title: Age-stratified outcome of a genotype-guided dosing algorithm for acenocoumarol and phenprocoumon.
abstract: Essentials The EU-PACT trial was used to investigate age on the interaction between coumarins and genotype. The results support the use of genotype-guided dosing for phenprocoumon in patients < 75 years. For patients ≥ 75 years the phenprocoumon algorithm should be revised and further tested. No influence of comorbidities and co-current drug use was found that could explain the differences.
  
  
  
  Background Age seemed to affect the interaction between coumarins and genotype in the acenocoumarol and phenprocoumon arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial. Objectives To investigate the effect of genotype-guided dosing stratified by age and the potential factors causing a difference. Patients/Methods Data from the acenocoumarol/phenprocoumon arm of the EU-PACT trial were used. The percentages of time below the therapeutic range, time above the therapeutic range and time in the therapeutic range (TTR) during the initial 12 weeks of therapy were compared between the genotype-guided group and the control group among younger (< 75 years) and older (≥ 75 years) patients by the use of independent t-tests, and adjusted for sex, height, weight and co-medications by the use of linear regression. Results Among younger phenprocoumon users, TTR during the first 12 weeks in the genotype-guided group (n = 55) was 9.5% (95% confidence interval [CI] 1.3 to 17.8) higher than in the control group (n = 63), with a remarkably lower percentage of time above this range (difference: - 9.6%, 95% CI - 19.0 to - 0.2) and a similar time below this range. Older patients dosed by the genotype-guided algorithm (n = 24) spent more time above the range (difference: 27.5%, 95% CI 12.9 to 42.0). For acenocoumarol users, there were no significant differences between the genotype-guided and control groups for most outcomes, except for a lower percentage of time below the range among older patients. Conclusions The genotype-guided algorithm for phenprocoumon in the EU-PACT trial benefitted younger patients more, but for older patients the algorithm needs to be revised and tested in further research.
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Boer
authors.affiliation: Department of Applied Health Research, University College London, London, UK.
authors.forename: T I
authors.initials: TI
authors.lastname: Verhoef
authors.affiliation: Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: F J M
authors.initials: FJ
authors.lastname: van der Meer
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: Clinical Pharmacology Unit, Academic General Hospital of Evros, Alexandroupolis, Greece.|Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: V G
authors.initials: VG
authors.lastname: Manolopoulos
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Maitland-van der Zee
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage*; D015897:Comorbidity; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D005060:Europe; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010644:Phenprocoumon / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases / Q000235:genetics
chemical_list: D000925:Anticoagulants; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol; D010644:Phenprocoumon
keywords: age groups; algorithms; coumarins; cytochrome P450 2C9; pharmacogenetics; vitamin K epoxide reductases