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Takotsubo syndrome in patients with cancer treated with immune checkpoint inhibitors: a new adverse cardiac complication

2019; Elsevier BV; Volume: 21; Issue: 7 Linguagem: Inglês

10.1002/ejhf.1497

1879-0844

Stéphane Éderhy, Charles Dolladille, Franck Thuny, Joachim Alexandre, Ariel Cohen,

Cancer Treatment and Pharmacology

European Journal of Heart FailureVolume 21, Issue 7 p. 945-947 RESEARCH LETTERFree Access Takotsubo syndrome in patients with cancer treated with immune checkpoint inhibitors: a new adverse cardiac complication Stephane Ederhy, Stephane Ederhy Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Department of Cardiology, Paris, France; INSERM U 856, Paris, France and UNICO APHP.6 Cardio-oncology ProgramThese authors contributed equally to this work.Search for more papers by this authorCharles Dolladille, Charles Dolladille Department of Pharmacology, CHU Caen, PICARO Cardio-Oncology Programme, Caen, France EA 4650, Signalisation, Électrophysiologie et Imagerie des Lésions d'Ischémie-Reperfusion Myocardique, Normandie University, UNICAEN, Caen, FranceThese authors contributed equally to this work.Search for more papers by this authorFranck Thuny, Franck Thuny Mediterranean University Cardio-Oncology Centre (Medi-CO centre); Unit of Heart Failure and Valve Heart Diseases (UNIV); Department of Cardiology, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Nord Hospital, Marseille, France Centre for CardioVascular and Nutrition research (C2VN), Aix-Marseille University, Marseille, France Assistance Publique-Hôpitaux de Marseille, Oncosafety Network of the Early Phases Cancer Trials Center (CLIP2), Aix-Marseille University, Marseille, FranceSearch for more papers by this authorJoachim Alexandre, Joachim Alexandre Department of Pharmacology, CHU Caen, PICARO Cardio-Oncology Programme, Caen, FranceSearch for more papers by this authorAriel Cohen, Corresponding Author Ariel Cohen [email protected] Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Department of Cardiology, Paris, France; INSERM U 856, Paris, France and UNICO APHP.6 Cardio-oncology ProgramEmail: [email protected]Search for more papers by this author Stephane Ederhy, Stephane Ederhy Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Department of Cardiology, Paris, France; INSERM U 856, Paris, France and UNICO APHP.6 Cardio-oncology ProgramThese authors contributed equally to this work.Search for more papers by this authorCharles Dolladille, Charles Dolladille Department of Pharmacology, CHU Caen, PICARO Cardio-Oncology Programme, Caen, France EA 4650, Signalisation, Électrophysiologie et Imagerie des Lésions d'Ischémie-Reperfusion Myocardique, Normandie University, UNICAEN, Caen, FranceThese authors contributed equally to this work.Search for more papers by this authorFranck Thuny, Franck Thuny Mediterranean University Cardio-Oncology Centre (Medi-CO centre); Unit of Heart Failure and Valve Heart Diseases (UNIV); Department of Cardiology, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Nord Hospital, Marseille, France Centre for CardioVascular and Nutrition research (C2VN), Aix-Marseille University, Marseille, France Assistance Publique-Hôpitaux de Marseille, Oncosafety Network of the Early Phases Cancer Trials Center (CLIP2), Aix-Marseille University, Marseille, FranceSearch for more papers by this authorJoachim Alexandre, Joachim Alexandre Department of Pharmacology, CHU Caen, PICARO Cardio-Oncology Programme, Caen, FranceSearch for more papers by this authorAriel Cohen, Corresponding Author Ariel Cohen [email protected] Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Department of Cardiology, Paris, France; INSERM U 856, Paris, France and UNICO APHP.6 Cardio-oncology ProgramEmail: [email protected]Search for more papers by this author First published: 28 July 2019 https://doi.org/10.1002/ejhf.1497Citations: 9 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Takotsubo syndrome (TTS) is increasingly being reported in patients with cancer and in those undergoing chemotherapy. Up to 29% of patients admitted with a final diagnosis of stress TTS have had cancer.1 Several cases of TTS have been described in patients taking oncology drugs including fluoropyrimidines (5-fluorouracil, capecitabine), molecular-targeted agents (sunitinib, bevacizumab, trastuzumab), and cisplatin.1 By stimulating the immune system, immune checkpoint inhibitors (ICIs) may induce immune-related adverse events that could involve the skin, endocrine glands, liver, and lungs.2 Recent reports have also highlighted the risk of cardiotoxicity related to ICI administration, including atrial fibrillation, atrioventricular block, pericardial effusion, and myocarditis.2 We have recently described cases of takotsubo-like syndrome occurring in patients receiving ICIs.3 To identify whether this is clinically important, we performed a disproportionality analysis using the World Health Organization (WHO) global database of individual case safety reports (ICSRs) (VigiBase®), including adverse drug reaction (ADR) reports, to evaluate the reporting odds ratios (RORs) of stress cardiomyopathy (preferred term) associated with ICIs. The WHO database contains more than 17 million ICSRs received from 127 full member countries worldwide since 1968.4 ICSRs include administrative information (country, type of report, qualification of reporter), patient data (sex, age), date of onset of drug reaction, and outcome using Medical Dictionary for Regulatory Activities (MedDRA) 20.1 terms, WHO assessment of causality, and drug(s) involved (name, drug start and stop dates, time to onset, indication, dose, de-challenge, re-challenge). Data extraction was carried out using Vigilyze® (Uppsala Monitoring Centre) for records between 1 January 2008 (the date the term ‘stress cardiomyopathy’ was first introduced in the database) and 1 June 2018. We extracted all ICSRs associated with ‘stress cardiomyopathy’ as the preferred term. ICIs (ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab) were selected as suspect or concomitant drug. Case/non-case analyses were performed for ICIs compared with negative (paracetamol) and positive (adrenaline and venlafaxine) controls. This method allowed us to compare the proportions of specific ADRs reported for each drug or group of drugs. Disproportionality was estimated by calculating RORs and their 95% confidence intervals (CIs), as previously described.5 The cut-off for signal detection was defined as a lower 95% CI ≥ 1. An association between TTS and ICI could be suspected if the stress cardiomyopathy proportion was greater in patients exposed to ICI compared with negative and positive control drugs. This method allows the detection of a potential pharmacovigilance safety signal. All analyses were performed using R software, v3.4.4 for Windows (R Foundation for Statistical Computing). Statistical significance was defined as P < 0.05. Among the 13 188 920 ICSRs reported in VigiBase® during the study period, 1333 were cases of stress cardiomyopathy and 38 310 were cases of adverse events related to ICI drugs. We identified 13 reports of TTS in patients who received ICI drugs: ipilimumab, pembrolizumab, and nivolumab monotherapy (Table 1). No cases of stress cardiomyopathy were reported when ICIs were prescribed in combination. The absence of TTS reported with atezolizumab, avelumab, and durvalumab is probably due to the recent labelling of these ICIs. Table 1. VigiBase® analysis: characteristics of patients with stress cardiomyopathy (preferred term) from 1 January 2008 to 1 June 2018 (total number of reports: 13 188 920) and the reporting odds ratios for each immune checkpoint inhibitor Drug exposure Ipilimumab Pembrolizumab Nivolumab ICI combination All three ICIs FDA approval, year 2011 2014 2014 NA NA Number of cases 4 5 4 0 13 Sex, n (%) Male 2 (50) 1 (20) 2 (50) NR 5 (39) Female 2 (50) 4 (80) 1 (25) NR 7 (54) Unknown 0 0 1 (25) NR 1 (8) Age, years, median (IQR) 81 (80–82) 56 (29–62) 82 (82–83) NR 79 (62–82) Cases in which ICI was suspected for causality, n (%) 4 (100) 5 (100) 4 (100) NR 13 (100) Number of non-cases 12 247 8275 21 203 3428 38 297 ROR (95% CI) 3.25 (1.22–8.67) 6.01 (2.50–14.48) 1.88 (0.71–5.03) NR 3.39 (1.96–5.86) CI, confidence interval; FDA, US Food and Drug Administration; ICI, immune checkpoint inhibitor; IQR, interquartile range; NR, not reported; ROR, reporting odds ratio. The cases included adults of both sexes with a median age of 79 years (Table 1). The most common cancer types (available in nine ICSRs) were lung cancer (n = 7) and melanoma (n = 2). Only three patients received concomitant cardiovascular or diabetes medications (this information was available in all 13 ICSRs). Data for the precise timing of onset from the initiation of ICI treatment were available in five ICSRs. Among these ICSRs, the median (interquartile range) time to TTS onset was 6 (4–96) days, the mean time to onset was 76 days, and three cases (60%) occurred during the first 6 weeks of treatment. Clinical evolution was available in eight ICSRs: one patient (13%) died, four (50%) recovered, and three (38%) did not recover. Overall, ICIs were associated with a higher proportion of TTS (13/38 310; ROR 3.39, 95% CI 1.96–5.86, P < 0.0001; Table 1). The RORs for adrenaline and venlafaxine (positive controls) were 74.25 (95% CI 62.11–88.76, P < 0.0001) and 5.02 (95% CI 3.65–6.90, P < 0.0001), respectively. Paracetamol (negative control) was not associated with TTS (ROR 1.21, 95% CI 0.88–1.67, P = 0.28). It must be noted that the ROR lower 95% CI for nivolumab was <1. However, this result could be explained by a Weber effect, as a large number of ADRs had been reported as nivolumab was labelled compared with other ICIs (Table 1). This analysis of the WHO pharmacovigilance database suggests that ICIs could provoke TTS. Clinicians should be aware of such a potentially severe cardiac condition, which should be cautiously characterized and evaluated. Acknowledgements Editorial support was provided by Jenny Lloyd and Sophie Rushton-Smith (MedLink Healthcare Communications) and was funded by the authors. Conflict of interest: none declared. References 1Coen M, Rigamonti F, Roth A, Koessler T. Chemotherapy-induced Takotsubo cardiomyopathy, a case report and review of the literature. BMC Cancer 2017; 17: 394 2Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J, Monestier S, Grob JJ, Scemama U, Jacquier A, Lalevee N, Barraud J, Peyrol M, Laine M, Bonello L, Paganelli F, Cohen A, Barlesi F, Ederhy S, Thuny F. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation 2017; 136: 2085– 2087. 3Ederhy S, Cautela J, Ancedy Y, Escudier M, Thuny F, Cohen A. Takotsubo-like syndrome in cancer patients treated with immune checkpoint inhibitors. JACC Cardiovasc Imaging 2018; 11: 1187– 1190. 4Bate A, Lindquist M, Edwards IR. The application of knowledge discovery in databases to post-marketing drug safety: example of the WHO database. Fundam Clin Pharmacol 2008; 22: 127– 140. 5Montastruc JL, Sommet A, Bagheri H, Lapeyre-Mestre M. Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database. Br J Clin Pharmacol 2011; 72: 905– 908. Citing Literature Volume21, Issue7July 2019Pages 945-947 ReferencesRelatedInformation