Immune Checkpoint Inhibitors and Cardiotoxicity: An Analysis of Spontaneous Reports in Eudravigilance

Abstract

Introduction: 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 (ADRs). Among immune-related ADRs, cardiac immune-related ADRs are rare, but also associated with high mortality rates.

Objective: The objective of this study was to evaluate the occurrence of cardiac ADRs reported with ICIs in the European spontaneous reporting system.

Methods: We retrieved individual case safety reports on ICI-induced cardiac ADRs from the website of suspected ADR ( www.adrreports.eu ) of the European pharmacovigilance database (Eudravigilance). Data were retrieved from the date of marketing authorization of each ICI (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) to 14 March, 2020. The reporting odds ratio and its 95% confidence interval were computed to assess the reporting frequency of cardiac ADRs for each ICI compared to all other ICIs.

Results: A total of 2478 individual case safety reports with at least one ICI as the suspected drug were retrieved from Eudravigilance, of which 249 (10%) reported more than one ICI. The three most reported ICIs were nivolumab (43.2%), pembrolizumab (32.5%), and the association of nivolumab/ipilimumab (9.4%). A total of 3388 cardiac ADRs were identified. Cardiac ADRs were serious (99.4%) and had a fatal outcome (30.1%). The most reported cardiac events were myocarditis, cardiac failure, atrial fibrillation, pericardial effusion, and myocardial infarction. Nivolumab was reported with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs (reporting odds ratio 1.09, 95% confidence interval 1.01-1.18).

Conclusions: Immune checkpoint inhibitor-induced cardiac ADRs were serious and had unfavorable outcomes. In our study, nivolumab was the only ICI with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs. In this regard, further head-to-head studies are needed.

Fig. 1

Time to the event of individual case safety reports (ICSRs) with ipilimumab, nivolumab, and pembrolizumab. IQR interquartile range

Fig. 2

Reporting odds ratio (ROR) of individual case safety reports with cardiac adverse events for each immune checkpoint inhibitor (ICI) compared to all other ICIs. CI confidence interval

Fig. 3

Reporting odds ratio (ROR) of individual case safety reports with cardiac adverse events for each immune checkpoint inhibitor (ICI) compared to all other ICIs belonging to the same drug class. CI confidence interval, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1

Fig. 4

Reporting odds ratio (ROR) of individual case safety reports with cardiac adverse events for anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) compared to anti-programmed cell death protein 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1). CI confidence interval