E van Meegen

Maastricht University, Maestricht, Limburg, Netherlands

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Publications (16)136.22 Total impact

  • European Heart Journal 04/2013; · 14.10 Impact Factor
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    ABSTRACT: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures. 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. 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. No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures. 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.
    Journal of Thrombosis and Haemostasis 03/2012; 10(5):767-72. · 6.08 Impact Factor
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    ABSTRACT: 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 dose, we aimed to develop algorithms for PHE and ACE. In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters. To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.
    European Heart Journal 06/2011; 32(15):1909-17. · 14.10 Impact Factor
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    ABSTRACT: Poor anticoagulant stability in patients using vitamin K antagonists is a risk factor for both bleeding and thrombosis. In previous studies supplementation with low dose vitamin K(1) was shown to improve the stability of anticoagulant control. We set up a study to confirm earlier reports and to determine the optimal daily dose of vitamin K(1) in preparation of a large study with clinical endpoints. Four hundred patients from two anticoagulation clinics starting with vitamin K antagonists, independently of a possible history of instable anticoagulation, were randomized to receive either placebo or 100, 150 or 200 μg of vitamin K(1) together with their treatment with vitamin K antagonists. The treatment was administered for 6 to 12 months. Anticoagulation stability, expressed as the percentage of time that the International Normalized Ratio was within the therapeutic range, was compared between the groups. After adjustment for age, sex, vitamin K antagonist used, anticoagulation clinic and interacting drugs as confounding factors the difference in percentage of time with the International Normalized Ratio within the therapeutic range between the placebo group and the vitamin K(1) groups was 2.1% (95% CI: -3.2% - 7.4%) for the group taking 100 μg, 2.7% (95% CI: -2.3% -7.6%) for the group taking 150 μg and 0.9% (95% CI: -4.5% - 6.3%) for the group taking 200 μg vitamin K(1) group, in favor of the vitamin K(1) groups. The patients from both the 100 μg group and the 150 μg group had a 2-fold higher chance of reaching at least 85% of time with the International Normalized Ratio within the therapeutic range. There were no differences in thromboembolic or hemorrhagic complications between the groups. In patients starting vitamin K antagonists, supplementation with low dose vitamin K(1) resulted in an improvement of time that anticoagulation was within the therapeutic range. Differences between doses were, however, small and the improvement is unlikely to be of clinical relevance. For future studies we recommend selecting only patients with instable anticoagulant control. (This study was registered at www.isrctn.org as ISRCTN37109430).
    Haematologica 12/2010; 96(4):583-9. · 5.94 Impact Factor
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    ABSTRACT: In a prospective follow-up study of the effects of VKORC1 and CYP2C9 genotypes on the anticoagulation status of patients, we assessed the CYP2C9 and the VKORC1 C1173T genotypes of patients during the initial 6 months of phenprocoumon treatment. We used linear regression models and Cox proportional hazard models to determine the effects of the VKORC1 and CYP2C9 genotypes on phenprocoumon dose requirements, overanticoagulation, and time to achieve stability. Allele frequencies of interest within the cohort (N=281) were 40.8% VKORC1 T-1173, 12.8% CYP2C9*2, and 6.9% CYP2C9*3. In patients with the VKORC1 CC genotype, carriers of a CYP2C9 polymorphism needed dosages that were nearly 30% lower than those for CYP2C9*1/*1 patients (P<0.001). In patients with a VKORC1 polymorphism, differences between carriers of a CYP2C9 polymorphism and CYP2C9*1/*1 were far smaller and largely not statistically significant. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (28.7% and 7.2%, respectively). Carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had a strongly increased risk of severe overanticoagulation (hazard ratio (HR) 7.20, P=0.002). Only carriers of a CYP2C9*2 allele had a decreased chance to achieve stability compared to CYP2C9*1/*1 patients (HR 0.61, P=0.004). In conclusion, the VKORC1 genotype modifies the effect of the CYP2C9 genotype on phenprocoumon dose requirements. A combination of polymorphisms of both genotypes is associated with a strongly increased risk of overanticoagulation, whereas delayed stabilization is mainly associated with the CYP2C9 genotype.
    Clinical Pharmacology &#38 Therapeutics 02/2007; 81(2):185-93. · 6.85 Impact Factor
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    ABSTRACT: Our objective was to assess whether there is an association between the presence of allelic variants of the gene for cytochrome P450 (CYP) 2C9 and anticoagulation problems during the initial phase of phenprocoumon treatment. A prospective follow-up study was performed at 2 anticoagulation clinics in The Netherlands. Included subjects started phenprocoumon during the study period, had their first check of the international normalized ratio (INR) on the third or fourth day of therapy, and had an indication for the low therapeutic range (INR, 2.0-3.5). CYP2C9 genotypes ( CYP2C9*1 , CYP2C9*2 , and CYP2C9*3 ) were assessed, and data on indication, INR checks, comedication, and comorbidity were collected. After genotyping, 284 subjects were available for analysis. Of these, 186 (65.5%) were homozygous carriers of the CYP2C9 wild-type allele ( CYP2C9*1/*1 ), 61 (21.5%) were carriers of the CYP2C9*2 allele, and 37 (13.0%) were carriers of the CYP2C9*3 allele. Compared with homozygous CYP2C9*1/*1 subjects, carriers of CYP2C9*2 or *3 had an increased risk of severe overanticoagulation (INR >6.0). The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 3.09 (95% confidence interval [CI], 1.56 to 6.13; P=.001), and the hazard ratio for CYP2C9*3 versus CYP2C9*1/*1 was 2.40 (95% CI, 1.03 to 5.57; P=.042). Carriers of CYP2C9*2 also had a lower chance to achieve stability in the follow-up period. The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 0.61 (95% CI, 0.43 to 0.85; P=.003). Carriers of the CYP2C9*2 or *3 allele needed a significantly lower phenprocoumon dosage compared with homozygous CYP2C9*1/*1 subjects. The presence of at least 1 CYP2C9*2 or *3 allele in phenprocoumon users is associated with an increased risk of severe overanticoagulation. Similar to warfarin and acenocoumarol, phenprocoumon had a lower dosage requirement in carriers of CYP2C9*2 or *3 compared with that in CYP2C9 wild-type subjects.
    Clinical Pharmacology &#38 Therapeutics 11/2004; 76(5):409-17. · 6.85 Impact Factor
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    ABSTRACT: Variability in the control of oral anticoagulant therapy has been associated with a heightened risk of complications. We compared control of anticoagulation between two commonly used coumarins, phenprocoumon and acenocoumarol, and among anticoagulation clinics. All qualifying patients were managed at six regional anticoagulation clinics in the Netherlands. This retrospective cohort study compiled data during a three-year period from a computerised dosing and management system. Anticoagulation control was expressed as the percent of time within the therapeutic range and stability expressed as the time-weighted variance in the international normalised ratio (INR). Data were available for 22,178 patients of whom 72% were treated with acenocoumarol. INRs of patients who received phenprocoumon were within the therapeutic range 50% of the time compared with 43% for acenocoumarol (OR 1.32, 95% CI 1.24-1.41). Moreover, patients on phenprocoumon required 15% fewer monitoring visits and had more stable INR values. These observations were consistent for all six clinics. There were also sizable differences between the clinics with respect to control and stability of anticoagulation that were stable from year-to-year and were unrelated to the drug used. With its longer half-life of three to five days, phenprocoumon produces more stable anticoagulation than acenocoumarol and should generally be the drug of choice when these are the available choices. The differences observed among clinics suggest that certain clinics employ policies and practices resulting in better control of anticoagulation.
    Thrombosis and Haemostasis 09/2003; 90(2):260-6. · 6.09 Impact Factor
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    ABSTRACT: Coumarin anticoagulants impair the biological activity of the vitamin K-dependent procoagulant and anticoagulant proteins. There are no reports that focus on the levels of these proteins in over-anticoagulated patients. Therefore, we determined the levels of factor II, factor VII, factor IX and factor X, protein C and protein S in 25 randomly selected over-anticoagulated patients (International Normalized Ratio >/= 6.0) and in 25 matched, therapeutically anticoagulated patients with an International Normalized Ratio within the therapeutic zone. Furthermore, to study a possible effect of the cause of over-anticoagulation, coagulant levels were compared between 16 over-anticoagulated patients with fever in the preceding 2 weeks and 24 over-anticoagulated patients with stable congestive heart failure. The pattern of procoagulant level reductions in the three groups of over-anticoagulated patients was largely the same as in therapeutically anticoagulated patients: factor X was the lowest and factor IX the highest. The difference was that, in over-anticoagulated patients, factor VII was relatively low among the procoagulant factors compared with therapeutically anticoagulated patients. Protein C was lower than protein S in over-anticoagulated patients with congestive heart failure, but was similar to protein S in the other study groups. In over-anticoagulated patients with fever, the vitamin K-dependent coagulation proteins except factor X were significantly lower than in over-anticoagulated patients with congestive heart failure, especially factor VII and protein S.
    Blood Coagulation and Fibrinolysis 12/2002; 13(8):733-9. · 1.25 Impact Factor
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    ABSTRACT: The risk of hemorrhage when using coumarin anticoagulants sharply increases when the International Normalized Ratio (INR) is > or =6.0. We performed a case-control study among outpatients of an anticoagulation clinic to identify sociodemographic-, lifestyle-, and dietary factors related to overanticoagulation. Three hundred cases with an INR > or =6.0 were compared with 302 randomly selected matched controls with an INR within the target zone. Age, sex, and level of education were not associated with overanticoagulation. Body mass index was negatively related to overanticoagulation, a beneath-average level of physical activity was positively related to overanticoagulation and never-smokers were more likely to have an INR > or =6.0 compared with smokers. Habitual alcohol consumption, even heavy drinking, was not related to overanticoagulation. However, a recent decrease of alcohol intake increased the risk of an INR > or =6.0. In addition, weight loss and a vacation were risk factors for overanticoagulation. Dietary factors were not associated with overanticoaguation. If risk factors can not be avoided, increased monitoring of INR values could prevent overanticoagulation and potential bleeding complications.
    Journal of Clinical Epidemiology 04/2002; 55(4):411-7. · 5.33 Impact Factor
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    ABSTRACT: The risk of hemorrhage when using coumarin anticoagulants sharply increases when the International Normalised Ratio (INR) is > or =6.0. We performed a prospective cohort study with a nested case-control design among 17,056 outpatients of an anticoagulation clinic to determine the incidence of overanticoagulation and to study the association between overanticoagulation and characteristics of anticoagulant therapy and comorbidity. The incidence rate of an INR > or =6.0 was 7.8 per 10,000 treatment days in prevalent users on the starting date and 22.5 per 10,000 treatment days in incident users during the study period. 300 cases with an INR > or =6.0 were compared with 302 randomly selected matched controls with an INR within the target zone. Patients on acenocoumarol had an increased risk of an INR > or =6.0 compared to patients on phenprocoumon. Regarding comorbidity, impaired liver function, congestive heart failure, diarrhea and fever were risk factors for overanticoagulation. Increased monitoring of INR values if risk factors are present or avoidance of risk factors could prevent excess anticoagulation and potential bleeding complications.
    Thrombosis and Haemostasis 09/2001; 86(2):569-74. · 6.09 Impact Factor
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    ABSTRACT: The risk of hemorrhage when coumarin anticoagulants are used sharply increases when the international normalized ratio (INR) is > or = 6.0. Such overanticoagulation may be caused by drug interactions. We performed a case-control study among previously stable outpatients of an anticoagulation clinic using phenprocoumon or acenocoumarol to identify changes in the use of potentially interacting drugs related to overanticoagulation. Three hundred case patients with INR values > or = 6.0 were compared with 302 randomly selected matched control subjects with INR values within the target zone. Information on changes in the use of 87 potentially interacting drugs in the 4 weeks before the index day was collected by interviewing patients and by reviewing the anticoagulant medical record. Forty-five potentially interacting drugs were not used in the 4-week study period, and only 15 drugs were used by at least 10 patients. For a number of drugs, too few patients had a relevant change in use to judge their association with overanticoagulation. A course of a combination product of sulfamethoxazole and trimethoprim strongly increased the risk of overanticoagulation (adjusted odds ratio, 24.2; 95% confidence interval [CI], 2.8 to 209.1; population attributable risk percentage [PAR%], 5.7%), especially in patients receiving acenocoumarol. Penicillins were associated with a risk of overanticoagulation of 2.4 (95% CI, 1.00 to 5.5); the corresponding PAR% was 3.4%. The effect was confined to amoxicillin (INN, amoxicilline) plus clavulanic acid. Drug interactions as a cause of overanticoagulation predominantly concerned antibacterial drugs. If possible, the use of sulfamethoxazole-trimethoprim and amoxicillin plus clavulanic acid should be avoided in patients receiving coumarins. If there is no therapeutic alternative available, increased monitoring of INR values is warranted to prevent overanticoagulation and potential bleeding complications.
    Clinical Pharmacology &#38 Therapeutics 06/2001; 69(6):451-7. · 6.85 Impact Factor
  • Journal of Hepatology 11/1999; 31(4):778-9. · 9.86 Impact Factor
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    ABSTRACT: Oral vitamin K1 is used for the treatment of excessive anticoagulation. Detailed information on changes in the International Normalized Ratio (INR) in response to vitamin K1 is not available. We therefore measured the INR for the first 7 d following the oral intake of 1-5 mg of vitamin K1 in 24 patients routinely treated with phenprocoumon who had an INR > or =6.0 at presentation. On the first 2 d after administration of vitamin K1, the mean INR decreased by 40% and 23% respectively. After day 2, the day-to-day proportional change in the mean INR depended on the dose of vitamin K1 and varied from a decrease of 12% to an increase of 21%. On day 7 the mean INR was higher than on day 2 in three out of five treatment groups. Between day 2 and day 7, in general, 32% of the patients had an INR value within the target zone, 25% had an INR value > or =6.0 and 8% had an INR value <2.0. These findings suggest that our routine treatment of overanticoagulation in patients on phenprocoumon should be intensified to improve its efficacy.
    British Journal of Haematology 02/1999; 104(2):241-5. · 4.94 Impact Factor
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    ABSTRACT: The objective of this study was to investigate whether the central analgesic tramadol influences the effects of the coumarin anticoagulant phenprocoumon during multiple-dose administration. Nineteen patients receiving long-term anticoagulant therapy who had been in a stable hypothrombinemic state for at least 3 months completed a double-blind, placebo-controlled, crossover study. Tramadol was administered in the usual therapeutic dose of 50 mg three times daily. The average daily phenprocoumon dose was identical for individual patients in both treatment periods. The equivalence ratio (tramadol/placebo) of the international normalized ratio (INR) values was 0.99 (90% confidence interval 0.89-1.10), thus fulfilling predetermined bioequivalence criteria (0.70-1.43). Therefore, tramadol does not affect INR in patients being treated with phenprocoumon. These data suggest a lack of interaction between tramadol and coumarin anticoagulants.
    The Journal of Clinical Pharmacology 11/1998; 38(10):966-70. · 2.84 Impact Factor
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    The Lancet 12/1997; 350(9090):1552-3. · 39.06 Impact Factor
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    ABSTRACT: The risk of hemorrhage when using coumarin anticoagulants sharply increases when the International Normalized Ratio (INR) is � 6.0. We per- formed a case-control study among outpatients of an anticoagulation clinic to identify sociodemographic-, lifestyle-, and dietary factors related to overanticoagulation. Three hundred cases with an INR � 6.0 were compared with 302 randomly selected matched controls with an INR within the target zone. Age, sex, and level of education were not associated with overanticoagulation. Body mass index was negatively related to overanticoag- ulation, a beneath-average level of physical activity was positively related to overanticoagulation and never-smokers were more likely to have an INR � 6.0 compared with smokers. Habitual alcohol consumption, even heavy drinking, was not related to overanticoagulation. However, a recent decrease of alcohol intake increased the risk of an INR � 6.0. In addition, weight loss and a vacation were risk factors for overanticoagulation. Di- etary factors were not associated with overanticoaguation. If risk factors can not be avoided, increased monitoring of INR values could prevent over- anticoagulation and potential bleeding complications. © 2002 Elsevier Science Inc. All right reserved.

Publication Stats

289 Citations
136.22 Total Impact Points

Institutions

  • 2002
    • Maastricht University
      Maestricht, Limburg, Netherlands
  • 1999–2002
    • Erasmus Universiteit Rotterdam
      • Department of Internal Medicine
      Rotterdam, South Holland, Netherlands
    • Red Cross
      Washington, Washington, D.C., United States
  • 1997
    • Leiden University
      Leyden, South Holland, Netherlands