Retrospective Study of National Danish Registry Sheds Light on Cardiotoxic Risks of Immune Checkpoint Inhibitors

Retrospective Study of National Danish Registry Sheds Light on Cardiotoxic Risks of Immune Checkpoint Inhibitors

Reporter: Adina Hazan, PhD


Immune checkpoint inhibitors are used to treat over 12 different types of cancers, as a way of encouraging T cells of the immune system to target and kill cancer cells. While this method has proved to be an incredibly important mechanism in fighting deadly cancers, the enhanced immune response has been documented to produce a wide array of side effects, including an increased incidence of cardiovascular events such as arrhythmias and sudden cardiac arrest. Due to the nature of the disease and treatment, most evidence of cardiotoxicity from the treatment comes from small cohorts of patients or individual case studies.

D’Souza and colleagues used four Danish healthcare registries to collect data from over 13,000 patients with malignant melanoma, and over 25,000 patients with lung cancer, starting from 2011 with the introduction of checkpoint inhibitors up until 2017. Each group included patients who received checkpoint inhibitors and those that did not, providing the basis of their retrospective study to determine the risk of developing cardiac events with treatment over a long period of time. The study was published in the European Heart Journal in December 2020.

The authors confirmed the increased risk of cardiac events with the treatment of immune checkpoint inhibitors PD1i and CTLA-4i.

  • The relative rate of cardiovascular deaths were increased in patients with lung cancer treated with PD1i by three-fold, and
  • eight times higher in patients with malignant melanoma treated with CTLA-4i.
  • Moreover, they show increased relative rates of arrhythmias in both diseases treated with PD1i, and malignant melanoma treated with CTLA-4i.
  • This was also true of the timeframe of treatment, where it was previously believed that most cardiac events would develop within the first six months of checkpoint inhibitor use.
  • By using data from patients over years, this study shows that these adverse events develop even after the first six months.

The myocardium, or heart muscle tissue, has previously been reported to be damaged with the use of checkpoint inhibitors, suspected to be due to

  • increasing inflammatory cytokines and enhanced inflammatory pathways. Significantly, previous pharmacovigilance studies have suggested a rate of developing myocarditis at less than 1%, but
  • data from this study shows that the 1 year risk was 1.8%, “suggesting that the risk may be higher than previously estimated”.

Even though Immune checkpoint inhibitors have been shown to be invaluable tools in the treatment of certain cancers, “the findings [in this study] urge increased awareness of cardiac events in patients receiving ICI”.


Original Research

The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study 

European Heart Journal, ehaa884, https://doi.org/10.1093/eurheartj/ehaa884
09 December 2020
 Article history



The study aimed to estimate the risk of cardiac events in immune checkpoint inhibitor (ICI)-treated patients with lung cancer or malignant melanoma.

Methods and results

The study included consecutive patients with lung cancer or malignant melanoma in 2011–17 nationwide in Denmark. The main composite outcome was cardiac events (arrhythmia, peri- or myocarditis, heart failure) or cardiovascular death. Absolute risks were estimated and the association of ICI and cardiac events was analysed in multivariable Cox models. We included 25 573 patients with lung cancer. Of these, 743 were treated with programmed cell death-1 inhibitor (PD1i) and their 1-year absolute risk of cardiac events was 9.7% [95% confidence interval (CI) 6.8–12.5]. Of the 13 568 patients with malignant melanoma, 145 had PD1i and 212 had cytotoxic T-lymphocyte-associated protein-4 inhibitor (CTLA-4i) treatment. Their 1-year risks were 6.6% (1.8–11.3) and 7.5% (3.7–11.3). The hazard rates of cardiac events were higher in patients with vs. without ICI treatment. Within 6 months from 1st ICI administration, the hazard ratios were 2.14 (95% CI 1.50–3.05) in patients with lung cancer and 4.30 (1.38–13.42) and 4.93 (2.45–9.94) in patients with malignant melanoma with PD1i and CTLA-4i, respectively. After 6 months, HRs were 2.26 (1.27–4.02) for patients with lung cancer and 3.48 (1.91–6.35) for patients with malignant melanoma and CTLA-4i.


Among patients with lung cancer and malignant melanoma, ICI treated had increased rates of cardiac events. The absolute risks were higher in these data compared with previous pharmacovigilance studies (e.g. 1.8% peri-/myocarditis 1-year risk).





Other related articles published in this Open Access Online Scientific Journal include the following:


Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

Curator: Larry H Bernstein, MD, FCAP



Cardiology & Oncology Drug Development & Regulation

Authors: Stuart L. Cantor, PhD, and Kadriye Ciftci, PhD



Cardio-oncology and Onco-Cardiology Programs: Treatments for Cancer Patients with a History of Cardiovascular Disease

Curator: Aviva Lev-Ari, PhD, RN


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