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Bruno H. Stricker - One of the best experts on this subject based on the ideXlab platform.
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validation of the Acenocoumarol eu pact algorithms similar performance in the rotterdam study cohort as in the original study
Pharmacogenomics, 2012Co-Authors: Rianne M F Van Schie, Tom Schalekamp, Judith A M Wessels, Talitha I Verhoef, Martina Teichert, Albert Hofman, Bruno H. Stricker, Nadia El Khedr, Peter N Buhre, Saskia Le CessieAbstract: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. R2, 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 R2 of 52.7 and 12.9% compared with an R2 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 erro...
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selective serotonin re uptake inhibiting antidepressants and the risk of overanticoagulation during Acenocoumarol maintenance treatment
British Journal of Clinical Pharmacology, 2011Co-Authors: Martina Teichert, A.g. Uitterlinden, Albert Hofman, Peter A. G. M. De Smet, Loes E. Visser, Peter J Buhre, Sabine M J M Straus, Bruno H. StrickerAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Coumarin anticoagulants and selective serotonin re-uptake inhibitors (SSRIs) have been reported to cause bleeding. Combination of these drug groups might enhance this risk. Case reports showed an increase of prothrombin time for the combination of warfarin with fluvoxamine and fluoxetine. This has not yet been confirmed by population based studies. WHAT THIS STUDY ADDS • Fluvoxamine and venlafaxine increased prothrombin time in users of Acenocoumarol above a critical value which is associated with an increased bleeding risk. The other SSRIs had no influence on Acenocoumarol effectiveness, however numbers of drug users were low. The combination of fluvoxamine and venlafaxine with Acenocoumarol should be monitored by measurements of the international normalized ratio to avoid overanticoagulation. 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.
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proton pump inhibitors and the risk of overanticoagulation during Acenocoumarol maintenance treatment
British Journal of Haematology, 2011Co-Authors: Martina Teichert, Albert Hofman, Peter A. G. M. De Smet, Bruno H. Stricker, Sabine M J M Straus, Peter N Buhre, Charlotte Van Noord, Andre G Uitterlinden, Loes E. VisserAbstract: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.
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A genome-wide association study of Acenocoumarol maintenance dosage
Human molecular genetics, 2009Co-Authors: Martina Teichert, Mark Eijgelsheim, Fernando Rivadeneira, A.g. Uitterlinden, Ron H.n. Van Schaik, Albert Hofman, Peter A. G. M. De Smet, Teun Van Gelder, Loes E. Visser, Bruno H. StrickerAbstract: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.
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the risk of overanticoagulation in patients with cytochrome p450 cyp2c9 2 or cyp2c9 3 alleles on Acenocoumarol or phenprocoumon
Pharmacogenetics, 2004Co-Authors: Loes E. Visser, Ron H.n. Van Schaik, Albert Hofman, Peter A. G. M. De Smet, Martin H Van Vliet, A A Kasbergen, Arnold G Vulto, Cornelia M Van Duijn, Bruno H. StrickerAbstract: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.
Frits R. Rosendaal - One of the best experts on this subject based on the ideXlab platform.
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an evaluation of gene gene interaction between the cyp2c9 and vkorc1 genotypes affecting the anticoagulant effect of phenprocoumon and Acenocoumarol
Journal of Thrombosis and Haemostasis, 2012Co-Authors: Rianne M F Van Schie, Tom Schalekamp, Judith A M Wessels, F J M Van Der Meer, A M V Babajeff, Le S Cessie, E Van Meegen, A. De Boer, Talitha I Verhoef, Frits R. RosendaalAbstract:Summary. Background: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures. Objectives: We aimed to provide a definite answer regarding the question whether there exists a gene–gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and Acenocoumarol. Patients/Methods: The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 Acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and Acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model – for the outcome measure maintenance dose – or to the Cox regression models – for the outcome measures time to severe over-anticoagulation and time to achieve stability. Results: No significant interactions – all P-values above 0.23 for phenprocoumon and 0.30 for Acenocoumarol – were observed for all outcome measures. Conclusions: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and Acenocoumarol.
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evaluation of the effect of statin use on the Acenocoumarol and phenprocoumon maintenance dose
Drug metabolism and drug interactions, 2012Co-Authors: Rianne M F Van Schie, Felix J M Van Der Meer, Saskia Le Cessie, Tom Schalekamp, Saskia B Boejharat, Judith A M Wessels, Talitha I Verhoef, Frits R. Rosendaal, Anthonius De BoerAbstract:BACKGROUND: Statins and coumarins are prescribed in combination on a regular basis. Some case reports suggested that statins might affect the dose requirements of coumarins. The aim of the study was to investigate whether Acenocoumarol and phenprocoumon maintenance doses are influenced by statin use. METHODS: The Pre-EU-PACT database was used, which contains information on 471 Acenocoumarol and 624 phenprocoumon users. The influence of individual statins on the Acenocoumarol and phenprocoumon maintenance dose was investigated by comparing unadjusted and adjusted mean differences of the maintenance dose between statin and non-statin users. RESULTS: Lower adjusted Acenocoumarol dose requirements were observed for patients using atorvastatin, simvastatin, pravastatin, and rosuvastatin. These patients had a reduction in adjusted mean Acenocoumarol maintenance dose of 0.11, 0.29, 0.38, and 0.69 mg/day, respectively, compared with a mean adjusted dose of 2.60 mg/day for the patients not using a statin. There was no significant effect of statin use on unadjusted and adjusted phenprocoumon maintenance dose (p=0.23 and p=0.35, respectively). CONCLUSIONS: Mean Acenocoumarol maintenance dosages were decreased when Acenocoumarol is co-administered with the different statins. Statin use does not affect phenprocoumon maintenance doses significantly.
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loading and maintenance dose algorithms for phenprocoumon and Acenocoumarol using patient characteristics and pharmacogenetic data
European Heart Journal, 2011Co-Authors: Rianne M F Van Schie, Saskia Le Cessie, Tom Schalekamp, Judith A M Wessels, Talitha I Verhoef, Anthonius De Boer, Frits R. Rosendaal, Felix J M Van Der Meer, Erik Van Meegen, Ankehilse Maitlandvan Der ZeeAbstract:AIMS: Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and Acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dos ...
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the relationship between maintenance dosages of three vitamin k antagonists Acenocoumarol warfarin and phenprocoumon
Thrombosis Research, 2008Co-Authors: Yvonne Van Leeuwen, Frits R. Rosendaal, Felix J M Van Der MeerAbstract:INTRODUCTION: Vitamin K antagonists of the coumarin type are widely used oral anticoagulants. OBJECTIVE: We developed a transition algorithm for the maintenance dosages of three frequently used coumarins: warfarin, phenprocoumon and Acenocoumarol. METHODS: The study was conducted at the Leiden Anticoagulation Clinic. Patients were participants in a trial of which the main objective was to compare the quality of an oral anticoagulant therapy with phenprocoumon to warfarin. We included patients who initiated oral anticoagulant therapy and patients who were already using Acenocoumarol. Patients were randomized to a treatment with warfarin or phenprocoumon. Patients who were randomized to warfarin switched to phenprocoumon at the end of follow-up. We analysed the switch from Acenocoumarol to warfarin or phenprocoumon at the start of follow-up and the switch of warfarin to phenprocoumon at the end of follow-up and calculated the transition factors for stable anticoagulation between these three vitamin K antagonists. RESULTS: Fifty-eight patients switched from warfarin to phenprocoumon, 39 from Acenocoumarol to phenprocoumon and 44 from Acenocoumarol to warfarin. The maintenance dose of warfarin was 0.41 (95%CI 0.39-0.43) times the maintenance dose of phenprocoumon. The transition factor between Acenocoumarol and phenprocoumon was 0.84 (95%CI 0.79-0.89) and between Acenocoumarol and warfarin 1.85 (95%CI 1.78-1.92). CONCLUSIONS: We determined the transition factors between warfarin, phenprocoumon and Acenocoumarol. With these transition factors physicians are able to estimate the maintenance dose when it is necessary for a patient to switch from one coumarin to the other.
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a c1173t dimorphism in the vkorc1 gene determines coumarin sensitivity and bleeding risk
PLOS Medicine, 2005Co-Authors: Pieter H Reitsma, Frits R. Rosendaal, Jeroen Van Der Heijden, Angelique P Groot, Harry R BullerAbstract:Background A C1173T polymorphism in intron 1 of the VKORC1 gene has been claimed to determine the interindividual variability in the response to vitamin K antagonist therapy (VKA), but it is unknown whether it also influences bleeding risk. We aimed to confirm the relationship between C1173T status and phenprocoumon or Acenocoumarol use, and to examine the risk of severe bleeding for the various genotypes. Methods and Findings We studied this in a case-control study of 110 patients who bled during VKA therapy and 220 control patients free of bleeding under the same therapy. To achieve the same target INR, CT genotype and TT genotype control patients required less phenprocoumon (CC genotype 2.9 mg/d [95% confidence interval (CI): 2.6–3.2], CT genotype 2.6 mg/d [95% CI: 2.1–3.1], TT genotype 1.4 mg/d [95 % CI: 1.1–1.7]) or Acenocoumarol (CC genotype 3.2 mg/d [95% CI: 2.9–3.5], CT genotype 2.3 mg/d [95% CI: 2.1–2.5], TT genotype 1.7 mg/d [95% CI: 1.3–2.1]) than CC genotype control patients. Compared with CC genotype individuals, carriers of at least one T allele had an increased risk of bleeding in the phenprocoumon users (crude odds ratio = 2.6, 95% CI: 1.2–5.7), but not in Acenocoumarol users (crude odds ratio = 1.2, 95% CI: 0.6–2.3). Conclusion These findings encourage taking further steps towards the evaluation of the use of VKORC1 genetic testing for bleeding prevention in individuals who receive VKA therapy.
Loes E. Visser - One of the best experts on this subject based on the ideXlab platform.
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selective serotonin re uptake inhibiting antidepressants and the risk of overanticoagulation during Acenocoumarol maintenance treatment
British Journal of Clinical Pharmacology, 2011Co-Authors: Martina Teichert, A.g. Uitterlinden, Albert Hofman, Peter A. G. M. De Smet, Loes E. Visser, Peter J Buhre, Sabine M J M Straus, Bruno H. StrickerAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Coumarin anticoagulants and selective serotonin re-uptake inhibitors (SSRIs) have been reported to cause bleeding. Combination of these drug groups might enhance this risk. Case reports showed an increase of prothrombin time for the combination of warfarin with fluvoxamine and fluoxetine. This has not yet been confirmed by population based studies. WHAT THIS STUDY ADDS • Fluvoxamine and venlafaxine increased prothrombin time in users of Acenocoumarol above a critical value which is associated with an increased bleeding risk. The other SSRIs had no influence on Acenocoumarol effectiveness, however numbers of drug users were low. The combination of fluvoxamine and venlafaxine with Acenocoumarol should be monitored by measurements of the international normalized ratio to avoid overanticoagulation. 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.
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proton pump inhibitors and the risk of overanticoagulation during Acenocoumarol maintenance treatment
British Journal of Haematology, 2011Co-Authors: Martina Teichert, Albert Hofman, Peter A. G. M. De Smet, Bruno H. Stricker, Sabine M J M Straus, Peter N Buhre, Charlotte Van Noord, Andre G Uitterlinden, Loes E. VisserAbstract: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.
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A genome-wide association study of Acenocoumarol maintenance dosage
Human molecular genetics, 2009Co-Authors: Martina Teichert, Mark Eijgelsheim, Fernando Rivadeneira, A.g. Uitterlinden, Ron H.n. Van Schaik, Albert Hofman, Peter A. G. M. De Smet, Teun Van Gelder, Loes E. Visser, Bruno H. StrickerAbstract: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.
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genotypes associated with reduced activity of vkorc1 and cyp2c9 and their modification of Acenocoumarol anticoagulation during the initial treatment period
Clinical Pharmacology & Therapeutics, 2009Co-Authors: Martina Teichert, A.g. Uitterlinden, Rhn Van Schaik, A Hofman, Pagm De Smet, B H Stricker, Loes E. VisserAbstract: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.
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the risk of overanticoagulation in patients with cytochrome p450 cyp2c9 2 or cyp2c9 3 alleles on Acenocoumarol or phenprocoumon
Pharmacogenetics, 2004Co-Authors: Loes E. Visser, Ron H.n. Van Schaik, Albert Hofman, Peter A. G. M. De Smet, Martin H Van Vliet, A A Kasbergen, Arnold G Vulto, Cornelia M Van Duijn, Bruno H. StrickerAbstract: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.
Martina Teichert - One of the best experts on this subject based on the ideXlab platform.
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validation of the Acenocoumarol eu pact algorithms similar performance in the rotterdam study cohort as in the original study
Pharmacogenomics, 2012Co-Authors: Rianne M F Van Schie, Tom Schalekamp, Judith A M Wessels, Talitha I Verhoef, Martina Teichert, Albert Hofman, Bruno H. Stricker, Nadia El Khedr, Peter N Buhre, Saskia Le CessieAbstract: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. R2, 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 R2 of 52.7 and 12.9% compared with an R2 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 erro...
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long term anticoagulant effects of the cyp2c9 and vkorc1 genotypes in Acenocoumarol users
Journal of Thrombosis and Haemostasis, 2012Co-Authors: Talitha I Verhoef, Tom Schalekamp, Judith A M Wessels, Le S Cessie, A. De Boer, F. J. M. Van Der Meer, W K Redekop, M M Buikema, R M F Van Schie, Martina TeichertAbstract:Summary. 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 ( 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.
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selective serotonin re uptake inhibiting antidepressants and the risk of overanticoagulation during Acenocoumarol maintenance treatment
British Journal of Clinical Pharmacology, 2011Co-Authors: Martina Teichert, A.g. Uitterlinden, Albert Hofman, Peter A. G. M. De Smet, Loes E. Visser, Peter J Buhre, Sabine M J M Straus, Bruno H. StrickerAbstract:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Coumarin anticoagulants and selective serotonin re-uptake inhibitors (SSRIs) have been reported to cause bleeding. Combination of these drug groups might enhance this risk. Case reports showed an increase of prothrombin time for the combination of warfarin with fluvoxamine and fluoxetine. This has not yet been confirmed by population based studies. WHAT THIS STUDY ADDS • Fluvoxamine and venlafaxine increased prothrombin time in users of Acenocoumarol above a critical value which is associated with an increased bleeding risk. The other SSRIs had no influence on Acenocoumarol effectiveness, however numbers of drug users were low. The combination of fluvoxamine and venlafaxine with Acenocoumarol should be monitored by measurements of the international normalized ratio to avoid overanticoagulation. 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.
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proton pump inhibitors and the risk of overanticoagulation during Acenocoumarol maintenance treatment
British Journal of Haematology, 2011Co-Authors: Martina Teichert, Albert Hofman, Peter A. G. M. De Smet, Bruno H. Stricker, Sabine M J M Straus, Peter N Buhre, Charlotte Van Noord, Andre G Uitterlinden, Loes E. VisserAbstract: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.
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A genome-wide association study of Acenocoumarol maintenance dosage
Human molecular genetics, 2009Co-Authors: Martina Teichert, Mark Eijgelsheim, Fernando Rivadeneira, A.g. Uitterlinden, Ron H.n. Van Schaik, Albert Hofman, Peter A. G. M. De Smet, Teun Van Gelder, Loes E. Visser, Bruno H. StrickerAbstract: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.
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comparison of dosing algorithms for Acenocoumarol and phenprocoumon using clinical factors with the standard care in the netherlands
Thrombosis Research, 2015Co-Authors: Yumao Zhang, Felix J M Van Der Meer, Saskia Le Cessie, Talitha I Verhoef, Anthonius De Boer, Rita Barallon, Ann K Daly, Ken W Redekop, Julia C StinglAbstract:Abstract Background It has not been investigated how much the use of clinical factors in a dosing algorithm improves the percentage of time in therapeutic range (TTR). The present study aimed to compare the effect of dosing algorithms for Acenocoumarol and phenprocoumon including clinical patient characteristics with standard care in the Netherlands. Setting: The pre-EU-PACT study, an observational study in the Netherlands, was used to obtain standard care data. Data from the Dutch patients in the EU-PACT trial (comparing the use of a clinical algorithm with and without genetic information) was used for the clinical dosing algorithm. Methods For both Acenocoumarol and phenprocoumon, the percentage of time in, below and above therapeutic International Normalized Ratio (INR) range during 12 weeks after treatment initiation were assessed in both studies. Results During the weeks 2-12, the clinical dosing algorithm of Acenocoumarol (80 patients) led to a higher TTR (74.3% versus 68.0% in range 2.0-3.5, 95% Confidence interval [CI] difference: 0.5% to 11.8%), and a reduced percentage of time below INR 2 and above INR 3.5, compared with standard care (272 patients). For phenprocoumon, compared with standard care (484 patients), 80 patients treated by the dosing algorithm did not obtained a significantly higher TTR in range 2.0-3.5 or a lower percentage of time above 3.5, however, they spent more time with INR below 2. Conclusion The use of a clinical dosing algorithm for Acenocoumarol seemed to improve the quality of anticoagulation therapy during the treatment of initial 2-12 weeks. For phenprocoumon, there was no statistically difference in anticoagulation control.
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validation of the Acenocoumarol eu pact algorithms similar performance in the rotterdam study cohort as in the original study
Pharmacogenomics, 2012Co-Authors: Rianne M F Van Schie, Tom Schalekamp, Judith A M Wessels, Talitha I Verhoef, Martina Teichert, Albert Hofman, Bruno H. Stricker, Nadia El Khedr, Peter N Buhre, Saskia Le CessieAbstract: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. R2, 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 R2 of 52.7 and 12.9% compared with an R2 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 erro...
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an evaluation of gene gene interaction between the cyp2c9 and vkorc1 genotypes affecting the anticoagulant effect of phenprocoumon and Acenocoumarol
Journal of Thrombosis and Haemostasis, 2012Co-Authors: Rianne M F Van Schie, Tom Schalekamp, Judith A M Wessels, F J M Van Der Meer, A M V Babajeff, Le S Cessie, E Van Meegen, A. De Boer, Talitha I Verhoef, Frits R. RosendaalAbstract:Summary. Background: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures. Objectives: We aimed to provide a definite answer regarding the question whether there exists a gene–gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and Acenocoumarol. Patients/Methods: The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 Acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and Acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model – for the outcome measure maintenance dose – or to the Cox regression models – for the outcome measures time to severe over-anticoagulation and time to achieve stability. Results: No significant interactions – all P-values above 0.23 for phenprocoumon and 0.30 for Acenocoumarol – were observed for all outcome measures. Conclusions: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and Acenocoumarol.
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long term anticoagulant effects of the cyp2c9 and vkorc1 genotypes in Acenocoumarol users
Journal of Thrombosis and Haemostasis, 2012Co-Authors: Talitha I Verhoef, Tom Schalekamp, Judith A M Wessels, Le S Cessie, A. De Boer, F. J. M. Van Der Meer, W K Redekop, M M Buikema, R M F Van Schie, Martina TeichertAbstract:Summary. 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 ( 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.
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evaluation of the effect of statin use on the Acenocoumarol and phenprocoumon maintenance dose
Drug metabolism and drug interactions, 2012Co-Authors: Rianne M F Van Schie, Felix J M Van Der Meer, Saskia Le Cessie, Tom Schalekamp, Saskia B Boejharat, Judith A M Wessels, Talitha I Verhoef, Frits R. Rosendaal, Anthonius De BoerAbstract:BACKGROUND: Statins and coumarins are prescribed in combination on a regular basis. Some case reports suggested that statins might affect the dose requirements of coumarins. The aim of the study was to investigate whether Acenocoumarol and phenprocoumon maintenance doses are influenced by statin use. METHODS: The Pre-EU-PACT database was used, which contains information on 471 Acenocoumarol and 624 phenprocoumon users. The influence of individual statins on the Acenocoumarol and phenprocoumon maintenance dose was investigated by comparing unadjusted and adjusted mean differences of the maintenance dose between statin and non-statin users. RESULTS: Lower adjusted Acenocoumarol dose requirements were observed for patients using atorvastatin, simvastatin, pravastatin, and rosuvastatin. These patients had a reduction in adjusted mean Acenocoumarol maintenance dose of 0.11, 0.29, 0.38, and 0.69 mg/day, respectively, compared with a mean adjusted dose of 2.60 mg/day for the patients not using a statin. There was no significant effect of statin use on unadjusted and adjusted phenprocoumon maintenance dose (p=0.23 and p=0.35, respectively). CONCLUSIONS: Mean Acenocoumarol maintenance dosages were decreased when Acenocoumarol is co-administered with the different statins. Statin use does not affect phenprocoumon maintenance doses significantly.
