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Edeltraut Garbe - One of the best experts on this subject based on the ideXlab platform.
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drug interactions with Phenprocoumon and the risk of serious haemorrhage a nested case control study in a large population based german database
European Journal of Clinical Pharmacology, 2011Co-Authors: Kathrin Jobski, Sigrid Behr, Edeltraut GarbeAbstract:Purpose Phenprocoumon is the most frequently used vitamin K antagonist in Germany. The aim of this study was to estimate the risk of serious bleeding as a result of the use of drugs with potential interaction with Phenprocoumon.
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risk of intracerebral hemorrhage associated with Phenprocoumon exposure a nested case control study in a large population based german database
Pharmacoepidemiology and Drug Safety, 2010Co-Authors: Sigrid Behr, Frank Andersohn, Edeltraut GarbeAbstract:PURPOSE: Intracerebral hemorrhage (ICH) is the most serious complication of oral anticoagulation. This study investigated the risk of ICH for Phenprocoumon which is the most widely used oral anticoagulant in Germany. METHODS: We conducted a nested case-control study in a cohort of 13.4 million insurants of 4 German statutory health insurances (SHIs) who were continuously enrolled for 6 months prior to cohort entry. Cases were patients hospitalized for ICH. Ten controls were matched to each case by SHI, birth year, and sex using incidence density sampling. Rate ratios (RR) of ICH for current Phenprocoumon use as compared to non-use were estimated from odds ratios calculated by conditional logistic regression analyses considering multiple risk factors. RESULTS: Analysis of the full cohort revealed a strong increase in incidence of ICH with increasing age. In the nested case-control study including 8138 cases of ICH and 81,373 matched controls, we observed an increased risk of ICH for current Phenprocoumon exposure that varied with age. The Phenprocoumon-associated risk of ICH was lower in older age groups with RRs from 4.20 (95% confidence interval (CI) 2.44-7.21) for Phenprocoumon users less than 55 years of age to 2.43 (95%CI, 1.81-3.27) for those older than 85 years. Our study confirmed known risk factors of ICH. DISCUSSION: Phenprocoumon exposure was associated with an increased risk of ICH. The interaction of risk for Phenprocoumon with age was unexpected and needs further study.
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: R M F Van Schie, Talitha I Verhoef, Tom Schalekamp, Judith A M Wessels, F J M Van Der Meer, A M V Babajeff, Le S Cessie, A De Boer, E Van Meegen, 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, Frits R Rosendaal, Felix J M Van Der Meer, Saskia Le Cessie, Talitha I Verhoef, Tom Schalekamp, Saskia B Boejharat, Judith A M Wessels, 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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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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therapeutic quality control of oral anticoagulant therapy comparing the short acting acenocoumarol and the long acting Phenprocoumon
British Journal of Haematology, 2002Co-Authors: Alain P A Gadisseur, Felix J M Van Der Meer, Henk J Adriaansen, Stephan D Fihn, Frits R RosendaalAbstract:Summary. To investigate whether the different pharmacokinetics of acenocoumarol (t1/2 = 11 h) and Phenprocoumon (t1/2 = 140 h) result in a different quality of anticoagulation, we studied patients from the Leiden anticoagulation clinic treated between 1998 and 1999 for more than 16 weeks. Two hundred and twenty-eight pairs were closely matched for indication for oral anticoagulant therapy (OAT), age, sex and date of start of treatment. Four hundred and fifty six patients with 7245 International Normalized Ratio (INR) checks yielded 230 patient-years. Quality of OAT calculated over the whole treatment period was higher with Phenprocoumon as expressed by the number of INR checks in the therapeutic range (Phenprocoumon: 42·7%, acenocoumarol: 36·5%, difference: 6·1%, CI95 of the difference: 3·0–9·3%) and by time in range (Phenprocoumon: 46·6%, acenocoumarol: 41·6%, difference: 5·0%, CI95 of the difference: 1·3–8·6%). After the initial 6 weeks of OAT, the differences became more pronounced (difference: 6·1%, CI95: 1·8–10·4%). The incidence of severe bleeding complications was similar (Phenprocoumon: 0·04/patient/year vs acenocoumarol: 0·03/patient/year) with a slight excess of minor bleeds with Phenprocoumon (0·19/patient/year vs 0·06/patient/year). We conclude that Phenprocoumon leads to a better quality of OAT than acenocoumarol. As there is no difference in major bleeding complications and only a small difference in minor bleeding complications, Phenprocoumon is preferable to acenocoumarol for prolonged OAT.
Felix J M Van Der Meer - One of the best experts on this subject based on the ideXlab platform.
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effects of age and genetic variations in vkorc1 cyp2c9 and cyp3a4 on the Phenprocoumon dose in pediatric patients
Pharmacogenomics, 2018Co-Authors: H Maagdenberg, Felix J M Van Der Meer, Marc B Bierings, Heleen C Van Ommen, Inge M Appel, Rienk Y J Tamminga, Saskia Le Cessie, Jesse J Swen, Tahar Van Der Straaten, Anthonius De BoerAbstract:AIM: To study the effects of clinical and genetic factors on the Phenprocoumon dose requirement in pediatric patients and to develop a dosing algorithm. METHODS: Pediatric patients who used Phenprocoumon were invited to participate in a retrospective follow-up study. Clinical information and genotypes of genetic variations in CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected and tested with linear regression for association with Phenprocoumon dose requirement. RESULTS: Of the 41 patients included in the analysis, age, VKORC1, CYP2C9*2/*3 and CYP3A4*1B were statistically significantly associated with dose requirement, and together explained 80.4% of the variability in Phenprocoumon dose requirement. CONCLUSION: Our study reveals that age and genetic variations explain a significant part of the variability in Phenprocoumon dose requirement in pediatric patients.
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the effect of omeprazole and esomeprazole on the maintenance dose of Phenprocoumon
British Journal of Clinical Pharmacology, 2012Co-Authors: Talitha I Verhoef, Felix J M Van Der Meer, Saskia Le Cessie, Miranda J L Zuurhout, Rianne M F Van Schie, W K Redekop, Tom Schalekamp, Anthonius De BoerAbstract:The response to vitamin K antagonists (VKAs) is determined by many different factors like age, weight, height, vitamin K intake and genetic polymorphisms [1]. The proton pump inhibitors (PPIs) omeprazole and esomeprazole may enhance the effect of VKAs by inhibition of the hepatic metabolism of coumarins [2]. Some isolated cases have been reported of clinically significant elevated INRs in patients concomitantly using omeprazole and Phenprocoumon, a VKA frequently used in Europe [3]. Practical experience suggests an interaction between omeprazole or esomeprazole and Phenprocoumon, but scientific evidence is still lacking. Van Schie et al. developed a dosing algorithm including age, gender, height, weight, CYP2C9 and VKORC1 genotypes and amiodarone use and a dosing algorithm without the genotypes to predict the Phenprocoumon maintenance dose [4]. Given the possibility that omeprazole use affects the stable Phenprocoumon maintenance dose, we examined whether information about its use would improve the predictive value of a dosing algorithm. Data from the pre-EU-PACT study were used to study the effect of omeprazole and esomeprazole on the stable Phenprocoumon maintenance dose [4]. More details about this study can be found elsewhere [4]. The main outcome measure of the present study was the mean stable Phenprocoumon maintenance dose in mg day−1 in the first stable period after initiation of Phenprocoumon therapy. Only patients who reached a stable dose within 1 year were included in the analyses. Multiple linear regression analysis was used to develop a genotype-guided algorithm and a non-genotype-guided algorithm to estimate the square root of the weekly Phenprocoumon maintenance dose. We included the same predictive variables used by van Schie et al. [4], but added an extra variable for omeprazole or esomeprazole use. A stable maintenance dose was reached within 1 year by 597 patients. Of these, 46 patients used omeprazole and 18 patients used esomeprazole. On average, non-users required 2.27 mg (SD 0.90) Phenprocoumon day−1, significantly higher than the average dose seen in both omeprazole users (1.78 mg day−1, SD 0.73, 95% CI of the difference 0.22, 0.75) and esomeprazole users (1.88 mg day−1, SD 0.52, 95% CI of the difference 0.12, 0.66)). Since the Phenprocoumon dose was not significantly different between omeprazole and esomeprazole users (95% CI of the difference −0.47, 0.28), we combined them into one group for inclusion in the algorithm. Five hundred and eighty-seven Phenprocoumon users were included in the analysis of the non-genotype-guided algorithm and 559 for the genotype-guided algorithm. Omeprazole/esomeprazole use significantly influenced the Phenprocoumon maintenance dose in the genotype-guided algorithm (P= 0.002) and the non-genotype-guided algorithm (P= 0.001) (Table 1). The genotype-guided algorithm was as follows: Table 1 Algorithms to predict stable Phenprocoumon maintenance dose SQRT (maintenance dose (mg week−1) = 2.870–0.254 (if CYP2C9*1/*2) – 0.356 (if CYP2C9*1/*3) – 0.431 (if CYP2C9*2/*2) – 0.708 (if CYP2C9*2/*3) – 0.693 (if CYP2C9*3/*3) – 0.594 (if VCORC1 CT) – 1.371 (if VCORC1 TT) – 0.015 × Age (years) + 0.034 (if female) + 0.009 × Weight (kg) + 0.011 × Height (cm) – 0.315 (if amiodarone use) – 0.234 (if omeprazole/esomeprazole use). With this genotype-guided algorithm, 56.7% of dose variation could be explained, 0.8% more than in the study of van Schie et al. [4]. With our non-genotype-guided algorithm, the predictive value was 18.9%, 1.6% more than the algorithm of van Schie et al. [4]. The information obtained in this study could help physicians determine the right Phenprocoumon dose for patients. If a patient is already using omeprazole or esomeprazole when Phenprocoumon treatment is started, the dosing algorithm can be used to predict the required dose. If a patient starts using omeprazole or esomeprazole during Phenprocoumon treatment the dose of Phenprocoumon should be lowered. This could help prevent overanticoagulation and thereby reduce the risk of bleeding events when Phenprocoumon and omeprazole or esomeprazole are used simultaneously. In this study we observed a lower Phenprocoumon dose requirement in omeprazole and esomeprazole users and developed a dosing algorithm using this information. We only demonstrated the effect of omeprazole and esomeprazole. An interaction between Phenprocoumon and other PPIs should be investigated in future research.
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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, Frits R Rosendaal, Felix J M Van Der Meer, Saskia Le Cessie, Talitha I Verhoef, Tom Schalekamp, Saskia B Boejharat, Judith A M Wessels, 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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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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therapeutic quality control of oral anticoagulant therapy comparing the short acting acenocoumarol and the long acting Phenprocoumon
British Journal of Haematology, 2002Co-Authors: Alain P A Gadisseur, Felix J M Van Der Meer, Henk J Adriaansen, Stephan D Fihn, Frits R RosendaalAbstract:Summary. To investigate whether the different pharmacokinetics of acenocoumarol (t1/2 = 11 h) and Phenprocoumon (t1/2 = 140 h) result in a different quality of anticoagulation, we studied patients from the Leiden anticoagulation clinic treated between 1998 and 1999 for more than 16 weeks. Two hundred and twenty-eight pairs were closely matched for indication for oral anticoagulant therapy (OAT), age, sex and date of start of treatment. Four hundred and fifty six patients with 7245 International Normalized Ratio (INR) checks yielded 230 patient-years. Quality of OAT calculated over the whole treatment period was higher with Phenprocoumon as expressed by the number of INR checks in the therapeutic range (Phenprocoumon: 42·7%, acenocoumarol: 36·5%, difference: 6·1%, CI95 of the difference: 3·0–9·3%) and by time in range (Phenprocoumon: 46·6%, acenocoumarol: 41·6%, difference: 5·0%, CI95 of the difference: 1·3–8·6%). After the initial 6 weeks of OAT, the differences became more pronounced (difference: 6·1%, CI95: 1·8–10·4%). The incidence of severe bleeding complications was similar (Phenprocoumon: 0·04/patient/year vs acenocoumarol: 0·03/patient/year) with a slight excess of minor bleeds with Phenprocoumon (0·19/patient/year vs 0·06/patient/year). We conclude that Phenprocoumon leads to a better quality of OAT than acenocoumarol. As there is no difference in major bleeding complications and only a small difference in minor bleeding complications, Phenprocoumon is preferable to acenocoumarol for prolonged OAT.
Sigrid Behr - One of the best experts on this subject based on the ideXlab platform.
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drug interactions with Phenprocoumon and the risk of serious haemorrhage a nested case control study in a large population based german database
European Journal of Clinical Pharmacology, 2011Co-Authors: Kathrin Jobski, Sigrid Behr, Edeltraut GarbeAbstract:Purpose Phenprocoumon is the most frequently used vitamin K antagonist in Germany. The aim of this study was to estimate the risk of serious bleeding as a result of the use of drugs with potential interaction with Phenprocoumon.
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risk of intracerebral hemorrhage associated with Phenprocoumon exposure a nested case control study in a large population based german database
Pharmacoepidemiology and Drug Safety, 2010Co-Authors: Sigrid Behr, Frank Andersohn, Edeltraut GarbeAbstract:PURPOSE: Intracerebral hemorrhage (ICH) is the most serious complication of oral anticoagulation. This study investigated the risk of ICH for Phenprocoumon which is the most widely used oral anticoagulant in Germany. METHODS: We conducted a nested case-control study in a cohort of 13.4 million insurants of 4 German statutory health insurances (SHIs) who were continuously enrolled for 6 months prior to cohort entry. Cases were patients hospitalized for ICH. Ten controls were matched to each case by SHI, birth year, and sex using incidence density sampling. Rate ratios (RR) of ICH for current Phenprocoumon use as compared to non-use were estimated from odds ratios calculated by conditional logistic regression analyses considering multiple risk factors. RESULTS: Analysis of the full cohort revealed a strong increase in incidence of ICH with increasing age. In the nested case-control study including 8138 cases of ICH and 81,373 matched controls, we observed an increased risk of ICH for current Phenprocoumon exposure that varied with age. The Phenprocoumon-associated risk of ICH was lower in older age groups with RRs from 4.20 (95% confidence interval (CI) 2.44-7.21) for Phenprocoumon users less than 55 years of age to 2.43 (95%CI, 1.81-3.27) for those older than 85 years. Our study confirmed known risk factors of ICH. DISCUSSION: Phenprocoumon exposure was associated with an increased risk of ICH. The interaction of risk for Phenprocoumon with age was unexpected and needs further study.
C Haanen - One of the best experts on this subject based on the ideXlab platform.
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a comparative study concerning the stability of the anticoagulant effect of acenocoumarol and Phenprocoumon
Acta Medica Scandinavica, 2009Co-Authors: W P M Breed, J P Hooff, C HaanenAbstract:Abstract Two comparable groups, each of which comprised 41 patients, were treated with long-acting Phenprocoumon and short-acting acenocoumarol, respectively, for six months. When Phenprocoumon was used, a significantly more stable anticoagulant effect was seen. This was reflected by a greater percentage of thrombotest values within the intended therapeutic zone ranging from 5 to 10% thrombotest activity, inclusive. Moreover, there was a difference in the facility with which patients could be kept in the therapeutic range: the number of alterations that had to be made in maintenance dose and control interval was less with Phenprocoumon than with acenocoumarol.
