Dosing algorithms for vitamin K antagonists across VKORC1 and CYP2C9 genotypes

BACKGROUND: The multicenter, single-blind, randomized EU-PACT trial compared safety and efficacy of genotype-guided and non-genetic dosing algorithms for acenocoumarol and phenprocoumon in patients with atrial fibrillation or deep venous 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 this secondary analysis of EU-PACT data evaluated the performance of both dosing algorithms across VKORC1-CYP2C9 genetic sub-groups.

PATIENTS/METHODS: Anticoagulation control measured by international normalized ratio (INR) below (INR<2), within (INR 2-3) and above (INR>3) the therapeutic range was compared across VKORC1-CYP2C9 sub-groups. Due to a low number of patients per sub-group, 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 therapeutic INR range (PTIR) in the VKORC1 GG-CYP2C9 *1*1 sub-group as compared to the non-genetic dosing (%-point difference 14.68, 95% CI [5.38; 23.98]). For the VKORC1 AA-CYP2C9 *1*1 sub-group, there was a higher risk of under-anticoagulation with the genotype-guided algorithm (19.9%-points; 95% CI, 11.6 to 28.2). Twelve weeks after therapy initiation no statistically significant differences in anticoagulation control between trial arms were noted across the VKORC1-CYP2C9 genetic sub-groups.

CONCLUSIONS: EU-PACT genetic-guided dose initiation algorithms for acenocoumarol and phenprocoumon could have predicted the dose extra cautiously in the VKORC1 AA-CYP2C9 *1*1 sub-group. Adjustment of the genotype-guided algorithm could lead to a higher benefit of genotyping. This article is protected by copyright. All rights reserved.