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Evaluation of Cardiac Adverse Events with Nivolumab Using a Japanese Real-World Database

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Abstract

Background

Nivolumab has been used for the treatment of various types of cancers and has achieved improvements in overall survival. However, nivolumab can cause a variety of adverse events (AEs). Among these, cardiac-specific AEs have received little attention in clinical trials, despite their life-threatening potential.

Objective

The present study aimed to determine the risk of nivolumab-induced cardiac AEs, time to onset, incidence rates, and post hoc outcomes using the Japanese Adverse Drug Event Report database.

Methods

We analyzed data for the period between April 2004 and March 2021. Data on cardiac AEs were extracted and relative risk of AEs was estimated using the reporting odds ratio (ROR).

Results

We analyzed 1,772,494 reports and identified 18,721 reports of AEs caused by nivolumab. Of these, 409 reports involved cardiac AEs. Signals were detected for four cardiac AEs: myocarditis; pericardial effusion; pericarditis; and immune-mediated myocarditis. Among these, myocarditis was the most frequently reported (35.0%) and included fatal cases. A histogram of times to onset showed nivolumab-associated AEs occurring 41–127 days after starting administration, with outlier cases of myocarditis or pericardial effusion occurring after more than one year, both with catastrophic consequences.

Conclusion

This study focused on cardiac AEs caused by nivolumab as post-marketing AEs. Myocarditis and pericardial effusion have been associated with some fatal cases after administration of nivolumab. Patients should be monitored for signs of onset for these AEs, not only at the start of administration, but also over an extended period after nivolumab administration.

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Acknowledgements

We are grateful to Professor Yoshihiro Uesawa of Meiji Pharmaceutical University's Department of Medical Molecular Informatics for providing a helpful discussion, and to Tadashi Hirooka (TAIHO PHARMA Corporation) for giving a talk on Hirooka techniques using the JADER database.

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Authors and Affiliations

  1. Department of Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan

    Yuko Kanbayashi

  2. School of Pharmacy, Hyogo Medical University, 1-3-6 Minatojima, Kobe, Hyogo, 650-8530, Japan

    Tadashi Shimizu

  3. Department of Education and Research Center for Pharmacy Practice, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, 97-1 Kodominamihokotate, Kyotanabe, Kyoto, 610-0395, Japan

    Miku Anzai, Rika Kawai & Mayako Uchida

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  1. Yuko Kanbayashi
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  3. Miku Anzai
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  4. Rika Kawai
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  5. Mayako Uchida
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Corresponding author

Correspondence to Yuko Kanbayashi.

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Funding

The authors have not disclosed any funding.

Conflict of interest

All authors declare no competing interests.

Ethical approval

Ethics approval was not sought for this study; given the database-related, observational design without direct involvement of any research subjects. All results were obtained from data openly available online from the PMDA website (https://www.pmda.go.jp/english/index.html, https://www.info.pmda.go.jp/fukusayoudb/CsvDownload.jsp). All data from the JADER database were fully anonymized by the relevant regulatory authority before we accessed them. Thus, all methods were performed in accordance with the relevant guidelines and regulations.

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Not applicable.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Author contributions

Yuko Kanbayashi and Tadashi Shimizu: data curation; Writing—original draft; Writing—review and editing. Miku Anzai and Rika Kawai: data curation; Writing—review and editing. Mayako Uchida: conceptualization; supervision; writing—review and editing.

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Kanbayashi, Y., Shimizu, T., Anzai, M. et al. Evaluation of Cardiac Adverse Events with Nivolumab Using a Japanese Real-World Database. Clin Drug Investig 43, 177–184 (2023). https://doi.org/10.1007/s40261-023-01246-x

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