Title: Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor–Related Cardiotoxicity
Abstract: HomeCirculationVol. 136, No. 21Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor–Related Cardiotoxicity Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBClinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor–Related Cardiotoxicity Marion Escudier, MD, Jennifer Cautela, MD, Nausicaa Malissen, MD, Yann Ancedy, MD, Morgane Orabona, MD, Johan Pinto, MD, Sandrine Monestier, MD, Jean-Jacques Grob, MD, PhD, Ugo Scemama, MD, Alexis Jacquier, MD, PhD, Nathalie Lalevee, PhD, Jeremie Barraud, MD, Michael Peyrol, MD, Marc Laine, MD, Laurent Bonello, MD, PhD, Franck Paganelli, MD, PhD, Ariel Cohen, MD, PhD, Fabrice Barlesi, MD, PhD, Stephane Ederhy, MD and Franck Thuny, MD, PhD Marion EscudierMarion Escudier Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Groupe Méditerranéen de Cardio-Oncologie (gMEDICO), France (M.E., J.C., M.O., J.P., F.T.) Search for more papers by this author , Jennifer CautelaJennifer Cautela Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Groupe Méditerranéen de Cardio-Oncologie (gMEDICO), France (M.E., J.C., M.O., J.P., F.T.) Search for more papers by this author , Nausicaa MalissenNausicaa Malissen Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Department of Dermatology, Hôpital Timone, Marseille, France (N.M. S.M., J.J.G.) Search for more papers by this author , Yann AncedyYann Ancedy Hôpitaux Universitaires Paris-Est, Hôpital Saint Antoine, Hôpital Tenon, Assistance Publique–Hôpitaux de Paris, Unité mixte de recherche, INSERM 856, Université Pierre et Marie Curie (Paris VI), France (Y.A., A.C., S.E.) Search for more papers by this author , Morgane OrabonaMorgane Orabona Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Groupe Méditerranéen de Cardio-Oncologie (gMEDICO), France (M.E., J.C., M.O., J.P., F.T.) Search for more papers by this author , Johan PintoJohan Pinto Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Groupe Méditerranéen de Cardio-Oncologie (gMEDICO), France (M.E., J.C., M.O., J.P., F.T.) Search for more papers by this author , Sandrine MonestierSandrine Monestier Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Department of Dermatology, Hôpital Timone, Marseille, France (N.M. S.M., J.J.G.) Search for more papers by this author , Jean-Jacques GrobJean-Jacques Grob Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Department of Dermatology, Hôpital Timone, Marseille, France (N.M. S.M., J.J.G.) Search for more papers by this author , Ugo ScemamaUgo Scemama Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Department of Radiology and Cardiovascular Imaging, Hopital Nord, Marseille, France (U.S., A.J.) Search for more papers by this author , Alexis JacquierAlexis Jacquier Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Department of Radiology and Cardiovascular Imaging, Hopital Nord, Marseille, France (U.S., A.J.) Search for more papers by this author , Nathalie LaleveeNathalie Lalevee Aix-Marseille University, Technological Advances for Genomics and Clinics (TAGC), Unité mixte de recherche/INSERM 1090, Marseille, France (N.L.) Search for more papers by this author , Jeremie BarraudJeremie Barraud Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Search for more papers by this author , Michael PeyrolMichael Peyrol Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Search for more papers by this author , Marc LaineMarc Laine Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Search for more papers by this author , Laurent BonelloLaurent Bonello Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Aix-Marseille University, Unité mixte de recherche, INSERM 1076, Marseille, France (L.B., F.P.) Search for more papers by this author , Franck PaganelliFranck Paganelli Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Aix-Marseille University, Unité mixte de recherche, INSERM 1076, Marseille, France (L.B., F.P.) Search for more papers by this author , Ariel CohenAriel Cohen Hôpitaux Universitaires Paris-Est, Hôpital Saint Antoine, Hôpital Tenon, Assistance Publique–Hôpitaux de Paris, Unité mixte de recherche, INSERM 856, Université Pierre et Marie Curie (Paris VI), France (Y.A., A.C., S.E.) Search for more papers by this author , Fabrice BarlesiFabrice Barlesi Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, Multidisciplinary Oncology & Therapeutic Innovations Department, Hôpital Nord, Marseille, France (F.B.). Search for more papers by this author , Stephane EderhyStephane Ederhy Hôpitaux Universitaires Paris-Est, Hôpital Saint Antoine, Hôpital Tenon, Assistance Publique–Hôpitaux de Paris, Unité mixte de recherche, INSERM 856, Université Pierre et Marie Curie (Paris VI), France (Y.A., A.C., S.E.) Search for more papers by this author and Franck ThunyFranck Thuny Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), France (M.E., J.C., M.O., J.P., J.B., M.P., M.L., L.B., F.P., F.T.) Groupe Méditerranéen de Cardio-Oncologie (gMEDICO), France (M.E., J.C., M.O., J.P., F.T.) Search for more papers by this author Originally published21 Nov 2017https://doi.org/10.1161/CIRCULATIONAHA.117.030571Circulation. 2017;136:2085–2087Immune checkpoint inhibitors (ICIs) represent a major advance in the treatment of cancer. Although clinical trials reported a low incidence of immune-related cardiovascular adverse events,1 the number of published life-threatening cases of cardiotoxicity is increasing.2 In this descriptive observational analysis, we aimed to describe the clinical manifestations, management, and outcomes of patients who developed ICI-related cardiotoxicity.The medical records of patients with a clinical suspicion of ICI-related cardiotoxicity were reviewed from the databases of 2 cardio-oncology units between March 2015 and April 2017. The patients are managed according to similar protocols. Because no specific follow-up had previously been established for patients receiving ICIs during the study period, the oncologists referred patients receiving ICIs only on the basis of their clinical suspicion of cardiovascular events. These patients had a standardized evaluation including clinical consultation, ECG, transthoracic echocardiography, and measurement of brain natriuretic peptide and troponin I serum levels. The management of cardiotoxicity was left to the physician’s discretion. The study was approved by our institutional review board, and informed consent has been obtained from the subjects. To create a pooled analysis, we also searched PubMed for English articles reporting cases of ICI-related cardiotoxicity until April 2017. We selected the cases reporting in detail the patient characteristics and the disease evolution. Among the selected cases, we excluded those for which data were considered insufficient to formally conclude that clinical manifestations were related to ICIs.A total of 30 patients with ICI-related cardiotoxicity were finally analyzed in this study, including 12 newly diagnosed patients in the 2 cardio-oncology units and 24 patients with sufficient data previously reported in 10 case series. The data of those 24 patients were summarized in a recent review2 and in 2 additional case reports.3,4 The characteristics of the 30 patients are summarized in the Table. Cardiotoxicity was diagnosed at a median of 65 days (range, 2–454 days) after the initiation of ICIs and occurred after a median of 3 (range, 1–33) infusions. The rate of cardiotoxicity was higher after the first and third infusions, corresponding to the period after the first and third infusions. Dyspnea, palpitation, and signs of congestive heart failure were the most frequent clinical manifestations. Left ventricular systolic dysfunction was reported in 79% of patients, and Takotsubo syndrome–like appearance occurred in 14%. Atrial fibrillation, ventricular arrhythmia, and conduction disorders were observed in 30%, 27%, and 17% of patients, respectively. They were isolated (without left ventricular systolic dysfunction) in 3%, 7%, and 13% of patients, respectively. Concomitant signs of myositis were present in 23% of patients. Of the 18 patients with available data on left ventricular ejection fraction evolution, complete reversibility of left ventricular systolic dysfunction was significantly associated with corticosteroid therapy (8 of 12 [67%] versus 1 of 6 [17%]; P=0.04). Eight patients (27%) died of cardiovascular complications. The causes of death were refractory ventricular arrhythmia (n=3), heart failure (n=2), pulmonary embolism (n=1), sudden death (n=1), and cardiac arrest after the diagnosis of a conductive disorder (n=1). Cardiovascular mortality was significantly associated with conduction abnormalities (80% versus 16%; P=0.003) and ipilimumab-nivolumab combination therapy (57% versus 17%; P=0.04). Immune therapy was administered again after the first episode of cardiotoxicity only in the 4 patients (14%) without any recurrences.Table. Characteristics of Patients With ICI-Related Cardiotoxicity (Pooled Analysis)Patients With Available Data, nValueAge, median (minimum–maximum), y3072 (23–88)Male, n (%)3023 (77)Previous cardiovascular disease, n (%)3015 (50)Cancer, n (%) Melanoma3023 (77) NSCLC304 (13) Others303 (10)ICIs, n (%) Ipilimumab3011 (37) Nivolumab3010 (33) Ipilimumab+nivolumab307 (23) Pembrolizumab303 (10) Atezolizumab301 (3)Type of cardiotoxicity, n (%) LVSD2923 (79) Takotsubo syndrome–like appearance294 (14) Atrial fibrillation309 (30) Ventricular arrhythmia308 (27) Conduction abnormalities305 (17) Pericardial effusion292 (7)Time after initiation of ICIs, median (minimum–maximum), d2965 (2–454)Infusions before ICIs, median (minimum–maximum), n273 (1–33)Initial clinical cardiovascular manifestations29 Dyspnea, n (%)2922 (76) Palpitation, n (%)294 (14) Chest pain, n (%)294 (14) Heart failure, n (%)2924 (83) Cardiac arrest, n (%)292 (7) ST-segment/T-wave abnormalities, n (%)2811 (39) LVEF, median (minimum–maximum), %2635 (15–73) LVEF ≤35%, n (%)2612 (46)MRI, n (%) LGE133 (23) Myocardial edema155 (33) BNP or NT–pro-BNP elevation1414 (100) Troponin elevation2612 (46) Lymphocyte infiltration (histology)98 (89) Corticosteroids3021 (70) LVSD completely reversible189 (50) Death resulting from cardiovascular causes308 (27)BNP indicates brain natriuretic peptide; ICI, immune checkpoint inhibitor; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction; MRI, magnetic resonance imaging; NSCLC, non–small cell lung cancer; and NT–pro-BNP, N-terminal probrain natriuretic peptide.The mechanisms of ICI-related cardiovascular events remain not well known, but this study provides a more comprehensive clinical description of this cardiotoxicity by analyzing a greater number of patients compared with previous studies. It shows that clinical manifestations are variable and associated with high cardiovascular mortality. Although we observed a higher incidence rate of cardiotoxicity during the first and third months of treatment, clinicians should keep in mind that cardiotoxicity can develop at any time; in our study, the interval varied from 2 to 454 days. Therefore, a comprehensive cardiac evaluation might be justified not only before the beginning of ICI therapy (as a reference) but also in cases of cardiovascular manifestations during treatment and systematically at the third month or after the third infusion. However, further data are needed to determine which cardiovascular investigations are relevant in this situation. In our analysis, cardiovascular mortality was high and significantly associated with the occurrence of conduction disorders. Although guidelines recommend a definite discontinuation of immune therapy in cases of life-threatening and severe adverse events,5 the management of each case should be individualized according to cancer status and the presence of toxicity regression. Indeed, corticosteroid use was associated with a higher probability of left ventricular function recovery, and no recurrence of cardiotoxicity was observed in the patients who underwent ICI readministration. This study has several limitations, including retrospective design, small sample size, and reporting bias.In conclusion, this work provides new insights into the cardiotoxicity observed in patients treated with ICIs. Because the number of patients exposed to this new immune therapy is expected to dramatically increase in the near future, our study encourages further work to define guidelines for cardiovascular monitoring and management.DisclosuresDr Cautela received consultant and lecture fees from MSD, Janssen, Merck, Novartis, and AstraZeneca. Dr Malissen received consultant fees and support for congress participation from Bristol-Myers Squibb, Novartis, and Amgen. Dr Thuny has received consultant and lecture fees from AstraZeneca, Novartis, Sanofi, Boston Scientific, and Bristol-Myers Squibb. Dr Grob participated in the Advisory Board for Bristol-Myers Squibb, MSD, Roche, Novartis, Amgen, and Pierre Fabre. Dr Cohen received consultant and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, and Sanofi-Aventis. Dr Ederhy received consultant and lecture fees from Lilly, Daiichy-Sankyo, Celgene, Pfizer, Esperare, Bristol-Myers Squibb, Janssen, Philips Healthcare, Bayer, Novartis, Amgen, and Ipsen. Dr Monestier received consultant fees and supports for congress participation from Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, and MSD. She participated in clinical trials promoted by Bristol-Myers Squibb, Roche, GlaxoSmithKline, and Amgen. Dr Barlesi received modest consultant fees from Bristol-Myers Squibb, Roche, Astra Zeneca, Mark, and MDS. The other authors report no conflicts.FootnotesCirculation is available at http://circ.ahajournals.org.Correspondence to: Franck Thuny, MD, PhD, Mediterranean University Cardio-Oncology Center, Unit of Heart Failure and Valvular Heart Diseases, Hôpital NORD, Chemin des Bourrely, 13015, Marseille, France. E-mail [email protected]References1. 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