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Effects of vitamin K epoxide reductase complex 1 gene polymorphisms on warfarin control in Japanese patients with left ventricular assist devices (LVAD)

  • Pharmacodynamics
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Abstract

Purpose

This study aimed to investigate relationships between times in therapeutic range (TTR) or warfarin sensitivity indexes (WSI) and VKORC1-1639G>A and CYP2C9 polymorphisms in patients with left ventricular assist devices (LVAD).

Methods

Severe heart failure patients who received LVAD from January 1, 2013 to October 31, 2017 were recruited. Relationships between TTR or WSI and VKORC1-1639G>A and CYP2C9 gene polymorphisms were investigated immediately after LVAD implantation (period 1) and immediately prior to hospital discharge (period 2).

Results

Among 54 patients, 31 (72.1%) had VKORC1-1639AA and CYP2C9*1/*1 (AA group) polymorphisms and 12 (27.9%) had VKORC1-1639GA and CYP2C9*1/*1 (GA group) polymorphisms. During period 1, mean prothrombin time-international normalized ratio (PT-INR) values were significantly higher in the AA group than in the GA group (2.21 vs. 2.05, p < 0.0001). Mean WSI values were 1.68-fold greater in the AA group than in the GA group (1.14 vs. 0.68, p < 0.0001). In addition, times below the therapeutic range (TBTR) in the GA group were significantly greater than in the AA group during period 1 (39.8 vs. 28.3%, p = 0.032), and insufficient PT-INR was more frequent in the GA group than in the AA group. However, mean PT-INR values during period 2 did not differ and no significant differences in TTR, TATR, and TBTR values were identified. In subsequent multivariable logistic regression analyses, the VKORC1-1639GA allele was significantly associated with insufficient anticoagulation.

Conclusion

Patients with the VKORC1-1639GA and CYP2C9*1/*1 alleles may receive insufficient anticoagulation therapy during the early stages after implantation of LVAD, and VKORC1-1639G>A and CYP2C9 genotyping may contribute to more appropriate anticoagulant therapy after implantation of LVAD.

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Acknowledgements

We would like to thank all the patients who participated in this study.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, Japan

    Kazuki Nakagita, Kyoichi Wada, Yutaro Mukai, Takaya Uno, Ryoji Nishino, Sachi Matsuda, Hiromi Takenaka, Nobue Terakawa & Akira Oita

  2. Division of Clinical Drug Informatics, Kindai University School of Pharmacy, 577-8502, 3-4-1, Kowakae, Higashi-osaka, Osaka, 577-8502, Japan

    Kazuki Nakagita, Yutaro Mukai, Takaya Uno & Mitsutaka Takada

Authors
  1. Kazuki Nakagita
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  2. Kyoichi Wada
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  5. Ryoji Nishino
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  8. Nobue Terakawa
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  10. Mitsutaka Takada
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Contributions

Participated in research design: Nakagita, Wada, Mukai, Uno, Nishino, Matsuda, Takenaka, and Takada.

Conducted experiments and clinical study: Nakagita, Wada, Uno, Nishino, Matsuda, Takenaka, and Takada.

Performed data analysis: Nakagita and Takada.

Wrote or contributed to the writing of the manuscript: Nakagita, Wada, Terakawa, Oita, and Takada.

Corresponding author

Correspondence to Mitsutaka Takada.

Ethics declarations

Ethical approval

This study was approved by the local ethic committee of the National Cerebral and Cardiovascular Center.

Informed consent

An informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

This study was conducted in the Department of Pharmacy, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, Japan

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Nakagita, K., Wada, K., Mukai, Y. et al. Effects of vitamin K epoxide reductase complex 1 gene polymorphisms on warfarin control in Japanese patients with left ventricular assist devices (LVAD). Eur J Clin Pharmacol 74, 885–894 (2018). https://doi.org/10.1007/s00228-018-2483-8

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  • DOI: https://doi.org/10.1007/s00228-018-2483-8

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