Pericardial Toxicities Associated With Immune Checkpoint Inhibitors: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Abstract

Introdution: Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes for a wide range of cancers but can also lead to serious or fatal immune-related adverse events (irAEs). Although ICI-related pericardial toxicities have been reported, the clinical features are not well characterized in real-world studies.Objective: To characterize the main features of ICI-related pericardial toxicities and identify factors associated with death.Methods: Data from January 1, 2011 to March 31, 2020 in the FDA Adverse Event Reporting System database were retrieved for disproportionality analysis. We used the reporting odds ratio and the information component (IC) to evaluate the association between ICIs and pericardial adverse events. Clinical characteristics of patients with ICI-associated pericardial toxicities were collected and compared between fatal and non-fatal groups. The time to onset following different ICI regimens was further investigated.Results: We identified a total of 705 ICI-associated pericardial toxicities which appeared to influence more men (53.90%) than women (36.03%), with a median age of 63 (interquartile range [IQR] 54–69) years. Patients with lung cancer accounted for the largest proportion (55.6%). ICI therapies were detected with pharmacovigilance signals of pericardial toxicities, corresponding to IC025 = 2.11 and ROR 4.87 [4.51–5.25]. Nevertheless, there was a lack of association between anti-CTLA-4 and pericardial toxicities. There was no difference in onset time among all ICI regimens. However, TTO of fatal cases (25 days (interquartile range [IQR] 6–70)) occurred statistically earlier than non-fatal cases (42 days (IQR 12–114), p = 0.003).Conclusion: ICI monotherapy (PD-1/PD-L1 therapy) and combination therapy can lead to pericardial toxicities that can result in serious outcomes and tend to occur early. Early recognition and management of ICI-related pericardial disorders should attract clinical attention. The findings require further clinical surveillance for the quantification.

Cardiovascular toxicities associated with immune checkpoint inhibitors: An updated comprehensive disproportionality analysis of the FDA adverse event reporting system

“…In addition, dual ICI treatments were detected with pharmacovigilance signals of cardiac arrhythmias, myocardial disorders and decreased and nonspecific blood pressure disorders and shock compared with monotherapy. There was no increased risk of pericardial toxicity with combination therapy relative to monotherapy, which was consistent with previous study 23 . Studies have shown that dual ICI therapies (e.g., a CTLA‐4 inhibitor combined with a PD‐1 inhibitor) lead to higher risk of myocarditis, as well as worse outcomes 24,25 …”

Adverse Events During Pregnancy Associated With Entecavir and Adefovir: New Insights From a Real-World Analysis of Cases Reported to FDA Adverse Event Reporting System

“…professionals ( Sakaeda et al, 2013 ). The analysis of the FAERS database has been exploited in pharmacovigilance for drug safety assessments, not only to detect drug-AE associations unidentified in pre-market clinical trials, but also protect patients from potential harms ( Chen et al, 2021 ; Eugene et al, 2021 ; Ma et al, 2021 ). It is worth noting that whether a drug is the causative agent of an AE occurring during its use, is something that can only be accurately judged through a rigorous causality assessment by healthcare professionals, while non-healthcare professional reports on their own appear to increase the risk of erroneous information ( Andreaggi et al, 2020 ).…”

“…The FAERS database, established for national post-market surveillance for drug safety, is a spontaneous reporting system for healthcare professionals, consumers, and drug manufacturers ( Sakaeda et al, 2013 ). As FAERS case reports have been increasing annually, the database is largely used to identify novel drug-associated AEs not previously observed in clinical trials ( Chen et al, 2021 ; Eugene et al, 2021 ; Ma et al, 2021 ). Moreover, data-mining of drug-related case reports from spontaneous reporting systems can provide us with a valuable source of information about the safety of specific drugs in real-life, especially for frail populations such as pregnant women ( Tkachenko et al, 2019 ; Carnovale et al, 2020 ).…”

Immune Checkpoint Inhibitors and the Heart

“…In a systematic review paper that included 705 cases of ICI-associated pericardial disease, the authors have stated that this condition is not as rare as initially believed but they have mentioned that there might be some biases coming from the fact that some malignancies complicate with pericardial effusion even in the absence of immunotherapy. Hence, the diagnosis of ICIs-related pericardial effusion is challenging ( 50 ).…”

“…Another confounding factor that might alter the percentage of pericarditis is the use of radiation in conjunction with immunotherapy. It appears that radiation primes an endogenous antigen specific immune response ( 17 , 50 ). They expose potential shared antigens to T cell recognition, and this in turn might contribute to the development of pericarditis ( 30 ).…”