RELY Genetics 2012ESC演讲PPT.ppt

Guillaume Pare MD Genetic determinants of dabigatran plasma levels and their relation to bleeding On behalf of RE-LY Genetics: Guillaume Pare MD, Niclas Eriksson PhD, Thorsten Lehr PhD, Stuart Connolly MD, John Eikelboom MD, Michael D. Ezekowitz MD PhD , Tomas Axelsson PhD, Sebastian Haertter PhD, Jonas Oldgren MD PhD, Paul Reilly PhD, Agneta Siegbahn MD PhD, Ann-Christine Syvanen PhD, Claes?Wadelius MD PhD, Mia Wadelius MD PhD, Heike Zimdahl-Gelling PhD, Salim Yusuf MD, Lars Wallentin MD PhD From the Population Health Research Institute, Uppsala Clinical Research Center, Thomas Jefferson Medical College, McMaster University, Uppsala University and Boehringer Ingelheim Pharma Inc. With support from Boehringer Ingelheim Pharma Inc. Background Dabigatran etexilate is effective and safe in prevention of stroke in AF patients compared with warfarin Dabigatran etexilate is an oral prodrug that is rapidly converted by esterases (CES1) to the active agent dabigatran We hypothesized genetic factors are responsible for some of the inter-individual variability in dabigatran exposure RE-LY Trial AF patients with at least one additional RF for stroke 18,113 patients with median follow-up of 2.0 years Randomized trial of two fixed doses of dabigatran etexilate (110 and 150 mg bid) and open-label warfarin 110 mg as effective as warfarin 150 mg superior to warfarin Both doses had lower minor and major bleeds Connolly et al. N Engl J Med. 2009 Sep 17;361(12):1139-51 Methods Summary Genome-wide analysis (551,203 markers) of dabigatran peak and trough concentration (N=1,490) Identification of genetic determinants of peak and trough concentration Association testing of genetic determinants of dabigatran concentration with safety and efficacy outcomes (N=1,694) Methods Primary efficacy endpoint defined as stroke or systemic embolism Primary safety endpoint define as any bleeding, minor and major 1,694 dabigatran etexilate-treated RE-LY participants of European ancestry s