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Dosing algorithms for vitamin K antagonists across VKORC1 and CYP2C9 genotypes.
J Thromb Haemost. 2017 03; 15(3):465-472.JT

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.

SUMMARY

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+Show Affiliations

Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.Department of Applied Health Research, University College London, London, UK.Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.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.Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.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.No affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28063245

Citation

Baranova, E V., et al. "Dosing Algorithms for Vitamin K Antagonists Across VKORC1 and CYP2C9 Genotypes." Journal of Thrombosis and Haemostasis : JTH, vol. 15, no. 3, 2017, pp. 465-472.
Baranova EV, Verhoef TI, Ragia G, et al. Dosing algorithms for vitamin K antagonists across VKORC1 and CYP2C9 genotypes. J Thromb Haemost. 2017;15(3):465-472.
Baranova, E. V., Verhoef, T. I., Ragia, G., le Cessie, S., Asselbergs, F. W., de Boer, A., Manolopoulos, V. G., & Maitland-van der Zee, A. H. (2017). Dosing algorithms for vitamin K antagonists across VKORC1 and CYP2C9 genotypes. Journal of Thrombosis and Haemostasis : JTH, 15(3), 465-472. https://doi.org/10.1111/jth.13615
Baranova EV, et al. Dosing Algorithms for Vitamin K Antagonists Across VKORC1 and CYP2C9 Genotypes. J Thromb Haemost. 2017;15(3):465-472. PubMed PMID: 28063245.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dosing algorithms for vitamin K antagonists across VKORC1 and CYP2C9 genotypes. AU - Baranova,E V, AU - Verhoef,T I, AU - Ragia,G, AU - le Cessie,S, AU - Asselbergs,F W, AU - de Boer,A, AU - Manolopoulos,V G, AU - Maitland-van der Zee,A H, AU - ,, Y1 - 2017/02/17/ PY - 2016/05/18/received PY - 2016/11/15/accepted PY - 2017/1/8/pubmed PY - 2018/2/2/medline PY - 2017/1/8/entrez KW - acenocoumarol KW - drug dosing biomarkers KW - pharmacogenetics KW - phenprocoumon KW - randomized controlled trial SP - 465 EP - 472 JF - Journal of thrombosis and haemostasis : JTH JO - J. Thromb. Haemost. VL - 15 IS - 3 N2 - : 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. SUMMARY: 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. SN - 1538-7836 UR - https://www.unboundmedicine.com/medline/citation/28063245/Dosing_algorithms_for_vitamin_K_antagonists_across_VKORC1_and_CYP2C9_genotypes_ L2 - https://doi.org/10.1111/jth.13615 DB - PRIME DP - Unbound Medicine ER -