title: Dosing algorithms for vitamin K antagonists across VKORC1 and CYP2C9 genotypes.
abstract: Essentials Prospective studies of pharmacogenetic-guided (PG) coumarin dosing produced varying results. EU-PACT acenocoumarol and phenprocoumon trials compared PG and non-PG dosing algorithms. Sub-analysis of EU-PACT identified differences between trial arms across VKORC1-CYP2C9 groups. Adjustment of the PG algorithm might lead to a higher benefit of genotyping.
  
  
  
  Background The multicenter, single-blind, randomized EU-PACT trial compared the safety and efficacy of genotype-guided and non-genetic dosing algorithms for acenocoumarol and phenprocoumon in patients with atrial fibrillation or deep vein thrombosis. The trial showed no differences in the primary outcome between the two dosing strategies. Objectives To explore possible reasons for the lack of differences between trial arms by performing a secondary analysis of EU-PACT data in order to evaluate the performance of both dosing algorithms across VKORC1-CYP2C9 genetic subgroups. Patients/Methods Anticoagulation control measured according to an International Normalized Ratio (INR) below (INR of < 2), within (INR of 2-3) and above (INR of > 3) the therapeutic range was compared across VKORC1-CYP2C9 subgroups. Owing to a low number of patients in each subgroup, trials for acenocoumarol and phenprocoumon were combined for analysis. Results Four weeks after therapy initiation, genotype-guided dosing increased the mean percentage of time in the therapeutic INR range (PTIR) in the VKORC1 GG-CYP2C9*1*1 subgroup as compared with the non-genetic dosing (difference of 14.68%, 95% confidence interval [CI] 5.38-23.98). For the VKORC1 AA-CYP2C9*1*1 subgroup, there was a higher risk of under-anticoagulation with the genotype-guided algorithm (difference of 19.9%; 95% CI 11.6-28.2). Twelve weeks after therapy initiation, no statistically significant differences in anticoagulation control between trial arms were noted across the VKORC1-CYP2C9 genetic subgroups. Conclusions EU-PACT genetic-guided dose initiation algorithms for acenocoumarol and phenprocoumon could have predicted the dose overcautiously in the VKORC1 AA-CYP2C9*1*1 subgroup. Adjustment of the genotype-guided algorithm could lead to a higher benefit of genotyping.
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.
authors.forename: E V
authors.initials: EV
authors.lastname: Baranova
authors.affiliation: Department of Applied Health Research, University College London, London, UK.
authors.forename: T I
authors.initials: TI
authors.lastname: Verhoef
authors.affiliation: Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Ragia
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.|Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: le Cessie
authors.affiliation: Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.|Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands.|Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
authors.forename: F W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Boer
authors.affiliation: Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: V G
authors.initials: VG
authors.lastname: Manolopoulos
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.|Department of Respiratory Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Maitland-van der Zee
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D000368:Aged; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage; D001281:Atrial Fibrillation / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D003627:Data Interpretation, Statistical; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010644:Phenprocoumon / Q000008:administration & dosage*; D011446:Prospective Studies; D016037:Single-Blind Method; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000235:genetics; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*
chemical_list: D000925:Anticoagulants; D014812:Vitamin K; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol; D010644:Phenprocoumon
keywords: acenocoumarol; drug dosing biomarkers; pharmacogenetics; phenprocoumon; randomized controlled trial