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 reports13,14, the incidence of myocarditis was very low: only one patient (0.24%) developed myocarditis. The time to myocarditis for this patient was 28 days after initiation of nivolumab, which was consistent with the reported median time to onset of 30 days by Salem and colleagues.13 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.13
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.15 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.16–19 In our study, we excluded patients with pre-existing cardiovascular disease from analysis, however this approach might have underestimated the rate of ICI-related cardiotoxicity in the real-world clinical setting as several studies have showed patients with baseline cardiovascular disease are more likely to develop cardiovascular toxicities from cancer therapies.4,20,21
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.14 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.10,22 The study of a multicenter registry by Mahmood and colleagues reported that 16 patients developed a major adverse cardiac events and 6 (38%) occurred in patients with a normal ejection fraction.10 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.23 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).24 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.22
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 changes in cardiac function using the echocardiographic measures of ejection fraction and/or global longitudinal strain.25–28 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. This small dataset is congruent with the findings from Awadalla et al, who demonstrated GLS decreases were lower in patients with ICI induced myocarditis compared to control patients and was associated with the development of major adverse cardiovascular events.29
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.30–32 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 a sicker population with more baseline cardiovascular disease and/or risk factors.
There are several limitations to our study that should be noted. First, varying definitions of cardiotoxicity have been utilized in the literature, and currently there is no standard reference definition. Also, this is a study of retrospectively collected clinical data from ICD codes. As such we were not able to confirm these findings with direct evaluation of the electronic medical records themselves. The use of ICD code groups such as “arrhythmia” and “heart failure” represent a heterogenous collection of diseases thereby impacting the interpretation of the findings. Key biomarkers and imaging (e.g., GLS, EF) data were not measured for all patients before and after therapy. Therefore, we cannot make definitive conclusions about these findings, and we could not definitively attribute cardiac diagnosis to ICI-induced cardiotoxicity. Another limitation is that there was no compliance assessment of medication use and the dose and duration of ICI use were not easily captured. We only had one patient diagnosed with ICI-related myocarditis, so we could not evaluate the effect of corticosteroids33 or CTLA-4 agonist abatacept34 on the outcome of myocarditis patients. Finally, we cannot attribute the finding of increased mortality in patients with ICI cardiotoxicity to the cardiotoxicity as we were not able to perform competing risk analyses and there was no control group. As such, due these various limitations, the data presented should be considered hypothesis generating only and not lead to definitive conclusions.