ABCG2 Gene Polymorphisms May Affect the Bleeding Risk in Patients on Apixaban and Rivaroxaban

Hamin Kim; Tae Jin Song; Jeong Yee; Dong Hyeok Kim; Junbeom Park; Hye Sun Gwak

doi:10.2147/DDDT.S417096

ABCG2 Gene Polymorphisms May Affect the Bleeding Risk in Patients on Apixaban and Rivaroxaban

Hamin Kim, Tae Jin Song, Jeong Yee, Dong Hyeok Kim, Junbeom Park, Hye Sun Gwak

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Purpose: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance protein, encoded by ABCG2, is known to be an efflux transporter of apixaban and rivaroxaban among DOACs. This study aimed to investigate the association between gene variants and bleeding complications during treatment with ABCG2 substrates (apixaban and rivaroxaban). Patients and Methods: Patients treated with apixaban and rivaroxaban were enrolled from June 2018 to December 2021. Five single nucleotide polymorphisms (SNPs) of ABCG2 were selected. Previously studied genes (ABCB1, CYP3A4, and CYP3A5) were further analyzed as possible confounders. Finally, a total of 16 SNPs were examined in this case–control study. The outcome was defined as major bleeding and clinically relevant non-major bleeding. Two models were constructed using the multivariable analysis. Results: Among 293 patients, 64 were cases. The mean age of the patients was 68.8 years, and males comprised 62.5% of the study population. Model I revealed that a history of bleeding, concurrent use of proton pump inhibitor (PPI), ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications; the AORs (95% CI) were 6.209 (2.210–17.442), 2.385 (1.064– 5.349), 2.188 (1.156–4.142), and 3.243 (1.371–7.671), respectively. Model II showed that modified HAS-BLED score, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications. Conclusion: The modified HAS-BLED score, a history of bleeding, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with the risk of bleeding complications in patients on apixaban and rivaroxaban, after adjusting for other confounders. These findings can be used to develop individualized treatment strategies for patients taking apixaban and rivaroxaban.

Original language	English
Pages (from-to)	2513-2522
Number of pages	10
Journal	Drug Design, Development and Therapy
Volume	17
DOIs	https://doi.org/10.2147/DDDT.S417096
State	Published - 2023

Bibliographical note

Funding Information:
This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant number: NRF-2020R1A2C1008120).

Publisher Copyright:
© 2023 Kim et al.

Keywords

ABCG2
apixaban
bleeding complications
polymorphism
rivaroxaban

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2147/DDDT.S417096

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@article{9f1c731effa14ceeb22c81cf6e4a0482,

title = "ABCG2 Gene Polymorphisms May Affect the Bleeding Risk in Patients on Apixaban and Rivaroxaban",

abstract = "Purpose: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance protein, encoded by ABCG2, is known to be an efflux transporter of apixaban and rivaroxaban among DOACs. This study aimed to investigate the association between gene variants and bleeding complications during treatment with ABCG2 substrates (apixaban and rivaroxaban). Patients and Methods: Patients treated with apixaban and rivaroxaban were enrolled from June 2018 to December 2021. Five single nucleotide polymorphisms (SNPs) of ABCG2 were selected. Previously studied genes (ABCB1, CYP3A4, and CYP3A5) were further analyzed as possible confounders. Finally, a total of 16 SNPs were examined in this case–control study. The outcome was defined as major bleeding and clinically relevant non-major bleeding. Two models were constructed using the multivariable analysis. Results: Among 293 patients, 64 were cases. The mean age of the patients was 68.8 years, and males comprised 62.5% of the study population. Model I revealed that a history of bleeding, concurrent use of proton pump inhibitor (PPI), ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications; the AORs (95% CI) were 6.209 (2.210–17.442), 2.385 (1.064– 5.349), 2.188 (1.156–4.142), and 3.243 (1.371–7.671), respectively. Model II showed that modified HAS-BLED score, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications. Conclusion: The modified HAS-BLED score, a history of bleeding, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with the risk of bleeding complications in patients on apixaban and rivaroxaban, after adjusting for other confounders. These findings can be used to develop individualized treatment strategies for patients taking apixaban and rivaroxaban.",

keywords = "ABCG2, apixaban, bleeding complications, polymorphism, rivaroxaban",

author = "Hamin Kim and Song, {Tae Jin} and Jeong Yee and Kim, {Dong Hyeok} and Junbeom Park and Gwak, {Hye Sun}",

note = "Funding Information: This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant number: NRF-2020R1A2C1008120). Publisher Copyright: {\textcopyright} 2023 Kim et al.",

year = "2023",

doi = "10.2147/DDDT.S417096",

language = "English",

volume = "17",

pages = "2513--2522",

journal = "Drug Design, Development and Therapy",

issn = "1177-8881",

publisher = "Dove Medical Press Ltd.",

}

TY - JOUR

T1 - ABCG2 Gene Polymorphisms May Affect the Bleeding Risk in Patients on Apixaban and Rivaroxaban

AU - Kim, Hamin

AU - Song, Tae Jin

AU - Yee, Jeong

AU - Kim, Dong Hyeok

AU - Park, Junbeom

AU - Gwak, Hye Sun

N1 - Funding Information: This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant number: NRF-2020R1A2C1008120). Publisher Copyright: © 2023 Kim et al.

PY - 2023

Y1 - 2023

N2 - Purpose: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance protein, encoded by ABCG2, is known to be an efflux transporter of apixaban and rivaroxaban among DOACs. This study aimed to investigate the association between gene variants and bleeding complications during treatment with ABCG2 substrates (apixaban and rivaroxaban). Patients and Methods: Patients treated with apixaban and rivaroxaban were enrolled from June 2018 to December 2021. Five single nucleotide polymorphisms (SNPs) of ABCG2 were selected. Previously studied genes (ABCB1, CYP3A4, and CYP3A5) were further analyzed as possible confounders. Finally, a total of 16 SNPs were examined in this case–control study. The outcome was defined as major bleeding and clinically relevant non-major bleeding. Two models were constructed using the multivariable analysis. Results: Among 293 patients, 64 were cases. The mean age of the patients was 68.8 years, and males comprised 62.5% of the study population. Model I revealed that a history of bleeding, concurrent use of proton pump inhibitor (PPI), ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications; the AORs (95% CI) were 6.209 (2.210–17.442), 2.385 (1.064– 5.349), 2.188 (1.156–4.142), and 3.243 (1.371–7.671), respectively. Model II showed that modified HAS-BLED score, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications. Conclusion: The modified HAS-BLED score, a history of bleeding, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with the risk of bleeding complications in patients on apixaban and rivaroxaban, after adjusting for other confounders. These findings can be used to develop individualized treatment strategies for patients taking apixaban and rivaroxaban.

AB - Purpose: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance protein, encoded by ABCG2, is known to be an efflux transporter of apixaban and rivaroxaban among DOACs. This study aimed to investigate the association between gene variants and bleeding complications during treatment with ABCG2 substrates (apixaban and rivaroxaban). Patients and Methods: Patients treated with apixaban and rivaroxaban were enrolled from June 2018 to December 2021. Five single nucleotide polymorphisms (SNPs) of ABCG2 were selected. Previously studied genes (ABCB1, CYP3A4, and CYP3A5) were further analyzed as possible confounders. Finally, a total of 16 SNPs were examined in this case–control study. The outcome was defined as major bleeding and clinically relevant non-major bleeding. Two models were constructed using the multivariable analysis. Results: Among 293 patients, 64 were cases. The mean age of the patients was 68.8 years, and males comprised 62.5% of the study population. Model I revealed that a history of bleeding, concurrent use of proton pump inhibitor (PPI), ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications; the AORs (95% CI) were 6.209 (2.210–17.442), 2.385 (1.064– 5.349), 2.188 (1.156–4.142), and 3.243 (1.371–7.671), respectively. Model II showed that modified HAS-BLED score, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications. Conclusion: The modified HAS-BLED score, a history of bleeding, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with the risk of bleeding complications in patients on apixaban and rivaroxaban, after adjusting for other confounders. These findings can be used to develop individualized treatment strategies for patients taking apixaban and rivaroxaban.

KW - ABCG2

KW - apixaban

KW - bleeding complications

KW - polymorphism

KW - rivaroxaban

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U2 - 10.2147/DDDT.S417096

DO - 10.2147/DDDT.S417096

M3 - Article

C2 - 37641689

AN - SCOPUS:85168985200

SN - 1177-8881

VL - 17

SP - 2513

EP - 2522

JO - Drug Design, Development and Therapy

JF - Drug Design, Development and Therapy

ER -

ABCG2 Gene Polymorphisms May Affect the Bleeding Risk in Patients on Apixaban and Rivaroxaban

Abstract

Bibliographical note

Keywords

UN SDGs

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