In this study, we observed that approximately 15% of patients receiving ICI therapy developed evidence for potential cardiotoxicity. This is likely an underestimate since a standardized surveillance was not in employed at the time of or following the ICI treatment and many cases are likely to be “subclinical” as is the case with most CVD. The most commonly observed types of cardiotoxicity were heart failure and arrhythmia. As suggested in previous reports11,12, the incidence of myocarditis was very low: only one patient (0.24%) developed myocarditis. This relatively low prevalence may be related to inadequate screening, particularly since the study includes data starting from 2011, when the autoimmune side effects of ICIs were just being recognized in a clinical setting. However, the observed incidence of other manifestations of cardiotoxicity was higher than previously suggested.11
Estimates of the incidence of ICI-induced cardiotoxicity vary substantially across reports. This might be explained, in part, by variations in case definitions and a specific focus on certain cardiac syndromes (e.g., myocarditis). Other case series on ICI-induced cardiotoxicity suggest that cardiomyopathy, myocarditis, and conduction abnormalities are under-reported.13 The manufacturer of both ipilimumab and nivolumab reported myocarditis (0.09%) from detailed clinical trial safety data but other cardiovascular irAEs were later described in case reports.14-17
Several studies have also characterized cardiac irAEs and their incidence. Myocarditis was one of the first recognized ICI-related AEs and has been the most studied of the ICI-related cardiotoxicities.12 A multicenter registry including patients from the US, Canada, and Germany and found that the prevalence of myocarditis after ICI therapy was 1.14% with a median time of onset of 34 days, whereas another study reported a median time of 65 days from initiation of treatment.10,18 Approximately 38% of patients within the multicenter registry also developed a major adverse cardiac event despite having a normal ejection fraction. Pooled Food and Drug Administration (FDA) data on reported ICI-related adverse events in clinical trials suggested that the risks of cardiomyopathy, arrhythmia, myocarditis, and pericardial disease were 0.53%, 5.56%, 0.03%, and 0.7%, respectively.19 A meta-analysis of clinical trials of PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, avelumab and durvalumab) for treatment of non-small cell lung cancer also reported lower cardiovascular adverse event rates (1% for cardiorespiratory arrest, 2% for heart failure, 1% for myocardial infarction, and 2% for strokes).20 A case series of 30 patients with ICI-related cardiotoxicity, suggested the most frequently observed cardiotoxicities were reduced ejection fraction, arrhythmias, and pericardial disease with almost 80% of patients having left ventricular systolic dysfunction.18
The incidence of irAEs has been noted to be dose dependent after ipilimumab and pembrolizumab with greater toxicity at higher dose levels.7 The differences in incidence of cardiac irAEs reported may be attributable to dose of ICI and future studies should provide details on ICI dosage, number of chemotherapy cycles, and their timing. Dosing of ICIs in clinical practice follows a predominantly fixed-dosing strategy (nivolumab – 240 mg, pembrolizumab – 200 mg) and extended dosing intervals (Q4 -Q6 weeks).
Previous studies have also explored early detection of chemotherapy-induced cardiotoxicity and have used echocardiography for monitoring cardiac function. GLS, which detects early changes in myocardial contractile function, has been used to monitor for cardiotoxicity caused by antineoplastic agents in patients receiving anthracyclines and/or trastuzumab.21–23 GLS has been utilized for early screening of cardiomyopathy and/or heart failure in patients receiving anti-neoplastic agents. There are limited GLS data on patients receiving ICIs. In the subset of patients in our study who developed cardiotoxicity and had pre- and post-treatment left ventricular ejection fraction (LVEF) and GLS data available, a GLS decline was observed in the absence of a meaningful decrease in LVEF. Our data also suggests that GLS could be a method of choice for early detection of ICI-induced cardiotoxicity. However, larger studies with baseline and post-treatment GLS measurements are needed to better elucidate the role of GLS in early detection of cardiotoxicity in patients receiving ICIs. A clinically relevant threshold of GLS decline has not been established, as not all patients with GLS decline develop evidence for clinical heart failure.
Several studies have suggested a potential role for the early initiation of cardioprotective medications including beta blockers and angiotensin system inhibitors to prevent the development of cardiotoxicity associated with anthracyclines and trastuzumab.24–26 There is limited data regarding their benefits in the setting of ICI induced cardiotoxicities. Interestingly, in our study we found that baseline beta-blocker use was associated with increased mortality. There is no reason to consider beta-blockers themselves problematic in patients treated with ICI, rather they likely are a marker of sicker population with more baseline cardiovascular disease and/or risk factors.
There are several limitations to our study that should be noted. First, we used ICD-9/ICD-10-based definitions of malignancy and cardiotoxicity. The sensitivity and specificity of these codes in this population is unknown. In the literature, varying definitions of cardiotoxicity have been utilized, and currently there is no reference standard definition. Also, this is a study of retrospectively collected clinical data in the electronic health record system. Key biomarkers and imaging (e.g., GLS, EF) data were not measured for all patients before and after therapy. Furthermore, we could not definitively attribute cardiac diagnosis to ICI-induced cardiotoxicity. To better identify patients with ICI-induced cardiotoxicity, we excluded patients with pre-existing disease and evaluated cardiac diseases known to be associated with ICI therapy. Establishing a causal relationship between ICI and arrhythmia is challenging as cancers may increase the risk of arrhythmia27 and many arrhythmias are clinically silent. In our study, only patients who developed a new diagnosis of an arrhythmia after ICI initiation were deemed to have a cancer-therapy induced arrhythmia. However, it is possible that some patients had preexisting undiagnosed arrhythmia. Furthermore, ICIs are often utilized to treat metastatic cancers, which makes it difficult to determine whether arrhythmias are secondary to ICIs, a delayed effect of prior therapy, or due to factors unrelated to their cancer or its therapy.