Warfarin Metabolites in Patients Following Cardiac Valve Implantation: A Contribution of Clinical and Genetic Factors

Abstract

Introduction: Warfarin, a racemic mixture of S- and R-enantiomers, is the cornerstone of therapy in patients following cardiac valve replacement. S-warfarin is metabolized to 7-S-hydroxywarfarin by the cytochrome P450 isoform 2C9 encoded by CYP2C9 gene. R-warfarin is metabolized by multiple cytochromes P450. We sought to assess the impact of clinical and genetic factors on circulating warfarin metabolites following valve implantation.

Material and methods: Venous blood was collected from 120 patients after 3 months since elective mitral and/or aortic valve replacement. Plasma S-warfarin, R-warfarin, S-7-hydroxywarfarin, and R-7-hydroxywarfarin were determined using high-performance liquid chromatography. The S-7-hydroxywarfarin/S-warfarin and S-warfarin/R-warfarin (S/R) ratios, along with warfarin sensitivity index (WSI), defined as INR/S-warfarin ratio, were calculated. Vitamin K epoxide reductase complex subunit 1 (VKORC1) c.-1639A, CYP2C9*3 and CYP2C9*2 alleles were determined using real-time polymerase chain reaction.

Results: The S-warfarin was higher in former smokers (p = 0.047) and the VKORC1 c.-1639A allele carriers (p < 0.0001). The S-7-hydroxywarfarin was lower in carriers of the VKORC1 c.-1639A allele (p = 0.0005) and CYP2C9*3 (p = 0.047). The S-7-hydroxywarfarin/S-warfarin ratio was lower in the carriers of CYP2C9*3 (p = 0.008), but not in those with VKORC1 -c.1639A allele. The S/R ratio was higher in patients with hypertension (p = 0.01). The independent predictors of elevated S/R ratio defined as the upper quartile were diabetes (p = 0.045), CYP2C9*3 (p < 0.0001) and CYP2C9*2 (p = 0.0002). The independent predictors of elevated WSI were current smoking (p = 0.049), implantation of mechanical valve (p = 0.006) and VKORC1c.-1639A allele (p = 0.007).

Conclusion: We conclude that not only genetic, but also several clinical factors affect warfarin metabolites in patients following cardiac valve implantation.