Sarah Bos

122 CHAPTER 7 patients versus patients with ASH cirrhosis, 14.8% versus 9.2% respectively.(18) The combined findings of these studies support the notion that patients with NASH cirrhosis have an increased risk of thrombotic events which is not readily explained on a hemostatic level. Possibly features of the metabolic syndrome as well as other cardiometabolic risk factors contribute to the increased risk of thrombosis.(17,19,20) From in vitro to in vivo As described in chapter one, there has been a shift fromusing vitamin K antagonists and LMWH as a therapy for patients with venous thrombo-embolism (VTE) and in patients with atrial fibrillation, in prevention of ischemic stroke. The convenience of dosing direct oral anticoagulants (DOACs) and route of administration together with less major side effects would propagate a suitable alternative for all patients. Unfortunately all the large phase 3 trials excluded patients with liver disease.(21– 24) Therefore clinicians were left with many gaps in their knowledge on the use of DOACs in patients with cirrhosis. In the last few years more information on the use of DOACS in patients with cirrhosis is emerging. Several in vitro studies on the effect of anticoagulation including DOACS in cirrhosis have been performed.(16,25,26). These studies provide essential information for new clinical trials. A rational first step would be to assess ex-vivo anticoagulant effects of drugs administered to patients without acute thrombotic disease. Such studies will reveal whether altered in vitro potency of anticoagulant drugs are also relevant in vivo. In addition, such studies are important to examine whether the pharmacokinetics of various anticoagulant drugs in patients with cirrhosis are similar to patients without liver disease. One small, single dose studies reported on the clearance of Xa-inhibitor edoxaban in patients with hepatic impairment.(27) Another small study reported on the pharmacokinetics and pharmacodynamics of a single dose of apixaban in a similar group.(28) When patients with CTP A cirrhosis are compared with healthy controls the clearance of a low dose of edoxaban is similar. The pharmacokinetics and pharmacodynamics of apixaban were not altered in the group with CTP A cirrhosis compared to healthy subject. Whether prolonged treatment of a Xa-inhibitor in cirrhosis leads to comparable drug concentrations, efficacy and safety, is not readily explained by these small studies. In chapter 4 we have shown the results of the first study to monitor the effect of prolonged edoxaban treatment in patients with CTP A/B cirrhosis. To reach steady state, a therapeutic dose of edoxaban for a full week was given. Normally steady state is reached after 3 days of edoxaban in healthy individuals.