Charles Dolladille1, Julia Akroun2, Pierre-Marie Morice3, Anne Dompmartin2, Emilien Ezine2, Marion Sassier4, Angélique Da-Silva5, Anne-Flore Plane6, Damien Legallois7, Jean-Mathieu L'Orphelin2, Joachim Alexandre1. 1. Normandie Univ, UNICAEN, EA 4650, Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, Rue des Rochambelles, Caen F-14000; CHU de Caen Normandie, PICARO Cardio-Oncology Program, Department of Pharmacology, Pharmacoepidemiology unit, Avenue de la Côte de Nacre, Caen F-14000, France. 2. CHU de Caen Normandie, Department of Dermatology, Avenue de la Côte de Nacre, Caen F-14000, France. 3. Normandie Univ, UNICAEN, INSERM U1086 ANTICIPE, Team 2 'Biology and Innovative Therapeutics for Ovarian Cancers' (BioTICLA), Avenue du Général Harris, Caen F-14000; CHU de Caen Normandie, Department of Pharmacology, Avenue de la Côte de Nacre, Caen F-14000, France. 4. Department of Pharmacology, CHU de Caen Normandie, PICARO Cardio-Oncology Program, Avenue de la Côte de Nacre, Caen F-14000, France. 5. Comprehensive Cancer Center F. Baclesse, Breast cancer unit, Unicancer, PICARO Cardio-Oncology Program, Avenue du Général Harris, Caen F-14000, France. 6. Department of Cardiology, CHU de Caen Normandie, PICARO Cardio-Oncology Program, Avenue de la Côte de Nacre, Caen F-14000, France. 7. Normandie Univ, UNICAEN, EA 4650, Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, Rue des Rochambelles, Caen F-14000, France; CHU de Caen Normandie, Department of Cardiology, PICARO Cardio-Oncology Program, Avenue de la Côte de Nacre, Caen F-14000, France.
Abstract
AIMS: The risk and incidence of cardiovascular (CV) immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in cancer patients remain unknown. METHODS AND RESULTS: We systematically reviewed all randomized clinical trials (RCTs) including at least one ICI-containing arm and available CV adverse event (CVAE) data in cancer patients in the ClinicalTrials.gov registry, Medline, and the Cochrane CENTRAL Register of Controlled Trials, up to 31 August 2020 (CRD42020165672). The primary outcome was the summary risk of 16 different CVAEs associated with ICI exposure vs. controls (placebo and non-placebo) in RCTs. CVAEs with an increased risk associated with ICI exposure were considered as CV irAEs. Summary incidences of CV irAEs identified in our primary outcome analyses were computed using all RCTs including at least one ICI-containing arm. We used a random-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% confidence intervals (CIs) and logit transformation and inverse variance weighting to compute summary incidences. Sixty-three unique RCTs with at least one ICI-containing arm (32 518 patients) were retrieved, among which 48 (29 592 patients) had a control arm. Among the 16 CVAEs studied, ICI use was associated with an increased risk of 6 CV irAEs including myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischaemia with higher risks for myocarditis (Peto OR: 4.42, 95% CI: 1.56-12.50, P < 0.01; I2 = 0%, P = 0.93) and dyslipidemia (Peto OR: 3.68, 95% CI: 1.89-7.19, P < 0.01; I2 = 0%, P = 0.66). The incidence of these CVAEs ranged from 3.2 (95% CI 2.0-5.1) to 19.3 (6.7-54.1) per 1000 patients, in studies with a median follow-up ranging from 3.2 to 32.8 months. CONCLUSION: In RCTs, ICI use was associated with six CV irAEs, not confined to myocarditis and pericarditis. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The risk and incidence of cardiovascular (CV) immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in cancer patients remain unknown. METHODS AND RESULTS: We systematically reviewed all randomized clinical trials (RCTs) including at least one ICI-containing arm and available CV adverse event (CVAE) data in cancer patients in the ClinicalTrials.gov registry, Medline, and the Cochrane CENTRAL Register of Controlled Trials, up to 31 August 2020 (CRD42020165672). The primary outcome was the summary risk of 16 different CVAEs associated with ICI exposure vs. controls (placebo and non-placebo) in RCTs. CVAEs with an increased risk associated with ICI exposure were considered as CV irAEs. Summary incidences of CV irAEs identified in our primary outcome analyses were computed using all RCTs including at least one ICI-containing arm. We used a random-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% confidence intervals (CIs) and logit transformation and inverse variance weighting to compute summary incidences. Sixty-three unique RCTs with at least one ICI-containing arm (32 518 patients) were retrieved, among which 48 (29 592 patients) had a control arm. Among the 16 CVAEs studied, ICI use was associated with an increased risk of 6 CV irAEs including myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischaemia with higher risks for myocarditis (Peto OR: 4.42, 95% CI: 1.56-12.50, P < 0.01; I2 = 0%, P = 0.93) and dyslipidemia (Peto OR: 3.68, 95% CI: 1.89-7.19, P < 0.01; I2 = 0%, P = 0.66). The incidence of these CVAEs ranged from 3.2 (95% CI 2.0-5.1) to 19.3 (6.7-54.1) per 1000 patients, in studies with a median follow-up ranging from 3.2 to 32.8 months. CONCLUSION: In RCTs, ICI use was associated with six CV irAEs, not confined to myocarditis and pericarditis. Published on behalf of the European Society of Cardiology. All rights reserved.