Couma-Gen: Implications for future randomized trials of pharmacogenetic-based warfarin therapy

Warfarin is an effective oral anticoagulant used to treat or prevent thromboembolic disorders in millions.of patients worldwide. Even with conscientious International Normalized Ratio (INR) monitoring, warfarin initiation carries a high risk of hemorrhage. Pharmacogenetic studies have determined that variants in the CYP2C9 and VKORC1 genes help to predict the therapeutic warfarin dose. Whether using this information prospectively will,prevent under- and over-dosing of warfarin is unknown. To answer this question, the CoumaGen investigators randomized half of a 200-patient cohort beginning warfarin therapy to clinical dosing and half to pharmacogenetic dosing. Overall, pharmacogenetic dosing slightly increased time in the therapeutic INR range (p = not significant) and decreased the number of INR tests required. The trial has important implications for the new NIH-funded multicentered trial. Here, we discuss the Couma-Gen study and its implications for the design, randomization, blinding and end point definition of future studies.