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

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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.

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Abbreviations

ALT:

Alanine aminotransferase

BMI:

Body mass index

CABG:

Coronary artery bypass graft

CAD:

Coronary artery disease

CI:

Confidence interval

CKD-EPI:

Chronic kidney disease epidemiology collaboration

CV:

Coefficients of variability

CYP2C9 :

Cytochrome P450 isoform 2C9 gene

eGFR:

Estimated glomerular filtration rate

HPLC-UV:

High performance liquid chromatography with ultraviolet detection

INR:

International normalized ratio

SNP:

Single nucleotide polymorphism

S/R ratio:

S-warfarin/R-warfarin ratio

TTR:

Time in therapeutic range

Vd:

Volume of distribution

VKORC1 :

Vitamin K epoxide reductase complex subunit 1 gene

WSI:

Warfarin sensitivity index

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Compliance with Ethical Standards

Conflict of Interest

The authors stated that there are no conflicts of interest regarding the publication of this article.

Research Funding

This study was supported by the grant from National Centre of Science (N N403152340, to A.U.).

Research Involving Human Participants

The study was approved by the University Bioethical Committee according to Declaration of Helsinki.

Informed Consent

All patients gave written informed consent.

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Authors and Affiliations

  1. Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202, Krakow, Poland

    Agata Bryk, Ewa Wypasek & Anetta Undas

  2. John Paul II Hospital, Krakow, Poland

    Ewa Wypasek, Magdalena Awsiuk & Anetta Undas

  3. Department of Genetics and Animal Breeding, Agriculture University of Krakow, Krakow, Poland

    Dorota Maj

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  1. Agata Bryk
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  2. Ewa Wypasek
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Correspondence to Anetta Undas.

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Bryk, A., Wypasek, E., Awsiuk, M. et al. Warfarin Metabolites in Patients Following Cardiac Valve Implantation: A Contribution of Clinical and Genetic Factors. Cardiovasc Drugs Ther 29, 257–264 (2015). https://doi.org/10.1007/s10557-015-6591-8

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