Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2018 Apr 24;71(16):1755-1764.
doi: 10.1016/j.jacc.2018.02.037. Epub 2018 Mar 19.

Myocarditis in Patients Treated With Immune Checkpoint Inhibitors

Syed S Mahmood  1 , Michael G Fradley  2 , Justine V Cohen  3 , Anju Nohria  4 , Kerry L Reynolds  3 , Lucie M Heinzerling  5 , Ryan J Sullivan  3 , Rongras Damrongwatanasuk  2 , Carol L Chen  6 , Dipti Gupta  6 , Michael C Kirchberger  5 , Magid Awadalla  7 , Malek Z O Hassan  7 , Javid J Moslehi  8 , Sachin P Shah  9 , Sarju Ganatra  9 , Paaladinesh Thavendiranathan  10 , Donald P Lawrence  3 , John D Groarke  4 , Tomas G Neilan  11
Affiliations
Multicenter Study

Myocarditis in Patients Treated With Immune Checkpoint Inhibitors

Syed S Mahmood et al. J Am Coll Cardiol. .

Abstract

Background: Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized.

Objectives: The authors sought to understand the presentation and clinical course of ICI-associated myocarditis.

Methods: After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block.

Results: The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates.

Conclusions: Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.

Keywords: cardio-oncology; checkpoint inhibitor; ipilimumab; myocarditis; nivolumab; pembrolizumab.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1. Clinical Presentation of Patients With ICI-Associated Myocarditis
Time from ICI to onset of clinical myocarditis in each of the 35 cases of myocarditis (A). The ICI was administered on day 0. A description of the results for the ECG (B), troponin (C), LVEF (D), and natriuretic peptides (E), standard tests performed at the time of presentation with myocarditis, in patients with myocarditis related to ICI. ECG = electrocardiography; ICI = immune checkpoint inhibitors; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro–B-type natriuretic peptide.
CENTRAL ILLUSTRATION
CENTRAL ILLUSTRATION. Algorithm for Work-Up and Management of Immune-Mediated Myocarditis
Algorithm based on study findings, and institutional experience with 35 cases of ICI-associated myocarditis. CVD = cardiovascular; ECG = electrocardiogram; ICI = immune checkpoint inhibitors.
See this image and copyright information in PMC

Comment in

References

    1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;2010: 711–23. - PMC - PubMed
    1. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364: 2517–26. - PubMed
    1. Approved Drugs - Nivolumab (Dec 22, 2014). Silver Spring, MD: U.S. Food and Drug Administration, 2014.
    1. Approved Drugs - Pembrolizumab (Sep 4, 2014). Silver Spring, MD: U.S. Food and Drug Administration, 2014.
    1. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375: 1749–55. - PMC - PubMed

Publication types