Risk analysis of myocarditis induced by immune checkpoint inhibitors: a real-world study based on the open FDA database_Chinese Journal of Evidence-Based Medicine

Authors：

LI Jianping , TANG Bin , HU Ying , XU Chuanjie ,  WANG Fei

The Third Affiliated Hospital of Zunyi Medical University/Department of Neurology and Critical Care Medicine, Zunyi First People's Hospital, Zunyi 563000, P. R. China;

Corresponding author：

WANG Fei, Email: 543010175@qq.com

Keywords：

Immune checkpoint inhibitors; Antitumor agents; Drug-related adverse reactions; Myocarditis

DOI：

10.7507/1672-2531.202302115

Video：

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Objective To investigate the risk of myocarditis caused by immune checkpoint inhibitors (ICI). Methods The adverse reaction (ADR) reports on myocarditis caused by atelizumab, duvalizumab, pabolizumab, and navulizumab were downloaded from the FDA Adverse Event Reporting System (FAERS) from January 1, 2014 to September 30, 2022. The relevant analysis was conducted on the gender, age, medication dosage, and occurrence time of ICI related myocarditis patients. Results A total of 1 892 reports of myocarditis induced by ICI were included. The proportion of myocarditis caused by ICI was higher in males than in females (1.9∶1). The incidence of myocarditis in patients with basic diseases such as diabetes and heart disease, and in the age group 65-75 was relatively high. The incidence of myocarditis caused by navulizumab was high within 30 days with the use of conventional doses, and that of the other three drugs were high within 31 to 90 days. And the incidence of myocarditis is higher when used in combination than when used alone. Conclusion Different varieties of ICI can lead to the occurrence of myocarditis, and male, elderly, underlying diseases, and combination therapy may be risk factors for myocarditis caused by ICI.

Citation： LI Jianping, TANG Bin, HU Ying, XU Chuanjie, WANG Fei. Risk analysis of myocarditis induced by immune checkpoint inhibitors: a real-world study based on the open FDA database. Chinese Journal of Evidence-Based Medicine, 2023, 23(8): 869-873. doi: 10.7507/1672-2531.202302115 Copy

1.	Nso N, Antwi-Amoabeng D, Beutler BD, et al. Cardiac adverse events of immune checkpoint inhibitors in oncology patients: a systematic review and meta-analysis. World J Cardiol, 2020, 12(11): 584-598.
2.	Guo X, Wang H, Zhou J, et al. Clinical manifestation and management of immune checkpoint inhibitor-associated cardiotoxicity. Thorac Cancer, 2020, 11(2): 475-480.
3.	Courand PY, Bouali A, Harbaoui B, et al. Myocarditis: Uncommon but severe toxicity of immune checkpoint inhibitors. Bull Cancer, 2019, 106(11): 1050-1056.
4.	Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol, 2018, 19(12): 1579-1589.
5.	Lyon AR, Yousaf N, Battisti NML, et al. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol, 2018, 19(9): e447-e458.
6.	Saygin D, Ghosh N, Reid P. Immune checkpoint inhibitor-associated myositis: a distinct form of inflammatory myopathy. J Clin Rheumatol, 2022, 28(7): 367-373.
7.	Chhabra N, Kennedy J. A review of cancer immunotherapy toxicity: immune checkpoint inhibitors. J Med Toxicol, 2021, 17(4): 411-424.
8.	Osinga TE, Oosting SF, van der Meer P, et al. Immune checkpoint inhibitor-associated myocarditis: case reports and a review of the literature. Neth Heart J, 2022, 30(6): 295-301.
9.	Wu NC, Feng YH, Kuo YH, et al. Clinical features and outcomes of immune checkpoint inhibitor-associated cardiovascular toxicities. Acta Cardiol Sin, 2022, 38(1): 39-46.
10.	赵艳艳, 张会鲜, 孟路华, 等. 基于美国FDA不良事件报告系统数据库的免疫检查点抑制剂致胆管炎风险分析. 药物不良反应杂志, 2022, 24(8): 424-428.
11.	Makunts T, Saunders IM, Cohen IV, et al. Myocarditis occurrence with cancer immunotherapy across indications in clinical trial and post-marketing data. Sci Rep, 2021, 11(1): 17324.
12.	Moslehi JJ, Salem JE, Sosman JA, et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet, 2018, 391(10124): 933.
13.	Zhou YW, Zhu YJ, Wang MN, et al. Immune checkpoint inhibitor-associated cardiotoxicity: current understanding on its mechanism, diagnosis and management. Front Pharmacol, 2019, 10: 1350.
14.	Jing Y, Zhang Y, Wang J, et al. Association between sex and immune-related adverse events during immune checkpoint inhibitor therapy. J Natl Cancer Inst, 2021, 113(10): 1396-1404.
15.	Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol, 2018, 71(16): 1755-1764.
16.	石宏伟, 唐恒, 韩光, 等. 免疫检查点抑制剂所致心肌炎研究进展. 中华肿瘤防治杂志, 2022, 29(16): 1159-1164, 1183.
17.	Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol, 2018, 4(12): 1721-1728.
18.	Dong H, Qi Y, Kong X, et al. PD-1/PD-L1 inhibitor-associated myocarditis: epidemiology, characteristics, diagnosis, treatment, and potential mechanism. Front Pharmacol, 2022, 13: 835510.
19.	Patil A, Goldust M, Wollina U. Herpes zoster: a review of clinical manifestations and management. Viruses, 2022, 14(2): 192.
20.	Tay WT, Fang YH, Beh ST, et al. Programmed cell death-1: programmed cell death-ligand 1 interaction protects human cardiomyocytes against T-cell mediated inflammation and apoptosis response in vitro. Int J Mol Sci, 2020, 21(7): 2399.
21.	Portolés Hernández A, Blanco Clemente M, Escribano García D, et al. Checkpoint inhibitor-induced fulminant myocarditis, complete atrioventricular block and myasthenia gravis-a case report. Cardiovasc Diagn Ther, 2021, 11(4): 1013-1019.
22.	Zhang L, Zlotoff DA, Awadalla M, et al. Major adverse cardiovascular events and the timing and dose of corticosteroids in immune checkpoint inhibitor-associated myocarditis. Circulation, 2020, 141(24): 2031-2034.

1. Nso N, Antwi-Amoabeng D, Beutler BD, et al. Cardiac adverse events of immune checkpoint inhibitors in oncology patients: a systematic review and meta-analysis. World J Cardiol, 2020, 12(11): 584-598.
2. Guo X, Wang H, Zhou J, et al. Clinical manifestation and management of immune checkpoint inhibitor-associated cardiotoxicity. Thorac Cancer, 2020, 11(2): 475-480.
3. Courand PY, Bouali A, Harbaoui B, et al. Myocarditis: Uncommon but severe toxicity of immune checkpoint inhibitors. Bull Cancer, 2019, 106(11): 1050-1056.
4. Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol, 2018, 19(12): 1579-1589.
5. Lyon AR, Yousaf N, Battisti NML, et al. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol, 2018, 19(9): e447-e458.
6. Saygin D, Ghosh N, Reid P. Immune checkpoint inhibitor-associated myositis: a distinct form of inflammatory myopathy. J Clin Rheumatol, 2022, 28(7): 367-373.
7. Chhabra N, Kennedy J. A review of cancer immunotherapy toxicity: immune checkpoint inhibitors. J Med Toxicol, 2021, 17(4): 411-424.
8. Osinga TE, Oosting SF, van der Meer P, et al. Immune checkpoint inhibitor-associated myocarditis: case reports and a review of the literature. Neth Heart J, 2022, 30(6): 295-301.
9. Wu NC, Feng YH, Kuo YH, et al. Clinical features and outcomes of immune checkpoint inhibitor-associated cardiovascular toxicities. Acta Cardiol Sin, 2022, 38(1): 39-46.
10. 赵艳艳, 张会鲜, 孟路华, 等. 基于美国FDA不良事件报告系统数据库的免疫检查点抑制剂致胆管炎风险分析. 药物不良反应杂志, 2022, 24(8): 424-428.
11. Makunts T, Saunders IM, Cohen IV, et al. Myocarditis occurrence with cancer immunotherapy across indications in clinical trial and post-marketing data. Sci Rep, 2021, 11(1): 17324.
12. Moslehi JJ, Salem JE, Sosman JA, et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet, 2018, 391(10124): 933.
13. Zhou YW, Zhu YJ, Wang MN, et al. Immune checkpoint inhibitor-associated cardiotoxicity: current understanding on its mechanism, diagnosis and management. Front Pharmacol, 2019, 10: 1350.
14. Jing Y, Zhang Y, Wang J, et al. Association between sex and immune-related adverse events during immune checkpoint inhibitor therapy. J Natl Cancer Inst, 2021, 113(10): 1396-1404.
15. Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol, 2018, 71(16): 1755-1764.
16. 石宏伟, 唐恒, 韩光, 等. 免疫检查点抑制剂所致心肌炎研究进展. 中华肿瘤防治杂志, 2022, 29(16): 1159-1164, 1183.
17. Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol, 2018, 4(12): 1721-1728.
18. Dong H, Qi Y, Kong X, et al. PD-1/PD-L1 inhibitor-associated myocarditis: epidemiology, characteristics, diagnosis, treatment, and potential mechanism. Front Pharmacol, 2022, 13: 835510.
19. Patil A, Goldust M, Wollina U. Herpes zoster: a review of clinical manifestations and management. Viruses, 2022, 14(2): 192.
20. Tay WT, Fang YH, Beh ST, et al. Programmed cell death-1: programmed cell death-ligand 1 interaction protects human cardiomyocytes against T-cell mediated inflammation and apoptosis response in vitro. Int J Mol Sci, 2020, 21(7): 2399.
21. Portolés Hernández A, Blanco Clemente M, Escribano García D, et al. Checkpoint inhibitor-induced fulminant myocarditis, complete atrioventricular block and myasthenia gravis-a case report. Cardiovasc Diagn Ther, 2021, 11(4): 1013-1019.
22. Zhang L, Zlotoff DA, Awadalla M, et al. Major adverse cardiovascular events and the timing and dose of corticosteroids in immune checkpoint inhibitor-associated myocarditis. Circulation, 2020, 141(24): 2031-2034.

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