Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors

Abstract

Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariableadjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.

Pre-Existing Cardiovascular Conditions as Clinical Predictors of Myocarditis Reporting with Immune Checkpoint Inhibitors: A VigiBase Study

“…In line with previous studies reporting a higher risk of ICI-related myocarditis with pre-ICI home angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment, a history of heart failure and/or a history of acute coronary syndrome [7,10], the results of our study provide further support to the hypothesis that pre-existing CV risk factors and/or CV diseases are associated with the reporting of myocarditis in patients treated with ICIs. In clinical practice, cancer patients with pre-existing CV conditions could thus be exposed to higher risk of developing myocarditis upon treatment with ICIs, and might benefit from a more intensive cardiac surveillance.…”

“…Diabetes (as a CV risk factor) and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (as pre-ICI home drugs for underlying CV diseases) were more commonly found in patients with ICI-related myocarditis than in patients without such an ADR in a case-control study within the medical records from a multicenter registry [7]. Data from the Mayo Clinic further revealed that a history of heart failure and a history of acute coronary syndrome were also associated with a higher risk of ICI-related myocarditis [10].…”

“…Observational studies to date, of real-world clinical data from patient registries, pharmacovigilance databases, and claim databases, have yielded heterogeneous information on clinical risk factors for ICI-related myocarditis [7][8][9][10][11]18]. In a retrospective cohort study within the Mayo Clinic database of cancer patients treated with ICIs, patient age over 80 years was found to be associated with an increased risk of ICI-related myocarditis, which occurred in a total of twelve patients [10]. Patient age of 75 years or older emerged as a clinical risk factor for ICI-related myocarditis in a pharmacovigilance study within FAERS.…”

“…Two distinct studies within the Food and Drug Administration Adverse Event Reporting System (FAERS) showed that the risk of ICI-related myocarditis is higher in female patients and in 75-years-old or older patients [8], and when either myositis, encephalitis or hepatitis develop concurrently with myocarditis upon ICI use [9]. In the Mayo Clinic database for cancer patients treated with ICIs, age over 80 years, a history of heart failure, and a history of acute coronary syndrome, were associated with a higher risk of ICI-related myocarditis, which occurred in 12 patients [10]. In a recent retrospective study of a cohort of 455 patients treated with ICIs for advanced melanoma from a single medical center, cross-referenced against a cohort of patients with similar characteristics extracted from VigiBase, the World Health Organization's (WHO) pharmacovigilance database, ICI-related myocarditis occurred with a significantly older age distribution (median age: 69 years) than other ICI-related adverse drug reactions (ADRs) [11].…”

Pandemic Perspective: Commonalities Between COVID-19 and Cardio-Oncology

“…ICIs can induce immune-mediated cardiotoxicity, including myocarditis, pericarditis, heart failure, arrhythmias, and MI. These events are uncommon, occurring in <3% of patients who receive ICIs, but carry high risk of mortality (90).…”