Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing
Julie A. Johnson,Li Gong,Michelle Whirl-Carrillo,Brian F. Gage,Stuart A. Scott,Charles M. Stein,Jeffrey L. Anderson,Stephen E. Kimmel,Ming Ta Michael Lee,Munir Pirmohamed,Mia Wadelius,Teri E. Klein,Russ B. Altman +12 more
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TLDR
The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician.Abstract:
Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K–epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene–drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field. 1 Focused Literature review The Supplementary Notes online include a systematic literature review of CYP2C9 and VKORC1 genotype and warfarin dosing, which forms the basis for this guideline. drug: w arF arin Warfarin (Coumadin and others) is the most commonly used oral anticoagulant worldwide, with annual prescriptions typically equaling 0.5–1.5% of the population. It is prescribed for treatment and prevention of thrombotic disorders. 2 Although highly efficacious, warfarin’s narrow therapeutic index and wide interindividual variability make its dosing notoriously challenging. 3–5 Complications from inappropriate warfarin dosing are among the adverse events most frequently reported to the US Food and Drug Administration (FDA) and one of the most common reasons for emergency room visits. 6 Warfarin is often dosed empirically: an initial dose is prescribed, typically followed by at least weekly measurement of the INR and subsequent dose adjustment. The initial dose is often based on population averages (e.g., 3–5 mg/day), but stable doses to achieve an INR of 2–3 can range from 1–20 mg/ day. The iterative process to define the appropriate dose can take weeks to months, and during this period patients are at increased risk of over- or under-anticoagulation and thus at risk of thromboembolism or bleeding.read more
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Genotype and risk of major bleeding during warfarin treatment
Vivian K. Kawai,Andrew Cunningham,Susan I. Vear,Sara L. Van Driest,Abimbola Oginni,Hua Xu,Min Jiang,Chun Li,Joshua C. Denny,Christian M. Shaffer,Erica Bowton,Brian F. Gage,Wayne A. Ray,Dan M. Roden,C. Michael Stein +14 more
TL;DR: The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days, and was the only allele that differed significantly among cases and controls.
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Pharmacogenomics and patient care: One size does not fit all
Kathleen M. Giacomini,Sook Wah Yee,Mark J. Ratain,Richard M. Weinshilboum,Naoyuki Kamatani,Yusuke Nakamura +5 more
TL;DR: The status of the field and approaches for addressing some of the open questions in pharmacogenomics research and use of genetic testing in guiding drug therapy are described.
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The molecular genetics of chemotherapy–induced peripheral neuropathy: A systematic review and meta-analysis
J.R. Cliff,J.R. Cliff,Andrea L. Jorgensen,R. Lord,R. Lord,F. Azam,L. Cossar,L. Cossar,Daniel F. Carr,Munir Pirmohamed +9 more
TL;DR: A systematic review was conducted to identify pharmacogenetic studies, assess their quality and findings and undertake meta-analysis where possible, finding SNPs in CYP2C8, CYP3A4, ARHGEF10, EPHA and TUBB2A genes (taxanes), FARS2, ACYP2 and TAC1 (oxaliplatin), and CEP75 and CYP5 (vincristine) are of potential interest.
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An analysis of allele, genotype and phenotype frequencies, actionable pharmacogenomic (PGx) variants and phenoconversion in 5408 Australian patients genotyped for CYP2D6, CYP2C19, CYP2C9 and VKORC1 genes.
TL;DR: A high frequency of actionable PGx variants in the Australian population is indicated and the addition of drug-induced phenoconversion provides further support for the utilisation of PGx testing in clinical practice as another tool assisting prescribers in the application of personalised medicine.
pharmacogenetics : an overview of study design, methodological and statistical issues
TL;DR: The objective of this review is to discuss the benefits of incorporating pharmacogenetics into clinical practice and address outstanding methodological and statistical issues that may lead to heterogeneity among reported pharmacogenetic studies and how they may be addressed.
References
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Dabigatran versus warfarin in patients with atrial fibrillation
Stuart J. Connolly,Michael D. Ezekowitz,John W. Eikelboom,Jonas Oldgren,Amit Parekh,Janice Pogue,Paul A. Reilly,Ellison Themeles,Jeanne Varrone,Susan Wang,Marco Alings,Denis Xavier,Jun Zhu,Rafael Diaz,Basil S. Lewis,Harald Darius,Hans-Christoph Diener,Campbell D. Joyner,Lars Wallentin +18 more
TL;DR: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage.
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Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
TL;DR: Guyatt et al. as mentioned in this paper presented the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) and provided specific management recommendations for the first 1 or 2 days for most individuals.
Journal ArticleDOI
Estimation of the warfarin dose with clinical and pharmacogenetic data
Teri E. Klein,Russ B. Altman,Niclas Eriksson,Brian F. Gage,Stephen E. Kimmel,Lee Mt,Nita A. Limdi,David C. Page,Dan M. Roden,Michael J. Wagner,Caldwell,Julie A. Johnson +11 more
TL;DR: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach.
Journal ArticleDOI
Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.
Mark J. Rieder,Alexander P. Reiner,Brian F. Gage,Deborah A. Nickerson,Charles S. Eby,Howard L. McLeod,David K. Blough,Kenneth E. Thummel,David L. Veenstra,Allan E. Rettie +9 more
TL;DR: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries.
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Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications
TL;DR: YP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.
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