An acenocoumarol dosing algorithm exploiting clinical and genetic factors in South Indian (Dravidian) population

Kumar, Dhakchinamoorthi Krishna; Shewade, Deepak Gopal; Loriot, Marie‐Anne; Beaune, Philippe; Chandran, B. V. Sai; Balachander, Jayaraman; Chandrasekaran, Adithan

doi:10.1007/s00228-014-1791-x

Cited by 16 publications

(10 citation statements)

References 46 publications

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“…Thus, in the study performed on the Northern Indian population [ 20 ], VKORC1 and CYP4F2 polymorphisms were the principal genetic variables, whereas in the algorithm developed for Southern Indians and those for the European population, VKORC1 and CYP2C9 are the genetic factors that contribute most to the performance of these algorithms. Furthermore, our algorithm differs from those published for the Indian population [ 20 , 21 ]; the authors of that algorithms included GGCX gene polymorphisms (rs11676382), which we do not.…”

Section: Discussionmentioning

confidence: 95%

“…Verde et al constructed an ‘‘acenocoumarol-dose genotype score” based on the number of alleles associated with a higher acenocoumarol dosage taken by each participant for each polymorphism [ 19 ]. Two algorithms have been published for Indian populations, which include demographic, clinical and genetic variants, and have obtained coefficients of determinations of 41% and 61.5%, respectively [ 20 , 21 ]. In addition, 3 other algorithms have been developed for European populations.…”

Section: Introductionmentioning

confidence: 99%

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A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population

Tong¹,

Dávila-Fajardo

Borobia

et al. 2016

PLoS ONE

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There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11–21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population

Tong¹,

Dávila-Fajardo

Borobia

et al. 2016

PLoS ONE

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show abstract

“…Verde et al (2010) constructed an "acenocoumarol-dose genotype score" based on the number of alleles associated with a higher required acenocoumarol dosage carried by each patient for each polymorphism. In addition, two algorithms that include demographic, clinical, and genetic factors have been published for Indian populations, with coefficients of determination of 41 and 61.5% (Rathore et al, 2012;Krishna-Kumar et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

A Pharmacogenetically Guided Acenocoumarol Dosing Algorithm for Chilean Patients: A Discovery Cohort Study

et al. 2020

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Background: Vitamin K antagonists (VKA) are used as prophylaxis for thromboembolic events in patients with cardiovascular diseases. The most common VKA are warfarin and acenocoumarol. These drugs have a narrow therapeutic margin and high inter-individual response variability due to clinical and pharmacogenetic variables. Objective: The authors aim to develop an algorithm comprised of clinical and genetic factors to explain the variability in the therapeutic dose of acenocoumarol among Chilean patients Methodology: DNA was obtained from 304 patients as a discovery cohort with an international normalized ratio (INR) range of 2.0-3.0. The non-genetic (demographic and clinical) variables were also recorded. Genotype analyses were performed using real-time PCR for VKORC1 (rs9923231), VKORC1 (rs7294), GGCx (rs11676382), CYP4F2 (rs2108622), ABCB1 (rs1045642), CYP2C9*2 (rs1799853), ApoE (rs429358), and CYP2C9*3 (rs1057910). Results: The clinical variables that significantly influenced the weekly therapeutic dose of VKA were age, sex, body mass index (BMI), and initial INR, collectively accounting for 19% of the variability, and the genetic variables with a significant impact were VKORC1 (rs9923231), CYP2C9*2 (rs1799853), and CYP2C9*3 (rs1057910), explaining for another 37% of the variability.

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“…A few studies from South Indian states have published data regarding the VKORC1 (−1639G>A) rs9923231 polymorphism and its effect on daily warfarin dose requirement 11, 12, 13, 14, 15, 16. Meanwhile, other studies on South Indian populations have also reported allele and genotypic frequencies without accessing association with dosage requirements 17, 18, 19, 20.…”

Section: Introductionmentioning

confidence: 99%

Value of VKORC1 (−1639G>A) rs9923231 genotyping in predicting warfarin dose: A replication study in South Indian population

Harikrishnan

Koshy

Subramanian

et al. 2018

Indian Heart Journal

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ObjectiveWarfarin is the most commonly prescribed oral anticoagulant, although having a narrow therapeutic index and wide interindividual variability. The aim of this study was to replicate the utility of VKORC1 (−1639G>A) rs9923231 genotyping in predicting the mean daily dose and to evaluate its ability to categorize warfarin-treated patients to high-, intermediate-, or low-dose categories in the South Indian population.Materials and methodsA cohort of 222 warfarin-treated patients was genotyped using restriction fragment length polymorphism method. The influence of the rs9923231 polymorphism on the variations in the mean daily dose was compared using one-way analysis of variance and linear regression analysis. Discriminatory ability of the rs9923231 polymorphism to group the patients into ordered dose categories was assessed by estimating the proportional odds ratios using the ordered logit regression analysis.ResultsThe frequency of AA genotype and A allele in the study sample was found to be 1.8% and 9.23%, respectively, which was similar to reports from other South Indian populations. The mean daily dose required to achieve the optimum international normalized ratio was significantly lower in AA homozygous genotype carriers (3.99 ± 1.67 mg/day) and GA heterozygous (4.26 ± 1.57 mg/day) compared to the GG genotype carriers (5.51 ± 2.13 mg/day), p = 0.003. The A allele carriers (GA+AA genotypes) had a 3.23 higher odds of being grouped as a low-dose requiring category compared to non-carriers (95% CI 1.49–6.98, p = 0.003).ConclusionsThese preliminary results strongly support the use of VKORC1 (−1639G>A) rs9923231 polymorphism for genetically guided initial warfarin dosing in South Indian patients with heart valve replacements.

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An acenocoumarol dosing algorithm exploiting clinical and genetic factors in South Indian (Dravidian) population

Abstract: VKORC1 rs9923231 polymorphism had the highest impact on acenocoumarol daily dose. A new pharmacogenetic algorithm was established to determine the acenocoumarol dose in South Indian population.

Cited by 16 publications

References 46 publications

A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population

A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population

A Pharmacogenetically Guided Acenocoumarol Dosing Algorithm for Chilean Patients: A Discovery Cohort Study

Value of VKORC1 (−1639G>A) rs9923231 genotyping in predicting warfarin dose: A replication study in South Indian population

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