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. adrre ports. 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.Annamaria Mascolo and Cristina Scavone share first authorship.Roberto Alfano and Annalisa Capuano share lead authorship.

The Reporting Frequency of Ketoacidosis Events with Dapagliflozin from the European Spontaneous Reporting System: The DAPA-KETO Study

“…The 94.31% of ICSRs were reported by HCPs in accordance with other studies [ 27 , 28 , 29 , 30 , 31 ]. In most ICSRs was reported one suspected drug and no concomitant drugs.…”

“…According to the Assessment Report of SGLT2 inhibitors published by the EMA [ 49 ], we identified a case of ketoacidosis by using the following preferred terms (PTs) of the Medical Dictionary for Regulatory Activities (MedDRA): acidosis, blood ketone body present, blood ketone body increased, blood ketone body, diabetic ketoacidosis, diabetic ketoacidotic hyperglycemic coma, diabetic ketosis, euglycaemic diabetic ketoacidosis, ketoacidosis, ketonuria, ketosis, metabolic acidosis, urine ketone body present, and urine ketone body. MedDRA terminology is described elsewhere [ 29 , 50 ].…”

Use of Pembrolizumab for Treatment of Progressive Multifocal Leukoencephalopathy in People Living with HIV

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Post-Marketing Safety Concerns With Secukinumab: A Disproportionality Analysis of the FDA Adverse Event Reporting System

“…AEs in the FAERS database were coded by Medical Dictionary for Regulatory Activities 24.0 (MedDRA). The structural hierarchy of the MedDRA terminology was divided into five levels: system organ class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term (PT), and lowest-level term (LLT) ( Mascolo et al, 2021 ). All AEs of secukinumab reports taken from the REAC files in the FAERS database were identified to describe the frequency and intensity based on MedDRA at SOC and PT levels in our study.…”