CYP2C9 and VKORC1 polymorphisms influence warfarin dose variability in patients on long-term anticoagulation

Santos, Paulo Caleb Júnior Lima; Dinardo, Carla Luana; Schettert, Isolmar Tadeu; Soares, Renata; Kawabata-Yoshihara, Liz Andrea; Lotufo, Paulo A.; Pereira, Alexandre C.

doi:10.1007/s00228-012-1404-5

Cited by 31 publications

(25 citation statements)

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“…Some of the studies have demonstrated significant effect on warfarin dose that is reduced in patients possessing variant alleles. 16,25,45,58,59 Other studies have reported similar results as ours, where CYP2C9*2 variant alleles did not show any significant effect on warfarin dose requirement. 10,17,32,43,46,50,60,61 Even within the same population, different studies presented different results, some exhibiting effect, others not.…”

Section: Discussionsupporting

confidence: 89%

Frequency of Common CYP2C9 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population

Qayyum

Najmi

Mansoor

et al. 2016

Clin Appl Thromb Hemost

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Polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9) gene result in interindividual variability in warfarin dose requirement. There is a need for characterization of genotype frequency distribution in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common CYP2C9 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations. Single blood sample was collected after informed consent. Genomic DNA was extracted, and genotype analysis for CYP2C9*2 and CYP2C9*3 polymorphisms was done by polymerase chain reaction-restriction fragment length polymorphism assay. A number of samples were also analyzed by direct DNA sequencing for validation of the results. Data were analyzed using SPSS version 20. Genotype frequency distribution of CYP2C9*2 and CYP2C9*3 was found to be different from other populations. Of these 2 polymorphisms, CYP2C9*2 did not demonstrate significant effect on warfarin dose requirement, whereas CYP2C9*3 did show significant effect ( P value = .012). It is concluded that there is a need to study genotype frequency distribution and their effect on warfarin dose variability among different populations due to diversity in outcome.

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Section: Discussionsupporting

confidence: 89%

Frequency of Common CYP2C9 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population

Qayyum

Najmi

Mansoor

et al. 2016

Clin Appl Thromb Hemost

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“…Age, body mass index, concomitant drugs, patient adherence and genetic factors can influence INR values [13–15]. However, the factors which can significantly influence TTR measures, i.e., warfarin anticoagulation therapy in the long-term are not fully understood [9, 16].…”

Section: Introductionmentioning

confidence: 99%

Age is associated with time in therapeutic range for warfarin therapy in patients with atrial fibrillation

et al. 2016

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BackgroundWarfarin is the most prescribed oral anticoagulant used for preventing stroke in patients with atrial fibrillation. Time in the therapeutic range (TTR) has been accepted as the best method to evaluate the quality of warfarin therapy. The main aim of the present study was to evaluate the impact of variables on the time in the therapeutic range for warfarin therapy in patients with atrial fibrillation from a referral cardiovascular hospital.MethodsThis retrospective study included 443 patients were included (190 patients with age < 65 years and 253 patients with age ≥65 years) from 2011 to 2014 and TTR was computed according to Rosendaal's method.ResultsPatients with age ≥65 years had higher TTR value (67±22%) compared with patients with < 65 years (60±24%) (p = 0.004). In a linear regression model, only age ≥65 years emerged as a significant predictor of greater TTR values. In multivariate logistic regression model, the variable age ≥65 years was associated with higher OR for having a TTR higher than the median value (OR = 2.17, p < 0.001).ConclusionWe suggest that the age influenced TTR through greater drug adherence. Strategies for increasing drug adherence might improve quality of warfarin anticoagulation.

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“…Patients will be divided into three distinct predicted phenotypes: extensive metabolizer (EM: wild-type genotypes for the CYP2C9 polymorphisms - *1/*1), intermediate metabolizer (IM: heterozygous genotypes for the loss-of-function CYP2C9 polymorphisms - *1/*2 or *1/*3) and poor metabolizer (PM: polymorphic homozygous or compound heterozygous genotypes for the loss-of-function CYP2C9 polymorphisms - *2/*2 or *3/*3 or *2/*3) [41, 42]. …”

Section: Methodsmentioning

confidence: 99%

Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range – study protocol for a randomized controlled trial

Marcatto

Sacilotto

Bueno

et al. 2016

BMC Cardiovasc Disord

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BackgroundTime in therapeutic range (TTR) is a measurement of quality of warfarin therapy and lower TTR values (<50%) are associated with greater risk of thromboembolic and bleeding events. Recently, we developed a pharmacogenetic-based warfarin dosing algorithm specifically calibrated for a Brazilian patient sample. The aims of this study are: to evaluate the impact of a genetic-based algorithm, compared to traditional anticoagulation, in the time to achieve the therapeutic target and in TTR percentage; and to assess the cost-effectiveness of genotype-guided warfarin dosing in a specific cohort of patients with low TTR (<50%) from a tertiary cardiovascular hospital.Methods/designThis study is a randomized controlled trial in patients (n = 300) with atrial fibrillation with TTR < 50%, based on the last three INR values. At the first consultation, patients will be randomized into two groups: TA group (traditional anticoagulation) and PA group (pharmacogenetic anticoagulation). For the first group, the physician will adjust the dose according to current INR value and, for the second group, a pharmacogenetic algorithm will be used. At the second, third, fourth and fifth consultations (with an interval of 7 days each) INR will be measured and, if necessary, the dose will be adjusted based on guidelines. Afterwards, patients who are INR stable will begin measuring their INR in 30 day intervals; if the patient’s INR is not stable, the patient will return in 7 days for a new measurement of the INR. Outcomes measures will include the time to achieve the therapeutic target and the percentage of TTR at 4 and 12 weeks. In addition, as a secondary end-point, pharmacoeconomic analysis will be carried out. Ethical approval was granted by the Ethics Committee for Medical Research on Human Beings of the Clinical Hospital of the University of São Paulo Medical School.DiscussionThis randomized study will include patients with low TTR and it will evaluate whether a population-specific genetic algorithm might be more effective than traditional anticoagulation for a selected group of poorly anticoagulated patients.Trial registrationClinicalTrials.gov, NCT02592980. Registered on 29 October 2015.

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CYP2C9 and VKORC1 polymorphisms influence warfarin dose variability in patients on long-term anticoagulation

Abstract: Genetic information on CYP2C9 and VKORC1 is important both for the initial dose-finding phase and during maintenance treatment with warfarin.

Cited by 31 publications

References 51 publications

Frequency of Common CYP2C9 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population

Frequency of Common CYP2C9 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population

Age is associated with time in therapeutic range for warfarin therapy in patients with atrial fibrillation

Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range – study protocol for a randomized controlled trial

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