Oral Anticoagulation in

Patients with Chronic Liver

Disease
Παπαθανασίου Σοφία
Μάρτιος 2023
Contents
1. Introduction
2. Indications for Oral Anticoagulation
3. Warfarin in Liver Disease
4. DOACs in Liver Disease
5. OACs Medication in Liver Disease
6. Pharmacology of OACs in Liver Disease
7. The imbalance between Thrombosis and Bleeding in Liver Disease
8. DOACs - Safety, Efficacy,and Risk of Liver Injury,Gastrointestinal
Tolerability
9. Management of Bleeding in Patients Who Are Taking DOACs Therapeutic
Methods
 Introduction- Misconceptions

• Anticoagulation treatment is contraindicated in chronic liver disease

due to high hemorrhagic risk
• Patients with liver disease are “auto-anticoagulated” and protected
from thrombotic events
 Introduction

• The administration of an anticoagulant in patients with liver disease is challenging

because there is an imbalance between thrombosis and bleeding

• Chronic liver disease ,such as NAFLD/NASH, chronic hepatitis, cirrhosis and/or HCC

• Indications for anticoagulation are AF, VTE , PE, PVT, prevention or treatment of liver
fibrosis

• The association between AF and NAFLD is common, due to same cardiometabolic risk
factors, such as smoking,obesity, dyslipidemia, diabetes mellitus, and sedentary behavior
• Using OAC in liver pathology is complicated because of the lack of evidence
(disqualified from clinical trials)
Indications for Oral Anticoagulation
 Mechanical valve(warfarin, INR 2-3)
 Nonvalvular AF
 DVT
 PE DOACs /Warfarin
 VTE and prophylaxis in orthopedic
surgery

 Patients with AF with liver cirrhosis had no improvement in hemorrhagic events on

using DOACs in contrast with VKAs
  Metabolism via the CYP450
enzymes and susceptible to severe
drug–drug interactions
 Supra/subtherapeutic INR levels
 Narrow therapeutic index (2Χ↑
bleeding risk)
 Depends on parameters such as
albumin and GFR
 24%↓ of ischemic strokes in patients
with liver fibrosis and CHA2DS2-
VASc Score>2
 Early administration linked to portal
vein recanalization (n=55)
 SE: 9% gastrointestinal
hemorrhage
Warfarin in Liver Disease
 Frequent INR measurement
 Interactions with food and
prescription drugs
 Phenotypic variation in reaction
 Increased rates of intracerebral
hemorrhage and death
 Improper use is one of the
important causes of emergency
admissions, especially in the
elderly
 INR monitoring
 Patients with liver disease may already have an elevated INR
at baseline
 Titrating to a supratherapeutic INR could result in bleeding
complications
 Lower mean time in therapeutic range (TTR)

 TTR is defined as the percentage of time the patients INR was

within the target range
 Patients with low TTR (< 65%) are at higher risk of poor
outcomes

 One possible intervention includes switching therapy to a

DOAC
 Warfarin is still preferable in hepatic dysfunction due to its
ability to be managed and adjusted appropriately, in contrast to
DOACs
Key points
 140 adult patients taking warfarin with a target INR 2-3 and compared to TTR
 TTR < 65% in 70 patients (50%), with the most common reasons being poor
adherence and diet fluctuations
 Patients with a greater BMI required a longer time to attain target INR

 NAFLD/NASH is related to decreased odds of having TTR>60% even in patients

without obesity and diabetes

 A systematic review process is required to ensure that a DOAC is a safe and effective
alternative
  No good monitoring measure for their
safety DOACs in Liver Disease
 Child–Pugh grading system and selection
criteria used in pivotal studies

 In severe hepatic disease (Child-Pugh C),

all DOACs are contraindicated
 In modest hepatic impairment,
dabigatran,apixaban, and edoxaban do not
require dosage changes

 Blood tests to assess liver function and

coagulation parameters should be obtained
  Exposed to some extent of liver
metabolism DOACs in Liver Disease
 Compromised liver functions
 ↑ drug levels and hemorrhage risk
 Patients with current or chronic liver
illness were often excluded from large-
scale RCTs

 Dabigatran ↓ RR of hepatotoxicity
 No statistically significace for
hepatotoxicity between DOACs and
warfarin
 Almost all DOACs lead to increased
transaminases
 OACs Medication in Liver Disease
 Before starting OACs : LFTs, platelet levels, serum creatinine, and coagulation profile
evaluated
 Platelet levels : 50,000 and 70,000/mm3 anticoagulation medication should be postponed
 All at-risk patients must be examined for varices and alcohol abuse
 Screening esophagogastroduodenoscopy (EGD) for the diagnosis of esophageal and gastric
varices is recommended

 Recanalization of the portal axis has been observed to 42% of patients with anticoagulation
 Cavernous transformation of the portal vein with the development of collaterals does not
require anticoagulant
 Patent main portal vein is associated with an increased posttransplant survival rate
Pharmacology of OACs in Liver Disease
 Different hepatic excretion rate for each DOAC
 Apixaban and Rivaroxaban have shown similar pharmacokinetic characteristics
in Child–Pugh A/B and non-hepatically unhealthy patients
 Warfarin: Antithrombotic proteins, such as proteins C and S, are also reduced
Maximum plasma concentration of 2 to 6 h

 Rivaroxaban achieves peak levels in 2 to 4 h

Pharmacology of OACs in Liver Disease
The imbalance between Thrombosis and Bleeding in Liver Disease
DOACs - Safety, Efficacy,and Risk of Liver Injury
 Patients on DOACs had a decreased risk of nonfatal cerebrovascular accident than
those taking warfarin

 In patients with liver cirrhosis and atrial fibrillation with a CHA2DS2-VASC score of 2,
the overall advantages of anticoagulation seem to exceed the risk of hemorrhage

 DOACs outperformed warfarin in terms of the composite outcome for patients with
hepatic diseases, including those with substantial active liver disease

 The risk of liver damage was lower in DOAC users is ranged between 0.1 and 1% than
enoxaparin or warfarin
 Gastrointestinal Tolerability

 PPIs should be considered in patients with gastropathy or peptic ulcer disease who have
an indication for antithrombotic therapy
 Patients should be counseled regarding the specific hazards of concomitant alcohol
intake or NSAIDs drug use
 Screening for H. pylori infection should be undertaken, and treatment should be
administered as appropriate
 Early collaboration with gastroenterologists may help guide screening and potential
intervention of high-risk lesions
Management of Bleeding in Patients Who Are Taking
DOACs/ Therapeutic Methods
 Take home messages
• Patients with liver disease represent a challenging subgroup of patients requiring OACs as
a result of their increased thrombotic and bleeding risks

• The old notion that patients with liver disease are “auto-anticoagulated” and protected
from thrombotic events has not been substantiated by clinical data
• Current clinical guidelines do not offer specific recommendations for the use of OACs
• DOACs are safe in the Child–Pugh A and B classes
• Patients with advanced liver disease (Child–Pugh C) were excluded from studies, so
VKAs are still recommended
• Collaboration among cardiology, gastroenterology/hepatology, and hematology should be
convened to guide clinicians prescribing OACs to patients with liver disease