intra-abdominal,retroperitoneal intra-articular, intra-muscular)

1924 Adv Ther (2020) 37:1910–1932

given that it may cause severe disability andrequire surgical procedures for haemostasis or(c) associated with a decrease of haemoglobin(Hb) C 2 g/dL (when baseline is known) orrequiring the transfusion of C 2 unit of packedred blood cells (RBC) [104]. Intra-luminal GIbleeding is not considered a critical bleedingsite; however, it can produce hemodynamicinstability.

Given the short half-lives of DOACs, mostnon-major bleeding complication can safely bemanaged only by treatment discontinuationand supportive measures including localhaemostasis, fluid replacement, diuresis pro-motion, monitoring and blood transfusionswhen appropriate, following a restrictive trans-fusion strategy (target Hb level of 7–8 g/dL)[101, 105]. Activated charcoal may be adminis-tered to reduce the intestinal absorption if theDOAC was ingested within 2 h, but it mayimpair endoscopic visualization in the case ofGI bleeding [106]. Procedural/surgical manage-ment of the bleeding site may also be consid-ered. Anti-fibrinolytic therapy with tranexamicacid should be considered in major bleedingespecially in trauma patients [67, 103].

In case of either critical-site/life-threateningbleeding or severe major bleeding notresponding to the above reported general mea-sures of control, reversal of anticoagulationrepresents a life-saving measure [67, 103].Idarucizumab, a humanized anti-dabigatranmonoclonal antibody, is available for reversingdabigatran anticoagulant activity [67, 103].Andexanet alfa, a factor Xa decoy already mar-keted in the USA and now entering Europe, isindicated as specific reversal agent for FXainhibitors. If it is not available, a 4-factor pro-thrombin complex concentrate (4F-PCC)should be administered to reverse the antico-agulant effect of a FXa-inhibitor. Specific coag-ulation assays measuring the anticoagulantactivity of DOACs [diluted thrombin time (dTT)and anti–Xa chromogenic assay] may assist inthe management of bleedings which are notimmediately life-threatening, aiding to selectpatients before administering reversal agents[107, 108].

Specific management measures may help incontrolling bleeding in patients with advanced

liver disease (Fig. 2b) [13, 99, 109]: optimizationof renal function to prevent uremic plateletdysfunction and haemostatic changes; platelettransfusion in actively bleeding patients withsevere thrombocytopenia (\50 9 109/L); stan-dard treatment of acute variceal bleeding with acombination of a vaso-active drugs (immediateuse of either terlipressin or somatostatin) andendoscopic procedures (\12 h); early antibioticprophylaxis to prevent infections (causingrelease of endothelial derived ‘‘heparinoids’’);proton-pump inhibitors (PPIs) have no efficacyon portal-hypertension-related bleeding andincrease the risk of spontaneous bacterial peri-tonitis, but a short course PPIs therapy after EVLmay reduce post-banding ulcer size; transjugu-lar intrahepatic portosystemic shunt (TIPS) asrescue therapy of choice in persistent bleeding;desmopressin (an endothelial stimulant thatincreases FVIII and vWF) can be used toimprove platelet function only in patients withliver disease complicated by hepato-renal syn-drome and uremia.

HEPATIC ADVERSE EFFECTSOF DOACS

DOACs pharmacokinetic properties (in particu-lar liver metabolism of anti-Xa inhibitors) haveraised concerns about potential drug inducedliver injury (DILI) (i.e. transami-nases[3 9 ULN with total biliru-bin[2 9 ULN). Apart from Ximelagatran, anoral direct thrombin inhibitor which wasrapidly withdrawn from the market in 2006owing to a high risk of hepatoxicity, DOACshave generally demonstrated an adequate liversafety profile [5].

A meta-analysis of 29 phase III RCTs hasshown that all DOACs as a class, and also theindividual drugs, do not increase the risk of DILIas compared to standard anticoagulation (VKA/LMWH) or placebo [110].

Real-life data have shown that all DOACsrarely cause DILI (incidence between 1:100 to1:1000 patients) which, after GI disorders, is thenon-bleeding leading cause of drug withdrawalworldwide. The underlying mechanism is

Adv Ther (2020) 37:1910–1932 1925

unknown but an idiosyncratic reaction is sus-pected [111, 112].

A recent study, using data from a largehealthcare utilization database in the UnitedStates, has shown a lower rate of hospitaliza-tions for DILI in patients on DOACs as com-pared to those on warfarin (5 vs. 9 per 1000person-years) among a cohort of 113,717patients with NVAF receiving a first-time oralanticoagulant prescription (50% warfarin and50% DOACs). Among DOACs, dabigatran hadthe lowest relative risk of hospitalization owingto DILI [113]. History of hepato-biliary disease,alcoholism, kidney disease, heart failure, ane-mia and cancer are risk factors for hospitaliza-tion owing to DILI [113].

Another study on 51,887 patients with AF(including 3778 patients with concomitant liverdisease) from a Canadian healthcare insurancedatabase, who were followed for 68,739 person-years, showed no significant difference in therates of serious DILI (i.e. hospitalization ordeath) with DOACs versus warfarin, irrespectiveof baseline liver status [114].

Currently available data reassure cliniciansand patients regarding the hepatic safety ofDOACs but, although rare, there is the possi-bility of clinically relevant DILI with DOACs.Therefore, clinical vigilance is necessary. Euro-pean Heart Rhythm Association (EHRA) guide-lines generally recommend annual monitoringof liver tests in patients treated with DOACs andcloser six months monitoring in older individ-uals, in those with CLD and unstable medicalconditions that may affect hepatic or renalfunction [67].

CONCLUSIONS

The proportion of patients affected by CLD inwhom anticoagulation is indicated will likely beincreasing owing to the ongoing NAFLD epi-demic. Data suggest that NAFLD and NASH areindependently associated with both AF andVTE, indicating a procoagulant state in thesepatients. Cirrhosis of any etiology features anunstable haemostatic balance making antico-agulant treatment challenging. Cardiovasculardoctors should be prepared to prescribe

anticoagulants to an ever-growing number ofpatients with CLD and cirrhosis in the forth-coming years. Optimal medical assistanceshould offer a multidisciplinary approach basedon a coordinated collaboration among the dif-ferent specialists involved. Based on accumu-lating real-world data showing at leastcomparable efficacy and better safety thanwarfarin, DOACs are a good option for thetreatment of AF and VTE in patients with liverdisease. The management of bleeding compli-cations in patients with liver disease may takeadvantage of specific reversal agents now avail-able for all DOACs. No data are available tosuggest a specific DOACs with better efficacy/safety profile to be preferentially used in cir-rhotic patients. RCTs on the use of DOACs inpatients with cirrhosis are urgently needed.

ACKNOWLEDGEMENTS

We are indebted to Doctor Maria Di Girolamo,MD and Alessandra Marrazzo, MD for their sci-entific collaboration.

Funding. No funding or sponsorship wasreceived for this study or the publication of thisarticle.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thismanuscript, take responsibility for the integrityof the work as a whole, and have given finalapproval for the version to be published.

Disclosures. Stefano Ballestri, MarianoCapitelli, Maria Cristina Fontana, Dimitriy Ari-oli, Elisa Romagnoli, Catia Graziosi, AmedeoLonardo, Marco Marietta, Francesco Dentaliand Giorgio Cioni have nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

1926 Adv Ther (2020) 37:1910–1932

Data Availability. All data generated oranalyzed during this study are included in thispublished article.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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