Search

Aim: To investigate whether the phenprocoumon and acenocoumarol maintenance doses are influenced by genetic variations in GATA-4, a transcription factor of CYP2C9., Patients & Methods: The influence of seven GATA-4 SNPs on the coumarin maintenance dose was investigated by performing an analysis of variance trend analysis, stratified for CYP2C9 genotypes. Results of the best-explaining SNP were validated in the Rotterdam Study cohort., Results: The largest dose differences were found for rs3735814 in patients using acenocoumarol and having the common allele for CYP2C9. The mean dosages decreased from 2.92 mg/day for the patients having the GATA-4 common alleles to 2.65 mg/day for the patients carrying one GATA-4 variant allele and to 2.37 mg/day for patients carrying two GATA-4 variant alleles (p = 0.004). Results could not be replicated in the validation cohort. For phenprocoumon, no significant effects were observed., Conclusion: Genetic variation in GATA-4 does not seem relevant for clinical implementation.

Aim: To evaluate the performance of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) acenocoumarol dose algorithms in an independent data set. The EU-PACT trial investigates the added value of pretreatment genotyping for use of warfarin, phenprocoumon and acenocoumarol., Patients & Methods: External validation was performed in the Rotterdam Study cohort using information about 707 acenocoumarol users. R(2), which measures the strength of correlation between the predicted and observed acenocoumarol dose, mean absolute error and mean squared error were calculated to evaluate the performance of the original algorithm., Results: Validation resulted in a R(2) of 52.7 and 12.9% compared with an R(2) of 52.6 and 17.8% in the original study for the genotype-guided and nongenotype-guided dose algorithm, respectively. For the genotype-guided dose algorithm, the mean absolute error was 0.48 mg/day and the mean squared error was 0.38 (mg/day)(2). For the nongenotype-guided dose algorithm, the mean absolute error was 0.62 mg/day and the mean squared error was 0.63 (mg/day)(2)., Conclusion: The EU-PACT acenocoumarol algorithm performs just as accurately in this study as in the original study, which implies applicability in various populations.

Background: The required acenocoumarol dose and the risk of underanticoagulation and overanticoagulation are associated with the CYP2C9 and VKORC1 genotypes. However, the duration of the effects of these genes on anticoagulation is not yet known., Objectives: In the present study, the effects of these polymorphisms on the risk of underanticoagulation and overanticoagulation over time after the start of acenocoumarol were investigated., Patients/methods: In three cohorts, we analyzed the relationship between the CYP2C9 and VKORC1 genotypes and the incidence of subtherapeutic or supratherapeutic International Normalized Ratio (INR) values (< 2 and > 3.5) or severe overanticoagulation (INR > 6) for different time periods after treatment initiation., Results: Patients with polymorphisms in CYP2C9 and VKORC1 had a higher risk of overanticoagulation (up to 74%) and a lower risk of underanticoagulation (down to 45%) in the first month of treatment with acenocoumarol, but this effect diminished after 1-6 months., Conclusions: Knowledge of the patient's genotype therefore might assist physicians to adjust doses in the first month(s) of therapy., (© 2012 International Society on Thrombosis and Haemostasis.)

Aim: The aim of this study was to investigate the effects of co-medication with selective serotonin re-uptake inhibitors (SSRIs) on overanticoagulation during acenocoumarol maintenance treatment., Methods: All subjects from The Rotterdam Study who received acenocoumarol maintenance treatment between April 1 1991 and September 9 2009 were followed for the event of an international normalized ratio (INR) ≥6, until death, end of treatment or end of the study period. With the Andersen-Gill extension of the Cox proportional hazards model, risks for repeated events of overanticoagulation in relation to concomitant SSRI use were calculated., Results: The risk for overanticoagulation during acenocoumarol maintenance treatment was increased in combination with fluvoxamine (HR 2.63, 95% CI 1.49, 4.66) and venlafaxine (HR 2.19, 95% CI 1.21, 3.99). There was no increase in risk for the other SSRIs, but numbers of exposed cases were low for all SSRIs except paroxetine., Conclusion: Fluvoxamine and venlafaxine were associated with a more than double risk of INR values ≥6 in acenocoumarol treated subjects., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

In the Netherlands, several reports have described a potentiation of acenocoumarol-induced anticoagulation by co-medication of omeprazole or esomeprazole and competitive inhibition of CYP2C19 has been suggested as a possible mechanism for this interaction. We conducted an observational cohort study to investigate the effects of various proton pump inhibitors (PPIs) on acenocoumarol effectiveness. All 2755 subjects from the Rotterdam Study who received acenocoumarol maintenance treatment between April 1st, 1991 and September 9th, 2009 were followed for events of an international normalized ratio (INR)≥6, until death, end of treatment, or end of the study period. The Andersen-Gill extension of the Cox proportional hazards model was used to calculate risks for repeated events of overanticoagulation in relation to concomitant PPI use. The risk for overanticoagulation was most pronounced for esomeprazole (HR 1·99, 95% CI 1·55-2·55) and lansoprazole (HR 1·49, 95% CI 1·05-2·10). There was also a lower and non-significant risk increase for the other PPIs. We did not detect a modification of these results by CYP2C19*2 genotype. Caution should be paid to co-medication with esomeprazole and lansoprazole during acenocoumarol treatment and possibly also with other PPIs., (© 2011 Blackwell Publishing Ltd.)

Several genome-wide association studies have been performed on warfarin. For acenocoumarol, the most frequently used coumarin in many countries worldwide, pharmacodynamic influences are expected to be comparable. Pharmacokinetics however might differ. We aimed to confirm known or identify new genetic variants contributing to interindividual variation on stabilized acenocoumarol dosage by a GWAS. The index population consisted of 1451 Caucasian subjects from the Rotterdam study and results were replicated in 287 subjects from the Rotterdam study extended cohort. Both cohorts were genotyped on the Illumina 550K Human Map SNP array. From polymorphisms tested for association with acenocoumarol dosage, 35 single nucleotide polymorphisms (SNPs) on chromosome 16 and 18 SNPs on chromosome 10 reached genome-wide significance. The SNP with the lowest P-value was rs10871454 on chromosome 16 linked to SNPs within the vitamin K epoxide reductase complex subunit 1 (VKORC1) (P = 2.0 x 10(-123)). The lowest P-value on chromosome 10 was obtained by rs4086116 within cytochrome P450 2C9 (CYP2C9) (P = 3.3 x 10(-24)). After adjustment for these SNPs, the rs2108622 polymorphism within cytochrome P450 4F2 (CYP4F2) gene on chromosome 19 reached genome-wide significance (P = 2.0 x 10(-8)). On chromosome 10, we further identified genetic variation in the cytochrome P450 2C18 (CYP2C18) gene contributing to variance of acenocoumarol dosage. Thus we confirmed earlier findings that acenocoumarol dosage mainly depends on polymorphisms in the VKORC1 and CYP2C9 genes. Besides age, gender, body mass index and target INR, one polymorphism within each of the VKORC1, CYP2C9, CYP4F2 and CYP2C18 genes could explain 48.8% of acenocoumarol dosage variation.

The objective of this study was to investigate the influence of genotypes associated with reduced activity of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) on anticoagulation with acenocoumarol during the first 6 weeks of treatment. In 1,525 patients from the Rotterdam Study who were started on anticoagulation therapy with acenocoumarol, the presence of VKORC1 1173C>T and CYP2C9*2 and *3 allele variants was determined. The first international normalized ratio (INR) after initial standard dose, risk of overanticoagulation, and mean dosage at the end of the initiation period were compared between genotypes. The initial standard dosage significantly increased the risk of severe overanticoagulation by 85% for each additional VKORC1 T-allele present. At the end of the initiation period, each VKORC1 T-allele present was shown to decrease the required acenocoumarol dosage by 5.1 mg/week, while each CYP2C9 variant allele present reduced the required dosage by 1.8 mg/week. Our conclusion was that an initial standard dosing regimen with acenocoumarol increases the risk of severe overanticoagulation in patients with variant alleles of the VKORC1 and CYP2C9 genes.

Introduction: Cytochrome P450 (CYP) plays a key role in the metabolism of coumarin anticoagulants and nonsteroidal anti-inflammatory drugs (NSAIDs). Because CYP2C9 is a genetically polymorphic enzyme, genetic variability could play an important role in the potential interaction between NSAIDs and coumarins. We investigated whether NSAIDs were associated with overanticoagulation during therapy with coumarins and evaluated the effect of the CYP2C9 polymorphisms on this potential interaction., Methods: We conducted a population-based cohort study among patients of an anticoagulation clinic who were treated with acenocoumarol or phenprocoumon between April 1, 1991, and May 31, 2003, and whose CYP2C9 status was known. Patients were followed up until an international normalized ratio (INR) of 6.0 or greater was reached or until the end of treatment, death, or the end of the study. Proportional hazards regression analysis was used to estimate the risk of an INR of 6.0 or greater in relation to concomitant use of a coumarin anticoagulant and NSAIDs after adjustment for several potentially confounding factors. To study effect modification by CYP2C9 genotype, stratified analyses were performed for wild-type patients and patients with a variant genotype., Results: Of the 973 patients in the cohort, 415 had an INR of 6.0 or greater. Several NSAIDs increased the risk of overanticoagulation. The risk of overanticoagulation was 2.98 (95% confidence interval, 1.09-7.02) in coumarin-treated patients taking NSAIDs with a CYP2C9*2 allele and 10.8 (95% confidence interval, 2.57-34.6) in those with a CYP2C9*3 allele., Conclusions: Several NSAIDs were associated with overanticoagulation. For NSAIDs that are known CYP2C9 substrates, this risk was modified by allelic variants of CYP2C9. More frequent INR monitoring of patients taking NSAIDs is warranted.

Heart failure has been identified as a risk factor for increased coumarin anticoagulant responsiveness in several small-scale experiments. Epidemiological studies quantifying the risk of overanticoagulation by heart failure in a non-selected population on coumarins are scarce. Therefore, we investigated whether patients with heart failure have an increased risk of overanticoagulation and determined the effect of incidental heart failure on coumarin dose requirements. A cohort study of all patients was performed from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon between 1 January 1990 and 1 January 2000. All cohort members were followed until the first occurrence of an international normalized ratio (INR) > or = 6.0, the last INR assessment, death, loss to follow-up, or end of the study period. Of the 1077 patients in the cohort, 396 developed an INR > or = 6.0. The risk of overanticoagulation was 1.66 [95% confidence interval (CI): 1.33-2.07] for cases of prevalent heart failure and 1.91 (95%CI: 1.31-2.79) for incidental cases. The decrease in dose requirements in patients with incidental heart failure showed a significant trend from the fifth INR measurement preceding the date of incidental heart failure to the third measurement after this date. Heart failure is an independent risk factor for overanticoagulation. Therefore, patients with heart failure should be closely monitored to prevent potential bleeding complications., (Copyright 2004 Blackwell Publishing Ltd)

The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatment-years, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.

Some medical textbooks on drug interactions take note of the potential interaction between laxatives and coumarin anticoagulants, but epidemiological evidence that this interaction is of practical importance is lacking. We conducted a follow-up study in a large population-based cohort to investigate which laxatives are associated with overanticoagulation during therapy with coumarins. Of the 1124 patients in the cohort, 351 developed an International Normalized Ratio > or = 6.0. The only laxative with a moderate but significantly increased relative risk of overanticoagulation was lactulose (relative risk 3.4, 95% confidence interval 2.2, 5.3). In view of the widespread use of lactulose, especially among the elderly, awareness of this potential drug interaction is required.

Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarin anticoagulant metabolism. The variant alleles CYP2C9*2 and CYP2C9*3 are associated with an increased response to warfarin. However, an effect on acenocoumarol dose requirements appears to be absent for the CYP2C9*2 allele and the consequences for the metabolism of phenprocoumon have not yet been established. We investigated CYP2C9 polymorphisms in relation to the international normalized ratio (INR) during the first 6 weeks of treatment and its effect on the maintenance dose in a cohort of 1124 patients from the Rotterdam Study who were treated with acenocoumarol or phenprocoumon. There was a statistically significant difference in first INR between patients with variant genotypes and those with the wild-type. Almost all acenocoumarol-treated patients with a variant genotype had a significantly higher mean INR and had a higher risk of an INR > or = 6.0 during the first 6 weeks of treatment. A clear genotype-dose relationship was found for acenocoumarol-treated patients. For patients on phenprocoumon, no significant differences were found between variant genotypes and the wild-type genotype. Individuals with one or more CYP2C9*2 or CYP2C9*3 allele(s) require a significantly lower dose of acenocoumarol compared to wild-type patients. Phenprocoumon appears to be a clinically useful alternative in patients carrying the CYP2C9*2 and *3 alleles.