Warfarin dosing strategies evolution and its progress in the era of precision medicine, a narrative review
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Abstract Background For decades, vitamin K antagonists and specifically warfarin, have been the sole agents used orally to manage thromboembolic conditions, including stroke and venous thromboembolism (VTE). Several factors lead to warfarin dose variability, including genetic and non-genetic factors which made warfarin management challenging especially at the initiation phase. To overcome the challenges with warfarin dosing at initiation, strategies other than conventional or fixed dosing were introduced and explored. Aim In this narrative review, we aim to discuss and critique the different dosing strategies for warfarin at initiation with more focus on genotype-guided warfarin dosing and the most recent supporting evidence for and against its use. Method Medline database was searched from 1965 to July 2021. Articles addressing different warfarin dosing methods were screened for inclusion. Results A number of methods exist for warfarin initiation. Studies comparing different dosing methods for initiation yielded conflicting outcomes due to differences in study design, population studied, comparator, and outcomes measured. Conclusions Looking at the big picture, the use of genetic dosing for warfarin initiation can lead to better outcomes. Whether these better outcomes are clinically or economically beneficial remains controversial.Keywords:
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Abstract Objectives Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 −1173C>T, CYP2C9*2 , and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events. Methods This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 −1173C>T, CYP2C9*2 , and CYP2C9*2 genotypes was performed. Results Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1 . However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding. Conclusions Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 −1173C>T, CYP2C9*2 , and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.
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A clinical effect of warfarin depends on highly polymorphic drug-metabolizing (CYP2C9) and drug-target (VKORC1) enzymes. The objective of this study was to investigate the impact of CYP2C9*2, CYP2C9*3, and VKORC1 (G-1639A) polymorphisms on the variability of warfarin dosage requirements in Lithuanian patients after heart valve replacement.The study included 83 patients with a mean age of 65.2 years (SD, 13.31) after heart valve replacement with an achieved stable international normalized ratio of 2-3.5. The restriction fragment length polymorphism method was used to identify polymorphisms of VKORC1 and CYP2C9.Daily warfarin dosage significantly correlated with weight (r=0.4087) and height (r=0.3883) of the patients. Patients younger than 60 years required significantly higher daily warfarin dosages than older patients. Two-thirds (66.3%) of the patients had the wild-type (WT) CYP2C9*1/*1 genotype; 38.6% and 54.2% of the patients had WT VKORC1 (G/G) and VKORC1 (G/A) genotypes, respectively. WT CYP2C9*1/*1 genotype was associated with a higher daily warfarin dosage (5.84 mg [SD, 2.84]) as compared to other CYP2C9 genotypes. Carriers of WT VKORC1 (G/G) required a higher warfarin dose as compared to (A/A) carriers (6.20±2.78 mg and 3.75±1.40 mg, respectively; P=0.04). Patients having CYP2C9*1/*1 or 1/*2 in combination with VKORC1 (G/G) or (G/A) genotypes required the highest daily warfarin dosage in comparison to other combinations of genotypes.The Lithuanian study sample is characterized by high a frequency (92.8%) of VKORC1 G/G and G/A genotypes that determines a higher warfarin-loading dose. Analysis of combined CYP2C9 and VKORC1 gene variants allows the prediction of warfarin dosage. These results can be used to individualize treatment with warfarin in the field of heart surgery in Lithuania.
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Acenocoumarol
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Pharmacogenetics of acenocoumarol: CYP2C9 *2 and VKORC1 c.-1639G>A, 497C>G, 1173C>T, and 3730G>A variants influence drug dose in anticoagulated patients -
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Abstract Background Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9 / VKORC1 / CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children. Procedure Clinical and genetic data for 93 children (age ≤18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay. Results With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1‐ 1639G/A and CYP2C9 *2/*3 , with genotypes accounting for 21.1% of variability. There was a strong correlation (R 2 = 0.68; P < 0.001) between actual and predicted warfarin dose using a pediatric genotype‐based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) ( P = 0.047) and time to over‐anticoagulation (INR > 4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose ( P = 0.020) in a multivariate clinical and genetic model. Conclusions This study confirms the importance of VKORC1 / CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children. Pediatr Blood Cancer 2014;61:1055–1062. © 2014 Wiley Periodicals, Inc.
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Warfarin is a commonly used oral anticoagulant with a narrow therapeutic range and large interindividual variability in daily dose. Compared with Caucasians, Chinese are known to require lower doses of warfarin. Differences between Caucasians and Chinese in the allelic frequencies of two genes, CYP2C9 and VKORC1 , largely explain the difference in dose requirement. There are other genetic polymorphisms that may further explain the response to warfarin. The VKORC1 genotype is an important determinant of response to warfarin in Chinese, but some genetic variants found in other ethnic groups that have a large effect on warfarin response and dosing are not commonly found in Chinese. Therefore, it is important to recognize and beware of ethnic differences in the pharmacogenetics of the response to warfarin, especially in the design of algorithms to aid dosing in clinical practice.
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Objectives To assess the contribution of CYP2C9 / VKORC1 genotypes and variation in other genes involved in warfarin biotransformation and coagulation pathways to warfarin‐related outcomes in children. Furthermore, to validate the performance of a previously published pediatric pharmacogenetics‐dosing model when predicting the required dose in an independent cohort of children. Methods Clinical and genetic data was collected from 93 patients ≤18 years of age who received warfarin therapy. Genotyping was performed using a custom 96 SNP genotyping assay. Results Together, VKORC1 –1639G/A and CYP2C9 *2/*3 accounted for 21.1% of dose variability. There was a strong correlation (R 2 =0.64; P <0.001) between actual and predicted warfarin dose using a pediatric pharmacogenetics‐dosing model. VKORC1 genotype also had a significant impact on time to therapeutic INR ( P =0.047), time to INR>;4 ( P =0.028), and risk of over‐anticoagulation (INR>;4) during the initiation of therapy (odds ratio, 3.3; P =0.014). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose in a multivariate model. Conclusions This study confirms the importance of VKORC1/CYP2C9 genotype for warfarin outcomes in children and validates a pediatric‐specific genotype‐based dosing algorithm. Research funding provided by CIHR‐DSEN and CFI.
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Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events.This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*2 genotypes was performed.Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1. However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding.Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.
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Aim: Our aim was to examine the effect of CYP2C9 and VKORC1 polymorphisms on warfarin dose requirements in Turkish patients. Materials & methods: 24 warfarin prescribed patients were included and analyzed for eight VKORC1 and 6 CYP2C9 polymorphisms in the study. Results: Patients with CYP2C9 *1/*1 and VKORC1 -1639 GG and GA genotypes required higher warfarin doses in comparison to wild type VKORC1 genotype. Patients with CYP2C9 *1/*3 and VKORC1 -1639 GG genotypes simultaneously, required the lowest dose of warfarin (4.64 mg/day). Patients with CYP2C9 *1/*1 and VKORC1 9041 AA genotype were found to require higher warfarin doses. Conclusion: Our results provide additional evidence to support the hypothesis that CYP2C9 *2, *3, VKORC1 9041 G > A polymorphisms explain considerable proportion of inter-individual variability in warfarin dose requirement.
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