Use of Pharmacogenetics and Clinical Factors To Predict the Maintenance Dose of Warfarin.

Abstract

Background Initiation of warfarin therapy using trial-and-error dosing can cause bleeding. Clinical factors explain only 20%–30% of the variability in the therapeutic dose of warfarin. Single nucleotide polymorphisms (SNPs) in the cytochrome P450 2C9 (CYP2C9) gene correlate with the clearance of S-warfarin and SNPs in the vitamin K epoxide reductase (VKORC1) gene predict warfarin sensitivity. We test the hypothesis that the combination of clinical and pharmacogenetic information can predict the therapeutic warfarin dose. Methods We collected DNA, demographic variables, laboratory values, and medication histories from patients taking warfarin. Subjects either attended an outpatient anticoagulation clinic or participated in the PREVENT (prevention of venous thromboembolism) study. After PCR amplification, we used Pyrosequencing® to genotype DNA regions for 2 coding CYP2C9 SNPs, *2 (C430T) and *3 (A1075C), and for 4 noncoding VKORC1 SNPs: C861A, A5808C, G6853C, and G9041A. Using multiple regression, we quantified the association between therapeutic warfarin dose and clinical and genetic factors in a derivation cohort of 900 participants and a validation cohort of 100 participants. Results The VKORC1 G6853C SNP was the first variable to enter the stepwise regression equation and was associated with a 27% decrease in the warfarin dose per allele in Caucasian patients. The VKORC1 A5808C SNP was associated with a 33% decrease per allele in warfarin dose in African-American patients. Other significant (p < 0.05) predictors of the therapeutic warfarin dose, in order of entry into the regression equation and their effect on warfarin dose were: body surface area (+12% per SD increase), CYP2C9*3 (−33% per allele), CYP2C9*2 (−20% per allele), age (−7% per decade), target INR (+8% per 0.5 unit increase), amiodarone use (−24%), African-American race (+12%), smoker (+9%), and simvastatin or fluvastatin use (−5%). A dosing equation that included these pharmacogenetic and clinical factors explained 52% of the dose variability in derivation cohort and 55% of the variability in the validation cohort. Conclusions The therapeutic warfarin dose can be estimated from clinical and pharmacogenetic factors that can be obtained when warfarin is started. Use of this dosing equation has potential to aid in the prediction of an optimal warfarin dose, which may decrease the risk of bleeding during the initiation of warfarin therapy.

Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements

“…Moreover, our data, consistent with previous work, indicate that the effect of the *2/*2 genotype on warfarin dose requirements is most similar to the *1/*2 and *1/*3 genotypes. 8,9 Thus these results add to the existing evidence of the association of CYP2C9 enzyme polymorphisms with decreased warfarin dose requirements. 7,37,38 An important part of this study was to determine the contribution of nongenetic factors to warfarin dose requirements.…”

“…7,8 Despite the evidence supporting CYP2C9 genotype and warfarin sensitivity, only a small portion of warfarin dose variability, approximately 10%, can be explained by CYP2C9-metabolizing enzyme polymorphisms. 9 Thus investigations of additional genetic predictors of warfarin dose requirements, addressing the complex interplay of proteins involved in warfarin's pharmacologic effect, are warranted.…”

“…Consistent with previous studies, we found CYP2C9 polymorphisms to be important determinants of warfarin dose requirements. [7][8][9][37][38][39] Approximately 29% of patients in our study carried a variant CYP2C9 allele. On average, patients carrying 1 variant allele (*2, *3, or *5) required 23.8% lower weekly doses of warfarin compared with those with the homozygous wild-type genotype (*1/*1).…”

CYP2C9 Genotype-guided Warfarin Prescribing Enhances the Efficacy and Safety of Anticoagulation: A Prospective Randomized Controlled Study

“…20,21 Carriers of CYP2C9 variant alleles require lower maintenance and cumulative induction doses and are more likely to exhibit supratherapeutic INR (i.e., INR43) and to experience bleeding during warfarin induction. [22][23][24][25][26][27][28][29][30] Selection of the correct warfarin dose is a challenging task, particularly during the loading period. Most physicians will attempt to tailor the dosing regimen to the patient's characteristics by taking into account the impact of factors that are known to influence warfarin pharmacokinetics and/ or pharmacodynamics.…”

Translating Innovation in Diagnostics: Challenges and Opportunities

“…Polymorphisms in this gene infl uence warfarin dosing requirements and warfarin-associated bleeding ( Wittkowsky, 2002 ). It has been demonstrated that the maintenance warfarin dose can be estimated from demographic, clinical, and pharmacogenetic factors ( Gage et al, 2004 ). A second gene, VKORC1 , has been associated with the average weekly warfarin dose required to maintain patients at their desired anticoagulation target.…”