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Determination of bleeding risk using genetic markers in patients taking phenprocoumon

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

In patients on oral anticoagulation with warfarin, genetic variations of the cytochrome P 450–CYP2C9 have recently been associated with very low warfarin requirements. Patients needing low doses had an increased risk for bleeding complications. In Germany, phenprocoumon (having a similar metabolic pathway) is the most commonly employed vitamin K antagonist. Treatment is usually monitored by general practitioners (GPs).

Objectives

To determine whether CYP2C9 variant alleles can serve as risk markers in general-practice patients anticoagulated with phenprocoumon.

Methods

All adult anticoagulated patients in 12 teaching general practices and one university outpatient clinic were to be recruited. Blood samples were taken from 185 patients during routine anticoagulation controls and tested for CYP2C9 mutations. Subjects answered a questionnaire concerning bleeding complications, drug intolerance, and personal and family medical history. Phenprocoumon dosages required for stable anticoagulation were recorded. Odds ratios (OR) with 95% confidence intervals (CI) were calculated based on 2-way cross-tabulations and multivariate logistic regression models, t-tests used where appropriate.

Results

Bleeding was reported by 19% of the patients, 2.2% of whom had suffered life-threatening bleeding. CYP2C9 variants were carried by 26.3% of 179 patients tested (17.9% *1/*2, 7.8% *1/*3, 0.6% *2/*3). While presence of a *2 allele was not associated with an increased risk (OR 0.35, CI 0.10–1.24), carriers of the rare *3 alleles had a higher risk of bleeding (OR 3.10, CI 1.02–9.40). With regard to bleeding, carrying CYP2C9*3 was highly specific (94%), though sensitivity was low at 17%; post-test probability of bleeding was 40%.

Conclusions

CYP2C9*3 variants are associated with an increased bleeding risk in patients anticoagulated with phenprocoumon. Screening can identify patients with a high risk of bleeding. Appropriate clinical consequences (restricted indication for anticoagulation, careful induction, adjustment of target INR, closer monitoring or self-testing of INR) as well as the cost-effectiveness of screening for variant CYP2C9 with regard to patient outcomes should be subject of further research.

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Acknowledgements

We thank all participating patients and GPs for their cooperation, and Sabine Buth, Susanne Herlt, and Ulrike Lenz for performing the DNA extraction. We are indebted to Prof. Jürgen Brockmöller, Göttingen, and Dr. Robert Walton, Oxford, for critically reviewing the manuscript.

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Authors and Affiliations

  1. Department of General Practice, University of Göttingen Medical School, Humboldtallee 38, 37073, Göttingen, Germany

    Eva Hummers-Pradier, Stephan Hess & Michael M. Kochen

  2. Department of Human Genetics, University of Göttingen Medical School, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany

    Ibrahim M. Adham & Thomas Papke

  3. Department of Cardiology and Pulmonology, University of Göttingen Medical School, Robert-Koch-Strasse 40, 37075, Göttingen, Germany

    Burkert Pieske

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  1. Eva Hummers-Pradier
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  2. Stephan Hess
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Correspondence to Eva Hummers-Pradier.

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Hummers-Pradier, E., Hess, S., Adham, I.M. et al. Determination of bleeding risk using genetic markers in patients taking phenprocoumon. Eur J Clin Pharmacol 59, 213–219 (2003). https://doi.org/10.1007/s00228-003-0580-8

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  • DOI: https://doi.org/10.1007/s00228-003-0580-8

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