Download DOACs in liver disease

DOACs in liver disease – is there a problem?
Ton Lisman, Department of Surgery, UMC Groningen, The Netherlands
Hemostatic alterations in liver disease
• Thrombocytopenia and platelet function defects
• Low levels of coagulation proteins & inhibitors
• Low levels of fibrinolytic proteins
• High VWF, FVIII, tPA, PAI-1
Hemostatic balance
Bleeding
Procoagulants
Thrombosis
Anticoagulants
Healthy individual
Liver disease: Hemostatic rebalance
Bleeding
Procoagulants
Thrombosis
Anticoagulants
Patient with liver disease
Clinical evidence for rebalanced hemostasis in
patients with liver disease
• Bleeding does occur in patients with cirrhosis. However, the
most common bleeding complication – bleeding varices – is
unrelated to hemostasis
• Liver transplantation – a major and lengthy surgical
procedure – can be performed without any requirements for
blood transfusion
• Patients with liver diseases are not ‘auto-anticoagulated’
Thrombotic complications in cirrhosis
• Venous thrombosis
• Portal vein thrombosis
• Coronary events
• Intrahepatic thrombosis
• ……
Coagulation affects fibrogenesis in mice
Warfarin
Control
Factor Vleiden
J Thromb Haemost. 2008 Aug;6(8):1336-43
Gastroenterology. 2012 Nov;143(5):1253-60
Indications for anticoagulant therapy
• Venous thrombosis
• Hepatic vascular diseases
• Coronary events
• Intrahepatic thrombosis
• ……
But: anticoagulants are underused as a result of the
perceived bleeding risk and difficulties with dosing and
monitoring
The current anticoagulants
• Vitamin K antagonists
• Heparins
• Direct factor Xa inhibitors (Rivaroxaban, Apixaban)
• Direct IIa inhibitors (Dabigatran)
• Other direct inhibitors in development
Monitoring of vitamin K antagonists – INR
What should the target INR in a patients with liver disease
(and already prolonged INR) be????
Enhanced anticoagulant potency of LMWH in
patients with liver disease
JTH, 2012;10:1823-9 & PLoS One. 2014;9:e88390
The anti-Xa assay underestimates LMWH mass
in patients with cirrhosis
Liver Int. 2011, 31(7):1063 & Br. J. Haematol 2013, 163(5):666-73
Pro’s of the direct oral anticoagulant drugs in the
general population
Pro’s over VKA’s:
• Predictable dose-response
• No need for monitoring (wider therapeutic range)
• Reduced need for dose-adjustments
• No food interactions
• Limited drug interactions
Pro’s over heparins:
• Oral
• No need for monitoring
Con’s of the direct oral anticoagulant drugs in the
general population
• No antidote yet
• Cost
• Laboratory monitoring
• Increased risk for non-compliance
Why consider direct oral anticoagulants for liver
disease?
• Long term LMWH is inconvenient (s.c.)
• Heparins have a risk of HIT
• Warfarin appears to have an increased bleeding risk in
patients with advancing disease (target INR unknown)
• Simpler mode of action
• Wider therapeutic window
Caveats of the new drugs in liver disease
• No experience
• No antidote (yet)
• (lower) GI bleeding risk increased in general
population…..
• Altered pharmacokinetics in liver and renal failure
Caveats of the new drugs in liver disease
Altered in vitro potency
Dabigatran
Rivaroxaban
PlosOne 2014, 9(2):e88390
Caveats of the new drugs in liver disease
If the altered potency proves relevant in vivo we ideally
require laboratory monitoring of drug levels and drug potency
Monitoring of the new drugs in liver disease appears
reliable (in contrast to LMWH/VKA monitoring)
Dabigatran
Rivaroxaban
Br. J. Haematol, 2013;163(5):666-73.
Conclusions
• New oral anticoagulants have theoretical advantages
and disadvantages over traditional anticoagulants in
patients with liver diseases
• Clinical studies on efficacy and safety are required
before widespread use of these drugs can be applied
• There are problems:
• Increasing use (not within context of clinical trials)
• Little interest from pharma