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
TLDR
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.Abstract:
Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.read more
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2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS
Paulus Kirchhof,Stefano Benussi,Dipak Kotecha,Anders Ahlsson,Dan Atar,Barbara Casadei,Manuel Castellá,Hans-Christoph Diener,Hein Heidbuchel,Jeroen M.L. Hendriks,Gerhard Hindricks,Antonis S. Manolis,Jonas Oldgren,Bogdan A. Popescu,Ulrich Schotten,Bart P. Van Putte,Panagiotis Vardas,Stefan Agewall,John Camm,Gonzalo Barón Esquivias,Werner Budts,Scipione Carerj,Filip Casselman,Antonio Coca,Raffaele De Caterina,Spiridon Deftereos,Dobromir Dobrev,José M. Ferro,Gerasimos Filippatos,Donna Fitzsimons,Bulent Gorenek,Maxine Guenoun,Stefan H. Hohnloser,Philippe Kolh,Gregory Y.H. Lip,Athanasios J. Manolis,John J.V. McMurray,Piotr Ponikowski,Raphael Rosenhek,Frank Ruschitzka,Irina Savelieva,Sanjay Sharma,Piotr Suwalski,Juan Tamargo,Clare J Taylor,Isabelle C. Van Gelder,Adriaan A. Voors,Stephan Windecker,José Luis Zamorano,Katja Zeppenfeld +49 more
TL;DR: The Task Force for the management of atrial fibrillation of the European Society of Cardiology has been endorsed by the European Stroke Organisation (ESO).
Journal ArticleDOI
2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Endorsed by the European Stroke Organisation (ESO)
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Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation
TL;DR: Recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s are reviewed.
Proceedings ArticleDOI
Model Inversion Attacks that Exploit Confidence Information and Basic Countermeasures
TL;DR: A new class of model inversion attack is developed that exploits confidence values revealed along with predictions and is able to estimate whether a respondent in a lifestyle survey admitted to cheating on their significant other and recover recognizable images of people's faces given only their name.
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The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: Proposal for a new dosing regimen
Elizabeth Sconce,Tayyaba Khan,Tayyaba Khan,Hilary Wynne,Hilary Wynne,Peter Avery,Peter Avery,Louise Monkhouse,Louise Monkhouse,Barry P. King,Barry P. King,Peter Wood,Peter Wood,Patrick Kesteven,Patrick Kesteven,Ann K. Daly,Ann K. Daly,Farhad Kamali,Farhad Kamali +18 more
TL;DR: The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%).
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