Specificity of definition of ICI-related myocarditis improved after minor change

ByScott Buzby

Fact checked byErik Swain

Key takeaways:

The IC-OS definition of immune checkpoint inhibitor-associated myocarditis demonstrated good diagnostic sensitivity but moderate specificity.
Specificity was improved with the addition one minor criterion.

A modified version of the International Cardio-Oncology Society definition of immune checkpoint inhibitor-associated myocarditis may improve its predictive value, researchers reported.

The definition proposed in a 2021 International Cardio-Oncology Society (IC-OS) consensus statement demonstrated excellent sensitivity but moderate specificity for the diagnosis of myocarditis related to immune checkpoint inhibitors (ICI) and was improved with the addition of time to symptom onset as a minor criterion.

cancer treatment — The IC-OS definition of ICI-associated myocarditis demonstrated good diagnostic sensitivity but moderate specificity.
*Image: Adobe Stock*

“Immune checkpoint inhibitors-associated myocarditis (ICI-M) is one of the most serious complications of this innovant therapy, with reported fatality rate ranging from 25% to 40%, that manifests in 1% to 2% of cases,” Francois Deharo, MD, of the unit of heart failure and valvular heart diseases, North Hospital, Assistance Publique-Hôpitaux de Marseille, and the department of cardiology, Aix-Marseille University, University Mediterranean Center of Cardio-Oncology, France, and colleagues wrote in a research letter published in the Journal of the American Heart Association.

Definition of ICI myocarditis

In December 2021, the IC-OC proposed a definition for suspected ICI myocarditis based on pathohistological findings and elevated cardiac troponin-associated criteria including symptoms/signs, ventricular arrhythmia, conduction disorders, left ventricular dysfunction, other immune related adverse events and cardiac MRI abnormalities, according to the researchers.

“Although it has been recently endorsed by the European Society of Cardiology Guidelines of Cardio-Oncology, this definition is empirical and has never been evaluated,” the researchers wrote. “We aimed to assess the diagnostic value of the IC-OS definition and to determine whether addition of new criteria would improve its performance.”

This analysis included 68 consecutive patients (mean age, 69 years) with suspected ICI myocarditis.

The researchers estimated the sensitivity, specificity, positive and negative likelihood ratios and positive and negative predictive values of the IC-OS definition based on either one major or two minor criteria for ICI myocarditis being met.

Researchers additionally tested a modified definition based on one major or three minor criteria being met, with the additional minor criteria being time of suspected myocarditis onset being less than 3 months after ICI initiation.

Diagnosis of ICI myocarditis

ICI myocarditis was diagnosed in 45 patients.

The IC-OS definition of ICI myocarditis was associated with a sensitivity of 93%, a specificity of 70%, a positive likelihood ratio of 3.1 and a negative likelihood ratio of 0.1.

After adding time of suspected myocarditis onset of less than 3 months after ICI initiation as a minor criterion to the definition of ICI myocarditis, and considering one major or three minor criteria to define ICI myocarditis, the new version of the IC-OS definition of ICI myocarditis was associated with a higher specificity of 83%, a sensitivity that remained the same, a higher positive likelihood ratio of 5 and a negative likelihood ratio that also remained the same; in addition, the changes increased the positive predictive value of the IC-OS definition from 86% to 91% and increased the negative predictive value from 85% to 86%, according to the study.

“Our work shows for the first time that the IC-OS definition has a high sensitivity but a moderate specificity that may lead to a misdiagnosis of [ICI myocarditis] and thus potentially worsen the cancer prognosis due to unnecessary interruption of ICI therapy,” the researcher wrote. “Adding time of onset of first events/symptoms < 3 months after the initiation of ICIs as a new minor criterion allowed for improving specificity. This criterion is relevant because, in pharmacovigilance analyses, the chronological criteria is a discriminating argument to confirm causality between the intake of a drug and the occurrence of an adverse event. Moreover, in many other studies, most of the [ICI myocarditis] cases occurred within this time.”