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Meta-Analysis
. 2024 Oct 1;10(10):1390-1399.
doi: 10.1001/jamaoncol.2024.3065.

Immune Checkpoint Inhibitor-Induced Cardiotoxicity: A Systematic Review and Meta-Analysis

Dorte Lisbet Nielsen  1 , Carsten Bogh Juhl  2   3 , Ole Haagen Nielsen  4 , Inna Markovna Chen  1 , Joerg Herrmann  5
Affiliations
Meta-Analysis

Immune Checkpoint Inhibitor-Induced Cardiotoxicity: A Systematic Review and Meta-Analysis

Dorte Lisbet Nielsen et al. JAMA Oncol. .

Abstract

Importance: Immune checkpoint inhibitors (ICIs) improve outcomes in a wide range of cancers; however, serious adverse effects, including cardiovascular adverse effects (CVAEs), can occur.

Objective: To determine the incidence of CVAEs and analyze data on the management of myocarditis in patients exposed to ICIs.

Data sources: PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception were searched on April 4, 2023.

Study selection: Two separate studies were performed. Key inclusion criteria for study 1 were phases 1 to 4 trials involving adults with malignant neoplasms treated with an ICI and toxicity data; for study 2, publications (case reports and retrospective analyses) on clinical manifestations and treatment of patients with ICI-induced CVAEs. Studies with dose escalation or fewer than 11 patients in each group and all case reports, retrospective analyses, letters, reviews, and editorials were excluded from study 1. Studies not published in English were excluded from study 2.

Data extraction and synthesis: The PRISMA guidelines and Cochrane Handbook for Systematic Reviews were followed. Data were extracted independently by 2 researchers. A meta-analysis of the incidence of CVAEs in clinical trials and a systematic review of the evidence for the management of myocarditis were performed. Data were pooled using a random-effects model.

Main outcomes and measures: In study 1, the primary outcome was incidence CVAEs in clinical trials with ICIs and ICI combination therapies. Study 2 examined evidence supporting specific management strategies that may decrease the mortality rate of myocarditis. The primary outcomes were planned before data collection began.

Results: In study 1, a total of 83 315 unique participants in 589 unique trials were included in the meta-analysis. Incidence of CVAEs induced by anti-programmed cell death 1 and/or programmed cell death ligand 1 was 0.80% (95% CI, 0%-1.66%) in clinical trials, with no differences between the compounds, except for cemiplimab, which was associated with a higher risk of CVAEs. Incidence of CVAEs following ipilimumab treatment was 1.07% (95% CI, 0%-2.58%). The incidence of myocarditis was significantly higher following treatment with dual ICIs. However, CVAE incidence was not higher with dual ICIs, ICI combination with chemotherapy, or tyrosine kinase inhibitors. Evidence from randomized clinical trials on recommended monitoring and treatment strategies for ICI-induced myocarditis was lacking. Study 2 showed that myocarditis-associated mortality occurred in 83 of 220 patients (37.7%). Prospective data from 40 patients with myocarditis indicated that systematic screening for respiratory muscle involvement, coupled with active ventilation, prompt use of abatacept, and the addition of ruxolitinib, may decrease the mortality rate.

Conclusions and relevance: Immune checkpoint inhibitor-induced CVAEs and/or myocarditis were recorded in 1.07% of patients in clinical trials. The CVAE mortality risk remains high, justifying the need for monitoring and management strategies for which evidence from randomized clinical trials is absent. Early recognition, ICI therapy cessation, prompt initiation of corticosteroid therapy, and escalation of therapy are all crucial elements for achieving optimal outcomes. Prospective clinical trials or at least prospective registration of treatments and outcomes are highly warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Chen reported receiving research funding from Roche, BMS, Celgene Corporation, Genesis Pharma, AstraZeneca, and Genmab A/S and having advisory relationships with Amgen, AstraZeneca, and Anocca AB. Dr Herrmann reported receiving consulting or advisory board fees from Pfizer, Astellas Pharma, and AstraZeneca and receiving royalties from and serving as editor for Elsevier outside the submitted work and having a patent, licensed to Anumana, for detection of myocarditis and tracking of disease progressions and the effectiveness of therapeutics. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Forest Plot of the Incidences of Cardiovascular Adverse Events (CVAEs) Following Immune Checkpoint Inhibitor Therapy
NA indicates not applicable; PD-1, programmed cell death 1; and PD-L1, programmed cell death ligand 1.
Figure 2.
Figure 2.. Forest Plot of Incidences of Myocarditis Following Checkpoint Inhibitor Therapy
NA indicates not applicable; PD-1, programmed cell death 1; and PD-L1, programmed cell death ligand 1.
See this image and copyright information in PMC

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