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

Caraco, Yoseph; Blotnick, Simcha; Muszkat, Mordechai

doi:10.1038/sj.clpt.6100316

Cited by 335 publications

(299 citation statements)

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“…Combined, polymorphisms in these 2 alleles plus age, sex, and weight account for 56% to 64% of warfarin dose variation. 56,[73][74][75] Table 7 summarizes the effects of CYP2C9 and VKO-RC1 variants on warfarin dose, the effects these variants have on sensitivity to warfarin, and variant prevalence as observed and reported in 3 previously published peerreviewed reports plus results from the current report (835 patients total). The findings from these 4 unrelated studies describing the association between warfarin daily dose and genotype show considerable agreement.…”

Section: Discussionmentioning

confidence: 99%

“…This pharmacogenetic equation explained 53% to 54% of the variability in the warfarin dose in a validation cohort of 292 patients. Caraco et al 73 studied 96 patients treated prospectively with warfarin and knowledge of warfarin sensitivity genotype. Patients treated in the genotyping arm of this study reached target INR 2.8 days earlier and stable warfarin dose 19 days earlier compared with 96 control patients matched for age, sex, body weight, body mass index, smoking status, indications for treatment, clinical characteristics, and co-medications treated without knowledge of genotype.…”

Section: Effect Of Allelic Variants On Warfarin Activitymentioning

confidence: 99%

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

Moyer

O’Kane

Baudhuin

et al. 2009

Mayo Clinic Proceedings

113

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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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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Allelic Variants On Warfarin Activitymentioning

confidence: 99%

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

Moyer

O’Kane

Baudhuin

et al. 2009

Mayo Clinic Proceedings

113

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show abstract

“…Results from two small trials have recently been reported [95,96]. One trial of 191 patients, using CYP2C9-based dosing (not including VKORC1 or clinical variables), demonstrated a significant improvement in both primary outcomes: the time to reach the first therapeutic INR (2.73 days earlier with CYP2C9-based dosing versus empiric dosing) and the time to reach maintenance dose (18 days earlier with CYP2C9-based dosing versus empiric dosing) [96].…”

Section: Expert Opinionmentioning

confidence: 99%

Warfarin therapy: in need of improvement after all these years

Kimmel

2008

Expert Opinion on Pharmacotherapy

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Background-Warfarin therapy has been used clinically for over 60 years, yet continues to be problematic because of its narrow therapeutic index and large inter-individual variability in patient response. As a result, warfarin is a leading cause of serious medication-related adverse events, and its efficacy is also suboptimal.Objective-To review factors that are responsible for variable response to warfarin, including clinical, environmental, and genetic factors, and to explore some possible approaches to improving warfarin therapy.Results-Recent efforts have focused on developing dosing algorithms that included genetic information to try to improve warfarin dosing. These dosing algorithms hold promise, but have not been fully validated or tested in rigorous clinical trials. Perhaps equally importantly, adherence to warfarin is a major problem that should be addressed with innovative and cost-effective interventions.Conclusion-Additional research is needed to further test whether interventions can be used to improve warfarin dosing and outcomes.

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“…However, in the prevention of thrombotic events with atrial fibrillation, the polymorphic cytochrome P450 2C9 (CYP2C9) protein is accepted as the rate-limiting drug-metabolizing enzyme of warfarin clearance and, to less extent, also to the clearance of alternative vitamin K antagonists, such as acenocoumarol and phenprocoumon. A prospective study addressing the question of whether a priori knowledge of CYP2C9 genotype may improve warfarin therapy demonstrated that patients who were treated applying a CYP2C9 genotype-adjusted algorithm reached a significantly earlier stable anticoagulation state and experienced less minor bleeding [3] than those who were not. Moreover, subjects who are carriers of variants in the vitamin K epoxide reductase complex, subunit 1 (VKORC1) gene require significantly higher warfarin doses than usually recommended [5,30].…”

Section: Application Of Personal Medicine In Clinical Practicementioning

confidence: 99%

The promises of personalized medicine

Cascorbi

2010

Eur J Clin Pharmacol

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

Cited by 335 publications

References 50 publications

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

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

Warfarin therapy: in need of improvement after all these years

The promises of personalized medicine

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