Effect of Co-Administration of Rivaroxaban and Clopidogrel on Bleeding Time, Pharmacodynamics and Pharmacokinetics A Phase I Study.docVIP

Pharmaceuticals 2012, 5, 279-296; doi:10.3390/ph5030279 OPEN ACCESS Pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Article Effect of Co-Administration of Rivaroxaban and Clopidogrel on Bleeding Time, Pharmacodynamics and Pharmacokinetics: A Phase I Study Dagmar Kubitza *, Michael Becka, Wolfgang Mück and Stephan Schwers Clinical Pharmacology, Bayer Pharma AG, D-42096 Wuppertal, Germany * Author to whom correspondence should be addressed; E-Mail: dagmar.kubitza@; Tel.: +49-202-36-4504; Fax: +49-202-35-4115. Received: 20 December 2011; in revised form: 18 January 2012 / Accepted: 20 February 2012 / Published: 24 February 2012 Abstract: Dual antiplatelet therapy with acetylsalicylic acid and a thienopyridine, such as clopidogrel, is effective for the secondary prevention of cardiovascular events in patients with acute coronary syndrome, but there is still a substantial residual risk of recurrence. Although anticoagulant therapy with a vitamin K antagonist (e.g. warfarin) in conjunction with antiplatelet therapy has been shown to reduce the risk of cardiovascular events, the rates of bleeding were increased with these combination therapies; hence, triple therapy with warfarin is currently only recommended in patients at low risk of bleeding. In addition, there are other limitations associated with vitamin K antagonist therapy, including the need for routine coagulation monitoring and dose adjustment to maintain the treatment within the therapeutic range. Rivaroxaban is an oral, direct Factor Xa inhibitor; in clinical practice, it is likely that rivaroxaban will be given to patients who also receive antiplatelet therapy, such as clopidogrel. This randomized, non-blinded, three-way crossover study investigated the effect of rivaroxaban on bleeding time when co-administered with clopidogrel. In addition, the influence of clopidogrel on the safety, tolerability, pha