Several-fold increase in risk of overanticoagulation by CYP2C9 mutations.
ABSTRACT Our objective was to prospectively study the impact of CYP2C9 polymorphism (*2 and *3) on the risk of overanticoagulation during the induction phase of warfarin therapy.
Blood samples for genotyping were collected from 219 patients requiring warfarin therapy, and clinical data were prospectively collected during the first 3 weeks of medication. Patients were divided into 3 groups according to CYP2C9 genotype, as follows: *1 (homozygous), *2 (*1/*2 and *2/*2), and *3 (any genotype containing the *3 allele).
During the first week of treatment, the relative risk of achieving at least 1 international normalized ratio (INR) value above the therapeutic interval (2-3) was 2.8 (95% confidence interval, 1.2-6.7) and 6.1 (2.7-13.6) in the *2 and *3 groups, respectively (with *1 used as control). During the second week, the corresponding values were 2.1 (1.2-3.7) and 3.5 (2.1-5.8), respectively. By the third week, the genetic impact was no longer evident, presumably as a result of successful dose individualization. Increased INR levels (compared with the *1 group) were already demonstrated in the *2 group on the fourth treatment day.
The CYP2C9*2 and *3 single-nucleotide polymorphisms significantly increase the risk of overanticoagulation during the first 2 weeks of warfarin treatment, with increased INR levels evident after only 4 days' treatment in *2 carriers. Our prospective data are consistent with results from previous retrospective studies and indicate that CYP2C9 genotyping may be a means of improving safety during warfarin induction.
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ABSTRACT: What is known and objectivePharmacogenetic studies of the genetic regulation of warfarin dose requirement have been reported, but few have been on the bleeding complications at therapeutic international normalized ratio (INR). This study aimed to evaluate the effect of gene polymorphisms of CYP2C9, VKORC1, thrombomodulin (THBD) and C-reactive protein (CRP) on the risk of bleeding complications of warfarin at therapeutic INR in Korean patients with mechanical cardiac valves. MethodsA retrospective warfarin pharmacogenetic association study was performed. One hundred and forty-two patients with mechanical cardiac valves who were on warfarin anticoagulation therapy and maintained INR levels of 2·0–3·0 for 3 consecutive time intervals were followed up. CYP2C9 rs1057910, VKORC1 rs9934438, CRP rs1205, THBD rs1042580 and THBD rs3176123 were genotyped. The association between genotypes and warfarin bleeding complications was evaluated using logistic regression analysis, adjusted for demographic and clinical factors. Results and discussionOf 142 eligible patients, 21 patients (14·8%) had bleeding complications at therapeutic INR. Patients with the G allele in THBD rs1042580 (AG or GG) had a lower risk of bleeding than patients with the AA genotype (adjusted OR: 0·210, 95% CI: 0·050–0·875, P = 0·032). The THBD rs3176123 polymorphism did not show any association with bleeding. For CRP rs1205, patients with the A allele (GA or AA genotype) had a higher risk of bleeding than patients with the GG genotype (adjusted OR: 5·575, 95% CI: 1·409–22·058, P = 0·014). Variant VKORC1 and CYP2C9 genotypes did not confer a significant increase in the risk for bleeding complications. What is new and conclusionsAs expected, no association could be found between bleeding complications and two dose-related genes (CYP2C9*3 and VKORC1 rs9934438). In contrast, our results suggest that two genetic markers (THBD rs1042580 and CRP rs1205) could be predictors of bleeding complications of warfarin at normal INR. Given the retrospective study design and the relatively small sample size, our hypothesis requires further independent validation using more robust prospective designs. However, additional retrospective studies similar to ours but in populations with different genetic backgrounds should also be useful.Journal of Clinical Pharmacy and Therapeutics 03/2014; · 2.10 Impact Factor
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ABSTRACT: Warfarin is the most widely prescribed anticoagulant for prevention and treatment of thromboembolic events. Although highly effective, the use of warfarin is limited by a narrow therapeutic range combined with a large dif-ference in the dose required for adequate anticoagulation. To achieve a fa-vourable balance between the wanted antithrombotic effect and the risk of bleeding, it is important to identify the right dose for individual patients. The challenge is to know beforehand what the right dose should be, but also how to adjust the dose once treatment has started to achieve and maintain the desired therapeutic effect, and at the same time minimise the risk of adverse bleeding events. Growing amount of data support that a large part of the variability in war-farin maintenance dose requirement can be explained by a combination of clinical and genetic factors. There are several dosing algorithms available that include both clinical (e.g. age, bodyweight) and genetic factors (VKORC1 and CYP2C9 genotype), and which can be used to pre-dict a more individualised warfarin maintenance dose in adults. In other words, there is a certain degree of understanding of the effect of clinical, demographic and genetic factors on the variability in warfarin maintenance dose in adults, but not how these factors influences dose requirements in children or how they influences the response to warfarin over time. Exam-ples of temporal outcomes of interest in warfarin therapy include the time delay between dose administration and INR response, extent and rate of drug accumulation, and time to stable treatment response. Pharmacometric models, which are based on mathematical and statistical models, can provide a better understanding of the dose-response relationship over time for a drug, and help identify and quantify factors that influences variability in drug response. With a better understanding of the dose-effect relationship, therapy can be truly individualised. In this thesis, pharmacometric models have been developed to describe the relationship between warfarin dose and anticoagulant effect over time for both adults and children. This type of models have the potential to provide individualised start doses, but more importantly, improve dose adjustment practices and provide more efficient individualisation of warfarin by integra-tion of modelling and simulation into clinical decision support systems.05/2013, Degree: Doctor of Philosophy, Faculty of Medicine, Supervisor: Mia Wadelius, E Niclas Jonsson and Lena E Friberg
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ABSTRACT: Clinical factors, demographic variables and variations in two genes, CYP2C9 and VKORC1, have been shown to contribute to the variability in warfarin dose requirements among adult patients. Less is known about their relative importance for dose variability in children. A few small studies have been reported, but the results have been conflicting, especially regarding the impact of genotypes. In this article, we critically review published pharmacogenetic-based prediction models for warfarin dosing in children, and present results from a head-to-head comparison of predictive performance in a distinct cohort of warfarin-treated children. Finally we discuss what properties a prediction model should have, and what knowledge gaps need to be filled, to improve warfarin therapy in children of all ages.Pharmacogenomics 02/2014; 15(3):361-74. · 3.43 Impact Factor