Meyer Michel Samama

Comparison of a direct Factor Xa inhibitor, edoxaban, with dalteparin and ximelagatran: A randomised controlled trial in healthy elderly adults☆

INTRODUCTION Edoxaban (the free base of DU-176b) is a new, oral direct Factor Xa inhibitor. This is the first study to compare the hemostatic response to edoxaban, ximelagatran, and dalteparin in healthy, elderly adults. MATERIALS AND METHODS In this open-label, active-controlled clinical trial, 40 adults (65-75 years), were randomised to: oral edoxaban (60 mg, twice-daily, 7 doses), subcutaneous dalteparin (5000 IU, once-daily, 4 doses), oral ximelagatran (24 mg, twice-daily, 7 doses) or no drug. Blood samples were taken before, and 1.5, 4, 12, 24, 72, 84, 96, 108, 120, and 144 hours after, the first dose. The primary outcomes were changes in thrombin-antithrombin complex, prothrombin fragment 1+2 and D-dimer, and adverse events. Additional biomarkers of coagulation, and endothelial cell and platelet activation were compared (ANOVA). RESULTS All subjects completed the study. Inhibition of thrombin generation lag time, peak, and constant velocity index were significantly greater, and extended for a longer period of time, following edoxaban administration, compared with dalteparin. We found that the traditional assay for anti-FXa activity was not appropriate for the new anticoagulants. Biomarker changes following edoxaban administration (including prolongation of prothrombin time) reflected inhibition of Factor Xa; there was no effect on platelet, tissue factor or endothelial activation. There were no clinically significant changes in primary outcomes. No serious adverse events were reported. CONCLUSION Oral administration of edoxaban resulted in effective Factor Xa and TG inhibition, and was well-tolerated. Studies are needed to confirm edoxaban (60 mg daily) use in clinical practice. SPONSORSHIP Daiichi Sankyo Pharma Development.

Risk assessment models for thromboprophylaxis of medical patients.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 What is a risk factor and how to classify? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Quantification of Risk in a Multifactorial Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 RAMs Objectives and Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Development of RAMs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 RAMs in the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Non-validated RAMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Validated RAMs in the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Non electronic alerts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 RAMs in medical outpatients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

In vitro effect of melagatran and lepirudin on clot-bound thrombin

Thrombin converts fibrinogen into fibrin monomers by cleaving fibrinopeptides A and B from aminoterminal regions of Aa and Bh chains of fibrinogen, respectively [1]. During this reaction, thrombin is adsorbed to fibrin through the fibrin(ogen)-binding site located within the E domain [2,3]. The fibrin-bound thrombin retains its enzymatic activity and has the potential to induce thrombosis extension [4]. Given this central role of thrombin, most treatment strategies for acute coronary syndromes are aimed at inhibiting its generation or blocking its activity [5–7]. In vitro studies have shown that fibrin-bound thrombin is relatively protected from inactivation by heparin-antithrombin and this inactivation requires ligation of both exosites 1 and 2 of thrombin [8,9]. These findings could explain why heparin is limited in its ability to inhibit the extension of venous thrombosis and to prevent rethrombosis after successful thrombolysis [3]. Thus, direct thrombin inhibitors may represent alternatives to the treatment with heparin. At present, most clinical benefits of recombinant (r)hirudin have been demonstrated in the management of patients with heparin-induced thrombocytopenia. For this reason, lepirudin (a form of r-hirudin) has recently been approved for anticoagulation in patients with heparin-induced thrombocytopenia and associated thromboembolic disease [10,11].