edoxaban and Liver-Diseases

To review current literature for target-specific oral anticoagulants (TSOACs) and provide critical analysis for dosing recommendations in special population groups.. A literature search was conducted in Medline (1996 to April week 2 2015) and Embase (1980 to 2015 week 16) using key terms dabigatran, rivaroxaban, apixaban, edoxaban, kidney diseases, liver diseases, elderly, obesity, and special populations.. Randomized controlled trials in English assessing efficacy and safety of TSOACs in healthy adults and special populations were selected for analysis.. Phase 3 trials for TSOACs predominately excluded patients with severe renal impairment or active liver disease. There were no exclusion criteria based on age, body weight or body mass index. Additional conclusions were made in special populations, including those with renal or liver impairment and obese and elderly patients, based on secondary analyses, pharmacokinetic, and pharmacodynamic studies.. Pharmacokinetic and pharmacodynamic changes associated special populations may alter clinical decision with regard to drug selection and dosing. It is valuable to understand the rationale for labeled dosing recommendations in nonvalvular atrial fibrillation and venous thromboembolism treatment and prevention, particularly in patients that fall into special population groups. Furthermore, the use of TSOACs is likely to increase as clinicians gain experience with these agents and additional TSOACs and indications are approved.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Dabigatran; Humans; Kidney Diseases; Liver Diseases; Obesity; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Venous Thromboembolism

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.

Topics: Absorption; Anticoagulants; Benzimidazoles; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Humans; Liver Diseases; Metabolic Clearance Rate; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thrombin; Tissue Distribution; Venous Thromboembolism

Edoxaban, a once-daily, oral, direct factor Xa inhibitor, is approved for stroke prevention in nonvalvular atrial fibrillation and venous thromboembolism treatment. This study examined the effects of mild or moderate hepatic impairment on the pharmacokinetics of edoxaban and its metabolite M4. Thirty-three subjects enrolled in 4 treatment cohorts-mild hepatic impairment (n = 8), moderate hepatic impairment (n = 9), and 2 cohorts of healthy controls matched for age, sex, and weight (each n = 8)-and received a single 15-mg dose of edoxaban. Plasma pharmacokinetics for edoxaban and M4, prothrombin time (PT), activated partial thromboplastin time (aPTT), and safety data were measured over 72 hours. Edoxaban and M4 exposures were similar in subjects with mild or moderate hepatic impairment compared with matched controls. Higher PT and aPTT values were observed at baseline and after edoxaban dosing in the hepatic impairment groups compared with healthy controls. Edoxaban 15 mg was well tolerated in all cohorts. These results suggest that edoxaban exposure does not significantly increase in patients with mild or moderate hepatic impairment. However, because of the potential for underlying coagulopathy, edoxaban is not recommended for use in patients with moderate or severe hepatic impairment. No dose reduction is recommended for patients with mild hepatic impairment.

Topics: Adolescent; Adult; Aged; Contraindications; Factor Xa Inhibitors; Female; Humans; Liver Diseases; Male; Middle Aged; Partial Thromboplastin Time; Prothrombin Time; Pyridines; Thiazoles; Young Adult

Portal vein thrombosis (PVT) is a lethal complication of hepatectomy if not properly treated. An 81-year-old woman diagnosed with postoperative PVT after right hepatectomy and caudate lobectomy for perihilar cholangiocarcinoma. Elevation of serum total bilirubin levels, D-dimer levels, and glossy ascites appeared on postoperative day 5 (POD5), and a contrast-enhanced CT confirmed PVT. Thrombi were found from the umbilical portion of the portal vein to the superior mesenteric vein. There were signs of acute liver failure due to thrombi obstructing the portal vein. Therefore, emergent catheter thrombus aspiration was performed under laparotomy. An aspiration catheter was inserted into the superior mesenteric vein from the ileocolic vein. We performed direct aspiration thrombectomy, followed by anticoagulant administration using urokinase via the catheter. Partial recanalization of the portal vein and superior mesenteric vein was observed. To dissolve residual thrombi, edoxaban administration was started on POD6. Contrast-enhanced CT 16 days after her additional operation showed the thrombi had completely disappeared. The patient was discharged on POD76. She had no recurrence of PVT over the next 6 months. Combination therapy of early intervention using aspiration catheter and systemic anticoagulant medication was useful for severe postoperative PVT accompanied with liver failure.

Topics: Aged, 80 and over; Anticoagulants; Bile Duct Neoplasms; Bilirubin; Female; Hepatectomy; Humans; Klatskin Tumor; Liver Diseases; Mesenteric Veins; Portal Vein; Pyridines; Thiazoles; Thrombectomy; Thrombosis; Urokinase-Type Plasminogen Activator; Venous Thrombosis

Topics: Anticoagulants; Atrial Fibrillation; Humans; Liver Diseases; Pyridines; Thiazoles; Warfarin

Topics: Atrial Fibrillation; Humans; Liver Diseases; Pyridines; Thiazoles; Warfarin

The direct oral anticoagulants (DOACs) are drugs used in clinical practice since 2009 for the prevention of stroke or systemic embolism in non-valvular atrial fibrillation, and for the treatment and secondary prevention of venous thromboembolism. The four DOACs, including the three factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and one direct thrombin inhibitor (dabigatran) provide oral anticoagulation therapy alternatives to Vitamin K antagonists (VKAs). Despite their clear advantages, the DOACs require on the part of the internist a thorough knowledge of their pharmacokinetic and pharmacodynamic characteristics to ensure their correct use, laboratory monitoring and the appropriate management of adverse events. This document represents a consensus paper on the use of DOACs by representatives of three Italian scientific societies: the Italian Society of Internal Medicine (SIMI), the Federation of the Associations of Hospital Managers (FADOI), and the Society for the Study of Haemostasis and Thrombosis (SISET). This document formulates expert opinion guidance for pragmatic managing, monitoring and reversing the anticoagulant effect of DOACs in both chronic and emergency settings. This practical guidance may help the internist to create adequate protocols for patients hospitalized ion internal medicine wards, where patients are often elderly subjects affected by poly-morbidities and renal insufficiency, and, thus, require particular attention to drug-drug interactions and peri-procedural protocols.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Clinical Competence; Consensus; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Food-Drug Interactions; Humans; Internal Medicine; Italy; Liver Diseases; Perioperative Period; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Time Factors; Venous Thromboembolism