A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon.

BACKGROUND: Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy. METHODS: We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks. RESULTS: A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events. CONCLUSIONS: Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. (Funded by the European Commission Seventh Framework Programme and others; EU-PACT ClinicalTrials.gov numbers, NCT01119261 and NCT01119274.).

Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon.

Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials.

Beliefs about medicines in Dutch acenocoumarol and phenprocoumon users.

AIMS: Adherence to the generally complex regimen of coumarin derivatives is vital in order to keep patients in the adequate International Normalized Ratio range. Patients' beliefs about medicines are associated with the level of therapy adherence. Our first aim was to assess beliefs about coumarins. Secondly, we compared the beliefs about coumarins with the beliefs about other cardiovascular drugs. METHODS: The Beliefs about Medicines Questionnaire was used to assess medication beliefs. The questionnaire was completed by new users of coumarins indicated for venous thromboembolism or atrial fibrillation. A necessity score and a concerns score were calculated for all patients. The analyses were repeated for users of antihypertensive drugs or statins (not using coumarins). RESULTS: Three hundred and twenty patients were included in the analysis of the beliefs about coumarins. The mean necessity score was 15.3, the concerns score 12.3 and the necessity-concerns differential 3.0. Patients with venous thromboembolism (n = 71) had higher necessity scores than patients with atrial fibrillation (n = 249; 16.8 vs. 14.9, P < 0.001). The mean necessity score in 493 users of other cardiovascular drugs was 16.1, the concerns score 13.5 and the necessity-concerns differential 2.6. The necessity score was higher in chronic cardiovascular drug users (n = 192) than in new users (n = 301; 17.9 vs. 14.9, P < 0.001). CONCLUSIONS: Coumarin users score higher on the necessity scale than on the concerns scale, which is also the case in users of other cardiovascular drugs. Patients with atrial fibrillation have a less positive attitude towards these drugs than patients with venous thromboembolism, and could therefore benefit more from specific attention.

Evaluation of the effect of statin use on the acenocoumarol and phenprocoumon maintenance dose.

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.

Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data.

AIMS: Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE. METHODS AND RESULTS: 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. CONCLUSION: 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.

Immunological risk of injectable drug delivery systems.

Injectable drug delivery systems (DDS) such as particulate carriers and water-soluble polymers are being used and developed for a wide variety of therapeutic applications. However, a number of immunological risks with serious clinical implications are associated with administration of DDS. These immunological events can compromise the efficacy and safety of these systems by changing the pharmacokinetics, biodistribution and targeting capability of DDS, and by inducing hypersensitivity reactions. Antibodies induced by administration of DDS can be directed against the carrier material, the drug and/or targeting ligands associated with the DDS. Complement activation and opsonization of DDS, which may or may not be associated with antibody formation, may lead to accelerated clearance, hypersensitivity reactions and formation of membrane attack complexes resulting in premature release of the drug. Also platelets have been reported to play a role in DDS immunogenicity. Despite our curtailed understanding of the relationships between physicochemical characteristics and immunogenicity of DDS, several risk factors have been identified. Insight into these factors should be employed in the development of novel DDS with low immunological risk.

Evaluation of the effect of genetic variations in GATA-4 on the phenprocoumon and acenocoumarol maintenance dose.

AIM: To investigate whether the phenprocoumon and acenocoumarol maintenance doses are influenced by genetic variations in GATA-4, a transcription factor of CYP2C9. PATIENTS & METHODS: The influence of seven GATA-4 SNPs on the coumarin maintenance dose was investigated by performing an analysis of variance trend analysis, stratified for CYP2C9 genotypes. Results of the best-explaining SNP were validated in the Rotterdam Study cohort. RESULTS: The largest dose differences were found for rs3735814 in patients using acenocoumarol and having the common allele for CYP2C9. The mean dosages decreased from 2.92 mg/day for the patients having the GATA-4 common alleles to 2.65 mg/day for the patients carrying one GATA-4 variant allele and to 2.37 mg/day for patients carrying two GATA-4 variant alleles (p = 0.004). Results could not be replicated in the validation cohort. For phenprocoumon, no significant effects were observed. CONCLUSION: Genetic variation in GATA-4 does not seem relevant for clinical implementation.

Validation of the acenocoumarol EU-PACT algorithms: similar performance in the Rotterdam Study cohort as in the original study.

AIM: To evaluate the performance of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) acenocoumarol dose algorithms in an independent data set. The EU-PACT trial investigates the added value of pretreatment genotyping for use of warfarin, phenprocoumon and acenocoumarol. PATIENTS & METHODS: External validation was performed in the Rotterdam Study cohort using information about 707 acenocoumarol users. R(2), which measures the strength of correlation between the predicted and observed acenocoumarol dose, mean absolute error and mean squared error were calculated to evaluate the performance of the original algorithm. RESULTS: Validation resulted in a R(2) of 52.7 and 12.9% compared with an R(2) of 52.6 and 17.8% in the original study for the genotype-guided and nongenotype-guided dose algorithm, respectively. For the genotype-guided dose algorithm, the mean absolute error was 0.48 mg/day and the mean squared error was 0.38 (mg/day)(2). For the nongenotype-guided dose algorithm, the mean absolute error was 0.62 mg/day and the mean squared error was 0.63 (mg/day)(2). CONCLUSION: The EU-PACT acenocoumarol algorithm performs just as accurately in this study as in the original study, which implies applicability in various populations.

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

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.

Conference Scene: Pharmacogenomics at the second PharmSciFair 2009: adverse drug reactions and clinical implementation.

From 8th to 12th June 2009, the second PharmSciFair took place in Nice, France. Sessions were organized on different types of pharmaceutical research. Two pharmacogenomics sessions were organized by the European Federation for Pharmaceutical Sciences Network on Research in Pharmacogenetics/Pharmacogenomics. The topics of the sessions were adverse drug reactions and clinical implementation. Important conclusions of the presentations were that there has been much progress in the field of pharmacogenomics and that implementation in clinical practice is not as easy as it was once thought. Large prospective trials might be necessary to prove clinical relevance.

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

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.