Anticoagulant Therapy with the Oral Direct Factor Xa Inhibitors Rivaroxaban, Apixaban and Edoxaban and the Thrombin Inhibitor Dabigatran Etexilate in Patients with Hepatic Impairment

• Published in: Clinical pharmacokinetics Vol. 52; no. 4; pp. 243 - 254
• Main Authors: Graff, Jochen, Harder, Sebastian
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing AG 01.04.2013; Adis International; Springer Nature B.V
• Subjects: Absorption; Anticoagulants - administration & dosage; Anticoagulants - pharmacokinetics; Anticoagulants - therapeutic use; Benzimidazoles - administration & dosage; Benzimidazoles - pharmacokinetics; Benzimidazoles - therapeutic use; Biological and medical sciences; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Gastroenterology. Liver. Pancreas. Abdomen; General pharmacology; Humans; Internal Medicine; Liver Diseases - complications; Liver Diseases - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Morpholines - administration & dosage; Morpholines - pharmacokinetics; Morpholines - therapeutic use; Other diseases. Semiology; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Pyrazoles - administration & dosage; Pyrazoles - pharmacokinetics; Pyrazoles - therapeutic use; Pyridines - administration & dosage; Pyridines - pharmacokinetics; Pyridines - therapeutic use; Pyridones - administration & dosage; Pyridones - pharmacokinetics; Pyridones - therapeutic use; Review Article; Rivaroxaban; Thiazoles - administration & dosage; Thiazoles - pharmacokinetics; Thiazoles - therapeutic use; Thiophenes - administration & dosage; Thiophenes - pharmacokinetics; Thiophenes - therapeutic use; Thrombin - antagonists & inhibitors; Tissue Distribution; Venous Thromboembolism - blood; Venous Thromboembolism - complications; Venous Thromboembolism - prevention & control; Rivaroxaban; Dabigatran; Prothrombin Complex Concentrate; Hepatic Impairment; Apixaban; Human; Serine endopeptidases; Edoxaban; Enzyme; Oral administration; Blood-coagulation factor Xa inhibitor; Enzyme inhibitor; Hepatic disease; Thrombin; Anticoagulant; Dabigatran etexilate; Antithrombin; Peptidases; Liver failure; Antithrombotic agent; Hydrolases; Digestive diseases
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-013-0034-0

The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. In subjects with moderately impaired liver function (i.e. Child-Pugh classification B), the area under the plasma concentration–time curve (AUC) of rivaroxaban (10 mg single dose) is increased by 2.27-fold, which is paralleled by an increase in FXa inhibition. The AUC of apixaban (5 mg single dose) is increased by 1.09-fold, whereas the AUC of edoxaban (15 mg single dose) is decreased by 4.8 % and the AUC of dabigatran (150 mg single dose) is decreased by 5.6 %. Specific labelling restrictions for rivaroxaban, apixaban and dabigatran regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal clinical trials. Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels >2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Dabigatran is not recommended in patients with elevated liver enzymes (>2× ULN). Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.