Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor–Associated Myocarditis

Zhang, Lili; Zlotoff, Daniel A.; Awadalla, Magid; Mahmood, Syed; Nohria, Anju; Hassan, M; Thuny, Franck; Zubiri, Leyre; Chen, Carol L.; Sullivan, Ryan J.; Alvi, Raza M.; Rokicki, Adam; Murphy, Sean; Jones‐O'Connor, Maeve; Heinzerling, Lucie; Barac, Ana; Forrestal, Brian J.; Yang, Eric H.; Gupta, Dhiraj; Kirchberger, Michael C.; Shah, Sachin; Rizvi, Muhammad A.; Sahni, Gagan; Mandawat, Anant; Mahmoudi, Michael; Ganatra, Sarju; Éderhy, Stéphane; Zataraín-Nicolás, Eduardo; Groarke, John D.; Tocchetti, Carlo G.; Lyon, Alexander R.; Thavendiranathan, Paaladinesh; Cohen, Justine V.; Reynolds, Kerry L.; Fradley, Michael G.; Neilan, Tomas G.

doi:10.1161/circulationaha.119.044703

Cited by 171 publications

(143 citation statements)

References 5 publications

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“…Another limitation is that there was no compliance assessment of medication use and the dose and duration of ICI use were not easily captured. We only had one patient diagnosed with ICI-related myocarditis, so we could not evaluate the effect of corticosteroids 33 or CTLA-4 agonist abatacept 34 on the outcome of myocarditis patients. Finally, we cannot attribute the nding of increased mortality in patients with ICI cardiotoxicity to the cardiotoxicity as we were not able to perform competing risk analyses and there was no control group.…”

Section: Discussionmentioning

confidence: 99%

Cardiotoxicity associated with immune checkpoint inhibitors: A retrospective analysis of patients at an academic tertiary care center

Waheed

Fradley

DeRemer

et al. 2020

Preprint

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Background Immune checkpoint inhibitors (ICIs) are a novel class of anticancer agents that have demonstrated clinical response for both solid and hematological malignancies. ICIs are associated with development of immune-related adverse events including cardiotoxicity. We estimated the incidence of newly diagnosed cardiovascular disease ICI-related cardiotoxicity in patients treated with ICIs at a large, tertiary care center. Methods All patients with a cancer diagnosis who received any ICI treatment in the University of Florida’s Integrated Data Repository from 2011-2017 were included. Cardiovascular disease was defined as a new ICD diagnosis code for cardiomyopathy, heart failure, arrhythmia, heart block, pericardial disease, or myocarditis after initiation of ICI treatment. Results Of 102,701 patients with a diagnosis of malignancy, 424 patients received at least one ICI. Sixty-two (14.6%) patients were diagnosed with at least one new cardiovascular disease after initiation of ICI therapy. Of the 374 patients receiving one ICI, 21 (5.6%) developed heart failure. Of the 49 patients who received two ICIs sequentially, three (6.1%) developed heart failure and/or cardiomyopathy. Incident cardiovascular disease was diagnosed at a median of 63 days after initial ICI exposure. One patient developed myocarditis 28 days after receiving nivolumab. Mortality in ICI treated patients with a concomitant diagnosis of incident cardiovascular disease was higher compared to those who did not (66.1% vs. 41.4%, odds ratio = 2.77, 1.55-4.95, p = 0.0006). Conclusions This study suggests a high incidence of newly diagnosed cardiovascular disease after the initiation of ICI therapy.

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Section: Discussionmentioning

confidence: 99%

Cardiotoxicity associated with immune checkpoint inhibitors: A retrospective analysis of patients at an academic tertiary care center

Waheed

Fradley

DeRemer

et al. 2020

Preprint

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“…Occurrence of MACE was inversely related to the initial dose of corticosteroids. High dose corticosteroid was associated with 73% lower risk of MACE independent of timing of initiation (HR 0.27 [95% CI, 0.09–0.84], p = 0.024) [ 33 •]. These results suggest that early, high dose corticosteroid administration is associated with improved clinical outcomes.…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…Current ASCO guidelines recommend high-dose corticosteroids (1 to 2 mg/kg of prednisone) either oral or IV depending on severity of symptoms to be continued for 4–6 weeks based on clinical response [ 32 ]. A recent large, international multicenter registry of 126 ICI-associated myocarditis patients investigated the role of timing and dosage of corticosteroids [ 33 •]. Patients who received early corticosteroids within 24 h of presentation had a lower rate of MACE compared to those receiving corticosteroids at 24–72 h or at > 72 h (7.0%, 34.3%, and 85.1% respectively, p < 0.001).…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Immunotherapy-Associated Cardiotoxicity of Immune Checkpoint Inhibitors and Chimeric Antigen Receptor T Cell Therapy: Diagnostic and Management Challenges and Strategies

et al. 2021

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“…A high dosage of corticosteroids, typically methylprednisolone 1000 mg/day for 3 days, followed by prednisone 1 mg/kg is considered the first-line therapy [ 7 ]. An international registry data of 126 patients showed that higher initial dose and prompt initiation (within 24 h of presentation) of corticosteroids were associated with improved outcomes [ 28 ••]. While both dosing and timing were important, the initiation time of corticosteroids appeared to play a stronger role, such that using high-dose corticosteroids could not overcome the effect of corticosteroids given later.…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…While both dosing and timing were important, the initiation time of corticosteroids appeared to play a stronger role, such that using high-dose corticosteroids could not overcome the effect of corticosteroids given later. Contrary to that, lower dose corticosteroids administered early still was associated with a better outcome as compared to patients who receive high-dose corticosteroids later [ 28 ••]. This emphasizes the need for prompt initiation of corticosteroids, even prior to confirmation of the diagnosis.…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Cardiotoxicity of Contemporary Anticancer Immunotherapy

Dalbo

Patel

Parikh

et al. 2020

Curr Treat Options Cardio Med

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Purpose of review Contemporary anticancer immunotherapy, particularly immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell therapy, has changed the landscape of treatment for patients with a variety of malignancies who historically had a poor prognosis. However, both immune checkpoint inhibitors and CAR T cell therapy are associated with serious cardiovascular adverse effects. As immunotherapy evolves to include high-risk patients with preexisting cardiovascular risk factors and disease, the risk and relevance of its associated cardiotoxicity will be even higher. Recent findings ICI can cause myocarditis, which usually occurs early after initiation, can be fulminant, and prompt treatment with high-dose corticosteroids is crucial. CAR T cell therapy frequently leads to cytokine release syndrome, which is associated with cardiomyopathy or arrhythmia development and may also result in circulatory collapse. Supportive treatment, as well as tocilizumab, an anti-interleukin-6 receptor antibody, is the cornerstone of treatment. Recent findings suggest that preexisting cardiovascular risk factors and disease may increase the risk of such cardiotoxicity, and prompt recognition, as well as treatment, may favorably alter the outcomes. Summary ICI and CAR T cell therapy have improved cancer-related outcomes; however, they both are associated with potentially therapy-limiting cardiotoxicity. Cardio-oncologists are required to play an important role in patient selection, pretherapy cardiovascular optimization, and prompt recognition and treatment of cardiotoxicity.

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Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor–Associated Myocarditis

Cited by 171 publications

References 5 publications

Cardiotoxicity associated with immune checkpoint inhibitors: A retrospective analysis of patients at an academic tertiary care center

Cardiotoxicity associated with immune checkpoint inhibitors: A retrospective analysis of patients at an academic tertiary care center

Immunotherapy-Associated Cardiotoxicity of Immune Checkpoint Inhibitors and Chimeric Antigen Receptor T Cell Therapy: Diagnostic and Management Challenges and Strategies

Cardiotoxicity of Contemporary Anticancer Immunotherapy

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