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Bruno H. Stricker - One of the best experts on this subject based on the ideXlab platform.
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allelic variants of cytochrome p450 2c9 modify the interaction between nonsteroidal anti inflammatory drugs and Coumarin Anticoagulants
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Loes E. Visser, Ron H.n. Van Schaik, Albert Hofman, Peter A. G. M. De Smet, Martin H Van Vliet, Arnold G Vulto, Cornelia M Van Duijn, Paul H Trienekens, Bruno H. StrickerAbstract: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.
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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.
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the risk of bleeding complications in patients with cytochrome p450 cyp2c9 2 or cyp2c9 3 alleles on acenocoumarol or phenprocoumon
Thrombosis and Haemostasis, 2004Co-Authors: Loes E. Visser, Albert Hofman, Peter A. G. M. De Smet, Arnold G Vulto, Ron H N Van Schaik, Martin H Van Vliet, Paul H Trienekens, Cornelia M Van Duijn, Bruno H. StrickerAbstract: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 treatmentyears, 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.
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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, Albert Hofman, Peter A. G. M. De Smet, A A Kasbergen, Arnold G Vulto, Ron H N Van Schaik, Martin H Van Vliet, 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
Loes E. Visser - One of the best experts on this subject based on the ideXlab platform.
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allelic variants of cytochrome p450 2c9 modify the interaction between nonsteroidal anti inflammatory drugs and Coumarin Anticoagulants
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Loes E. Visser, Ron H.n. Van Schaik, Albert Hofman, Peter A. G. M. De Smet, Martin H Van Vliet, Arnold G Vulto, Cornelia M Van Duijn, Paul H Trienekens, Bruno H. StrickerAbstract: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.
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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.
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the risk of bleeding complications in patients with cytochrome p450 cyp2c9 2 or cyp2c9 3 alleles on acenocoumarol or phenprocoumon
Thrombosis and Haemostasis, 2004Co-Authors: Loes E. Visser, Albert Hofman, Peter A. G. M. De Smet, Arnold G Vulto, Ron H N Van Schaik, Martin H Van Vliet, Paul H Trienekens, Cornelia M Van Duijn, Bruno H. StrickerAbstract: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 treatmentyears, 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.
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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, Albert Hofman, Peter A. G. M. De Smet, A A Kasbergen, Arnold G Vulto, Ron H N Van Schaik, Martin H Van Vliet, 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
Albert Hofman - One of the best experts on this subject based on the ideXlab platform.
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allelic variants of cytochrome p450 2c9 modify the interaction between nonsteroidal anti inflammatory drugs and Coumarin Anticoagulants
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Loes E. Visser, Ron H.n. Van Schaik, Albert Hofman, Peter A. G. M. De Smet, Martin H Van Vliet, Arnold G Vulto, Cornelia M Van Duijn, Paul H Trienekens, Bruno H. StrickerAbstract: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.
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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.
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the risk of bleeding complications in patients with cytochrome p450 cyp2c9 2 or cyp2c9 3 alleles on acenocoumarol or phenprocoumon
Thrombosis and Haemostasis, 2004Co-Authors: Loes E. Visser, Albert Hofman, Peter A. G. M. De Smet, Arnold G Vulto, Ron H N Van Schaik, Martin H Van Vliet, Paul H Trienekens, Cornelia M Van Duijn, Bruno H. StrickerAbstract: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 treatmentyears, 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.
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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, Albert Hofman, Peter A. G. M. De Smet, A A Kasbergen, Arnold G Vulto, Ron H N Van Schaik, Martin H Van Vliet, 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
Arnold G Vulto - One of the best experts on this subject based on the ideXlab platform.
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allelic variants of cytochrome p450 2c9 modify the interaction between nonsteroidal anti inflammatory drugs and Coumarin Anticoagulants
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Loes E. Visser, Ron H.n. Van Schaik, Albert Hofman, Peter A. G. M. De Smet, Martin H Van Vliet, Arnold G Vulto, Cornelia M Van Duijn, Paul H Trienekens, Bruno H. StrickerAbstract: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.
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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.
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the risk of bleeding complications in patients with cytochrome p450 cyp2c9 2 or cyp2c9 3 alleles on acenocoumarol or phenprocoumon
Thrombosis and Haemostasis, 2004Co-Authors: Loes E. Visser, Albert Hofman, Peter A. G. M. De Smet, Arnold G Vulto, Ron H N Van Schaik, Martin H Van Vliet, Paul H Trienekens, Cornelia M Van Duijn, Bruno H. StrickerAbstract: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 treatmentyears, 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.
-
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, Albert Hofman, Peter A. G. M. De Smet, A A Kasbergen, Arnold G Vulto, Ron H N Van Schaik, Martin H Van Vliet, 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
Peter A. G. M. De Smet - One of the best experts on this subject based on the ideXlab platform.
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allelic variants of cytochrome p450 2c9 modify the interaction between nonsteroidal anti inflammatory drugs and Coumarin Anticoagulants
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Loes E. Visser, Ron H.n. Van Schaik, Albert Hofman, Peter A. G. M. De Smet, Martin H Van Vliet, Arnold G Vulto, Cornelia M Van Duijn, Paul H Trienekens, Bruno H. StrickerAbstract: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.
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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.
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the risk of bleeding complications in patients with cytochrome p450 cyp2c9 2 or cyp2c9 3 alleles on acenocoumarol or phenprocoumon
Thrombosis and Haemostasis, 2004Co-Authors: Loes E. Visser, Albert Hofman, Peter A. G. M. De Smet, Arnold G Vulto, Ron H N Van Schaik, Martin H Van Vliet, Paul H Trienekens, Cornelia M Van Duijn, Bruno H. StrickerAbstract: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 treatmentyears, 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.
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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, Albert Hofman, Peter A. G. M. De Smet, A A Kasbergen, Arnold G Vulto, Ron H N Van Schaik, Martin H Van Vliet, 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
