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Impact of genetic and clinical factors on warfarin therapy in patients early after heart valve replacement surgery

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

Abstract

Purpose

Factors influencing responsiveness to warfarin at treatment onset time were not well identified in Chinese patients undergoing heart valve replacement. We sought to select the most relevant factors that associated with patient response to warfarin early after heart valve surgery.

Methods

In this observational study, 289 patients starting warfarin therapy early after heart valve replacement surgery were enrolled. CYP2C9 *1, *2, *3, and *5; VKORC1-1639 G>A, CYP4F2 V433M, and GGCX rs11676382 genotypes; clinical characteristics, response to therapy, and bleeding and thrombosis events were collected. The primary outcomes were the time to the first INR equal to or more than lower limit of therapeutic range and the warfarin dose requirements. Stepwise multiple linear regression was performed to develop a dosing algorithm to predict the warfarin dose requirements.

Results

The results of univariate analysis showed lone VKORC1-1639 G>A, CYP2C9 *1/*3, cefazolin, cefoperazone-sulbactam, increased BMI, Δhemoglobin, and white blood cell count could significantly affect patient responsiveness to warfarin in the initial period of anticoagulation. Multivariate analysis resulted in an equation: Accumulated warfarin doses (mg) = 17.068 VKORC1-1639 G>A − 4.261 hypertension + 0.593 BMI − 0.115 age − 4.852 CYP2C9 *1/*3 − 2.617 cefazolin − 4.902 cefoperazone-sulbactam − 4.537, which could explain 40.2% of the variability in warfarin dose needed to reach the first INR equal to or more than lower limit of therapeutic range.

Conclusions

Both genetic and clinical factors contributed to anticoagulation effect of warfarin in the initial period of treatment. Our findings could provide a basis for the personalized management of warfarin use in the early stage of anticoagulation in northern Chinese patients.

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Acknowledgments

We wish thank Min Zhang, Pharm D (Boston Medical Center) for linguistic assistance during the preparation of this manuscript.

Funding

This study was performed with support from Science Foundation for Young Scientists of Gansu province (1506RJYA264); Scientific Research Foundation of Clinical Pharmacy Branch of Chinese Medical Association, Wu Jieping Medical Foundation (LCYX-Q030/320.6750.19090-40); and Hospital Funds of First Hospital of Lanzhou University (ldyyyn2014-03, ldyyyn2018-03).

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Author notes

  1. Boxia Li and Ruisheng Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China

    Boxia Li, Fan Zhang, Jianping Zhang, Yuhui Wei & Xinan Wu

  2. Department of Cardiovascular Surgery, The First Hospital of Lanzhou University, Lanzhou, China

    Ruisheng Liu, Shiming Zhang, Shidong Liu & Bing Song

  3. Infectious Diseases Global Health Department, University of South Florida, C.W., Tampa, FL, USA

    Chengqi Wang

  4. School of Life Science, Lanzhou University, Lanzhou, China

    Changan Ren

  5. Department of Pharmacy, Gansu Provincial Hospital, Lanzhou, China

    Wenjing Liu

Authors
  1. Boxia Li
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Contributions

Study design: B.L., X.W., and B.S. Sample and data collection: R.L., S.Z., J.Z., and S.L. Genetic testing and analysis: C.R. and F.Z. Data analysis: C.W., B.L., Y.W., and W.L. Data interpretation: B.L., R.L., X.W., and B.S. Figure preparation: B.L. and R.L. Drafting of article: B.L., R.L. Critical revision and final approval of article: all authors.

Corresponding author

Correspondence to Xinan Wu.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Li, B., Liu, R., Wang, C. et al. Impact of genetic and clinical factors on warfarin therapy in patients early after heart valve replacement surgery. Eur J Clin Pharmacol 75, 1685–1693 (2019). https://doi.org/10.1007/s00228-019-02747-5

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  • DOI: https://doi.org/10.1007/s00228-019-02747-5

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