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Toward Genetic Testing of Rivaroxaban? Insights from a Systematic Review on the Role of Genetic Polymorphism in Rivaroxaban Therapy

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Abstract

Background

Investigations into the rivaroxaban response from the perspective of genetic variation have been relatively recent and wide in scope, whereas there is no consensus on the necessity of genetic testing of rivaroxaban. Thus, this systematic review aims to thoroughly evaluate the relationship between genetic polymorphisms and rivaroxaban outcomes.

Methods

The PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Chinese databases were searched to 23 October 2022. We included cohort studies reporting the pharmacogenetic correlation of rivaroxaban. Outcomes measured included efficacy (all-cause mortality, thromboembolic events and coagulation-related tests), safety (major bleeding, clinically relevant non-major bleeding [CRNMB] and any hemorrhage), and pharmacokinetic outcomes. A narrative synthesis was performed to summarize findings from individual studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the reporting guideline for Synthesis Without Meta-Analysis.

Results

A total of 12 studies published between 2019 and 2022 involving 1364 patients were included. Ten, one, and six studies focused on the ABCB1, ABCG2, and CYP gene polymorphisms, respectively. Pharmacokinetic outcomes accounted for the majority of the outcomes reported (n = 11), followed by efficacy (n = 5) [including prothrombin time (PT) or international normalized ratio (n = 3), platelet inhibition rate (PIR) or platelet reactivity units (PRUs; n = 1), thromboembolic events (n = 1)], and safety (n = 5) [including major bleeding (n = 2), CRNMB (n = 2), any hemorrhage (n = 1)]. For ABCB1 gene polymorphism, the relationship between PT and ABCB1 rs1045642 was inconsistent across studies, however there was no pharmacogenetic relationship with other efficacy outcomes. Safety associations were found in ABCB1 rs4148738 and major bleeding, ABCB1 rs4148738 and CRNMB, ABCB1 rs1045642 and CRNMB, and ABCB1 rs2032582 and hemorrhage. Pharmacokinetic results were inconsistent among studies. For ABCG2 gene polymorphism, no correlation was observed between ABCG2 rs2231142 and dose-adjusted trough concentration (Cmin/D). For CYP gene polymorphisms, PIR or PRUs have a relationship with CYP2C19 rs12248560, however bleeding or pharmacokinetic effects did not show similar results.

Conclusions

Currently available data are insufficient to confirm the relationship between clinical or pharmacokinetic outcomes of rivaroxaban and gene polymorphisms. Proactive strategies are advised as a priority in clinical practice rather than detection of SNP genoty**.

Clinical Trials Registration

PROSPERO registration number CRD42022347907.

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Author information

Author notes

  1. Yi Ma and Zaiwei Song contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Peking University Third Hospital, Bei**g, 100191, China

    Yi Ma, Zaiwei Song, **nya Li, Dan Jiang, Rongsheng Zhao & Zhanmiao Yi

  2. Institute for Drug Evaluation, Peking University Health Science Center, Bei**g, 100191, China

    Yi Ma, Zaiwei Song, **nya Li, Dan Jiang, Rongsheng Zhao & Zhanmiao Yi

  3. Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University, Bei**g, 100191, China

    Yi Ma, Zaiwei Song, **nya Li, Dan Jiang, Rongsheng Zhao & Zhanmiao Yi

  4. Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Bei**g, 100191, China

    **nya Li & Dan Jiang

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Correspondence to Rongsheng Zhao or Zhanmiao Yi.

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Funding

This work was supported by the National Key R&D Program of China (2020YFC2008305) and the National Natural Science Foundation of China (NSFC) [72074005, 72104003].

Conflicts of Interest

Yi Ma, Zaiwei Song, **nya Li, Dan Jiang, Rongsheng Zhao, and Zhanmiao Yi declare they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

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Data Availability Statement

All data generated and/or analyzed during this study are included in this published article (and its supplementary information files).

Authors’ Contributions

ZMY and RSZ conceived and designed the study. YM and ZWS collected and analyzed the data and performed the statistical analysis. YM and ZWS wrote the article. XYL and DJ prepared the pictures and tables. ZMY and RSZ provided suggestions and participated in the revision of the article. All authors read and approved the final manuscript.

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Ma, Y., Song, Z., Li, X. et al. Toward Genetic Testing of Rivaroxaban? Insights from a Systematic Review on the Role of Genetic Polymorphism in Rivaroxaban Therapy. Clin Pharmacokinet 63, 279–291 (2024). https://doi.org/10.1007/s40262-024-01358-3

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