Joachim Alexandre1, Joe-Elie Salem2,3, Javid Moslehi3, Marion Sassier4, Camille Ropert5, Jennifer Cautela6,7,8,9, Franck Thuny6,7,8,9, Stéphane Ederhy10, Ariel Cohen10, Ghandi Damaj11, Jean-Pierre Vilque11, Anne-Flore Plane5, Damien Legallois12, Laure Champ-Rigot12, Paul Milliez12, Christian Funck-Brentano3, Charles Dolladille1. 1. PICARO Cardio-oncology Program, Department of Pharmacology, Normandie University, UNICAEN, CHU de Caen Normandie, EA 4650, Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, F-14000 Caen, France. 2. Department of Pharmacology, AP-HP, Pitié-Salpêtrière Hospital, CIC-1421, INSERM, UMR ICAN 1166, Sorbonne Université, APHP.6 Cardio-oncology Program, F-75013 Paris, France. 3. Department of Medicine, Cardio-oncology Program, Vanderbilt University Medical Center, Nashville, TN 37240, USA. 4. Department of Pharmacology, CHU de Caen Normandie, PICARO Cardio-oncology Program, F-14000 Caen, France. 5. Department of Cardiology, CHU de Caen Normandie, F-14000 Caen, France. 6. Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center, Hôpital Nord, Marseille 13915, France. 7. Centre de Recherche Cardiovasculaire et Nutrition, Inserm 1263, Inra, Marseille 13915, France. 8. Groupe Méditerranéen de Cardio-Oncologie, Marseille 13915, France. 9. Oncosafety Network of the Early Phases Cancer Trials Center, Marseille 13915, France. 10. Hôpitaux Universitaires Paris-Est, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Service de cardiologie, Unico, Unité de cardio-oncologie APHP.6, GRC Groupe de recherche clinique en cardio oncologie, Inserm 856, Université Pierre et Marie Curie, Paris, France. 11. Department of Hematology, CHU de Caen Normandie, F-14000 Caen, France. 12. Department of Cardiology, Normandie University, UNICAEN, CHU de Caen Normandie, EA 4650, Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, F-14000 Caen, France.
Abstract
AIMS: The explosion of novel anticancer therapies has meant emergence of cardiotoxicity signals including atrial fibrillation (AF). Reliable data concerning the liability of anticancer drugs in inducing AF are scarce. Using the World Health Organization individual case safety report database, VigiBase®, we aimed to determine the association between anticancer drugs and AF. METHODS AND RESULTS: A disproportionality analysis evaluating the multivariable-adjusted reporting odds ratios for AF with their 99.97% confidence intervals was performed for 176 U.S. Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-labelled anticancer drugs in VigiBase®, followed by a descriptive analysis of AF cases for the anticancer drugs identified in VigiBase®. ClinicalTrial registration number: NCT03530215. A total of 11 757 AF cases associated with at least one anticancer drug were identified in VigiBase® of which 95.8% were deemed serious. Nineteen anticancer drugs were significantly associated with AF of which 14 (74%) are used in haematologic malignancies and 9 (45%) represented new AF associations not previously confirmed in literature including immunomodulating agents (lenalidomide, pomalidomide), several kinase inhibitors (nilotinib, ponatinib, midostaurin), antimetabolites (azacytidine, clofarabine), docetaxel (taxane), and obinutuzumab, an anti-CD20 monoclonal antibody. CONCLUSION: Although cancer malignancy itself may generate AF, we identified 19 anticancer drugs significantly associated with a significant increase in AF over-reporting. This pharmacovigilance study provides evidence that anticancer drugs themselves could represent independent risk factors for AF development. Dedicated prospective clinical trials are now required to confirm these 19 associations. This list of suspected anticancer drugs should be known by physicians when confronted to AF in cancer patients, particularly in case of haematologic malignancies. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The explosion of novel anticancer therapies has meant emergence of cardiotoxicity signals including atrial fibrillation (AF). Reliable data concerning the liability of anticancer drugs in inducing AF are scarce. Using the World Health Organization individual case safety report database, VigiBase®, we aimed to determine the association between anticancer drugs and AF. METHODS AND RESULTS: A disproportionality analysis evaluating the multivariable-adjusted reporting odds ratios for AF with their 99.97% confidence intervals was performed for 176 U.S. Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-labelled anticancer drugs in VigiBase®, followed by a descriptive analysis of AF cases for the anticancer drugs identified in VigiBase®. ClinicalTrial registration number: NCT03530215. A total of 11 757 AF cases associated with at least one anticancer drug were identified in VigiBase® of which 95.8% were deemed serious. Nineteen anticancer drugs were significantly associated with AF of which 14 (74%) are used in haematologic malignancies and 9 (45%) represented new AF associations not previously confirmed in literature including immunomodulating agents (lenalidomide, pomalidomide), several kinase inhibitors (nilotinib, ponatinib, midostaurin), antimetabolites (azacytidine, clofarabine), docetaxel (taxane), and obinutuzumab, an anti-CD20 monoclonal antibody. CONCLUSION: Although cancer malignancy itself may generate AF, we identified 19 anticancer drugs significantly associated with a significant increase in AF over-reporting. This pharmacovigilance study provides evidence that anticancer drugs themselves could represent independent risk factors for AF development. Dedicated prospective clinical trials are now required to confirm these 19 associations. This list of suspected anticancer drugs should be known by physicians when confronted to AF in cancer patients, particularly in case of haematologic malignancies. Published on behalf of the European Society of Cardiology. All rights reserved.
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