Stable Warfarin Dose Research Articles

Influence of NR3C1 and VDR polymorphisms on stable warfarin dose in patients with mechanical cardiac valves

ObjectivesThe aim of this study was to evaluate the associations between polymorphisms of VKORC1, CYP2C9, CYP4F2, NR3C1 and VDR genes and stable warfarin doses in Korean patients with mechanical heart valves. MethodsSeventeen single-nucleotide polymorphisms (SNPs) in 204 patients with stable warfarin dose were analyzed: VKORC1 (rs9934438), CYP2C9 (rs1057910), CYP4F2 (rs2108622), NR3C1 (rs41423247, rs1800445, rs56149945, rs10052957, rs6198, rs33388, rs6196, and rs244465), and VDR (rs1544410, rs11568820, rs731236, rs757343, rs7975232, and rs2228570). Statistical analyses were conducted to evaluate the associations of gene variations with stable warfarin dose. Number needed to genotype was obtained by calculating the percentage of patients whose predicted dose was at least 20% higher or lower than the actual stable dose. ResultsThe combined genotypes of rs7975232 and rs2228570 of the VDR gene revealed a significant association with stable warfarin dose, along with VKORC1, CYP2C9, and CYP4F2 polymorphisms. Patients with the genotype combination GT,TT/CT,CC of VDR rs7975232/rs2228570 required significantly higher stable warfarin dose (5.79±2.02mg) than those with the other genotypic combinations (5.19±1.78mg, p=0.034). Multivariate analysis showed that VDR rs7975232/rs2228570 explained 2.0% of the 47.5% variability in overall warfarin dose. Adding VDR SNP combinations to the base model including non-genetic variables (age, sex, and body weight) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 41. ConclusionsThis study showed that stable warfarin dose is associated with VDR SNPs along with VKORC1, CYP2C9, and CYP4F2 SNPs.

Identification of novel variants associated with warfarin stable dosage by use of a two‐stage extreme phenotype strategy

Background The variation among patients in warfarin response complicates the management of warfarin therapy, and an improper therapeutic dose usually results in serious adverse events. Objective To use a two-stage extreme phenotype strategy in order to discover novel warfarin dose-associated mutations in heart valve replacement patients. Patients/method A total of 1617 stable-dose patients were enrolled and divided randomly into two cohorts. Stage I patients were genotyped into three groups on the basis of VKORC1-1639G>A and CYP2C9*3 polymorphisms; only patients with the therapeutic dose at the upper or lower 5% of each genotype group were selected as extreme-dose patients for resequencing of the targeted regions. Evaluation of the accuracy of the sequence data and the potential value of the stage I-identified significant mutations were conducted in a validation cohort of 420 subjects. Results A group of mutations were found to be significantly associated with the extreme warfarin dose. The validation work finally identified four novel mutations, i.e. DNMT3A rs2304429 (24.74%), CYP1A1 rs3826041 (47.35%), STX1B rs72800847 (7.01%), and NQO1 rs10517 (36.11%), which independently and significantly contributed to the overall variability in the warfarin dose. After addition of these four mutations, the estimated regression equation was able to account for 56.2% (R2Adj = 0.562) of the overall variability in the warfarin maintenance dose, with a predictive accuracy of 62.4%. Conclusion Our study provides evidence linking genetic variations in STX1B, DNMT3A and CYP1A1 to warfarin maintenance dose. The newly identified mutations together account for 2.2% of warfarin dose discrepancy.

Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement

The effects of genetic variants on warfarin dosing vary among different ethnic groups, especially in the Chinese population. The objective of this study was to recruit patients through a rigorous experimental design and to perform a comprehensive screen to identify gene polymorphisms that may influence warfarin dosing in northern Han Chinese patients with mechanical heart valve replacement. Consenting patients (n = 183) with a stable warfarin dose were included in this study. Ninety-six single nucleotide polymorphisms (SNPs) in 30 genes involved in warfarin pharmacological pathways were genotyped using the Illumina SNP GoldenGate Assay, and their associations with warfarin dosing were assessed using univariate regression analysis with post hoc comparison using least significant difference analysis. Multiple linear regression was performed by incorporating patients' clinical and genetic data to create a new algorithm for warfarin dosing. From the 96 SNPs analyzed, VKORC1 rs9923231, CYP1A2 rs2069514, CYP3A4 rs28371759, and APOE rs7412 were associated with higher average warfarin maintenance doses, whereas CYP2C9 rs1057910, EPHX1 rs2260863, and CYP4F2 rs2189784 were associated with lower warfarin doses (P < 0.05). Multiple linear regression analysis could estimate 44.4% of warfarin dose variability consisting of, in decreasing order, VKORC1 rs9923231 (14.2%), CYP2C9*3 (9.6%), body surface area (6.7%), CYP1A2 rs2069514 (3.7%), age (2.7%), CYP3A4 rs28371759 (2.5%), CYP4F2 rs2108622 (1.9%), APOE rs7412 (1.7%), and VKORC1 rs2884737 (1.4%). In the dosing algorithm we developed, we confirmed the strongest effects of VKORC1, CYP2C9 on warfarin dosing. In the limited sample set, we also found that novel genetic predictors (CYP1A2, CYP3A4, APOE, EPHX1, CYP4F2, and VKORC1 rs2884737) may be associated with warfarin dosing. Further validation is needed to assess our results in larger independent northern Chinese samples.

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review.

BackgroundWarfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing.ObjectiveTo explore the prevalence of CYP2C9 and VKORC1 variants in MENA, and the effect of these variants along with other non-genetic factors in predicting warfarin dose.MethodsIn this systematic review, we included observational cross sectional and cohort studies that enrolled patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose as the primary outcome. We searched PubMed, Medline, Scopus, PharmGKB, PHGKB, Google scholar and reference lists of relevant reviews.ResultsWe identified 17 studies in eight different populations: Iranian, Israeli, Egyptian, Lebanese, Omani, Kuwaiti, Sudanese and Turkish. Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively. Variants in the CYP2C9 were less common, with the highest MAF for CYP2C9*2 among Iranians (27%). Variants in the VKORC1 and CYP2C9 were the most significant predictors of warfarin dose in all populations. Along with other genetic and non-genetic factors, they explained up to 63% of the dose variability in Omani and Israeli patients.ConclusionVariants of VKORC1 and CYP2C9 are the strongest predictors of warfarin dose variability among the different populations from MENA. Although many of those populations share the same ancestry and are similar in their warfarin dose predictors, a population specific dosing algorithm is needed for the prospective estimation of warfarin dose.

Mean Stable Warfarin Doses Versus CYP2C9*2 and VKORC11639G&gt;A Genotypes in Sudanese Population

Warfarin is a potent anticoagulant with a confirmed effectiveness when anticoagulation targets are attained, an issue, that is troublesome to reach due to the fact that warfarin has a narrow therapeutic index (NTI), that means they have a narrow window between their effective doses and those at which they produce adverse toxic effects. However, oral anticoagulation throughout genetics recommended a genotype guided dosing, but is it favourable over clinical based dosing? Objectives: To analyze the mean stable warfarin doses attained clinically within CYP2C9*2 and VKORC11639G&amp;gt;A wild-type and variant genotype status in Sudanese patients. Method: Genotyping for the CYP2C9*2 and VKORC1-1639G&amp;gt;A polymorphisms were accomplished with polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) technique. The mean stable warfarin dose per genotype was defined as the mean stable warfarin dose related to the stable INR within target range within a genotype of each of CYP2C9*2 or VKORC11639G&amp;gt; Agenes, using Analysis of Variance (ANOVA) as the statistical method. Results: Fifty-three stable patients with wild-type CYP2C9*1*1 genotype had a mean stable warfarin dose of 4.9 ± 2.1 mg, 5 patients who were heterozygous CYP2C9*1*2 genotype, had a mean stable warfarin dose of 5.0 ± 0.71mg, and 2 patients were homozygous mutant CYP2CP*2*2 genotype had a mean stable warfarin dose of 4.8 ± 0.3 mg. The results were statistically insignificant, P = 0.992.Sixteen unstable patients were of wild-type CYP2C9*1*1 genotype, 40 patients with heterozygous CYP2C9*1*2 genotype, and 4 with homozygous mutant CYP2CP*2*2 genotype, had mean stable doses of 5.32 ± 2.9, 6.5 ± 2.7 and 4.5 ± 0.71 mg respectively. The result was statistically insignificant, P = 0.508. Fifty-two stable patients were having wild-type VKORC1G/G genotype, 3 patients had heterozygous VKORC1G/A genotype and 3 patients had homozygous mutant VKORC1/AA genotype, these patients had mean stable doses of 5.41 ± 1.63, 4.8 ± 2.19 and 5.4 ± 0.99 mg respectively. The mean warfarin stable dose among homozygous mutant VKORC1A/A genotype was lower than among wild-type and heterozygous genotype profiles. This result was statistically not significant, P = 0.729.In the unstable group, 8 patients of wild-type VKORC1G/G genotype, had a mean stable warfarin dose of 7.34 ± 3.9 mg, 40 patients of heterozygous VKORC1G/A genotype had a mean stable warfarin dose of 5.21 ± 2.76 mg, and 10 patients of homozygous VKORC1A/A genotype had a mean stable warfarin dose of 4.3 ± 1.83 mg. The result was statistically insignificant, P = 0.067.Conclusion: In our study, as there were no significant differences between warfarin mean stable doses related to different CYP2C9*2 and VKORC11639G&amp;gt;A genotypes, the evidence is not satisfactory to conclude that the conventional use of genotype guided warfarin dosing will correct stable warfarin dose among Sudanese patients.

Mean Stable Warfarin Doses Versus CYP2C9*2 and VKORC11639G&gt;A Genotypes in Sudanese Population

Warfarin is a potent anticoagulant with a confirmed effectiveness when anticoagulation targets are attained, an issue, that is troublesome to reach due to the fact that warfarin has a narrow therapeutic index (NTI), that means they have a narrow window between their effective doses and those at which they produce adverse toxic effects. However, oral anticoagulation throughout genetics recommended a genotype guided dosing, but is it favourable over clinical based dosing? Objectives: To analyze the mean stable warfarin doses attained clinically within CYP2C9*2 and VKORC11639G&amp;gt;A wild-type and variant genotype status in Sudanese patients. Method: Genotyping for the CYP2C9*2 and VKORC1-1639G&amp;gt;A polymorphisms were accomplished with polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) technique. The mean stable warfarin dose per genotype was defined as the mean stable warfarin dose related to the stable INR within target range within a genotype of each of CYP2C9*2 or VKORC11639G&amp;gt; Agenes, using Analysis of Variance (ANOVA) as the statistical method. Results: Fifty-three stable patients with wild-type CYP2C9*1*1 genotype had a mean stable warfarin dose of 4.9 ± 2.1 mg, 5 patients who were heterozygous CYP2C9*1*2 genotype, had a mean stable warfarin dose of 5.0 ± 0.71mg, and 2 patients were homozygous mutant CYP2CP*2*2 genotype had a mean stable warfarin dose of 4.8 ± 0.3 mg. The results were statistically insignificant, P = 0.992.Sixteen unstable patients were of wild-type CYP2C9*1*1 genotype, 40 patients with heterozygous CYP2C9*1*2 genotype, and 4 with homozygous mutant CYP2CP*2*2 genotype, had mean stable doses of 5.32 ± 2.9, 6.5 ± 2.7 and 4.5 ± 0.71 mg respectively. The result was statistically insignificant, P = 0.508. Fifty-two stable patients were having wild-type VKORC1G/G genotype, 3 patients had heterozygous VKORC1G/A genotype and 3 patients had homozygous mutant VKORC1/AA genotype, these patients had mean stable doses of 5.41 ± 1.63, 4.8 ± 2.19 and 5.4 ± 0.99 mg respectively. The mean warfarin stable dose among homozygous mutant VKORC1A/A genotype was lower than among wild-type and heterozygous genotype profiles. This result was statistically not significant, P = 0.729.In the unstable group, 8 patients of wild-type VKORC1G/G genotype, had a mean stable warfarin dose of 7.34 ± 3.9 mg, 40 patients of heterozygous VKORC1G/A genotype had a mean stable warfarin dose of 5.21 ± 2.76 mg, and 10 patients of homozygous VKORC1A/A genotype had a mean stable warfarin dose of 4.3 ± 1.83 mg. The result was statistically insignificant, P = 0.067.Conclusion: In our study, as there were no significant differences between warfarin mean stable doses related to different CYP2C9*2 and VKORC11639G&amp;gt;A genotypes, the evidence is not satisfactory to conclude that the conventional use of genotype guided warfarin dosing will correct stable warfarin dose among Sudanese patients.

Genetic polymorphisms of patients on stable warfarin maintenance therapy in a Ghanaian population.

BackgroundWarfarin is a widely prescribed anticoagulant with narrow therapeutic window for thromboembolic events. Warfarin displays large individual variability in dose requirements. The purpose of this study is to assess the contribution of patient-specific and genetic risk factors to dose requirements of patients on either high or low warfarin maintenance dose in Ghana. Blood samples were collected from 141 (62 males, 79 females) Ghanaian patients on stable warfarin dose to determine their INR. Influence of patient specific factors and gene variations within VKORC1, CYP2C9 and CYP4F2 were determined in patients on either high or low warfarin maintenance dose.ResultsOne hundred and forty-one patients took part in the study with 79 (56%) participants being Female. The median age of the study participants was 48 years [IQR: 34–58]. The median duration for patients to be on warfarin therapy was 24 months [IQR: 10–72]. Majority of the study participants (80.9%, n = 114) did not have any side effects to warfarin. CYP2C9*2 and CYP2C9*3 variant alleles were not detected. VKORC1 variant allele was observed at 6% and CYP4F2 variant allele was observed at 41%. Duration of patients on warfarin therapy was marginally associated with high warfarin dose (adjusted OR = 1.01 [95% CI 1.00–1.02], p = 0.033) while the odds of heterozygous individuals (G/A) for VKORC1 gene to have high warfarin dose compared to persons with homozygous (G/G) (adjusted OR = 0.06 [95% CI 0.01–0.63], p = 0.019). Age, gender, diagnosis, presence of side effects and other medications were not associated with warfarin dose (p = 0.05).ConclusionThis study provides data on VKORC1 and CYP4F2 variants among an indigenous African population. Duration of patients on warfarin therapy was marginally associated with high warfarin dose. CYP2C9*2 and *3 variants were not detected and may not be the most important genetic factor for warfarin maintenance dose among Ghanaians.

STRATEGIES FOR EQUITABLE PHARMACOGENOMIC-GUIDED WARFARIN DOSING AMONG EUROPEAN AND AFRICAN AMERICAN INDIVIDUALS IN A CLINICAL POPULATION.

The blood thinner warfarin has a narrow therapeutic range and high inter- and intra-patient variability in therapeutic doses. Several studies have shown that pharmacogenomic variants help predict stable warfarin dosing. However, retrospective and randomized controlled trials that employ dosing algorithms incorporating pharmacogenomic variants under perform in African Americans. This study sought to determine if: 1) including additional variants associated with warfarin dose in African Americans, 2) predicting within single ancestry groups rather than a combined population, or 3) using percentage African ancestry rather than observed race, would improve warfarin dosing algorithms in African Americans. Using BioVU, the Vanderbilt University Medical Center biobank linked to electronic medical records, we compared 25 modeling strategies to existing algorithms using a cohort of 2,181 warfarin users (1,928 whites, 253 blacks). We found that approaches incorporating additional variants increased model accuracy, but not in clinically significant ways. Race stratification increased model fidelity for African Americans, but the improvement was small and not likely to be clinically significant. Use of percent African ancestry improved model fit in the context of race misclassification.

Use of an extended INR follow-up interval for Veteran patients in an anticoagulation clinic.

A prospective, single-arm study of 50 participants evaluated an extended INR follow-up interval to determine the implementation feasibility and safety of an extended interval in Veterans on a stable dose of warfarin. A protocol was designed to allow for a rigorous, yet pragmatic evaluation of a 12-week INR follow-up interval. Feasibility was determined by study enrollment, retention, and participant achievement rates for the extended INR interval. Safety was determined by bleeding and thromboembolism rates. Participants were monitored for 6months. Despite the long-term stability of participants prior to enrollment, only 56% achieved a 12-week follow-up interval and only 34% of enrolled participants maintained a 12-week interval. Sixteen percent of participants were never eligible for an extension of their INR follow-up interval despite meeting initial enrollment criteria. There were two major bleeding events and one participant who experienced a thromboembolic event. Implementation of an extended interval of INR follow-up appears feasible as participant enrollment goals were met and pharmacists were able to follow the study protocol. However, a lower than expected proportion of participants were able to achieve and maintain an extended INR follow-up interval. Future evaluations are needed to confirm the safety of an extended INR interval.

Clinical Predictors Associated With Warfarin Sensitivity.

Our study aimed to identify predictors of warfarin sensitivity like demographic, clinical, and genetic data from a previously collected cohort of patients (n = 4272) with a stable warfarin dose who were able to achieve an observed international normalized ratio of 2-3. Predictors of warfarin sensitivity (dose ≤21 mg/wk) were identified using a 2-stage approach. First, bivariate analysis, using analysis of variance for continuous variables and χ test for categorical variables, was performed to identify possible predictors of warfarin sensitivity (P < 0.05). Second, logistic regression with backward stepwise selection was then performed using predictors identified in bivariate analysis step to produce final model containing independent predictors at P < 0.05. Increased warfarin sensitivity was associated with increased age; CYP2C9 genotypes 2/3, 1/3, and 3/3; VKORC1 genotypes AA and AG; and amiodarone use. Decreased warfarin sensitivity (ie, weekly warfarin dose of >21 mg) was associated with increased height, increased weight, having diabetes mellitus, VKORC1 genotype GG, and CYP2C9 genotype 1/1. In conclusion, we identified patients' characteristics associated with warfarin sensitivity. This project is expected to improve patient care by identifying patients who need a low warfarin dose before warfarin administration. Early identification of this subset of patients helps minimize the incidence of bleeding.

Linkage disequilibrium between the CYP2C19*2,*17 and CYP2C9*1 alleles and impact of VKORC1, CYP2C9, CYP2C19 gene polymorphisms and gene-gene interactions on warfarin therapy.

Warfarin therapy is complicated by its large inter-individual and intra-individual variability. Both genetic and non-genetic factors can affect warfarin therapy. This study aims to investigate the allele distribution of VKORC1, CYP2C9 and CYP2C19, contribution of different allele variants and possible gene-gene interaction on warfarin therapy. Four hundreds and ninety-two patients were enrolled and single nucleotide polymorphisms for vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 CYP2C9 and cytochrome P450 CYP2C19 were genotyped. CYP2C9*1 allele is in complete linkage disequilibrium with CYP2C19*2 and CYP2C19*17 (D' = 1) in our study population. Patient with VKORC1-1639 G > A, CYP2C9*2 and CYP2C9*3 genetic variants need significant lower warfarin dose than patient with wild type allele of VKORC1 1639 G or CYP2C9*1. There is no significant differences between CYP2C19 allele variants for warfarin stable dose and INR > 5 event. Because of the complete linkage disequilibrium between CYP2C19*2,*17 and CYP2C9*1, patient with CYP2C19 *2/*2, *2/*17 and *17/*17 genotypes tend to have higher warfarin dose than patient with CYP2C19*1/*1 genotype. Stepwise regression analysis showed that VKORC1, CYP2C9, body mass index (BMI), age and gender were included as a factor significantly contributing to warfarin dose, whereas CYP2C19 did not contribute to warfarin dose. No statistically significant interaction between CYP2C9 and VKORC1 on warfarin dose and INR > 5 event was detected in univariate general linear model analysis. Our study suggests that polymorphic variants of VKORC1 and CYP2C9 affect warfarin dose independently, whereas CYP2C19 did not contribute to warfarin therapy.

Genetic and Non-Genetic Factors Association with Warfarin Long Term Therapy Stability in Sudan

Anticoagulation with warfarin is characterized by a wide inter-individual variations in dose requirements and INR (International Normalised Ratio) stability, as there are evidences that warfarin response variability is associated with CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (Vitamin K epoxide reductase complex1) genetic polymorphisms. Carriers of CYP2C9*2 and VKORC11639G&amp;gt;A variant alleles are at greater risk of unstable anticoagulation therapy. Objectives: This retrospective case control study was directed to analyze the impact of genetic and non-genetic factors on warfarin therapy in Sudanese out-patients who were on long term warfarin therapy. Method: 118 Sudanese outpatients receiving warfarin treatment for at least six months, were interviewed for their non-genetic factors that included age, sex, indication for warfarin therapy, compliance, Vitamin K rich foods intake and concomitant drug therapy, in addition to their blood samples which were taken for DNA extraction and genotyping of CYP2C9*2 and VKORC11639G&amp;gt;A gene polymorphisms to study the genetic factors. INR stability % index was calculated, accordingly patients were classified into 2 groups, stable and unstable groups. Results: The frequencies of VKORC11639G&amp;gt;A alleles in Sudanese out-patients who were on long term warfarin therapy were 70.3% and 29.7% for the VKORC1/G and VKORC1/A alleles respectively. The frequencies of CYP2C9*2 alleles in Sudanese out-patients were 92.4% and 7.6% for CYP2C9*1 and CYP2C9*2 alleles respectively. Variables associated with low INR stability were VKCOR1/AA genotype (p-value = 0.028) and sex (p = 0.017). Variables that showed no association with INR stability were age (p-value = 0.259), compliance (p-value = 0.058). Vitamin K rich foods intake (p- value = 0.743), and mean stable warfarin dose (p-value = 0.439). Conclusion: Polymorphism in warfarin drug target gene VKORC1-11639G&amp;gt;A and sex are important elements of INR stability in Sudanese out- patients on long term warfarin therapy.

092 - Vitamin K (Phytonadione) Administration in 6 Left Ventricular Assist Device (LVAD) Patients to Stabilize INR

Background/Aims: Careful INR management to mitigate risk of LVAD hemolysis/thrombosis is complicated by dietary variability in vitamin K consumption. Patients may struggle with supratherapeutic and subtherapeutic INR values despite stable warfarin dosing which poses risks for both bleeding and thrombosis. We describe a patient for whom daily vitamin K administration was successfully utilized to stabilize INR. Methods: We identified 6 patients who had erratic INR readings despite stable doses of warfarin for whom low dose Vitamin K was initiated; 3 patients were supported with HeartWare LVADs, 2 with HeartMate III, and 1 with HeartMate II. Patients were evenly divided with regard to gender and indication as the cohort consisted of 3 males and 3 female, and 3 bridge to transplant (BTT) candidates and 3 destination therapy (DT) candidates. Results: Patients were supported with LVAD on average 153 days prior to Vitamin K administration (range 20 days to 371 days), spent on average 6.7 days in the hospital related to INR concerns, and had an average of 0.8 admissions prior to Vitamin K administration. Post Vitamin K administration, average hospitalizations per patient decreases to 0.7, number of days spent in the hospital related to INR admission fell to 2.8 days. Patients were followed on average for 114 days (range 1 day to 398 days) post vitamin K administration and did not experience any mortality or adverse events related to Vitamin K administration. Conclusion: Clotting factors II, VII, IX, and X and Protein C and S require vitamin K which is inhibited by Warfarin. Inconsistent vitamin K intake will increase and decrease clotting ability. Providing daily baseline vitamin k dosing reduces influence of daily variability of dietary vitamin K consumption and with frequent INR monitoring was safely done in this patient population. Baseline vitamin K dosing may reduce thrombus risk in LVAD patients with labile INRs and allows for improved outpatient INR management.

Effect of VKORC1, CYP2C9, CFP4F2, and GGCX Gene Polymorphisms on Warfarin Dose in Japanese Pediatric Patients.

Warfarin dosage requirements show considerable inter-individual variability. There are some reports of warfarin dose regimens correlating with single nucleotide polymorphisms (SNP) for CYP2C9, VKORC1 and other genes in adults. In children, however, reports are scarcer than in adults and the number of genes examined is more limited. We explored the effects of genetic variation on warfarin dose requirement in Japanese pediatric patients. A total of 45 patients who were prescribed warfarin at the Yokohama City University Hospital were included in this study. The influence of genetic polymorphisms on stable warfarin dosage requirement was investigated by genotyping SNPs of the VKORC1, CYP2C9, CYP4F2, and GGCX genes (rs9923231, rs1057910, rs2108622, and rs699664, respectively) in each patient. Patients with the TT genotype in rs9923231 in VKORC1 required significantly lower maintenance dosages than those with the TC genotype (p=0.001). Multiple regression analysis showed that, while VKORC1 status and patient height account for 78.2% of the variability in maintenance warfarin dosage, genetic polymorphisms in VKORC1 account for 27%, although polymorphisms in CYP4F2 and GGCX had no effect on dosage and the effect of CYP2C9 could not be evaluated. Polymorphisms in VKORC1 partially affected daily warfarin dosage requirements. VKORC1 genotype and height are the primary determinants influencing warfarin dosage in Japanese pediatric patients. Further studies with larger sample sizes are needed to confirm our results.

Prediction of Warfarin Dose in Pediatric Patients: An Evaluation of the Predictive Performance of Several Models.

The objective of this study was to evaluate the performance of pediatric pharmacogenetic-based dose prediction models by using an independent cohort of pediatric patients from a multicenter trial. Clinical and genetic data (CYP2C9 [cytochrome P450 2C9] and VKORC1 [vitamin K epoxide reductase]) were collected from pediatric patients aged 3 months to 17 years who were receiving warfarin as part of standard care at 3 separate clinical sites. The accuracy of 8 previously published pediatric pharmacogenetic-based dose models was evaluated in the validation cohort by comparing predicted maintenance doses to actual stable warfarin doses. The predictive ability was assessed by using the proportion of variance (R(2)), mean prediction error (MPE), and the percentage of predictions that fell within 20% of the actual maintenance dose. Thirty-two children reached a stable international normalized ratio and were included in the validation cohort. The pharmacogenetic-based warfarin dose models showed a proportion of variance ranging from 35% to 78% and an MPE ranging from -2.67 to 0.85 mg/day in the validation cohort. Overall, the model developed by Hamberg et al showed the best performance in the validation cohort (R(2) = 78%; MPE = 0.15 mg/day) with 38% of the predictions falling within 20% of observed doses. Pharmacogenetic-based algorithms provide better predictions than a fixed-dose approach, although an optimal dose algorithm has not yet been developed.

Review of Warfarin; A Cytochrome P450 Metabolizing Drug, in Clinical Practice

Context: For the prevention and management of thromboembolic complications, warfarin is the most extensively recommended anticoagulant. It is categorized as a drug with a narrow therapeutic window. Therefore, warfarin prescription requires special at- tention related to therapeutic drug monitoring. Evidence Acquisition: By categorizing the clinical implications of warfarin, this manuscript aims to provide a comprehensive (albeit somewhat brief) conclusion associated with its pharmacotherapy. The key words relevant to the topic were searched. Con- sequently, articles relevant to the pharmacotherapeutic management of warfarin were selected and reviewed in their entirety. Results: To obtain a reasonable level of stability between the required antithrombotic treatment and the risk of bleeding, an anal- ysis of the literature revealed that the prothrombin time in terms of the international normalized ratio (INR) was found for each individual. The best model for stable warfarin dosage prediction was found to be based on multiple linear regression. Genotype- guided procedures were established to: 1, improve the time in the therapeutic range; 2, reduce time to the first therapeutic INR; and 3, reduce the time for the stable doses. Vitamin K epoxide reductase is an enzyme with an important role in vitamin K metabolism, and warfarin is metabolized in hepatocytes via a monooxygenase, cytochrome P450 2C9. In patients carrying 2C9*1/*2 and 2C9*2/*2 or 2C9*1/*3 alleles, the dose is recommended to be reduced by 18% - 40% and 21% - 49%, respectively. Conclusions: Race, age, body surface area, chronic kidney disease, CYP2C9*3 level, and VKORC1 variants could aect the dose of warfarin. To administer the proper doses of warfarin, patients and physicians might achieve the best results with the pharmacol- ogist proficient anticoagulation database and recommended continuation program. Owing to its' unpredictability, caution must be taken when prescribing warfarin. More advanced warfarin pharmacotherapy studies are recommended based on a linear regres- sion model specifically in the Iranian population.

Establishment and evaluation of a warfarin-dosing algorithm in Chinese Han population

To develop and evaluate a warfarin-dosing algorithm method which can be used to guide the adjustment of warfarin maintenance dose in Chinese Han population. A total of 512 patients with steady warfarin taking were recruited from Beijing Hospital during May 2012 to December 2014. Indications for warfarin prescribing included prosthetic heart valve, atrial fibrillation and pulmonary embolism. Genomic DNAs were extracted from blood samples and used for the genetic polymorphism analysis of VKORC1 and CYP2C9 (include (*)3 and (*)13 alleles). Warfarin dose, demographic variabilities and amiodarone compliance were recorded during regular visit. These patients were randomly divided into groups using the method of random number table, 384 patients were randomly selected as derivation group, the remaining 128 cases as the validation group.Using data from derivation group, a warfarin-dosing algorithm was established based on the genetic information, demographic characteristics and concomitant compliance by a multiple linear regression analysis parameter. Then the accuracy of newly developed algorithm method was further evaluated by comparing the predicting dose with the actual dose in the validation group. The stable dose of warfarin was tightly associated with factors like age, height, weight, VKORC1 -1639G>A, CYP2C9(*)3, CYP2C9(*)13 and amiodarone usage. Newly developed algorithm method exhibited better prediction effect (R(2)=0.682, P<0.01) as compared with that of previously reported algorithm methods. The weights of VKORC1 and CYP2C9 for predicting of warfarin dosage were estimated to more than 50%. Using this method, 62.5% of patients in the validation group could be well recognized, in which the predicting dose of warfarin was within 20% of the actual dose, and only 7.81% patients showed underestimated prediction warfarin dose while 29.69% patients showed overestimated values. Newly developed algorithm method can be used for the guidance of warfarin maintenance dose adjustment in Chinese Han population.

Association of apolipoprotein E (APOE) polymorphisms with warfarin maintenance dose in a northern Han Chinese population.

BackgroundApolipoprotein E (apoE) induces the uptake of vitamin K-rich lipoproteins by the liver, which likely affects inter-individual variation of warfarin dosing requirements. Associations between APOE polymorphisms and warfarin dosing were previously reported inconsistently among different ethnic groups, so the present study investigated this association in northern Han Chinese patients with mechanical heart valve prosthesis.MethodsA total of 186 patients who underwent mechanical heart valve replacement and attained a stable warfarin dose were included. APOE single nucleotide polymorphisms (SNPs) rs7412 and rs429358 were genotyped using Illumina SNP GoldenGate Assay. Genotyping results were confirmed by direct sequencing. PHASE v2.1 software was used to construct rs7412 and rs429358 haplotypes. The effects of different APOE genotypes on warfarin dose were analyzed statistically.ResultsThe mean warfarin maintenance dose was 3.10 ± 0.96 mg/day, and the mean international normalized ratio (INR) was 2.09 ± 0.24. APOE E2, E3, and E4 allele frequencies were 11.6 %, 82.5 %, and 5.9 %, respectively. No E2/E2 or E4/E4 genotypes were detected in this population. E2/E3, E3/E3, E2/E4, and E3/E4 genotype frequencies were 21.0 %, 67.2 %, 2.2 %, and 9.7 %, respectively. Significant differences in warfarin dose requirements were observed among patients with E2/E3, E3/E3, and E3/E4 genotypes (p < 0.05). In post hoc comparison, daily warfarin maintenance doses were significantly higher in E2/E3 heterozygotes compared with E3/E3 homozygotes (p < 0.05), but no differences in dose requirements were found between E3/E4 and E3/E3, or E2/E3 and E3/E4 (p > 0.05). Patients were divided into low-intensity anticoagulant treatment group (1.6 ≤ INR <2.0) and relatively high-intensity anticoagulant treatment group (2.0 ≤ INR ≤2.5), and significantly higher warfarin dose requirements were observed in E2/E3 heterozygotes compared with E3/E3 homozygotes in both subgroups (p < 0.05). Multivariable analysis adjusting for other confounders showed that E2/E3 genotype was associated with a significantly higher warfarin dose compared with E3/E3 genotype (p < 0.05).ConclusionsAPOE allele and genotype frequencies in the northern Han Chinese population appear to differ from other racial groups or populations living in other regions of China. The APOE E2 variant was associated with a significantly higher warfarin maintenance dose. Thus, APOE polymorphisms could be one of the predictors influencing warfarin doses in this population.

Impact of GGCX, STX1B and FPGS Polymorphisms on Warfarin Dose Requirements in European-Americans and Egyptians.

Genotype‐based algorithms that include VKORC1 and CYP2C9 genotypes are less predictive of warfarin dose variability in Africans as opposed to Europeans. Polymorphisms in GGCX, FPGS, or STX1B are associated with warfarin dose requirements in African‐Americans. We sought to determine if they influenced warfarin dose in European‐Americans, and another African population, specifically Egyptians. We genotyped 529 adults (n = 325 European‐Americans, 204 Egyptians) on a stable warfarin dose for GGCX rs12714145 and rs10654848, FPGS rs7856096, and STX1B rs4889606. Rs12714145, rs10654848, and rs7856096 were not associated with warfarin dose, whereas STX1B rs4889606 was a significant determinant in univariate analysis (P < 0.0001) in both cohorts. However, STX1B rs4889606 was in high linkage disequilibrium with VKORC1‐1639 G>A, and was no longer significant after including VKORC1‐1639 G>A in the regression model. Based on these data, the polymorphisms do not appear to influence, in a clinically important way, warfarin dose requirements in European‐Americans and Egyptians.

Development and Comparison of Warfarin Dosing Algorithms in Stroke Patients.

PurposeThe genes for cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) have been identified as important genetic determinants of warfarin dosing and have been studied. We developed warfarin algorithm for Korean patients with stroke and compared the accuracy of warfarin dose prediction algorithms based on the pharmacogenetics.Materials and MethodsA total of 101 patients on stable maintenance dose of warfarin were enrolled. Warfarin dosing algorithm was developed using multiple linear regression analysis. The performance of all the algorithms was characterized with coefficient of determination, determined by linear regression, and the mean of percent deviation was used to predict doses from the actual dose. In addition, we compared the performance of the algorithms using percentage of predicted dose falling within ±20% of clinically observed doses and dividing the patients into a low-dose group (≤3 mg/day), an intermediate-dose group (3–7 mg/day), and high-dose group (≥7 mg/day).ResultsA new developed algorithms including the variables of age, body weight, and CYP2C9 and VKORC1 genotype. Our algorithm accounted for 51% of variation in the warfarin stable dose, and performed best in predicting dose within 20% of actual dose and intermediate-dose group.ConclusionOur warfarin dosing algorithm may be useful for Korean patients with stroke. Further studies to elucidate clinical utility of genotype-guided dosing and find the additional genetic association are necessary.