Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor–Associated Myocarditis
Authors: Lili Zhang, Daniel A. Zlotoff, Magid Awadalla, Syed S. Mahmood, Anju Nohria, Malek Z.O. Hassan, Franck Thuny, Leyre Zubiri, Carol L. Chen, Ryan J. Sullivan, Raza M. Alvi, Adam Rokicki, Sean P. Murphy, Maeve Jones-O’Connor, Lucie M. Heinzerling, Ana Barac, Brian J. Forrestal, Eric H. Yang, Dipti Gupta, Michael C. Kirchberger, Sachin P. Shah, Muhammad A. Rizvi, Gagan Sahni, Anant Mandawat, Michael Mahmoudi, Sarju Ganatra, Stephane Ederhy, Eduardo Zatarain-Nicolas, John D. Groarke, Carlo G. Tocchetti, Alexander R. Lyon, Paaladinesh Thavendiranathan, Justine V. Cohen, Kerry L. Reynolds, Michael G. Fradley, Tomas G. Neilan
Journal: Circulation (2020)

HomeCirculationVol. 141, No. 24Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor–Associated Myocarditis Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBMajor Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor–Associated Myocarditis Lili Zhang, MD, ScM, Daniel A. Zlotoff, MD, PhD, Magid Awadalla, MD, Syed S. Mahmood, MD, MPH, Anju Nohria, MD, Malek Z.O. Hassan, MD, Franck Thuny, MD, PhD, Leyre Zubiri, MD, PhD, Carol L. Chen, MD, Ryan J. Sullivan, MD, Raza M. Alvi, MD, Adam Rokicki, BS, Sean P. Murphy, MB, BCh, BAO, Maeve Jones-O'Connor, MD, Lucie M. Heinzerling, MD, MPH, Ana Barac, MD, PhD, Brian J. Forrestal, MD, Eric H. Yang, MD, Dipti Gupta, MD, MPH, Michael C. Kirchberger, MD, Sachin P. Shah, MD, Muhammad A. Rizvi, MD, Gagan Sahni, MD, Anant Mandawat, MD, Michael Mahmoudi, MD, PhD, Sarju Ganatra, MD, Stephane Ederhy, MD, Eduardo Zatarain-Nicolas, MD, PhD, John D. Groarke, MB, BCh, MPH, Carlo G. Tocchetti, MD, PhD, Alexander R. Lyon, MD, PhD, Paaladinesh Thavendiranathan, MD, Justine V. Cohen, DO, Kerry L. Reynolds, MD, Michael G. Fradley, MD and Tomas G. Neilan, MD, MPH Lili ZhangLili Zhang Tomas G. Neilan, MD, MPH, Cardio-Oncology Program, Cardiovascular Imaging Research Center, Massachusetts General Hospital, 165 Cambridge St, Suite 400, Boston, MA 02114. Email E-mail Address: [email protected] Cardiovascular Imaging Research Center, Division of Cardiology and Department of Radiology (L. Zhang, M.A., M.Z.O.H., R.M.A., A.R., T.G.N.), Massachusetts General Hospital, Boston. Cardio-Oncology Program, Division of Cardiology, Department of Medicine (L. Zhang, D.A.Z., M.A., S.P.M., M.J.-O., T.G.N.), Massachusetts General Hospital, Boston. , Daniel A. ZlotoffDaniel A. Zlotoff Cardio-Oncology Program, Division of Cardiology, Department of Medicine (L. Zhang, D.A.Z., M.A., S.P.M., M.J.-O., T.G.N.), Massachusetts General Hospital, Boston. , Magid AwadallaMagid Awadalla Cardiovascular Imaging Research Center, Division of Cardiology and Department of Radiology (L. Zhang, M.A., M.Z.O.H., R.M.A., A.R., T.G.N.), Massachusetts General Hospital, Boston. Cardio-Oncology Program, Division of Cardiology, Department of Medicine (L. Zhang, D.A.Z., M.A., S.P.M., M.J.-O., T.G.N.), Massachusetts General Hospital, Boston. , Syed S. MahmoodSyed S. Mahmood Cardiology Division, New York-Presbyterian Hospital, Weill Cornell Medical Center (S.S.M.). , Anju NohriaAnju Nohria Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (A.N., J.D.G.). , Malek Z.O. HassanMalek Z.O. Hassan Cardiovascular Imaging Research Center, Division of Cardiology and Department of Radiology (L. Zhang, M.A., M.Z.O.H., R.M.A., A.R., T.G.N.), Massachusetts General Hospital, Boston. , Franck ThunyFranck Thuny Aix-Marseille University, Assistance Publique – Hôpitaux de Marseille, University Mediterranean Center of Cardio-Oncology, Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Nord Hospital, Center for Cardiovascular and Nutrition Research, France (F.T.). Mediterranean Group of Cardio-Oncology, Marseille, France (F.T.). , Leyre ZubiriLeyre Zubiri Division of Oncology and Hematology, Department of Medicine (L. Zubiri, R.J.S., J.V.C., K.L.R.), Massachusetts General Hospital, Boston. , Carol L. ChenCarol L. Chen Cardiology Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York (C.LC., D.G.). , Ryan J. SullivanRyan J. Sullivan Division of Oncology and Hematology, Department of Medicine (L. Zubiri, R.J.S., J.V.C., K.L.R.), Massachusetts General Hospital, Boston. , Raza M. AlviRaza M. Alvi Cardiovascular Imaging Research Center, Division of Cardiology and Department of Radiology (L. Zhang, M.A., M.Z.O.H., R.M.A., A.R., T.G.N.), Massachusetts General Hospital, Boston. , Adam RokickiAdam Rokicki Cardiovascular Imaging Research Center, Division of Cardiology and Department of Radiology (L. Zhang, M.A., M.Z.O.H., R.M.A., A.R., T.G.N.), Massachusetts General Hospital, Boston. , Sean P. MurphySean P. Murphy Cardio-Oncology Program, Division of Cardiology, Department of Medicine (L. Zhang, D.A.Z., M.A., S.P.M., M.J.-O., T.G.N.), Massachusetts General Hospital, Boston. , Maeve Jones-O'ConnorMaeve Jones-O'Connor Cardio-Oncology Program, Division of Cardiology, Department of Medicine (L. Zhang, D.A.Z., M.A., S.P.M., M.J.-O., T.G.N.), Massachusetts General Hospital, Boston. , Lucie M. HeinzerlingLucie M. Heinzerling Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Germany (L.M.H., M.C.K.). , Ana BaracAna Barac Cardio-Oncology Program, MedStar Heart and Vascular Institute, Georgetown University, Washington, DC (A.B., B.J.F.). , Brian J. ForrestalBrian J. Forrestal Cardio-Oncology Program, MedStar Heart and Vascular Institute, Georgetown University, Washington, DC (A.B., B.J.F.). , Eric H. YangEric H. Yang UCLA Cardio-Oncology Program, Division of Cardiology, Department of Medicine, University of California at Los Angeles (E.H.Y.). , Dipti GuptaDipti Gupta Cardiology Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York (C.LC., D.G.). , Michael C. KirchbergerMichael C. Kirchberger Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Germany (L.M.H., M.C.K.). , Sachin P. ShahSachin P. Shah Cardiology Division, Lahey Hospital and Medical Center, Burlington, MA (S.P.S., S.G.). , Muhammad A. RizviMuhammad A. Rizvi Division of Oncology and Hematology, Department of Medicine, Lehigh Valley Hospital, Allentown, PA (M.A.R.). , Gagan SahniGagan Sahni Mount Sinai Hospital, New York (G.S.). , Anant MandawatAnant Mandawat Cardio-Oncology Program, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, GA (A.M.). , Michael MahmoudiMichael Mahmoudi Faculty of Medicine, University of Southampton, United Kingdom (M.M.). , Sarju GanatraSarju Ganatra Cardiology Division, Lahey Hospital and Medical Center, Burlington, MA (S.P.S., S.G.). , Stephane EderhyStephane Ederhy AP-HP, Saint-Antoine Hospital, Department of Cardiology, UNICO-GRECO Cardio-Oncology Program, Paris, France (S.E.). , Eduardo Zatarain-NicolasEduardo Zatarain-Nicolas Service of Cardiology, General University Hospital Gregorio Marañón, Madrid, Spain (E.Z.-N.). , John D. GroarkeJohn D. Groarke Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, MA (A.N., J.D.G.). , Carlo G. TocchettiCarlo G. Tocchetti Department of Translational Medical Sciences, Federico II University, Naples, Italy (C.G.T.). , Alexander R. LyonAlexander R. Lyon Cardio-Oncology Program, Royal Brompton Hospital, and Imperial College London, United Kingdom (A.R.L.). , Paaladinesh ThavendiranathanPaaladinesh Thavendiranathan Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Center, Division of Cardiology, Toronto General Hospital, University of Toronto, Ontario, Canada (P.T.). , Justine V. CohenJustine V. Cohen Division of Oncology and Hematology, Department of Medicine (L. Zubiri, R.J.S., J.V.C., K.L.R.), Massachusetts General Hospital, Boston. , Kerry L. ReynoldsKerry L. Reynolds Division of Oncology and Hematology, Department of Medicine (L. Zubiri, R.J.S., J.V.C., K.L.R.), Massachusetts General Hospital, Boston. , Michael G. FradleyMichael G. Fradley Cardio-Oncology Program, Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, Philadelphia (M.G.F.). and Tomas G. NeilanTomas G. Neilan Cardiovascular Imaging Research Center, Division of Cardiology and Department of Radiology (L. Zhang, M.A., M.Z.O.H., R.M.A., A.R., T.G.N.), Massachusetts General Hospital, Boston. Cardio-Oncology Program, Division of Cardiology, Department of Medicine (L. Zhang, D.A.Z., M.A., S.P.M., M.J.-O., T.G.N.), Massachusetts General Hospital, Boston. Originally published15 Jun 2020https://doi.org/10.1161/CIRCULATIONAHA.119.044703Circulation. 2020;141:2031–2034Immune checkpoint inhibitors (ICIs) are being increasingly applied to a broader range of cancers. Myocarditis is an uncommon but potentially fulminant toxicity associated with ICIs, with a case fatality rate of 30% to 50%.1,2 Corticosteroids are the first-line treatment; however, because of the limited data, guidelines vary significantly in terms of initial corticosteroid dose and treatment strategies.3,4An international multicenter registry of ICI-associated myocarditis from 23 sites was established by retrospectively collecting consecutive patients with ICI-associated myocarditis. The diagnosis was made in 1 of 2 ways: (1) histopathology or (2) clinically suspected myocarditis based on the European Society of Cardiology guidelines.5 The study was approved by each center's institutional review board. The dose of corticosteroids was converted to methylprednisolone equivalents. Patients were categorized into low-dose (<60 mg/d), intermediate-dose (60–500 mg/d), and high-dose (501–1000 mg/d) groups based on initial methylprednisolone equivalent administered on the first day of treatment. The time of initiation was the time from admission to the first dose of corticosteroids, separated into groups of ≤24 hours, 24 to 72 hours, and >72 hours. Major adverse cardiac events (MACE) were a composite of cardiovascular death, cardiac arrest, cardiogenic shock, and hemodynamically significant complete heart block requiring pacemaker. The beginning of follow-up was the time of index admission for myocarditis, and the end of follow-up was May 1, 2019.In total, 126 patients were treated with corticosteroids, with 65 diagnosed by histopathology and 61 with clinical criteria. Sixteen of the 126 patients used additional immunosuppressant drugs, with similar characteristics as patients who received corticosteroids only. The median time from ICI administration to the admission was 51 days (interquartile range, 23–120 days). Eighty-four patients (67%) presented with signs or symptoms typical for heart failure, and 39 (31%) presented with arrhythmia. The initial corticosteroid was either methylprednisolone (96 [76%]), prednisone (25 [20%]), hydrocortisone (2 [2%]), or dexamethasone (3 [2%]). Twenty-one patients (16.7%) received low-dose corticosteroids, 55 (43.7%) received intermediate-dose corticosteroids, and 50 (39.6%) received high-dose corticosteroids; groups were broadly similar in characteristics. Patients who received corticosteroids within 24 hours (43 [34.1%]), between 24 and 72 hours (35 [27.8%]), and after 72 hours (43 [38.1%]) also appeared similar in characteristics. Patients who received corticosteroids within 24 hours were less likely to have persistent troponin elevation at discharge (reduction of <50% of the peak troponin levels; 32.4%) than those treated between 24 and 72 hours (66.7%) and after 72 hours (41.4%; P=0.026). There was an inverse relationship between initial dose of corticosteroids and the occurrence of MACE (low dose, 61.9%; intermediate dose, 54.6%; high dose, 22.0%; P<0.001; Figure [A]). Compared with low-dose corticosteroids, high dose was associated with a 73% lower risk of MACE independent of age, sex, lowest left ventricular ejection fraction, and time of initiation (hazard ratio, 0.27 [95% CI, 0.09–0.84]; P=0.024). Patients receiving corticosteroids within 24 hours of admission also had a lower rate of MACE (7.0%) than those receiving corticosteroids between 24 and 72 hours (34.3%) and those receiving corticosteroids at >72 hours (85.1%; P<0.001; Figure [B]). Compared with after 72 hours, initiation of corticosteroids within 24 hours of admission (hazard ratio, 0.03 [95% CI, 0.004–0.23]; P=0.001) and between 24 and 72 hours (hazard ratio, 0.30 [95% CI, 0.12–0.73]; P=0.008) was associated with a lower risk of MACE after adjustment for age, sex, lowest left ventricular ejection fraction, and initial corticosteroid dose. Patients were further categorized into time and dose combination groups, by dividing the cohort into ≤24 hours, 24 to 72 hours, and >72 hours and high-dose (methylprednisolone 1000 mg/d) and non–high-dose corticosteroids (any dose <1000 mg/d) groups. The time of initiation impacted MACE-free survival, whereby patients receiving corticosteroids within 24 hours, regardless of dosage (blue curves), showed the best outcome, and patients receiving corticosteroids after 72 hours, regardless of dosage (red curves), showed the worst outcome (Figure [C]).Download figureDownload PowerPointFigure. Relationship between initial corticosteroids dose and timing and MACE-free survival. Kaplan-Meier curves by initial corticosteroids dose (A), by time of initiation (B), and by initial dose of corticosteroids and time of initiation combination (C). MACE indicates major adverse cardiovascular events.These results raise the possibility that myocardial damage can be mitigated by early and intensive corticosteroid therapy.3,4 There appeared to be a graded reduction in the risk of MACE as the time of initiation became shorter and initial dose became higher. 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. In contrast, non–high-dose corticosteroids administered within 24 hours may lead to a better outcome as compared to patients who receive high-dose corticosteroids later (24–72 or >72 hours).This was a retrospective observational study; therefore, the association of corticosteroid dosing and time is hypothesis generating, and future randomized, controlled trials will be needed to provide more definitive evidence and closely monitor cancer outcomes. Specifically, the effect of high-dose corticosteroids on cancer outcomes with ICIs is unclear; initial data suggested that cancer outcomes were unchanged by high-dose corticosteroids, but more recent data suggest that cancer survival may be reduced. Therefore, there is likely a pressing need for therapies beyond corticosteroids that will not affect cancer outcomes.In conclusion, higher initial dose (ie, intravenous methylprednisolone 1000 mg/d) and earlier initiation of corticosteroids in a retrospective study were associated with improved cardiac outcomes with ICI-associated myocarditis.Sources of FundingThis work was supported by the Sarnoff Cardiovascular Research Foundation and the New York Academy of Medicine's Glorney-Raisbeck Award to Dr Mahmood. Dr Sullivan was supported in part through the National Institutes of Health (NIH)/National Cancer Institute (NCI) (RO1CA229851, UH2CA207355, RO1CA193970). Drs Chen and Gupta were supported in part through the NIH/NCI (P30CA008748). Dr Thavendiranathan was supported in part through the Canadian Institutes of Health Research New Investigator Award (FRN 147814). Dr Tocchetti was supported by a Ricerca di Ateneo/Federico II University grant. Dr Neilan was supported in part through a kind gift from A. Curt Greer and Pamela Kohlberg, NIH/National Heart, Lung, and Blood Institute (1RO1HL130539, 1RO1HL137562, and K24HL150238), and NIH/Harvard Center for AIDS Research (P30 AI060354).DisclosuresDr Mahmood has received consultancy fees from OMR Globus, Alpha Detail, and Opinion Research Team. Dr Nohria has received research support from Amgen and has been a consultant for Takeda Oncology. Dr Heinzerling has received consultancy, advisory board, and speaker fees from MSD, BMS, Roche, Novartis, Amgen, Curevac, Sanofi and Pierre Fabre. Dr Sullivan has been a consultant to Merck and Novartis. Dr Groarke has received research support from Amgen. Dr Neilan has received advisory fees from Parexel, BMS, H3-Biomedicine, Syros Pharmaceuticals, Aprea Therapeutics, and Intrinsic Imaging. The other authors report no conflicts.FootnotesThe full author list is available on page 2033.https://www.ahajournals.org/journal/circTomas G. Neilan, MD, MPH, Cardio-Oncology Program, Cardiovascular Imaging Research Center, Massachusetts General Hospital, 165 Cambridge St, Suite 400, Boston, MA 02114. Email [email protected]harvard.eduReferences1. Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, et al. Myocarditis in patients treated with immune checkpoint inhibitors.J Am Coll Cardiol. 2018; 71:1755–1764. doi: 10.1016/j.jacc.2018.02.037CrossrefMedlineGoogle Scholar2. Awadalla M, Mahmood SS, Groarke JD, Hassan MZO, Nohria A, Rokicki A, Murphy SP, Mercaldo ND, Zhang L, Zlotoff DA, et al. Global longitudinal strain and cardiac events in patients with immune checkpoint inhibitor-related myocarditis.J Am Coll Cardiol. 2020; 75:467–478. doi: 10.1016/j.jacc.2019.11.049CrossrefMedlineGoogle Scholar3. 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