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Screening for clinically relevant drug-drug interactions between direct oral anticoagulants and antineoplastic agents: a pharmacovigilance approach

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Abstract

Background

Use of direct oral anticoagulants (DOACs) in patients with cancer remains suboptimal due to the concern regarding potential drug-drug interactions (DDIs) with antineoplastic treatments. However, the clinical relevance of these DDIs is unknown.

Methods

We conducted a pharmacovigilance study of adverse event (AE) reports from the US Food and Drug Administration Adverse Event Reporting System from 1/1/2004 to 12/31/2021. AE reports containing DOACs and antineoplastic agents with CYP3A4/P-gp inhibitory or inducing activity suggested by published pharmacokinetic studies were included (n = 36,066). The outcomes of interest were bleeding or stroke, identified by MedDRA dictionary version 25.0. We used disproportionality analyses (DPA), logistic regression models (LR), and Multi-item Gamma-Poisson Shrinker (MGPS) (Empirical Bayes Geometric Means (EBGM) and 90% credible intervals (90% CIs)) algorithms to identify the safety signal of DDIs.

Results

The highest bleeding reporting rates for each drug class were the combination of DOACs with neratinib (39.08%, n = 34), tamoxifen (21.22%, n = 104), irinotecan (20.54%, n = 83), and cyclosporine (19.17%, n = 227). The highest rate of stroke was found for prednisolone (2.43%, n = 113). In the primary analysis, no signal of DDIs by the antineoplastic therapeutic class was detected by MGPS, DPA, and LR approaches. By individual antineoplastic drug, DOACs-neratinib was the only signal detected [EBGM (EB05-EB95) = 2.71 (2.03–3.54)].

Conclusion

No signal of DDIs between DOACs and antineoplastic agents was detected, except for DOAC-neratinib. Most DDIs between DOACs and antineoplastic agents may not be clinically relevant. The DDIs between DOACs and neratinib should be further examined in future research.

Highlights

Using a pharmacovigilance approach, this study examined the adverse event reporting risk in bleeding/stroke with concurrent DOACs and antineoplastic agents (kinase inhibitors, hormonal therapy, chemotherapeutic agents, immunomodulating agents, and antineoplastic CYP3A4/P-gp inducers) from real-world data.

Most of the assessed drug-drug interactions (DDIs) between DOACs and antineoplastic agents (kinase inhibitors, hormonal therapy, chemotherapeutic agents, immunomodulating agents, and antineoplastic CYP3A4/P-gp inducers) did not exhibit significant risk signals.

The combination of DOACs and neratinib showed an elevated risk signal and should be further examined in future research.

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Data Availability

The datasets generated during and/or analyzed during the current study are publicly available in the US FDA FAERS repository, https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

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Acknowledgements

We thank Ms. Adelia Grabowsky, health sciences librarian at Auburn University, for her help in getting access to MedDRA dictionary version 25.0.

Funding

This research did not receive extramural funding from public, commercial, or not-for-profit funding agencies.

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Authors and Affiliations

  1. Department of Health Outcomes Research and Policy, Auburn University Harrison College of Pharmacy, 4306D Walker Building, Auburn, AL, 36849, USA

    Bang Truong, Brent I. Fox, Chiahung Chou & Jingjing Qian

  2. Department of Pharmacy Practice, Auburn University Harrison College of Pharmacy, Auburn, AL, USA

    Lori Hornsby

  3. Department of Mathematics and Statistics, Auburn University College of Sciences and Mathematics, Auburn, AL, USA

    Jingyi Zheng

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  1. Bang Truong
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  2. Lori Hornsby
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Contributions

Truong: Conceptualization; Data curation; Formal analysis; Methodology; Writing - original draft. Hornsby: Methodology; Validation; Writing - review and editing. Fox: Methodology; Validation; Writing - review and editing. Chou: Methodology; Validation; Writing - review and editing. Zheng: Methodology; Validation; Writing - review and editing. Qian: Conceptualization; Methodology; Supervision; Validation; Writing - review and editing.

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Correspondence to Jingjing Qian.

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Truong, B., Hornsby, L., Fox, B.I. et al. Screening for clinically relevant drug-drug interactions between direct oral anticoagulants and antineoplastic agents: a pharmacovigilance approach. J Thromb Thrombolysis 56, 555–567 (2023). https://doi.org/10.1007/s11239-023-02879-7

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