Sarah Bos

52 CHAPTER 4 Cautious use of the DOACs in patients with advancing cirrhosis is recommended by the manufacturers. Since all the DOACs are cleared by the liver and kidney, drug accumulation with a potentially increased bleeding risk is a main concern. In addition, in vitro studies have indicated altered anticoagulant effects of all registered DOACs in plasma from patients with cirrhosis. In vitro studies showed an altered anticoagulant effect of both the traditional anticoagulants and DOACs in patients with cirrhosis.(13) The Xa inhibiting DOACs were shown to be less potent in patients with cirrhosis, whereas IIa inhibitors showed an increased potency.(13) In a small group of patients with Child Pugh A and B cirrhosis, a single gift of edoxaban 15 mg resulted in a comparable pharmacokinetic effect with healthy matched controls(10). The route of clearance of Edoxaban is mainly renal (50%). The remainder of the drug is cleared through the hepatobiliary route.(14) Despite the contribution of the hepatobiliary system to clearance, the overall exposure of edoxaban was similar between the patients with Child Pugh A or B cirrhosis and their matched healthy controls, suggesting the drug might be safely used in patients with mild to moderate cirrhosis. However, altered potency of edoxaban as identified in our previous in vitro studies was not taken into account. Whether prolonged treatmentwithaDOAC, suchas edoxaban, leads toaccumulation of the drug in patients with cirrhosis is unknown. However, the clinical importance of such a question is obvious. We therefore monitored the drug levels and analysed the ex-vivo anticoagulant effects during a one week therapeutic dose of edoxaban (60 mg once daily) in cirrhotic patients and healthy subjects. Methods Study design We performed a prospective case-controlled mono center intervention study to analyze the ex-vivo potency of edoxaban in patients with Child Pugh A and B cirrhosis. Patients Sixteen adult patients with an established diagnosis of cirrhosis were enrolled from the outpatient hepatology clinic of the University Medical Center Groningen, The Netherlands. In addition, 16 healthy volunteers were included as a control group. Cirrhosis had to be confirmed via fibroscan suggestive for F4 fibrosis, histology compatible with cirrhosis, or via diagnostic imaging. Exclusion criteria were the presence of malignancy, renal failure requiring intervention with drugs or dialysis, weight under 60 kg, active infection, a known hereditary bleeding disorder, use of anticoagulant drugs in the past 10 days, use of cyclosporine, dronedarone, erythromycin or ketoconazol, history of thrombotic disease, recent variceal bleeding or known varices grade 2 or 3, pregnancy, or HIV positivity.