Blockade of the Renin-angiotensin-aldosterone System in Patients With ARVD

Official title

Blockade of the Renin-angiotensin-aldosterone System in Patients With ARVD: a Double-blind Multicentre Prospective Randomized Study.

Overview

Arrhythmogenic right ventricular dysplasia (ARVD) is a rare cardiomyopathy characterized by the progressive replacement of cardiomyocytes by fatty and fibrous tissue in the right ventricle (RV). These infiltrations lead to cardiac electrical instability and ventricular arrhythmia. Current treatment for ARVD is empirical and essentially based on treatment of arrhythmia. Thus, there is no validated treatment that will prevent the deterioration of the RV function in patients with ARVD. The investigator's hypothesis is that the use of anti-fibrotic medications will prevent or at least reduce the deterioration of the RV function. The aim of this project is to evaluate the effect of spironolactone, a Potassium-sparing diuretic on ventricular myocardial remodeling and on arrhythmia burden in patients with ARVD. The trial is a double-blind parallel multicenter prospective randomized phase II drug study. Patients will be randomized in the two groups: spironolactone or placebo. 13 centers in France will enroll the 120 patients (60 per group). Patients will be followed for 3 years (6 months, 1 year and 3 years) with all examinations (ECG, HA ECG, 24-hour Holter, trans-thoraciqc echocardiography (TTE), biological analyses) according to standard of care. A decrease in right and/or left ventricular deterioration and in arrhythmia burden are expected in ARVD patients treated with spironolactone. This reduction will improve the quality of life of patients and will reduce the number of hospitalizations and the risk of terminal heart failure.

Interventions

• Drug Spironolactone
  The doses used in the study are the doses used in standard clinical practice. Initial dose is 25 mg/day until study end . The duration of treatment for each patient is 12 months.
• Drug Placebo
  Placebo will be taken once a day at the same time of day. The duration of treatment for each patient is 12 months.

Primary outcome measures

• Right ventricle longitudinal strain measured by echocardiography [Time frame: at year 1]
• Right ventricle infundibulum diameter measured by echocardiography [Time frame: at year 1]
• number of ventricular extrasystoles > 500 on 24h-Holter ECG [Time frame: at year 1]

Secondary outcome measures (12)

• number of ventricular extrasystoles on 24h-Holter ECG [Time frame: at year 1]
• number of palpitations [Time frame: at year 1]
• number of palpitations [Time frame: at year 3]
• number of ventricular tachycardia [Time frame: at year 1]
• number of ventricular tachycardia [Time frame: at year 3]
• number of dyspnea [Time frame: at year 1]
• number of dyspnea [Time frame: at year 3]
• number of syncope [Time frame: at year 1]
• number of syncope [Time frame: at year 3]
• number of sudden death [Time frame: at year 1]
• number of sudden death [Time frame: at year 3]
• number of thoracic pain [Time frame: at year 1]

Eligibility criteria

Inclusion criteria

• >18years old
• Diagnosis of ARVD based on Task Force criteria. Two major criteria: 1 morphologic and one rhythmic or 1 major and 2 minor criteria established by the European Society of Cardiology/International Society and Federation of Cardiology.
• Left Ventricular Ejection Fraction >40%
• Written informed consent.

Exclusion criteria

• Patients under judicial protection.
• Female patient who is pregnant or lactating, or is of child bearing potential (defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤ 55 years or 12 months if > 55 years) and who did not agree to use highly effective methods of birth control throughout the study.
• No health insurance.
• Right heart failure patient (RV volume>150ml).
• Spironolactone contraindication: anuria, hyperkalemia (K+>5 mmol/l), renal failure (DFGCréat>22 mL/min/1,73 m2), end-stage liver failure, Addison's Disease, hypersensitivity to spironolactone or to any of the excipients (patients with galactose intolerance, lapp lactase deficiency or glucose or galactose malabsorption syndrome), association with eplerenone, association with other hyperkalemic diuretics, association with potassium salts, not recommended in cirrhotic patients (natraemia<125 mmol/l) or in patients likely to present an acidosis.
• Mandatory indication for a combination of ACE inhibitor and sartan or renin inhibitor (each authorized separately).
• Acute phase of systemic disease.
• Uncompensated hypothyroidism.
• Acute hyperthyroidism.
• Normal right ventricular volume.
• Heart transplantation.
• Swallowing disorders.
• Participation in any other interventional clinical investigation that may have an impact on our study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 13 centers

• CHU Amiens Picardie — Amiens
• Hôpital Cardiologique Louis Pradel — Bron
• Hôpital Gabriel Montpied — Clermont-Ferrand
• CHU Dijon — Dijon
• Hôpital Michallon — Grenoble
• Hôpital de la Timone — Marseille
• Hôpital Arnaud de Villeneuve — Montpellier
• Hôpital Laennec — Nantes
• … and 5 more centers

Publications

• Alexandrino FB, Faaborg-Andersen CC, daSilva-deAbreu A. Anticoagulation in patients with atrial fibrillation and heart failure: More than meets the eye? Int J Cardiol. 2024 Feb 15;397:131591. doi: 10.1016/j.ijcard.2023.131591. Epub 2023 Nov 17. No abstract available. PMID 37979797

Identifiers

NCT: NCT03593317 · 69HCL18_0038 · 2023-505048-20-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗