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Cited by 1,271Cancer Immunotherapy and BiomarkersPharmacovigilance and Adverse Drug ReactionsChemotherapy-induced cardiotoxicity and mitigation

Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study

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Salem, Joe-Elie, Manouchehri, Ali, Moey, Melissa, Lebrun-Vignes, Bénédicte, Bastarache, Lisa, Pariente, Antoine, Gobert, Aurélien, Spano, Jean-Philippe +5 more·2018·The Lancet Oncology
DOI 10.1016/s1470-2045(18)30608-9PMC PMC6287923
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Abstract

Background Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs. Methods In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHO's global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. We evaluated the association between ICIs and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC 025 is the lower end of the IC 95% credibility interval, and an IC 025 value of more than zero is deemed significant. This study is registered with ClinicalTrials.gov, number NCT03387540. Findings We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs, ROR 11·21 [95% CI 9·36-13·43]; IC 025 3·20), pericardial diseases (12 800 vs 95, 3·80 [3·08-4·62]; IC 025 1·63), and vasculitis (33 289 vs 82, 1·56 [1·25-1·94]; IC 025 0·03), including temporal arteritis (696 vs 18, 12·99 [8·12-20·77]; IC 025 2·59) and polymyalgia rheumatica (1709 vs 16, 5·13 [3·13-8·40]; IC 025 1·33). Pericardial diseases were reported more often in patients with lung cancer (49 [56%] of 87 patients), whereas myocarditis (42 [41%] of 103 patients) and vasculitis (42 [60%] of 70 patients) were more commonly reported in patients with melanoma (χ 2 test for overall subgroup comparison, p<0·0001). Vision was impaired in five (28%) of 18 patients with temporal arteritis. Cardiovascular irAEs were severe in the majority of cases (>80%), with death occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases, and five (6%) of 82 vasculitis cases (χ 2 test for overall comparison between pericardial diseases, myocarditis, and vasculitis, p<0·0001). Interpretation Treatment with ICIs can lead to severe and disabling inflammatory cardiovascular irAEs soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy). Funding The Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014-2019; US National Cancer Institute, National Institutes of Health; the James C. Bradford Jr. Melanoma Fund; and the Melanoma Research Foundation.

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  • ICI myocarditis is linked to recent initiation of immunotherapy, typically occurring within 90 days after therapy initiation, with a median onset of 30 days.

    “ICI myocarditis is linked to recent initiation of immunotherapy, typically occurring within 90 days after therapy initiation, with a median onset of 30 days.”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [181]

  • A single dose of ICI therapy can be sufficient to trigger ICI myocarditis.

    “with even a single dose being sufficient to trigger the disease.”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [181]

  • ICI myocarditis can manifest rapidly after initiating ICI therapies.

    “ICI myocarditis can manifest rapidly after initiating ICI therapies”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [181]

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Authors
Salem, J.-E., Manouchehri, A., Moey, M., Lebrun-Vignes, B., Bastarache, L., Pariente, A., Gobert, A., Spano, J.-P., Balko, J. M., Bonaca, M. P., Roden, D. M., Johnson, D. B., & Moslehi, J. J.
Affiliations
  • Inserm (FR)
  • Vanderbilt University Medical Center (US)
  • Université de Bordeaux (FR)
  • Brigham and Women's Hospital (US)
Corresponding author
Moslehi, Javid J
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2018-12
Volume
19
Issue
12
Pages
1579-1589
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(18)30608-9
PMC
PMC6287923
OpenAlex
W2901191795
Cited by
1,271
References
3
Citations by year
2026: 180 · 2025: 180 · 2024: 184 · 2023: 162 · 2022: 193 · 2021: 167 · 2020: 141 · 2019: 59 · 2018: 3
FWCI
34.77
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Oncology (acceptedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
Funders
  • Melanoma Research Foundation
  • Alliance Nationale pour les Sciences de la Vie et de la Santé
  • National Institutes of Health (K23 CA204726)
  • National Cancer Institute
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
Keywords
immune checkpoint inhibitors, immune-related adverse events, cardiovascular adverse events, myocarditis, pericardial disease, vasculitis, giant cell arteritis, drug safety, pharmacovigilance, VigiBase, reporting odds ratio, information component, immunotherapy side effects, cancer immunotherapy, pericardial effusion
MeSH terms
Antineoplastic Agents, Immunological, Adult, Aged, Aged, 80 and over, Bayes Theorem, Cardiovascular Diseases, Female, Humans, Immunotherapy, Male, Middle Aged, Retrospective Studies, Risk Factors, Time Factors, Databases, Factual, Adverse Drug Reaction Reporting Systems, Risk Assessment, Pharmacovigilance, Cardiotoxicity

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