Cardiovascular adverse events are associated with usage of immune checkpoint inhibitors in real-world clinical data across the United States

P. Jain, J. Gutierrez Bugarin, A. Guha, C. Jain, N. Patil, T. Shen, I. Stanevich, V. Nikore, K. Margolin, M. Ernstoff, V. Velcheti, J. Barnholtz-Sloan, A. Dowlati

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Background: Immune checkpoint inhibitors (ICIs) can cause life-threatening cardiovascular adverse events (CVAEs) that may not be attributed to therapy. The outcomes of clinical trials may underestimate treatment-related adverse events due to restrictive eligibility, limited sample size, and failure to anticipate selected toxicities. We evaluated the incidence and clinical determinants of CVAEs in real-world population on ICI therapy. Patients and methods: Among 2 687 301 patients diagnosed with cancer from 2011 to 2018, 16 574 received ICIs for any cancer. Patients in the ICI and non-ICI cohorts were matched in a 1: 1 ratio according to age, sex, National Cancer Institute comorbidity score, and primary cancer. The non-ICI cohort was stratified into patients who received chemotherapy (N = 2875) or targeted agents (N = 4611). All CVAEs, non-cardiac immune-related adverse events occurring after treatment initiation, baseline comorbidities, and treatment details were identified and analyzed using diagnosis and billing codes. Results: Median age was 61 and 65 years in the ICI and non-ICI cohorts, respectively (P < 0.001). ICI patients were predominantly male (P < 0.001). Lung cancer (43.1%), melanoma (30.4%), and renal cell carcinoma (9.9%) were the most common cancer types. CVAE diagnoses in our dataset by incidence proportion (ICI cohort) were stroke (4.6%), heart failure (3.5%), atrial fibrillation (2.1%), conduction disorders (1.5%), myocardial infarction (0.9%), myocarditis (0.05%), vasculitis (0.05%), and pericarditis (0.2%). Anti-cytotoxic T-lymphocyte-associated protein 4 increased the risk of heart failure [versus anti-programmed cell death protein 1; hazard ratio (HR), 1.9; 95% confidence interval (CI) 1.27-2.84] and stroke (HR, 1.7; 95% CI 1.3-2.22). Pneumonitis was associated with heart failure (HR, 2.61; 95% CI 1.23-5.52) and encephalitis with conduction disorders (HR, 4.35; 95% CI 1.6-11.87) in patients on ICIs. Advanced age, primary cancer, nephritis, and anti-cytotoxic T-lymphocyte-associated protein 4 therapy were commonly associated with CVAEs in the adjusted Cox proportional hazards model. Conclusions: Our findings underscore the importance of risk stratification and cardiovascular monitoring for patients on ICI therapy.

Original languageEnglish (US)
Article number100252
JournalESMO Open
Issue number5
StatePublished - Oct 2021
Externally publishedYes


  • anti-CTLA4
  • anti-PD-1
  • anti-PD-L1
  • cardiovascular adverse events
  • immune checkpoint inhibitors
  • real-world evidence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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