Cardiotoxicity risk factors with immune checkpoint inhibitors

Abstract

Background Checkpoint-inhibitor immunotherapies have had a profound effect in the treatment of cancer by inhibiting down-regulation of T-cell response to malignancy. The cardiotoxic potential of these agents was first described in murine models and, more recently, in numerous clinical case reports of pericarditis, myocarditis, pericardial effusion, cardiomyopathy, and new arrhythmias. The objective of our study was to determine the frequency of and associated risk factors for cardiotoxic events in patients treated with immune checkpoint inhibitors. Methods Medical records of patients who underwent immunotherapy with durvalumab, ipilimumab, nivolumab, and pembrolizumab at Wake Forest Baptist Health were reviewed. We collected retrospective data regarding sex, cancer type, age, and cardiovascular disease risk factors and medications. We aimed to identify new diagnoses of heart failure, atrial fibrillation, ventricular fibrillation/tachycardia, myocarditis, and pericarditis after therapy onset. To assess the relationship between CVD risk factors and the number of cardiac events, a multivariate model was applied using generalized linear regression. Incidence rate ratios were calculated for every covariate along with the adjusted P-value. We applied a multivariate model using logistic regression to assess the relationship between CVD risk factors and mortality. Odds ratios were calculated for every covariate along with the adjusted P-value. Adjusted P-values were calculated using multivariable regression adjusting for other covariates. Results Review of 538 medical records revealed the following events: 3 ventricular fibrillation/tachycardia, 12 pericarditis, 11 atrial fibrillation with rapid ventricular rate, 0 myocarditis, 8 heart failure. Significant risk factors included female gender, African American race, and tobacco use with IRR 3.34 (95% CI 1.421, 7.849; P = 0.006), IRR 3.39 (95% CI 1.141, 10.055; P = 0.028), and IRR 4.21 (95% CI 1.289, 13.763; P = 0.017) respectively. Conclusions Our study revealed 34 significant events, most frequent being pericarditis (2.2%) and atrial fibrillation (2.0%) with strongest risk factors being female gender, African American race, and tobacco use. Patients who meet this demographic, particularly those with planned pembrolizumab treatment, may benefit from early referral to a cardio-oncologist. Further investigation is warranted on the relationship between CTLA-4 and PD-L1 expression and cardiac adverse events with ICIs, particularly for these subpopulations.

Comparative cardiotoxicity risk of pembrolizumab versus nivolumab in cancer patients undergoing immune checkpoint inhibitor therapy: A meta-analysis

“…Previous studies regarding the cardiotoxicity risks of ICIs and comparisons between anti-PD1 and anti CTLA4 ( 45 ) were made; however, this paper addressed the direct comparison between nivolumab and pembrolizumab cardiotoxicity potentials. Contrary to what was recently reported ( 46 , 47 ), the descriptive proportions described herein have provided a clear indication that nivolumab-induced cardiotoxicities are reported more in the literature over the past years than pembrolizumab-induced cardiotoxicities. The discrepancy between these findings and previous ones highlights the need for a prospective analysis on a larger sample cohort.…”

Equity in Cardio-Oncology Care and Research: A Scientific Statement From the American Heart Association

“…Clinical and population-level data have established that African American/Black patients face a substantially increased risk for severe cardiotoxicity. 5,10,[21][22][23][24][25][26][27] Most available research has focused on women with breast cancer. 10 Black patients have consistently demonstrated a 3-fold increased risk of cardiotoxicity after anthracyclines therapies.…”

Clinical Manifestations, Monitoring, and Prognosis: A Review of Cardiotoxicity After Antitumor Strategy

“…A recent retrospective study proposed demographic risk factors for ICI cardiotoxicity. According to review 538 medical records of patients who underwent immunotherapy, Brumberger et al found that there was a significantly higher percentage of women experiencing cardiac events compared to men (8.1 vs. 2.9%; P = 0.011) as well as a higher percentage of African Americans with cardiac events than Caucasians with cardiac events (12 vs. 4%; P = 0.02) (26). Patients undergoing treatment with Pembrolizumab (n = 243) had higher cardiac events rates compared to Nivolumab (n = 220) (7 vs. 4%) (26).…”

“…According to review 538 medical records of patients who underwent immunotherapy, Brumberger et al found that there was a significantly higher percentage of women experiencing cardiac events compared to men (8.1 vs. 2.9%; P = 0.011) as well as a higher percentage of African Americans with cardiac events than Caucasians with cardiac events (12 vs. 4%; P = 0.02) (26). Patients undergoing treatment with Pembrolizumab (n = 243) had higher cardiac events rates compared to Nivolumab (n = 220) (7 vs. 4%) (26). The risk of myocarditis and the mortality rate are higher when ICI is combined with other drugs that also have cardiotoxic effects or more than two ICIs treatment (20,22,27).…”