Sarah Bos

58 CHAPTER 4 Discussion This is the first study to monitor the effect of repeated exposure to edoxaban in a therapeutic dose in patients with cirrhosis. We chose to study a 7 day-exposure time to ensure we would reach steady state, which is achieved after 3 days of dosing in healthy individuals. We found that edoxaban reduces ex vivo hemostatic potential and in vivo activation of coagulation less efficiently in patients compared to controls, despite similar plasma levels. Specifically, the relative decrease of the ETP was lower in patients compared to controls. In addition, the absolute on-drug ETP level was two-fold higher in patients, suggesting insufficient anticoagulant activity in patients. Indeed, d-dimer levels clearly decreased over time in controls, but remained similar in patients. These results are in line with in vitro studies that showed Xa-inhibiting DOACs to have decreased anticoagulant effects in plasma from patients with cirrhosis.(13,15) However, although we find evidence of a less effective downregulation of coagulation by edoxaban in patients with cirrhosis, clinical studies are required to assess whether this translates to a less effective antithrombotic effect in patients in both a prophylactic and a treatment setting.(3) Our data show that edoxaban accumulation due to decreased clearance does not occur in patients with mild cirrhosis. Whether drug accumulation occurs in patients with more advanced cirrhosis, or in patients with cirrhosis combined with poor renal function requires further study. DOACs are cleared in part by metabolic inactivation in the liver, and in part by renal excretion. The route of elimination of edoxaban is approximately 50% hepatic and 50% renal, which is roughly comparable to that of rivaroxaban (65 vs 35%) and apixaban (75 vs 25%), whereas dabigatran is cleared primarily by the kidneys (20% vs 80%). Future studies will be required to examine whether the slightly increased role of the liver in clearing rivaroxaban and apixaban results in drug accumulation at lower levels of hepatic failure. Based on our data, plasma levels of edoxaban should be as high or perhaps somewhat higher in patients with cirrhosis compared to patients with intact liver function to obtain optimal anticoagulant effects. Although therapeutic drug levels of edoxaban have not yet been firmly established, peak levels between 120 ng/ml and 250 ng/ml have been found in patients considered to be adequately treated with 60 mg once daily.(16) As edoxaban clearance may change when patients develop worsening liver disease, we propose to monitor drug levels in patients with cirrhosis using edoxaban-calibrated anti-Xa assays, that previously has been shown to be suitable for DOAC monitoring of patients with cirrhosis to obtain values considered therapeutic or slightly supratherapeutic in the general population.(3,17,18)