Verhoef, T.I.

Long-term anticoagulant effects of CYP2C9 and VKORC1 genotypes in phenprocoumon users (Article)

2012-12-01T00:00:00Z

Anticoagulant treatment with phenprocoumon is challenging because of the narrow therapeutic range and the wide inter- and intra-patient variability in dose response. Frequent monitoring of the international normalized ratio (INR) is therefore required. Polymorphisms in two genes, CYP2C9 and VKORC1 explain approximately one third of the variation in dose requirements [1-3]. CYP2C9 encodes the main metabolizing enzyme of coumarins, the cytochrome P450 2C9 enzyme (CYP2C9), while VKORC1 encodes the pharmacodynamic target enzyme for coumarins, vitamin K epoxide reductase multiprotein complex 1 (VKORC1).

The effect of omeprazole and esomeprazole on the maintenance dose of phenprocoumon (Letter To Editor)

2012-12-01T00:00:00Z

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.

Cost-effectiveness of pharmacogenetics in anticoagulation: International differences in healthcare systems and costs (Article)

2012-09-01T00:00:00Z

Genotyping patients for CYP2C9 and VKORC1 polymorphisms can improve the accuracy of dosing during the initiation of anticoagulation with vitamin K antagonists (coumarin derivatives). The anticipated degree of improvement in the safety of anticoagulation with coumarins through genotyping may vary depending on the quality of patient care, which varies both with and among countries. The management and the cost of anticoagulant care can therefore influence the cost-effectiveness of genotyping within any given country. In this article, we provide an overview of the cost-effectiveness of pharmacogenetics-guided dosing of coumarin derivatives. We describe the organization of anticoagulant care in the UK, Sweden, The Netherlands, Greece, Germany and Austria, where a genotype-guided dosing algorithm is currently being investigated as part of the EU-PACT trial. We also explore the costs of anticoagulant care for the treatment of atrial fibrillation in these countries.

Long-term anticoagulant effects of the CYP2C9 and VKORC1 genotypes in acenocoumarol users (Article)

2012-04-01T00:00:00Z

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

Future of Pharmacogenetics in Cardiovascular Diseases (In Book)

2012-01-01T00:00:00Z

Introduction: Pharmacogenetics is the study of variations in DNA sequence as related to drug response (European Medicines Agency [EMA], 2007). Several gene-drug interactions have been discovered in the field of cardiovascular diseases (CVDs). These gene-drug interactions can help to identify nonresponse to drugs, estimate dose requirements or identify an increased risk of developing adverse drug reactions. An individualized approach based on pharmacogenetic testing will provide physicians and pharmacists with tools for decision making about pharmacotherapy. While pharmacogenetic testing is already part of everyday practice in oncology, it is not widely implemented in the field of CVDs. However, in the near future, pharmacogenetics will probably also play a valuable role in this field as well.

Clinical and economic consequences of pharmacogenetic-guided dosing of warfarin (Article)

2010-08-01T00:00:00Z

Patients using warfarin for oral anticoagulant therapy need to be frequently monitored because of warfarins narrow therapeutic range and the large variation in dose requirements among patients. Patients receiving the wrong dose have an increased risk of bleeding or thromboembolic events. The required dose is influenced by environmental factors, such as gender, age, diet and concomitant medication, as well as genetic factors. Pharmacogenetic testing prior to warfarin initiation might improve dosing accuracy and, therefore, safety and efficacy of warfarin treatment. Meckley et al. studied the clinical consequences and costs of genotyping before warfarin treatment. The results of their study suggest that pharmacogenetic-guided dosing of patients initiating warfarin could improve health (quality-adjusted life-years) but at a high cost per quality-adjusted life-year gained. Owing to the inevitable assumptions that have to be made in all cost-effectiveness models, great uncertainty remains regarding the cost-effectiveness of pharmacogenetic-guided warfarin dosing.

A systematic review of cost-effectiveness analyses of pharmacogenetic- guided dosing in treatment with coumarin derivatives (Article)

2010-07-01T00:00:00Z

Anticoagulant therapy with coumarin derivatives is often sub-or supra-therapeutic, resulting in an increased risk of thromboembolic events or hemorrhage, respectively. Pharmacogenetic-guided dosing has been proposed as an effective way of reducing bleeding rates. Clinical trials to confirm the safety, efficacy and effectiveness of this strategy are ongoing, but in addition, it is also necessary to consider the cost-effectiveness of this strategy. This article describes the findings of a systematic review of published cost-effectiveness analyses of pharmacogenetic-guided dosing of coumarin derivatives. Similarities and differences in the approaches used were examined and the quality of the analyses was assessed. The results of the analyses are not sufficient to determine whether or not pharmacogenetic-guided dosing of coumarins is cost effective. More reliable cost-effectiveness estimates need to become available before it is possible to recommend whether or not this strategy should be applied in clinical practice.

Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design (Article)

2009-10-01T00:00:00Z

The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.