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DOACs: Whack or Matter of Fact in Liver Transplant Recipients

Lauren T. Moreno, Pharm.D.

PGY1 Pharmacy Resident

Department of Pharmacotherapy Services, University Health System

Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, UT Health San Antonio

October 10 and 18, 2019

Learning Objectives

a. Describe differences of coagulopathy in patients with end stage liver disease and after liver transplantationb. List concerns associated with using direct oral anticoagulants after liver transplantationc. Discuss evidence and guidance for the use of direct oral anticoagulants after liver transplantation

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DOACs: Whack or Matter of Fact in Liver Transplant Recipients

Lauren Moreno, Pharm.D. PGY1 Pharmacy Resident October 10 and 18, 2019

Assessment Questions:

1. In what state of coagulopathy is a liver transplant recipient considered to be? a. Hemostasis b. Hypercoagulability c. Hypocoagulability d. None of the above

2. The dose of edoxaban should be adjusted in which of the following scenarios?

a. Concomitant use with a P-glycoprotein inhibitor b. Creatinine clearance >95 mL/min c. Child-Pugh Class A hepatic impairment d. Concomitant use with cyclosporine

3. What is the level of evidence for direct oral anticoagulant use in liver transplant recipients?

a. Randomized control trials b. Cohort studies c. Case studies d. Meta-analyses

***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com ***

Faculty (Speaker) Disclosure: Lauren Moreno has indicated she has no relevant financial relationships to disclose relative to the content of her presentation.

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DOACs: Whack or Matter of Fact in Liver Transplant Recipients

Background

I. Liver transplantation is the standard of care for patients with end stage liver disease II. Multiple vascular complications requiring use of anticoagulation post-liver transplantation such as: 1−2

a. Intrahepatic thrombosis and stenosis b. Deep vein thrombosis (DVT) c. Pulmonary embolism d. Stroke prevention for atrial fibrillation

III. Risk factors for thrombus formation include those that apply to the general population as well as those specific to liver transplantation 1−2

Table 1. Risk Factors for Thrombosis 1−3

General Population Liver Transplant Population

▪ Major surgery ▪ Orthopedic surgery ▪ Age >40 years old ▪ Immobilization ▪ Obesity ▪ Stroke ▪ Trauma ▪ Cancer ▪ Pregnancy ▪ Previous venous

thromboembolism ▪ Smoking ▪ Thrombophilia ▪ Use of estrogen containing

products or erythropoietin stimulating agents

▪ Central venous catheter

▪ Use of corticosteroids ▪ Pre-transplant diagnosis ▪ Use of intraoperative blood products ▪ High early post-operative hematocrit and

hemoglobin levels ▪ Transplantation across ABO blood group

IV. Coagulopathy

a. Healthy patients 4 i. Primary hemostasis: Platelet adhesion via von Willebrand factor (VWF) to bind at injury site and

form a platelet plug ii. Balanced system through natural anticoagulants and fibrinolytic pathway

1. Natural anticoagulants: Antithrombin, plasmin, plasminogen and proteins C and S 2. Fibrinolytic pathway: Tissue plasminogen activator and plasmin

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Figure 1. Coagulation Cascade

Key

Red dashed outline = clot activators Ia = fibrin II = prothrombin TF= tissue factor

PLOG = plasminogen I = fibrinogen IIa = thrombin VWF= von Willebrand factor

b. End stage liver disease 5−8 i. Metabolic diseases increase risk of thrombus formation

ii. Both pro-coagulant and anticoagulant factors are impaired, as well as anti-fibrinolytic mechanisms, resulting in hemostatic instability

1. Reduced coagulation factors: II, VII, IX, X, XI 2. Reduced anticoagulants: Antithrombin, proteins C and S, plasminogen, and anti-plasmin 3. Increased VWF and factor VIII 4. Increased tissue factor: Propagates extrinsic coagulation pathway

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c. During transplantation 5−9 i. Increased risk of thrombus formation

1. Intraoperative blood product transfusions a. Fresh frozen plasma contains all coagulation factors b. Red blood cell transfusions associated with pro-inflammatory state and

stimulate thrombus development 2. Transplantation across ABO blood groups impacts VWF and factor VIII levels and can

increase risk of clotting ii. Baseline coagulopathies are further complicated by intraoperative phases

1. Reperfusion leads to platelet adhesion and ischemia 2. Shift in coagulopathy favoring hypercoagulability

d. Post-transplant 5−10 i. Increased risk of thrombus formation

1. Early post-operative elevations in hematocrit and hemoglobin 2. Corticosteroid use enhances synthesis of VWF resulting in impaired fibrinolysis

ii. Pro-coagulation, anticoagulation and pro-fibrinolytic cascade imbalances can lead to thrombus formation at anastomotic sites

iii. Stahl R, et al. A Hypercoagulable State Follows Orthotopic Liver Transplant (OLT) 1. Most clotting factors reached normal values on post-operative day 1 (POD1) 2. Anticoagulant proteins demonstrated delayed recovery 3. State of coagulopathy favoring hypercoagulability

Figure 2. Coagulopathy Timeline 5−10

V. Anticoagulation standard of care for liver transplant recipients 11−14

a. No current guidelines dictate the use of oral anticoagulants post-transplant

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i. American College of CHEST Physicians and American Society of Hematology guidelines do not mention anticoagulation considerations in this patient population

ii. Practice Guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation

1. Discusses potential for development of hepatic artery thrombosis, but does not mention prevention methods or anticoagulation therapy

iii. European Association for the Study of the Liver Clinical Practice Guidelines for Liver Transplantation

1. Recommends short-term use of heparin for portal vein thrombosis prior to transplant iv. Most commonly used agents in practice are low-molecular weight heparin products (LMWH)

and vitamin K antagonists, such as warfarin

b. LMWH 15−17 i. Mechanism of action: Propagates antithrombin III inhibition of clotting factor Xa, disrupting

normal hemostasis ii. Coagulation monitoring: Not routinely recommended, however may be beneficial in settings of

obesity, renal insufficiency, pregnancy, mechanical heart valves, and pediatrics iii. Concerns: Daily injections resulting in non-compliance, dosing and safety in renal dysfunction,

and limited data to support safety and efficacy post-transplant c. Warfarin 12,17,20−21

i. Mechanism of action: Competitively inhibits VKORC1, depleting vitamin K reserves and impairing synthesis of factors II, VII, IX, and X, as well as proteins C and S

ii. Coagulation monitoring: Routine international normalized ratio (INR) monitoring required to target a specified goal

iii. Concerns: Drug and food interactions, frequent INR monitoring, potentially frequent dose titrations resulting in non-compliance, potential for elevated baseline INR in hepatic impairment causing difficulty in monitoring

Figure 3. Anticoagulation Standard of Care in Liver Transplant Recipients: Pros and Cons

Pros

•Some data to support use

Cons

•Injections

•Non-compliance

•Safety in renal dysfunction

LMWH

Pros

•More data to support use

Cons

•Drug-drug interactions

•Drug-food interactions

•INR monitoring

•Non-compliance

•Difficult INR interpretation

Warfarin

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VI. Mechanisms of action of DOACs 18

a. Dabigatran: Directly binds to and inhibits both free and fibrin-bound factor IIa (thrombin) b. Edoxaban, rivaroxaban, and apixaban: Directly bind to and inhibit both free and clot-bound factor Xa

Figure 4. Anticoagulant Mechanisms of Action

Should the use of direct oral anticoagulants (DOACs) be considered in liver transplant recipients?

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VII. Pharmacokinetics and pharmacodynamics of DOACs

Table 2. DOAC Pharmacokinetics and Pharmacodynamics 18,21−22

Parameter Dabigatran Rivaroxaban Apixaban Edoxaban

Bioavailability 3-7% 10 mg: 80-100% 20 mg: 66%

50% 62%

Volume of Distribution

60-70 L 50 L 21 L 107 L

Protein Binding 30-35% 92-95% 87% 55%

Metabolism Esterases CYP3A4/5, 2J2, hydrolysis

CYP3A4, 1A2, 2C8, 2C9, 2C19,

2J2

Minimal metabolism via

hydrolysis, conjugation or

oxidation

Hepatic Elimination

20% 65% 75% 65%

Renal Elimination 80% 35% 25% 50%

Tmax 0.5-2 hrs 2-4 hrs 3-4 hrs 1.5 hrs

Half-life 10-11 hrs 5-9 hrs 12 hrs 10-14 hrs

VIII. Figure 3. Concerns for Use of DOACs in Liver Transplant Recipients

Concerns for use of

DOACs

Renal and hepatic

impairment

Drug-Drug interactions

Therapeutic drug

monitoring

Availability of reversal

agents

Cost

Literature and

experience

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IX. Concerns with pharmacokinetic parameters a. Renal impairment considerations 23−27

i. Kidney function post-transplant 1. Calcineurin-inhibitor (CNI)-based immunosuppression is the most common cause of

kidney injury 2. Other potential risk factors for post-transplant renal dysfunction include increasing age,

diabetes mellitus, viral-associated glomerulonephritis, hepatorenal syndrome, pre-transplant renal dysfunction

ii. Dabigatran 1. Significant increase in AUC up to 6.3 fold higher in patients with CrCl < 50 ml/min 2. Landmark trials excluded patients with CrCl < 30 ml/min

iii. Rivaroxaban 1. Small increase in AUC up to 1.64 fold higher in patients with CrCl < 30 ml/min 2. Landmark trials excluded patients with CrCl < 30 ml/min

iv. Apixaban 1. Moderate increases in AUC up to 36% in patients on dialysis 2. Landmark trials excluded patients with SCr > 2.5 mg/dL or CrCl < 25 ml/min 3. Meta-analysis of six phase III trials

a. Lower bleed rates vs. warfarin with CrCl 50-80 ml/min b. Similar bleed rates vs. warfarin with CrCl < 50 ml/min

v. Edoxaban 1. Increase in AUC up to 32% in patients with CrCl 50-80 ml/min 2. Contraindicated with CrCl > 95 ml/min for stroke prevention in nonvalvular atrial

fibrillation 3. Landmark trials excluded patients with CrCl < 30 ml/min

Table 3. DOAC Renal Function Considerations

FDA approved uses Exclusion from trials

CrCl (ml/min) < 15 15-30 30-50 50-95 > 95

Dabigatran ✔ ✔ ✔ ✔

CrCl < 30 ml/min Rivaroxaban ✔ ✔ ✔ ✔ ✔

Edoxaban ✔ ✔ ✔

Apixaban* ✔ ✔ ✔ ✔ ✔ SCr > 2.5 mg/dL CrCl < 25 ml/min

* SCr ≥ 1.5 mg/dL, age ≥ 80, body weight ≤ 60 kg: criteria for determining need for dose adjustments

b. Hepatic impairment considerations 23−30 i. After transplantation, the liver continues to still be impaired to some degree

ii. Medication doses are commonly dose adjusted based on Child-Pugh classification (See appendix)

1. Not validated for use in liver transplant recipients 2. Lack of validated scoring system in liver transplant recipients

iii. Limited clinical data for DOAC use in hepatic impairment iv. Only minor changes in AUC and drug exposure have been demonstrated in pharmacokinetic

studies v. Dabigatran

1. No change in drug exposure noted in Child-Pugh Class B patients 2. Not studied in Child-Pugh Class C patients

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3. Slower conversion of prodrug to active dabigatran, however overall drug exposure not affected

4. Not highly protein bound vi. Rivaroxaban

1. Increase in AUC up to 127% in Child-Pugh Class B patients 2. Not studied in Child-Pugh Class C patients 3. Highly protein bound

vii. Apixaban 1. Minor increases in anti-Factor Xa activity and AUC observed in Child-Pugh Class A and B

patients 2. Not studied in severe hepatic impairment (Child-Pugh Class C) 3. Highly protein bound

viii. Edoxaban 1. No dose reductions in Child-Pugh Class A patients recommended 2. Not recommended for use in Child-Pugh Class B and C patients 3. Not highly protein bound

c. Drug-drug interactions with CNIs 23−26,31−33 i. CNIs are substrates of CYP3A4 and P-glycoprotein (P-gp)

1. Tacrolimus inhibits P-gp 2. Cyclosporine inhibits CYP3A4 and P-gp

ii. Increased exposure of DOACs when used concomitantly with CYP3A4 or P-gp inhibitors is possible, however alternative metabolic pathways for the DOACs are available

iii. Dabigatran 1. Inactive prodrug, dabigatran exeilate, is a substrate of P-gp 2. Concomitant use of P-gp inhibitors increased dabigatran exposure without impacting

thrombotic events or major bleeding rates 3. When used concomitantly with tacrolimus, retrospective studies demonstrate that

prescribers are more likely to dose reduce dabigatran compared to anti-Xa inhibitors iv. Rivaroxaban

1. Substrate of CYP3A4 and P-gp 2. Avoid concomitant use with dual P-gp and strong CYP3A4 inhibitors due to risk of

increased rivaroxaban exposure 3. Tacrolimus causes minor increases in rivaroxaban exposure 4. Cyclosporine substantially increases rivaroxaban exposure

v. Apixaban 1. Substrate of CYP3A4 and P-gp 2. Dose reduce by 50% when used concomitantly with dual P-gp and strong CYP3A4

inhibitors due to risk of increased exposure 3. Patients already requiring the lowest dose of 2.5mg twice daily should avoid use with P-

gp and strong CYP3A4 inhibitors vi. Edoxaban

1. Substrate of P-gp 2. Patients on a P-gp inhibitor who received a half dose of edoxaban compared to patients

not on a P-gp inhibitor who received a full dose demonstrated lower edoxaban blood concentrations

3. No dose reductions recommended with concomitant P-gp inhibitors 4. European Summary of Product Characteristics recommends a 50% dose reduction in

patients concomitantly take cyclosporine

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Table 4. Special Pharmacokinetic Considerations

Considerations Dabigatran Rivaroxaban Apixaban Edoxaban

Renal impairment

• Significantly higher drug levels in CrCl < 30 ml/min; avoid use

• Small increases in drug levels in CrCl < 30 ml/min; use with caution

• Dose reduction for SCr >1.5 may be necessary based on age, weight and indication for use

• Avoid in CrCl > 95 ml/min

• Consider dose reduction in CrCl 15-50 ml/min

Hepatic impairment

• Prodrug

• Slower conversion to active drug

• Highly protein bound

• Avoid use in Child-Pugh Class B or C

• Highly protein bound

• Avoid use in Child-Pugh Class C

• Avoid use in Child-Pugh Class B and C

Drug-Drug interaction

• Dose reductions with CNI use might be necessary

• Avoid dual P-gp/ strong CYP3A4 inhibitors

• Increased drug levels with cyclosporine

• 50% dose reduction with dual P-gp/strong CYP3A4 inhibitor

• Avoid use if dose is 2.5mg

• No dose reduction recommended

X. Therapeutic drug monitoring 12,34−36 a. Not routinely recommended due to predictable pharmacokinetic profiles and lack of evidence for

benefit in most patients b. Tests used to measure DOAC concentrations not widely available due to complexity, cost, lack of

necessity and lack of FDA approved assays c. No established standard available for therapeutic drug concentrations d. Widely available coagulation tests such activated partial thromboplastin time (aPTT) and prothrombin

time (PT) exhibit non-linear correlation to drug concentration

XI. Bleeding risk 37−40 a. Lower rates of major bleeding and similar rates of minor bleeding events with DOACs compared to

warfarin b. Retrospective analysis of patients with Child-Pugh Class A or B hepatic impairment receiving rivaroxaban

or apixaban had similar rates of moderate and severe bleeding compared to those receiving LMWH + warfarin

i. Any bleeding events: 4/20 DOAC group vs. 3/19 traditional group (p=0.99) ii. Major bleeding events: 1/20 DOAC group vs. 2/19 traditional group (p=0.6)

c. Retrospective study of major bleeding incidence in solid organ transplant recipients i. Warfarin + CNI vs. DOACs + CNI

ii. No statistical difference between groups (10.8% DOAC group vs. 5% warfarin group, p=0.419) XII. Reversal options 41−48

a. Traditional anticoagulants i. Warfarin: Vitamin K, 4 factor prothrombin complex concentrates (4FPCC)

ii. LMWH: Protamine

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b. DOACs i. Dabigatran: Idarucizumab, activated charcoal, dialysis, off-label activated PCC

ii. Rivaroxaban: Andexanet alfa, off-label 4FPCC iii. Apixaban: Andexanet alfa, off-label 4FPCC, activated charcoal iv. Edoxaban: Off-label 4FPCC, off-label andexanet alfa

XIII. Cost 49−50

a. Warfarin: Cost of appointments, travel for routine laboratory monitoring, and medication have shown to be similar to that of the cost of a DOAC

b. LMWH: High medication cost

XIV. Evidence of DOAC Use in Hepatic Impairment and Transplant Recipients Table 5. Evidence of DOAC use in Heart Transplant Recipients

Kim M, Gabardi S, Townsend KR, et al. Post-transplant thrombosis and atrial arrhythmia may be safely managed by direct oral anticoagulants in cardiac transplant patients. [abstract]. J Heart Lung Transplant. 2016;35(4):S123.

Single center, retrospective cohort analysis

Population 18 heart transplant recipients

Intervention • DOAC (dabigatran or rivaroxaban): n=8

• Traditional anticoagulants (LMWH, fondaparinux or warfarin): n=10

Objective Assess safety and efficacy of DOACs compared to traditional anticoagulants

Outcome • No difference in the incidence of bleeding between groups (p=0.39)

• No cases of deep vein thrombosis recurrence or stroke between groups

Conclusion • DOACs demonstrated safety and efficacy in heart transplant recipients when compared to

traditional anticoagulants

• Indicator that DOACs may be used safely in other thoracic organ transplant recipients Table 6. Evidence of DOAC use in Thoracic Transplant Recipients

Lichvar A, Ensor NC Moore C, et al. Evaluation of Direct Oral Anticoagulation Therapy in Heart and Lung Transplant. Progress in Transplant. 2016; 26:263 – 269.

Design and Methods

Single-center, retrospective review of thoracic transplant patients initiated on DOAC therapy

Population Thoracic transplant recipients initiated on DOACs (apixaban, rivaroxaban and dabigatran) between May 2011 and March 2015

Intervention • Heart transplant recipients: Initiated on warfarin and managed by an outpatient pharmacist o Switched to a DOAC if considered to be noncompliant with INR monitoring, had low

time in therapeutic range or by patient request

• Lung transplant recipients: Initiated on a DOAC as first line therapy according to the following protocol for VTE treatment: o CrCl > 30 ml/min: Rivaroxaban was the treatment of choice o CrCl < 30 ml/min or nonvalvular atrial fibrillation: Apixaban was the treatment of choice o DOAC doses reduced by half with concomitant CYP3A4 inhibitor or macrolide antibiotic

Objectives Primary Objective: To describe a thoracic transplant population initiated on DOAC therapy Secondary Objectives

• Adverse reactions

• Venous thromboembolism (VTE) recurrence

• Drug-drug interactions

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Results

Outcomes Transplant type (n= 37):

• Heart: 5 (13.5%)

• Single lung: 4 (10.8%)

• Double lung: 28 (75.7%)

Demographics

Median age at DOAC initiation (IQR) 60.7 (50.4-65.44) Male, n (%) 27 (73%)

Caucasian 32 (86.5%)

Hypercoagulable state 33 (89.2%)

Anemia at DOAC initiation 33 (89.2%) Primary Objectives

• Mean time to initiation of DOAC post-transplant: 438.5 days (IQR 58-1119.5)

• Baseline renal function at DOAC initiation: 59.6 ml/min (IQR 48.6-82.6)

• Mean duration of DOAC therapy: 118 days (IQR 79.5-252.5)

• VTE most common indication (86.5%)

• Most commonly used DOAC: rivaroxaban (78.4%)

• Preemptive dose reductions: o Drug interactions: 37.8% o Renal insufficiency: 10.8% o Both: 8.1%

• Dose adjustments due to changing renal function: 15 (40.5%)

Secondary Objectives

• Adverse reactions: one hypersensitivity related reaction to rivaroxaban

• Bleeding: 8 events in 7 patients, 1 of which was major

• Drug-drug interactions: no difference between incidence of bleeding events in patients with identified drug interactions versus those without drug interactions

Interacting Drug Number of Patients (n=27)

Cyclosporine 9 (24.3%)

Fluconazole 1 (2.7%)

Itraconazole 5 (13.5%)

Posaconazole 1 (2.7%)

Voriconazole 11 (29.7%)

• VTE recurrence: 2 patients o 1 heart transplant recipient on rivaroxaban o 1 lung transplant recipient: attributed to dose reduced rivaroxaban in the setting of

initial poor renal function which later improved

Reviewer’s Critique

Strengths • Included factors associated with thrombus post-transplant in baseline characteristics

• Evaluated patients’ renal function and drug interactions to optimize DOAC therapy and avoid adverse events

• Uniformity among immunosuppression regimens

• One of the first studies to retrospectively analyze outcomes and potential confounding variables in a sizable cohort of the transplant population

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Limitations • Retrospective chart review with small sample size

• Variation in first line anticoagulation therapy

• Other potential drug-drug interactions such as CYP inducers or other P-gp inhibitors not reported

Conclusion • Demonstrated an insignificant correlation between bleeding and drug-drug interaction with cyclosporine and rivaroxaban

• Establishes a potential need for preemptive dose reductions in patients with major drug-drug interactions or renal insufficiency

• Reinforces need for adequate follow up of renal function for dose adjustments Table 7. Pharmacokinetic Study of DOAC use in Hepatic Impairment

Graff J, Harder S. Anticoagulant Therapy with the Oral Direct Factor Xa Inhibitors Rivaroxaban, Apixaban and Edoxaban and the Thrombin Inhibitor Dabigatran Etexilate in Patients with Hepatic Impairment. Clin Pharmacokinet. 2013;52:243-254.

Single-center, pharmacokinetic study

Population • Patients with Child-Pugh Class A (n=8) and B (n=8) hepatic impairment

• Patients matched with healthy volunteers (n=16) for each DOAC

Intervention • All subjects received one dose of a DOAC

• Rivaroxaban 10 mg, apixaban 5 mg, edoxaban 15 mg, dabigatran 150 mg

Comparison Differences in AUC and Cmax between Child-Pugh class A and B versus healthy patients

Outcome Ratio (90% CI) of AUC and Cmax in healthy volunteers and patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for dabigatran, rivaroxaban, and apixaban or percent change relative to healthy volunteers for edoxaban

Child-Pugh A Child-Pugh B

Dabigatran AUC Cmax

Not assessed Not assessed

0.94 (0.52-1.17) 0.70 (0.39-1.28)

Rivaroxaban AUC Cmax

1.15 1.05

2.27 (1.63-3.07) 1.27 (0.99-1.63)

Apixaban AUC Cmax

1.03 (0.80-1.32) Not reported

1.09 (0.85-1.17) Not reported

Edoxaban AUC Cmax

-4.2% -10%

-4.8% -32%

Reviewer’s Critique

Strengths • Evaluated four different DOACs

• Assessed pharmacokinetic changes in two classes of hepatic impairment

Limitations • Baseline characteristics were not reported

• Patients received one dose of study medication therefore outcomes not evaluated at steady state

• Child-Pugh Class C patients not included

• Authors retrieved data on apixaban and edoxaban from abstracts

Conclusion • Weak evidence to support use of DOACs in Child-Pugh Class A and B hepatic impairment

• Potential for use of dabigatran, rivaroxaban and apixaban in Child-Pugh Class A

• Can consider dabigatran or apixaban in Child-Pugh Class B and refrain from using edoxaban or rivaroxaban

• Stronger studies evaluating use of DOACs at steady state in patients with hepatic impairment including Child-Pugh Class C are needed to support their use in this patient population

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Table 8. Case Reports in Liver Transplant Recipients

Reshetnyak T, et al. Liver transplantation in a patient with primary antiphospholipid syndrome and Budd-Chiari syndrome. World J Hepatol. 2015; 2229-2236.

Obed A, Bashir A, Jarrad, et al. A Case of Live Donor Liver Transplantation In Acute-on-Chronic Liver Failure with Budd-Chiari Syndrome: Donor and Recipient with Antiphospholipid Antibody Syndrome. Am J Case Rep. 2018; 767-772.

Patient Background

• 15 year old male, with Budd-Chiari, antiphospholipid syndrome (APLS) and genetic predispositions to inherent thrombophilia and recurrent thrombi

• Developed sequelae of end-stage liver disease for which he received an OLT

• 47 year old female with Budd Chiari, APLS and Factor V Leiden mutation

• Presented with rapidly progressive liver failure

• Severely narrowed retrohepatic vena cava and occluded main hepatic veins

• Liver donation by daughter with APLS and Factor V Leiden mutation

Post-Liver Transplant

• Standard immunosuppression regimen: mycophenolate mofetil, tacrolimus, steroids

• Transitioned to dabigatran with improvement of hepatic veins

• Discharged home without complications

• Immediately post-operatively, both patient and donor were started on heparin targeting a therapeutic PTT

• Both donor and recipient were discharged on rivaroxaban 20 mg daily for at least 6 months

Reviewer’s Critique

Conclusion • Use of IV heparin immediately post-operatively may be preferential due to fluctuating renal function, quick onset of action and short half-life

• Effectiveness of dabigatran and rivaroxaban in patients with high risk of thrombus post-liver transplant implies that DOACs might have a place in therapy

Limitations • Patients received different anticoagulation therapy prior to transplant

• Decision process for picking dabigatran or rivaroxaban is unknown

• Post-transplant monitoring parameters not disclosed

Table 9. Case Report in Liver Transplant Recipient with Autoimmune Hepatitis

Ferreira G, Watanabe A, Trevizoli N, et al. Extensive Interior Vena Cava Thrombosis in a Liver Transplant Patient: A Case Report. Transplantation Proceedings. 2019; 51:1629-1632.

Patient Background

• 28 year old female with autoimmune hepatitis and Budd-Chiari, was diagnosed with thrombus extending from the renal veins to the inferior vena cava

• Patient underwent thrombectomy and OLT

Post-Liver Transplant

• Diagnosed with re-thrombosis prompting second thrombectomy then graft dysfunction resulted in second OLT

• POD5 patient was switched from heparin to warfarin, which was then replaced on POD22 with rivaroxaban 20mg daily

• After a year and four months post-transplant patient is still asymptomatic and will continue rivaroxaban 20mg daily indefinitely

Reviewer’s Critique

Conclusion • In a patient having to undergo multiple thrombectomy procedures, rivaroxaban was safe and effective in preventing re-thrombosis post-liver transplant

Limitations • Utilized multiple anticoagulants post-transplant

• No follow-up procedures listed

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XV. Literature Summary

a. Studies examining the safety and efficacy of DOAC use in heart and lung transplant recipients evaluated bleeding, renal function and drug-drug interactions

i. Demonstrated potential need for preemptive dose reductions with renal impairment and drug-drug interactions

ii. Overall, DOACs were seen to be safe and effective in thoracic transplant recipients b. In patients with liver disease, pharmacokinetic studies have demonstrated the use of DOACs to be safe

in patients with minor liver impairment i. In moderate liver impairment (Child-Pugh Class B), use of apixaban or dabigatran is preferred

ii. Due to a lack of data in severe liver impairment (Child-Pugh Classes C), DOACs are currently not recommended

c. Case reports in patients with high risk of re-thrombosis demonstrated effectiveness of rivaroxaban and dabigatran in liver transplant recipients

XVI. Recommendations

a. Reminders when deciding to use a DOAC in liver transplant recipients

Hepatic function

•Monitor at baseline and frequently post-transplant

•Avoid edoxaban and rivaroxaban in Child-Pugh Class B

•Avoid use of DOACs in Child-Pugh Class C

Renal function

•Monitor at baseline and frequently post transplant

•Some DOACs require dose adjustments based on CrCl

Drug-drug interactions

•Consider effect of CYP3A4 and P-gp inhibitors/inducers

•Dose reductions warranted with cyclosporine

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b. Recommended algorithm for DOAC use in liver transplant recipients

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Appendix 58−59

Child-Pugh Classifications

Clinical and Lab Criteria Points

1 2 3

Encephalopathy None Grade 1 or 2 Grade 3 or 4

Ascites None Diuretic responsive Diuretic refractory

Bilirubin < 2 mg/dL 2-3 mg/dL > 3 mg/dL

Albumin > 3.5 g/dL 2.8-3.5 g/dL < 2.8 g/dL INR <1.7 1.7-2.3 >2.3

Child-Pugh scored by adding total points for each parameter: Class A: 5-6 points (mild impairment) Class B: 7-9 points (moderate impairment) Class C: 10-15 points (severe impairment)

Grades of hepatic encephalopathy

• Grade 0: normal consciousness, personality, neurological examination, electroencephalogram • Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves • Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves • Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves • Grade 4: unarousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity