SUMMARY: Immune checkpoint inhibitors (ICIs) have dramatically transformed the management and prognosis of various malignancies. By enhancing the immune systems ability to identify and destroy cancer cells, ICIs have provided significant improvements in treatment outcomes across a range of tumor types. However, the introduction of these therapies has also been accompanied by a spectrum of immune-related Adverse Events (irAEs), including those affecting the cardiovascular system. These CardioVascular Adverse Events (CVAEs) present a serious concern due to their potential impact on patient health and treatment outcomes.
The cardiovascular manifestations associated with ICIs encompass a range of conditions such as myocarditis, pericarditis, acute coronary syndrome, heart failure, arrhythmias, conduction abnormalities, and cardiac arrest. Although the incidence of these events is relatively low (less than 1% of patients), their severity can be profound. Myocarditis, in particular, is a critical concern due to its association with a high mortality rate, which can be as high as 60%. This underscores the need for vigilant monitoring and management strategies to mitigate these risks.
The objective of the systematic review and meta-analysis was to elucidate the incidence and outcomes of CVAEs associated with ICIs and to assess the effectiveness of various management strategies for myocarditis. This analysis sought to update the clinical understanding of these adverse effects and provide recommendations based on the most recent data.
The researchers review process involved searching several databases, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials, up to April 4, 2023, and with the gathered data, two separate analyses were performed:
1. Phase 1 to 4 Trials Analysis: Focused on trials involving adults with malignant neoplasms treated with FDA- or EMA-approved ICIs. This analysis aimed to gather data on the incidence of CVAEs associated with these therapies.
2. Case Reports and Retrospective Studies Analysis: Concentrated on clinical manifestations and treatment outcomes for patients who developed CVAEs due to ICIs.
Data were meticulously extracted by two independent investigators, with stringent criteria applied to ensure the relevance and quality of the studies included. For instance, studies with dose escalation, small sample sizes, or non-English publications were excluded. The Primary outcome measure was the incidence of CVAEs.
Incidence of Cardiovascular Adverse Events
The meta-analysis of clinical trials included data from 83,315 participants across 589 trials. The therapies investigated included several ICIs such as Pembrolizumab (KEYTRUDA®:), Nivolumab (OPDIVO®), Cemiplimab (LIBTAYO®), Atezolizumab (TECENTRIQ®), Durvalumab (IMFINZI®), Avelumab (BAVENCIO®), and Ipilimumab (YERVOY®). The overall incidence of CVAEs in patients treated with anti-PD-1 or anti-PD-L1 therapies was found to be 0.8%. Notably, Cemiplimab was associated with a higher risk of high-grade cardiovascular adverse events compared to other ICIs (2.91% for Cemiplimab versus 0.69% overall).
The incidence of myocarditis specifically was reported as 0.24% for any grade and 0.2% for high-grade myocarditis. While dual ICI therapy was linked to a higher incidence of myocarditis compared to other regimens, the overall incidence of CVAEs did not significantly differ between dual ICI therapy, ICI plus chemotherapy, or ICI plus Tyrosine Kinase Inhibitors.
Management and Outcomes of Myocarditis
In the analysis of myocarditis cases, which included 223 patients (64.5% men), the majority had received PD-1 or PD-L1 inhibitors. A substantial proportion of these patients had cardiovascular risk factors: 41.1% had hypertension, 16.3% had diabetes, and 46.5% had other risk factors. Among 220 evaluable patients, the mortality rate for myocarditis was alarmingly high at 37.7%.
Management strategies for myocarditis varied, with treatments including high-dose Corticosteroids, Methylprednisolone, IV immunoglobulin, Plasma exchange, Mycophenolate mofetil, Infliximab, and Antithymocyte globulin. Outcomes of these treatments showed mixed results. For instance, high-dose Corticosteroids were associated with a 63.5% improvement rate but also a 26% cardiac mortality rate. Abatacept showed promise with an improvement rate of 91.7% among those who received it. Prospective data suggested that systematic screening for respiratory muscle involvement, active ventilation, prompt use of Abatacept, and the addition of Ruxolitinib might reduce mortality rates. However, the review emphasized that the current management strategies are largely empirical, and there is no definitive evidence on the most effective approach.
Recommendations and Conclusions
The review highlighted a critical need for standardized diagnostic and therapeutic approaches due to the variability in management strategies and the lack of prospective clinical trials. The findings underscore the importance of early recognition, cessation of ICI therapy, and prompt initiation of corticosteroid therapy for optimal management of myocarditis. The review also suggests that further research, including prospective clinical trials and the establishment of international registries, is necessary to enhance the understanding and management of ICI-induced CVAEs.
In summary, while cardiovascular adverse events related to ICIs are rare, their potential severity, particularly myocarditis, warrants heightened awareness and proactive management by clinicians. Early identification and intervention are crucial to improving patient outcomes and reducing mortality associated with these adverse effects.
Immune Checkpoint Inhibitor–Induced Cardiotoxicity. A Systematic Review and Meta-Analysis. Nielsen DL, Juhl CB, Nielsen OH, et al. JAMA Oncol. 2024;doi:10.1001/jamaoncol.2024.3065.
