Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to fluindione

Abstract

Aim: Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to fluindione.

Methods: Four hundred sixty-five patients with a venous thromboembolic event treated by fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, fluindione doses and bleeding events were collected.

Results: VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001) and on the time to obtain a first INR value > 4 (P= 0.0002). The average daily dose of fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7mg (±6.2) for VKORC1 CT and 8.2mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to fluindione.

Conclusions: VKORC1 genotype strongly affected anticoagulation induced by fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.

Figure 1

The graphs show the association between the time to first international normalized ratio (INR) within the therapeutic range for patients carrying genetic variants for VKORC1 (A), CYP2C9 (B), CYP4F2 (C) and EPHX1 (D). The results presented on the graphs are limited to the first 30-day period. P values correspond to the log-rank test results. (A) VKORC1 CC (); VKORC1 CT (); VKORC1 TT (); (B) 2C9 *1/*1 (); 2C9 *1/*2 or *1/*3 (); 2C9 *2/*2 or *2/*3 or *3/*3 (); (C) CYP4F2 CC (); CYP4F2 CT (); CYP4F2 TT (); (D) EPHX1 GG (); EPHX1 GA (); EPHX1 AA ()

Figure 2

The graphs show the association between the time to first international normalized ratio (INR) of more than 4 for patients carrying genetic variants for VKORC1 (A), CYP2C9 (B), CYP4F2 (C) and EPHX1 (D). The results presented on the graphs are limited to the first 60-day period. P values correspond to the log-rank test results. (A) VKORC1 CC (); VKORC1 CT (); VKORC1 TT (); (B) 2C9 *1/*1 (); 2C9 *1/*2 or *1/*3 (); 2C9 *2/*2 or *2/*3 or *3/*3 (); (C) CYP4F2 CC (); CYP4F2 CT (); CYP4F2 TT (); (D) EPHX1 GG (); EPHX1 GA (); EPHX1 AA ()