Hugo Ten Cate1, Anthonie W A Lensing2, Jeffrey I Weitz3, Saskia Middeldorp4, Jan Beyer-Westendorf5, Dagmar Kubitza6, Timothey Brighton7, Gary E Raskob8, Patrick Mismetti9, Paolo Prandoni10, Martin Gebel11, Martin H Prins12. 1. Departments of Internal Medicine and Biochemistry, Cardiovascular Research Institute Maastricht (CARIM) and Thrombosis Expertise Center, Maastricht University Medical Center (MUMC+), Maastricht, the Netherlands. Electronic address: h.tencate@maastrichtuniversity.nl. 2. Bayer AG, Wuppertal, Germany. Electronic address: anthonie.lensing@bayer.com. 3. Thrombosis & Atherosclerosis Research Institute and McMaster University, Hamilton, Ontario, Canada. Electronic address: weitzj@taari.ca. 4. Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: s.middeldorp@amc.uva.nl. 5. Thrombosis Research Unit, Department of Medicine I, Division Hematology, University Hospital "Carl Gustav Carus", Dresden, Germany; Kings Thrombosis Service, Department of Hematology, Kings College London, UK. Electronic address: Jan.Beyer@uniklinikum-dresden.de. 6. Bayer Pharma AG, Wuppertal, Germany. Electronic address: dagmar.kubitza@bayer.com. 7. Department of Haematology, NSW Health pathology, Prince of Wales Hospital, Sydney, Australia. Electronic address: timothy.brighton@health.nsw.gov.au. 8. University of Oklahoma Health Sciences Center, College of Public Health, Oklahoma City, OK, USA. Electronic address: gary-raskob@ouhsc.edu. 9. Service de Médecine Vasculaire et Thérapeutique, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France. Electronic address: mismetti@univ-st-etienne.fr. 10. Department of Cardiovascular Sciences, Vascular Medicine Unit, University of Padua, Padua, Italy. 11. Bayer Healthcare, Wuppertal, Germany. Electronic address: martin.gebel@bayer.com. 12. Maastricht University Medical Center, Maastricht, the Netherlands. Electronic address: mh.prins@maastrichtuniversity.nl.
Abstract
INTRODUCTION: For treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), rivaroxaban is given in fixed doses without routine coagulation monitoring. PATIENTS AND METHODS: To determine whether monitoring would enhance its benefit-risk profile, we examined whether peak and trough prothrombin time (PT) values measured in 3797 rivaroxaban-treated patients included in the EINSTEIN DVT and PE studies correlated with subsequent recurrent VTE and major bleeding. In addition, we examined the stability of PT values over time and the impact of clinical variables on PT values. RESULTS: The mean peak PT values at months 3 and 6 or 12 were 21.9 ± 5 and 21.7 ± 6.0 s, respectively, while the mean trough PT values at months 2 and 6 were 15.1 ± 5.1 and 15.3 ± 2.9 s, respectively. Although peak and through PT values were higher in females, and with older age, frailty, active cancer, low body weight, impaired renal function and use of moderate to strong inhibitors of CYP3A4 and/or P-glycoprotein, and were lower in patients taking strong CYP 3A4 inducers, the differences were small and results were overlapping. Neither peak nor trough PT values correlated with recurrent VTE or major bleeding. CONCLUSIONS: PT monitoring is unlikely to improve the benefit-risk profile of rivaroxaban in patients with DVT or PE. The study was registered at www.clinicaltrials.gov as #NCT00440193 (EINSTEIN-DVT) and #NCT00439777 (EINSTEIN-PE).
INTRODUCTION: For treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), rivaroxaban is given in fixed doses without routine coagulation monitoring. PATIENTS AND METHODS: To determine whether monitoring would enhance its benefit-risk profile, we examined whether peak and trough prothrombin time (PT) values measured in 3797 rivaroxaban-treated patients included in the EINSTEIN DVT and PE studies correlated with subsequent recurrent VTE and major bleeding. In addition, we examined the stability of PT values over time and the impact of clinical variables on PT values. RESULTS: The mean peak PT values at months 3 and 6 or 12 were 21.9 ± 5 and 21.7 ± 6.0 s, respectively, while the mean trough PT values at months 2 and 6 were 15.1 ± 5.1 and 15.3 ± 2.9 s, respectively. Although peak and through PT values were higher in females, and with older age, frailty, active cancer, low body weight, impaired renal function and use of moderate to strong inhibitors of CYP3A4 and/or P-glycoprotein, and were lower in patients taking strong CYP 3A4 inducers, the differences were small and results were overlapping. Neither peak nor trough PT values correlated with recurrent VTE or major bleeding. CONCLUSIONS: PT monitoring is unlikely to improve the benefit-risk profile of rivaroxaban in patients with DVT or PE. The study was registered at www.clinicaltrials.gov as #NCT00440193 (EINSTEIN-DVT) and #NCT00439777 (EINSTEIN-PE).
Authors: Alexander Solms; Matthias Frede; Scott D Berkowitz; Anne Hermanowski-Vosatka; Dagmar Kubitza; Wolfgang Mueck; Theodore E Spiro; Stefan Willmann; Xiaoyu Yan; Liping Zhang; Dirk Garmann Journal: CPT Pharmacometrics Syst Pharmacol Date: 2019-07-05