Immune Checkpoint Inhibitors and Cardiotoxicity: Reverse Translational Research by Using Real World Safety Data from the European Spontaneous Reporting System

Background: Immune checkpoint inhibitors (ICIs) are widely used in the treatment of many cancers as they improve clinical outcomes. However, ICIs have also been associated with the development of immune-related adverse drug reactions (irADRs). Among irADRs, cardiac ones are rare, but also associated with higher mortality rates. Here, we evaluate the occurrence of cardiac ADRs associated with ICIs. Methods: We retrieved Individual Case Safety Reports (ICSRs) on ICIs-induced cardiac ADRs from the website of suspected ADR (www.adrreports.eu) of the European pharmacovigilance database (Eudravigilance, EV). Data were retrieved from the date of marketing authorization of each ICI (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) to March 14th, 2020. The Reporting Odds Ratio (ROR) and its’ 95% confidence interval (95%CI) was computed to assess the reporting probability of cardiac ADRs for each ICI compared to all other ICIs. Findings: A total of 2,478 ICSRs with at least one ICI as suspected drug were retrieved from EV, of which 249 (10%) were related to combined treatments. The three most reported ICIs were nivolumab (43 . 2%), pembrolizumab (32 . 5%), and the association nivolumab and ipilimumab (9 . 4%). A total of 3,388 cardiac ADRs were identified. Cardiac ADRs were serious (99%) and associated with a fatal outcome (30 . 1%). The most reported cardiac events were myocarditis, cardiac failure, atrial fibrillation, pericardial effusion, and myocardial infarction. Nivolumab was associated with a small increased reporting probability of ICSRs with cardiac ADRs compared to all other ICIs (ROR 1 . 09, 95%CI 1 . 01–1 . 18). Interpretation: ICIs-induced cardiac ADRs were serious and associated with unfavorable outcomes. In our study, nivolumab was the only ICI associated with a small increased reporting probability of ICSRs with cardiac ADRs compared to all other ICIs. In this regards, further head-to-head studies are needed. Funding: This research was funded under grant n. 2017NR7W5K_002 (PRIN 2017) from MIUR, Italy. Declaration of Interests: No conflict to declare. Ethics Approval Statement: Safety data deriving from the spontaneous reporting system are anonymous and in compliance with the ethical standard. Therefore, no further ethical measure was required.