Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin

Gage, Brian F.; Eby, Charles S.; Milligan, Paul E.; Banet, Gerald A.; Duncan, Jill R.; McLeod, Howard L.

doi:10.1160/th03-06-0379

Cited by 285 publications

(97 citation statements)

References 65 publications

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“…This compares favourably with the recently published value of 39% that was obtained using a predictive dosage algorithm based on CYP2C9 and seven clinical and demographic factors. 44 Verification of our findings and continued search for additional factors will be performed in a larger patient cohort. These results will eventually enable prediction of individualised dosage in the initiation phase of warfarin therapy, and minimise the risk of early haemorrhage without compromising anticoagulant effect.…”

Section: Wadelius Et Almentioning

confidence: 72%

Common VKORC1 and GGCX polymorphisms associated with warfarin dose

et al. 2005

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We report a novel combination of factors that explains almost 60% of variable response to warfarin. Warfarin is a widely used anticoagulant, which acts through interference with vitamin K epoxide reductase that is encoded by VKORC1. In the next step of the vitamin K cycle, gamma-glutamyl carboxylase encoded by GGCX uses reduced vitamin K to activate clotting factors. We genotyped 201 warfarin-treated patients for common polymorphisms in VKORC1 and GGCX. All the five VKORC1 single-nucleotide polymorphisms covary significantly with warfarin dose, and explain 29-30% of variance in dose. Thus, VKORC1 has a larger impact than cytochrome P450 2C9, which explains 12% of variance in dose. In addition, one GGCX SNP showed a small but significant effect on warfarin dose. Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or failure to prevent thromboembolism. Genotype-based dose predictions may in future enable personalised drug treatment from the start of warfarin therapy.

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Section: Wadelius Et Almentioning

confidence: 72%

Common VKORC1 and GGCX polymorphisms associated with warfarin dose

et al. 2005

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“…Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 correlated with INR and plasma R-and S-warfarin concentrations. The mean warfarin daily dose requirement was highest in patients with the allelic variant CYP2C9 *1/*1 compared with those with the variant *2 and *3 alleles and highest 64 Gage et al, 65 Bodin et al, 66 Voora et al, 67 Hillman et al, 68 Kimura et al, 69 Loebstein et al, 39 and Borgiani et al 50 reported similar findings when genotypes were distributed by race. Studies articulating combined CYP2C9 and VKORC1 allelic frequencies and associated warfarin doses are summarized in Table 5.…”

Section: Effect Of Allelic Variants On Warfarin Activitymentioning

confidence: 83%

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Moyer

O’Kane

Baudhuin

et al. 2009

Mayo Clinic Proceedings

111

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ADE = adverse drug event; AEI = American Enterprise Institute; ASPE = allele-specific primer extension; CYP2C9 = cytochrome P450 2C9; INR = international normalized ratio; PCR = polymerase chain reaction; SNP = single-nucleotide polymorphism; VitKH 2 = vitamin K hydroquinone; VKOR = vitamin K epoxide reductase; VKORC1 = VKOR complex, subunit 1 W arfarin is a well-accepted therapy used for the prevention of stroke in patients with atrial fibrillation, for prophylaxis of venous thromboembolism and pulmonary embolism in patients with prosthetic heart valves and myocardial infarction, and for prevention of pulmonary embolism or deep venous thrombosis in patients undergoing orthopedic surgery or with a history of venous or arterial thromboembolism. Many reviews and clinical practice guidelines (summarized by Ansell et al, 1 Baglin et al, 2 Flockhart et al, 3 Husted et al, 4 and Singer et al 5 ) outline the substantial benefits of warfarin therapy for the prevention of strokes in these patients. The American Enterprise Institute (AEI)-Brookings Joint Center for Regulatory Studies Report, which reviewed the use of warfarin in the United States, estimates that approximately 2 million US citizens are prescribed warfarin annually. 6 In 2003, a total of 21.2 million prescriptions were written for oral warfarin in the United States. 7 Warfarin interferes with coagulation by inhibiting regeneration of the reduced form of vitamin K, a cofactor in the γ-glutamyl-carboxylase -mediated activation of coagulation factors II, VII, IX, and X ( Figure 1). The oxidized, inactive form of vitamin K is converted to the reduced form of vitamin K by vitamin K epoxide reductase (VKOR); warfarin inhibits VKOR, resulting in less of the reduced form of vitamin K available to support the factor carboxylation required to sustain the coagulation cascade. 8 Warfarin has a narrow therapeutic index that contributes either to therapeutic failure (potentially leading to stroke or other complications) or therapeutic excess (potentially leading to bleeding and hemorrhage). Many surveys have described the incidence of warfarin-related adverse drugThe antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to ach...

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“…The high-dose and low-dose haplotypes can be identified in patients by screening a small number of polymorphisms (haplotype tag SNPs) [1]. Previously, factors such as CYP2C9 genotype have also been described as predictors for warfarin dose [4,5]. VKORC1 haplotype accounts for 21-25% of the variation in warfarin dose, and adding CYP2C9*2 and *3 genotypes improved the prediction model to 31% [4].…”

mentioning

confidence: 99%

“…Previously, factors such as CYP2C9 genotype have also been described as predictors for warfarin dose [4,5]. VKORC1 haplotype accounts for 21-25% of the variation in warfarin dose, and adding CYP2C9*2 and *3 genotypes improved the prediction model to 31% [4]. As warfarin has a narrow therapeutic index, and over-or under-dosing can be lifethreatening, screening of VKORC1 and CYP2C9 prior to initiating therapy are likely to provide essential information for improving dose selection and more cost effective monitoring strategies.…”

mentioning

confidence: 99%