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| |  Good News and Bad News About Genetic Profiling for Warfarin Dosing: Presented at AHA By Carole Bullock ORLANDO, FL -- November 9, 2007 -- Pharmacogenetic (PG)-guided dosing of warfarin reduced dosing changes, but didn't reach the study's primary endpoint -- an out-of-range reduction in clotting time -- investigators reported here at the American Heart Association (AHA) 2007 Scientific Sessions. The study, named COUMA-GEN, tested genotyping as a means to "personalize" therapy for warfarin, a drug prescribed to more than 2 million patients to prevent thrombosis, Jeffrey Anderson, MD, Professor of Medicine, University of Utah, Salt Lake City, Utah, said in news conference on November 7. The study randomized prospectively 206 patients receiving warfarin therapy for specific, qualifying clinical reasons (atrial fibrillation, deep vein thrombosis, or postorthopedic surgery prophylaxis) to a genotype-based warfarin dose initiation and maintenance algorithm or to a standard, empiric-dosing algorithm in a double-blind fashion. The variants (CYP2C9 and VKORC) plus age and weight account for one half of the dose variability, according to Dr. Anderson. This is the first study aimed at putting in practice "real-time" dosing based on a person's own genetic-linked response to therapy, with the goal of improving warfarin dosing. "Clinical benefit of PG-guidance is unproven, but promise was shown in the wild-type patients where a greater dose was required and in multiple-variant carriers where much lower doses were required. We haven't identified the precise setting or patient group where they will be the most helpful," he added at a news conference. The study used a validated PG-guided warfarin-dosing algorithm to assess the impact on prothrombin time international normalized ratio (INR-base efficacy, safety endpoint). Standard dosing followed an empirical protocol, whereas PG-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. INR was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses, resulting in smaller and fewer dosing changes and INRs. The initial weekly PG-calculated dose was 35.5 mg, but the maintenance ranged from a high of 44.7 mg/wk for the wild type (n = 56), to a low of 8 mg/wk for the 4-variant category (n = 1). "While the algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation, there was no reduction in out-of-range INRs," said Dr. Anderson. "The percent of out-of-range INRs was 30.7[%] in the PG group versus 33.1[%] in the STD group, with 54% being subtherapeutic and 45% supratherapeutic." The initial-to-final stable dose changes by genotype subset and dosing group in the wild type was 13.6 mg/wk, 2.4 mg/wk for one variant, and -10 mg/wk for 4 or more variants. Multiple-variant allele carriers were at increased risk of an INR of 4. Support for this study was provided by Deseret Foundation and the Heart and Lung Institute; LDS Hospital; Intermountain Healthcare, Salt Lake City, Utah; and Critical-Path Institute, Tucson, Arizona.
[Presentation title: A Double-Blind, Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiated on Oral Anticoagulation: The Couma-Gen Study.]
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