Risk of Cardiac Events in Patients Receiving Immune Checkpoint Inhibitors

Quick Takes

  • Immune checkpoint inhibitor (ICI) therapy is associated with a 2- to 4-fold increased risk of cardiac events including myocarditis, arrhythmias, and heart failure.
  • The 1-year absolute risk of cardiac events in patients with ICI ranged between 7-10%.
  • Identifying risk factors and underlying mechanisms for ICI-related cardiac events is necessary to mitigate the expected increase in cardiac morbidity related to the expansion of ICI use.

Study Questions:

What is the risk of cardiac events in patients receiving immune checkpoint inhibitors (ICI) for lung cancer or malignant melanoma?

Methods:

The authors leveraged Danish administrative registries to perform a nationwide retrospective cohort study, which included all consecutive patients with incident lung cancer or malignant melanoma who were diagnosed any time from 2011-2017. Patients were followed from the date of cancer diagnosis until development of a cardiac outcome, death emigration, or end of 2017. The main composite outcome was cardiac events (arrhythmia, peri- or myocarditis, heart failure) or cardiovascular death. They identified a total of 13,636 patients with malignant melanoma of whom 357 received ICI, and 25,573 with lung cancer of whom 746 received ICI.

Results:

Among lung cancer patients on ICI, the vast majority (n = 743) received programmed cell death-1 inhibitors (PD1i, pembrolizumab or nivolumab). Patients treated with PD1i had an overall lower burden of comorbidities compared to other lung cancer patients. Their 1-year absolute risk of cardiac events was 9.7% (95% confidence interval [CI], 6.8-12.5). Lung cancer patients on PD1i had a 2-fold increase in the risk of cardiac events compared to those not on ICI. Noncardiac mortality in patients with lung cancer on PD1i was 50.3%. Among patients with malignant melanoma, 145 received PD1i and 212 were treated with cytotoxic T-lymphocyte-associated protein-4 inhibitor (CTLA4i). The 1-year absolute risk of cardiac events was 6.6% (95% CI, 1.8-11.3) for those on PD1i and 7.5% (95% CI, 3.7-11.3), respectively. The relative risk of cardiac events was increased 4-fold in the first 6 months after PD1i and CTLA4i treatment. The 1-year noncardiac mortality was 22.8% for those on PD1i and 44.8% on CTLA4i. When examining individual outcomes, ICI were associated with increased relative risk of myocarditis, arrhythmias, heart failure, and cardiovascular death, and can extend to >6 months.

Conclusions:

Patients treated with ICI are at increased risk of cardiac events.

Perspective:

Cardiovascular adverse effects of ICI are increasingly recognized as evidenced by the rising number of reports on the topic. This nationwide cohort places the increased risk of cardiac death in the context of dramatically elevated incidence of noncardiac death suffered by patients with cancer. ICI-related cardiac events extend beyond the first 30 days of use and are not limited to the dreaded myocarditis. Unfortunately, the lack of granular clinical characterization does not allow for the identification of patient-specific risk factors for ICI-related cardiac events, and data on the risk of cardiac events with dual ICI use cannot be determined from this dataset. Identifying risk factors and underlying mechanisms for ICI-related cardiac events is necessary to mitigate the expected increase in cardiac morbidity related to the expansion of ICI use.

Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Novel Agents, Acute Heart Failure

Keywords: Antibodies, Monoclonal, Humanized, Arrhythmias, Cardiac, Cardiotoxicity, Heart Failure, Lung Neoplasms, Melanoma, Myocarditis, Risk Factors, Secondary Prevention, Skin Neoplasms, T-Lymphocytes, Cytotoxic


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