Genetic-based Dosing in Orthopedic Patients Beginning Warfarin Therapy

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2007 Mar 28

PMID 17387222

Citations 65

Authors

Eric A Millican

Petra A Lenzini

Paul E Milligan

Leonard Grosso

Charles Eby

Elena Deych

Gloria Grice

John C Clohisy

Robert L Barrack

R Stephen J Burnett

Deepak Voora

Susan Gatchel

Amy Tiemeier

Brian F Gage

Affiliations

Soon will be listed here.

Abstract

High variability in drug response and a narrow therapeutic index complicate warfarin therapy initiation. No existing algorithm provides recommendations on refining the initial warfarin dose based on genetic variables, clinical data, and international normalized ratio (INR) values. Our goal was to develop such an algorithm. We studied 92 patients undergoing primary or revision total hip or knee replacement. From each patient we collected a blood sample, clinical variables, current medications, and preoperative and postoperative laboratory values. We genotyped for polymorphisms in the cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase (VKORC1) genes. Using stepwise regression, we developed a model for refining the warfarin dose after the third warfarin dose. The algorithm explained four fifths of the variability in therapeutic dose (R(2)(adj) of 79%). Significant (P > .05) predictors were INR value after 3 doses (47% reduction per 0.25-unit rise), first warfarin dose (+7% per 1 mg), CYP2C9*3 and CYP2C9*2 genotype (-38% and -17% per allele), estimated blood loss (interacting with INR(3)), smoking status (+20% in current smokers), and VKORC1 (-11% per copy of haplotype A). If validated, this model should provide a safer, more effective process for initiating warfarin therapy.

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