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Title: Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy
Authors: Benjamin D. Horne
Petra A. Lenzini
Mia Wadelius
Andrea L. Jorgensen
Stephen E. Kimmel
Paul M. Ridker
Niclas Eriksson
Jeffrey L. Anderson
Munir Pirmohamed
Nita A. Limdi
Robert C. Pendleton
Gwendolyn A. Mcmillin
James K. Burmester
Daniel Kurnik
C. Michael Stein
Michael D. Caldwell
Charles S. Eby
Anders Rane
Jonatan D. Lindh
Jae Gook Shin
Ho Sook Kim
Pantep Angchaisuksiri
Robert J. Glynn
Kathryn E. Kronquist
John F. Carlquist
Gloria R. Grice
Robert L. Barrack
Juan Li
Brian F. Gage
Intermountain Medical Center
University of Utah
Washington University in St. Louis
Uppsala Universitet
University of Liverpool
University of Pennsylvania
Harvard Medical School
Brigham and Women's Hospital
Akademiska Sjukhuset
University of Alabama
ARUP Laboratories
Marshfield Clinic
Vanderbilt University
Karolinska Institutet
Inje University, College of Medicine
Mahidol University
Kaiser Permanente
St. Louis College of Pharmacy
Keywords: Medicine
Issue Date: 10-Feb-2012
Citation: Thrombosis and Haemostasis. Vol.107, No.2 (2012), 232-240
Abstract: By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index. Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R 2 was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R 2 = 69.1% (p < 0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy. © Schattauer 2012.
ISSN: 03406245
Appears in Collections:Scopus 2011-2015

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