CardioTOxicity Induced by andRogeNICS and Their Antagonists (TORNICS) (TORNICS)

Cardiotoxicity of Androgenic Agonists and Antagonists in the National French Pharmacovigilance Database and EudraCT Database

Anti-androgenic therapies relying on peripheral and/or central blockade for the treatment of prostate cancer seems to have an impact on the cardio-vascular system. This study investigates reports of cardiovascular toxicities for treatment including Anatomical Therapeutic Chemical (ATC) classification: sex hormones (G03), hypothalamic hormones (H01C) and sex hormones used in treatment of neoplastic diseases (L02) in the French pharmacovigilance database and European Clinical Trials (EudraCT) database.

Study Overview

• Status: Completed
• Conditions: Heart Diseases
• Intervention / Treatment: Drug: Hormonal therapies: G03, H01C and L02 in the ATC classification

Detailed Description

Hormone replacement therapies and contraceptive pills are responsible of a wide range of cardio-vascular side effects, particularly thrombo-embolic disorders and ischemic heart disease. The difference of incidence and type of cardio-vascular events between men and women are strongly related to sex hormones. Androgenic agonists and antagonists are used in various indication including prostate cancer or hormone replacement therapies. This study investigates the main characteristics of patients affected by cardiovascular side effects (of which ventricular arrhythmia's, QT prolongation and Torsade de Pointe) imputed to drugs classified as G03, H01C and L02 according to ATC. A causality assessment according to both Begaud's method and the World Health Organization-The Uppsala Monitoring Centre (WHO-UMC) is systematically applied.

• Study Type: Observational
• Enrollment (Actual): 3096

Contacts and Locations

Study Locations

• France
  • Ile De France
    • Paris, Ile De France, France, 75013
      • Centre Régional de Pharmaco-vigilance - Paris, Pitié-Salpétrière

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

The population is selected in the French pharmacovigilance database and EudraCT database from 01/01/1985 to 14/04/2017 and included patients treated with hormonal therapies included in the ATC classification references: G03, H01C and L02.

Description

Inclusion Criteria:

• Case reported in the French pharmacovigilance database and EudraCT database from 01/01/1985 to 14/04/2017
• Adverse event reported were including the MedDRA terms: SOC Cardiac Affections and the HLT Death and Sudden Death
• Patients treated with hormonal therapies included in the ATC classification references: G03, H01C and L02

Exclusion Criteria:

• Chronology not compatible between the drug and the toxicity

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification and report of the cardio-vascular toxicity of anti-androgenic therapies (reference G03 in the ATC classification) with a causality assessment using Begaud's and WHO's method.	The research includes the report with MedDRA terms: System Organ Class (SOC) Cardiac Disorders and High Level Term (HLT) Death and Sudden Death. Drugs investigated are hormonal therapies with the reference G03 in the ATC classification	Immediate evaluation
Identification and report of the cardio-vascular toxicity of anti-androgenic therapies (reference H01C in the ATC classification) with a causality assessment using Begaud's and WHO's method.	The research includes the report with MedDRA terms: System Organ Class (SOC) Cardiac Disorders and High Level Term (HLT) Death and Sudden Death. Drugs investigated are hormonal therapies with the reference H01C in the ATC classification	Immediate evaluation
Identification and report of the cardio-vascular toxicity of anti-androgenic therapies (reference L02 in the ATC classification) with a causality assessment using Begaud's and WHO's method.	The research includes the report with MedDRA terms: System Organ Class (SOC) Cardiac Disorders and High Level Term (HLT) Death and Sudden Death. Drugs investigated are hormonal therapies with the reference L02 in the ATC classification	Immediate evaluation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Causality assessment of reported cardiovascular events	Causality assessment of reported cardiovascular events according to the WHO-UMC system	Immediate evaluation
Type of cardiotoxicity depending on the category and type of hormonal therapy	Description of the type of cardiotoxicity depending on the category and type of hormonal therapy	Immediate evaluation
Duration of treatment when the toxicity happens	Description of the duration of treatment when the toxicity happens (role of cumulative dose)	Immediate evaluation
Drug-drug interactions associated with adverse events	Description of the drug-drug interactions associated with adverse events (particularly heart failure, ischemic heart disease and cardiac arrhythmia's)	Immediate evaluation
Pathologies for which the incriminated drugs have been prescribed	Description of the pathologies (cancer, hormonal insufficiency) for which the incriminated drugs have been prescribed	Immediate evaluation
Population of patients having a cardio-vascular adverse event	Description of the population of patients having a cardio-vascular adverse event	Immediate evaluation

Collaborators and Investigators

• Sponsor: Groupe Hospitalier Pitie-Salpetriere

Publications and helpful links

General Publications

• Salem JE, Yang T, Moslehi JJ, Waintraub X, Gandjbakhch E, Bachelot A, Hidden-Lucet F, Hulot JS, Knollmann BC, Lebrun-Vignes B, Funck-Brentano C, Glazer AM, Roden DM. Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSC-Cardiomyocytes. Circulation. 2019 Sep 24;140(13):1070-1080. doi: 10.1161/CIRCULATIONAHA.119.040162. Epub 2019 Aug 5.
• Salem JE, Waintraub X, Courtillot C, Shaffer CM, Gandjbakhch E, Maupain C, Moslehi JJ, Badilini F, Haroche J, Gougis P, Fressart V, Glazer AM, Hidden-Lucet F, Touraine P, Lebrun-Vignes B, Roden DM, Bachelot A, Funck-Brentano C. Hypogonadism as a Reversible Cause of Torsades de Pointes in Men. Circulation. 2018 Jul 3;138(1):110-113. doi: 10.1161/CIRCULATIONAHA.118.034282. No abstract available.
• Barber M, Nguyen LS, Wassermann J, Spano JP, Funck-Brentano C, Salem JE. Cardiac arrhythmia considerations of hormone cancer therapies. Cardiovasc Res. 2019 Apr 15;115(5):878-894. doi: 10.1093/cvr/cvz020.
• Salem JE, Yang T, Moslehi JJ, Waintraub X, Gandjbakhch E, Bachelot A, Hidden-Lucet F, Hulot JS, Knollmann BC, Lebrun-Vignes B, Funck-Brentano C, Glazer AM, Roden DM. Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes. Ann Endocrinol (Paris). 2021 Jun;82(3-4):132-133. doi: 10.1016/j.ando.2020.02.008. Epub 2020 Feb 29.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 7, 2017
• Primary Completion (ACTUAL): June 21, 2017
• Study Completion (ACTUAL): June 21, 2017

Study Registration Dates

• First Submitted: June 12, 2017
• First Submitted That Met QC Criteria: June 16, 2017
• First Posted (ACTUAL): June 20, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 25, 2019
• Last Update Submitted That Met QC Criteria: September 24, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Cardiotoxicity; Testosterone; Androgens; Hormone Replacement Therapy; Androgen Antagonists
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Cardiovascular Diseases; Wounds and Injuries; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Heart Diseases; Cardiotoxicity
• Other Study ID Numbers: CIC1421-17-06

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No