Elsevier

International Journal of Cardiology

Volume 296, 1 December 2019, Pages 113-121
International Journal of Cardiology

Diagnosis of immune checkpoint inhibitor-associated myocarditis: A systematic review

https://doi.org/10.1016/j.ijcard.2019.07.025Get rights and content

Highlights

  • Largest systematic review of immune checkpoint inhibitor-induced myocarditis cases

  • Cases show elevated cardiac biomarkers, nonspecific electrocardiographic changes.

  • Cases with poor prognosis reported conduction defects and arrhythmias.

  • High negative predictive value of coronary angiography may help in prompt diagnosis.

Abstract

Background

Myocarditis is a rare but severe adverse event associated with immune checkpoint inhibitors, its diagnosis depending on a high index of suspicion and appropriate investigations. Our objective was to systematically review the diagnostic approaches to myocarditis associated with immune checkpoint inhibitors.

Methods

The systematic review was conducted according to the PRISMA guidelines (PROSPERO Registration: CRD42018097247). We searched Medline and Embase for case reports, case series, and observational studies published in journal articles or presented as conference abstracts that describe patients who developed myocarditis after immune checkpoint inhibitor therapy.

Results

After a review of 2326 citations, we included 88 cases (53 case reports/series published in journal articles and 35 cases in the observational study). Serum troponin was elevated in 98% of the case reports and 94% of participants in the observational study. ST changes including ST elevation were present in almost a third of case reports. Echocardiography revealed preserved left ventricular ejection fraction in 32% of case reports and 51% of cases in the observational study; however, preserved systolic function did not predict greater survival. Patients who suffered poorer prognosis tended to have major conduction defects or ventricular arrhythmias more frequently than patients who did not. Acute myocardial ischemia was ruled out in all cases (n = 31) when the diagnostic workup included coronary angiography.

Conclusions

Immune checkpoint inhibitor-associated myocarditis is characterized by elevation of cardiac troponin levels and non-specific electrocardiographic changes. Early coronary angiography may distinguish it from myocardial ischemia or myocardial infarction.

Introduction

Immune checkpoint inhibitors (ICI) have a wide range of immune-related adverse events affecting different organs of the body. Myocarditis is one such rare yet severe adverse event, with the highest case fatality rate among the immune-related adverse events of ICIs [1].

There have been reports of myocarditis among ICI users in the World Health Organization pharmacovigilance database Vigibase [2] and the US Food and Drug Administration Adverse Event Reporting System (FAERS) [3]. Since ICI-associated myocarditis is rare, occurring at a frequency of 0.09% [4] to 1% [5,6], a high index of clinical suspicion is needed to diagnose and manage this condition. Recent studies [[7], [8], [9]] have identified the clinical features of ICI-associated myocarditis but a full understanding of the diagnostic approaches to evaluate this condition is needed. The objective of this systematic review was to characterize the diagnostic approaches to ICI-associated myocarditis.

Section snippets

Study design

We conducted a systematic review according to the PRISMA Harms guidelines [10] (Supplementary Material 1). Our protocol was registered in PROSPERO CRD42018097247 (Supplementary Material 2).

Search strategy

We searched Medline and Embase on 10th June 2018 to find studies on heart conditions (searched using terms denoting cardiac diseases involving endocardium, myocardium, or pericardium) associated with ICIs. We limited our search to studies published after the approval of the first ICI in the US in 2011. We did

Study inclusion

After a review of 2326 citations in PubMed and Embase, we included 46 case reports, 4 case series, and one observational study. This resulted in a total of 88 cases of ICI-associated myocarditis, including 53 cases from reports published in journals or conference abstracts and 35 cases from a single observational study. Fig. 1 describes the PRISMA flow sheet.

Completeness of reporting elements and risk of bias

Of the published case reports, none provided complete demographic description. Only 29% of the cases commented on the presence or absence

Discussion

Our review suggests that ICI-associated myocarditis is accompanied by elevated cardiac biomarker levels, nonspecific ST and arrhythmic changes on EKG, lack of correlation between preserved systolic function and survival, and negative results on coronary angiography.

Conclusion

In summary, immune checkpoint inhibitor-associated myocarditis is characterized by elevation of cardiomyocyte damage biomarker levels and non-specific electrocardiographic changes. Early coronary angiography may distinguish it from myocardial ischemia or myocardial infarction. Cardiac arrhythmias are frequently reported in ICI-associated myocarditis patients with poorer prognosis, while reduction in left ventricular ejection fraction does not correlate with survival. Prospective studies with

Funding

None.

Declaration of Competing Interest

The authors report no relationships that could be construed as a conflict of interest.

Acknowledgement

The authors would like to acknowledge the help of Dr. Govind Jha in data extraction for this paper.

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    Authorship statement: All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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