Cardiovascular toxicity following immune checkpoint inhibitors: A systematic review and meta-analysis

Xavier, Camila Bragança; Lopes, Carlos Diego Holanda; Harada, Guilherme; Peres, Eduardo Dante Bariani; Katz, Artur; Jardim, Denis Leonardo Fontes

doi:10.1016/j.tranon.2022.101383

Cited by 8 publications

(13 citation statements)

References 74 publications

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“…This circumstance can lead to bias, and we will manage these patients as a separate subgroup during analysis, as stated above. Recent research reported the cardiotoxicity risk of relatively new classes of targeted therapies such as KIs or ICIs [ 33 , 34 , 35 , 36 ]. We exclude those who are administered the mentioned treatments to minimize the subgroups under analysis.…”

Section: Discussionmentioning

confidence: 99%

Early Diagnosis of Chemotherapy-Linked Cardiotoxicity in Breast Cancer Patients Using Conventional Biomarker Panel: A Prospective Study Protocol

et al. 2022

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The prognosis of cancer treatment depends on, among other aspects, the cardiotoxicity of chemotherapy. This research aims to create a feasible algorithm for the early diagnosis of antitumor therapy cardiotoxicity in breast cancer patients. The paper represents a protocol for a prospective cohort study with N 120 eligible participants admitted for treatment with anthracyclines and/or trastuzumab. These patients will be allocated into four risk groups regarding potential cardiotoxic complications. Patients will be examined five times every three months for six biomarkers,: cardiac troponin I (cTnI), brain natriuretic peptide (BNP), C-reactive protein (CRP), myeloperoxidase (MPO), galectin-3 (Gal-3), and D-dimer, simultaneously with echocardiographic methods, including speckle tracking. The adjusted relative risk (aOR) of interrupting an entire course of chemotherapy due to cardiotoxic events will be assessed using multiple analyses of proportional Cox risks. The Cox model will also assess associations between baseline biomarker values and time to cardiotoxic events. Moreover, partly conditional survival models will be applied to determine associations between repeated assessments of changes in biomarkers from baseline and time to cancer therapy-related cardiac dysfunction. All models will be adjusted for cancer therapy regimen, baseline LVEF, groups at risk, baseline biomarker values, and age. The decision-tree and principal component analysis (PCA) methods will also be applied. Thus, feasible patterns will be detected.

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Section: Discussionmentioning

confidence: 99%

Early Diagnosis of Chemotherapy-Linked Cardiotoxicity in Breast Cancer Patients Using Conventional Biomarker Panel: A Prospective Study Protocol

et al. 2022

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“…Most previous studies have revealed the cardiotoxicity between ICI plus chemotherapy or targeted therapy versus chemotherapy or targeted therapy. 10,[12][13][14] A number of chemotherapy and targeted therapy known to be potentially increasing different type of cardiovascular risk. Chemotherapy (eg, anthracyclines, alkylating agents, etc.)…”

Section: J Chin Med Assocmentioning

confidence: 99%

A retrospective cohort study on the cardiotoxicity incidence rates of immune checkpoint inhibitors for oncology patients

Tsai

et al. 2023

Journal of the Chinese Medical Association

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Background: This present study investigated the incidence rates of cardiotoxicity among cancer patients treated with immune checkpoint inhibitors (ICIs) plus other anticancer drugs. Methods: This was a retrospective hospital-based cohort study using the medical records and the Cancer Registry records from the Taipei Veterans General Hospital. We enrolled patients diagnosed with cancer between 2011 and 2017, who were over 20 years old and had received ICI therapy, including pembrolizumab, nivolumab, atezolizumab, and ipilimumab. Cardiotoxicity was defined by the diagnosis of myocarditis, pericarditis, arrhythmia, heart failure, and Takotsubo syndrome. Results: We identified 407 patients who were eligible to participate in this study. We defined the three treatment groups as follows: ICI therapy, ICI combined with chemotherapy, and ICI combined with targeted therapy. Using ICI therapy as a reference group, the cardiotoxicity risk was not significantly higher compared to the ICI combined with chemotherapy group (adjusted hazard ratio 2.1, 95% confidence interval 0.2-21.1, p = 0.528] or to the ICI combined with targeted therapy group (adjusted hazard ratio 1.2, 95% confidence interval 0.1-9.2, p = 0.883). The total incidence rate of cardiotoxicity was 3.6 of 100 person-years, indicating an average incidence time of 1.0 ± 1.3 years (median: 0.5 years; range: 0.1-4.7 years) for 18 cardiotoxicity patients. Conclusion:The incidence rate of ICI-related cardiotoxicity is low. Combination of ICI with either chemotherapy or targeted therapy might not significantly increase the risk of cardiotoxicities among cancer patients. Nevertheless, it is recommend being careful in patients treated high-risk cardiotoxicity medications to avoid drug-related cardiotoxicity with a combination of ICI therapy.

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“…Pathology reports of patients with ICI-related myocarditis show an imbalance in immune tolerance and autoimmunity ( Xavier et al, 2022 ). A report of two lethal cases of myocarditis in melanoma patients receiving combination anti-CTLA-4/anti-PD-1 therapy showed T-cell infiltrates in the myocardium and skeletal muscle ( Johnson et al, 2016 ).…”

Section: Cardiac Immune Checkpointsmentioning

confidence: 99%

“…PD-1, PD-L1, CTLA-4, and LAG-3 are currently approved therapeutical targets in cancer therapy. However, in nearly 10% of patients treated with ICI potentially life-threatening cardiovascular irAE occur ( Xavier et al, 2022 ). And with the growing number of ICI being approved and used in the clinics, the incidence of cardiovascular irAE is expected to increase.…”

Section: Perspectivementioning

confidence: 99%

“…As IC inhibition of T-cells is systemic and not localized to the tumor and its environment, it can cause auto-immune damage to multiple organs ( Okazaki et al, 2003 ; Blansfield et al, 2005 ; Iwama et al, 2014 ). A meta-analysis showed an incidence of cardiovascular events of 8.32% (95% CI = 6.35–10.53%) among over 21,000 patients receiving ICI in randomized clinical and while that cardiovascular irAE pose a serious threat to patient health, ranging in severity from mild arrhythmias to myocarditis, the latter with a mortality of up to 50% trials ( Salem et al, 2018 ; Xavier et al, 2022 ) ( Xavier et al, 2022 ) ( Salem et al, 2018 ). This was prudently observed in another meta-analysis which found that while cardiovascular irAE were among the three least occurring ones (8%), they were the second most leading cause of death (25%) ( Wang et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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The role of immune checkpoints in cardiovascular disease

et al. 2022

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Immune checkpoint inhibitors (ICI) are monoclonal antibodies which bind to immune checkpoints (IC) and their ligands to prevent inhibition of T-cell activation by tumor cells. Currently, multiple ICI are approved targeting Cytotoxic T-lymphocyte antigen 4 (CTLA-4), Programmed Death Protein 1 (PD-1) and its ligand PD-L1, and Lymphocyte-activation gene 3 (LAG-3). This therapy has provided potent anti-tumor effects and improved prognosis for many cancer patients. However, due to systemic effects, patients can develop immune related adverse events (irAE), including possible life threatening cardiovascular irAE, like atherosclerosis, myocarditis and cardiomyopathy. Inhibition of vascular IC is associated with increased atherosclerotic burden and plaque instability. IC protect against atherosclerosis by inhibiting T-cell activity and cytokine production, promoting regulatory T-cell differentiation and inducing T-cell exhaustion. In addition, PD-L1 on endothelial cells might promote plaque stability by reducing apoptosis and increasing expression of tight junction molecules. In the heart, IC downregulate the immune response to protect against cardiac injury by reducing T-cell activity and migration. Here, inhibition of IC could induce life-threatening T-cell-mediated-myocarditis. One proposed purpose behind lymphocyte infiltration is reaction to cardiac antigens, caused by decreased self-tolerance, and thereby increased autoimmunity because of IC inhibition. In addition, there are several reports of ICI-mediated cardiomyopathy with immunoglobulin G expression on cardiomyocytes, indicating an autoimmune response. IC are mostly known due to their cardiotoxicity. However, t his review compiles current knowledge on mechanisms behind IC function in cardiovascular disease with the aim of providing an overview of possible therapeutic targets in prevention or treatment of cardiovascular irAEs.

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Cardiovascular toxicity following immune checkpoint inhibitors: A systematic review and meta-analysis

Cited by 8 publications

References 74 publications

Early Diagnosis of Chemotherapy-Linked Cardiotoxicity in Breast Cancer Patients Using Conventional Biomarker Panel: A Prospective Study Protocol

Early Diagnosis of Chemotherapy-Linked Cardiotoxicity in Breast Cancer Patients Using Conventional Biomarker Panel: A Prospective Study Protocol

A retrospective cohort study on the cardiotoxicity incidence rates of immune checkpoint inhibitors for oncology patients

The role of immune checkpoints in cardiovascular disease

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