Short summary

The development and maintenance of atrial fibrillation (AF) is highly complex. Several clinical trials point to an important association between the activation of the renin-angiotensin II- aldosterone system (RAAS) and AF. Of the RAAS components, especially aldosterone induces cellular hypertrophy, fibroblast proliferation and tissue fibrosis. Atrial fibrosis leads to disruption of the electrical side-to-side junctions between muscle bundles and has potentially arrhythmogenic mechanisms. Recent research suggests that upstream therapy with an aldosterone antagonist can diminish the potentially harmful effects of aldosterone, preventing occurrence and maintenance of AF through its antifibrotic properties.

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Rationale

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia present in 1% of population under 60 years of age and reaching up to 15 % at 80 years. Due to demographic changes in the Danish population, the incidence and prevalence of AF is expected to double within the next 30 years. AF increases mortality and causes important morbidity, mainly due to thromboembolic complications and increases health economic costs. Additionally, AF is associated with reduced quality of life.

The onset and maintenance of AF is highly complex and the most frequent pathoanatomic changes in AF are diffuse myocardial fibrosis (DMF). In recent years, experimental and clinical studies have demonstrated that particularly atrial remodelling and dilation in AF depending on cellular hypertrophy, fibroblast proliferation and tissue fibrosis. DMF leads to disruption of the electrical side-to-side junctions between muscle bundles and has potentially arrhythmogenic mechanisms.  The association of diffuse myocardial fibrosis and AF has been the subject of intense recent investigation, and it is now widely accepted that interstitial fibrosis creates a substrate for arrhythmia. It is believed that when myocardial fibre bundles are separated by connective tissue, the conduction properties are altered because of the effects on axial resistance, leading to arrhythmia. Myocardial fibrosis is preceded by a growing activity of extracellular matrix (ECM), pro-inflammatory cytokines and at the same time more pronounced collagen (type I and III) expression. Histological studies in patients with both AF and sick sinus syndrome have shown extensive fibrosis of the atrial muscle in the sinus node and internodal tracts. These results suggest that myocardial interstitial fibrosis plays a crucial role in AF.

Recent research suggests that many of the structural and electrophysiological changes that lead to AF can be attenuated or reversed through treatment targeting RAAS. Previous studies showed that inhibition of RAAS in patients with heart failure with angiotensin converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB) or mineralocorticoid receptor antagonist (MRA) reduce mortality and number of hospitalisations and lower the incident of AF, but data on the effect on the incidence of AF in patients without systolic heart failure are still limited.

The present study is designed to test the hypothesis that add-on therapy with a daily low dose of a mineralocorticoid receptor antagonist, in this case spironolactone, will reduce diffuse myocardial fibrosis and remodeling in the left atrium and left ventricle, improve left atrial function thus prevent recurrent episodes of AF and decrease inflammatory and neurohumoral biomarkers as compared with conventional treatment in patients with symptomatic recurrent episodes of paroxysmal or persistent atrial fibrillation.

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Description of the cohort

This study is designed as a prospective, randomized, parallel-group, double-blind, placebo-controlled, single center study at OUH Svendborg Hospital.

The study population will consist of patients with 1 episodes or more of paroxysmal or persistant AF detected on either 12-lead ECG or Holter monitoring within the last 12 months prior to the enrollment in to the study, preserved left ventricular ejection fraction (LVEF) above 40 %, with or without hypertension, symptomatic recurrence of AF estimated by European Heart Rhythm Association (EHRA) score above or equal to II, no intolerance or contraindication to spironolactone and age 18 years or older. 

Major inclusion criteria:

• Patients 18 years of age or older, male or female.
• Paroxysmal or persistent AF on one or more occasions, detected on 12-lead ECG or Holter monitoring with each AF-episode lasting 30 seconds or more, within the last 12 months prior to the screening visit.
• Symptomatic episodes of AF estimated by EHRA class II-IV.
• Written informed consent signed before any study-specific procedure. 

Major exclusion criteria:

• Chronic AF.
• Radiofrequency ablation of AF prior to the screening visit or previous surgical treatment of AF.
• Heart failure (New York Heart Association (NYHA) class above or equal to II and/or LVEF less than 40%).
• Severe coronary artery disease (acute myocardial infarction within 6 months prior to the screening visit, previous coronary artery bypass graft (CABG) or stabile angina pectoris (Canadian Cardiovascular Society (CCS) class above or equal to II).
• Stroke or transient ischemic cerebral attack within 6 months prior to the screening visit.
• Pregnant women or women of childbearing potential not on adequate birth control. Only women with a highly effective method of contraception (oral contraception, intra-uterine device or sterile women) can be randomized.
• Severe valve disease.
• Any disease that limits life expectancy to less than 1 year.
• Participation in another clinical trial, either within the last 30 days or ongoing.
• Breastfeeding women.
• Ongoing therapy with class IC antiarrhythmics (flecainide, propafenone), amiodarone, dronedarone or sotalol.
• Chronic kidney disease (estimated glomerular filtration rate (eGFR) lower or equal to 45 ml/min/1,73m² (MDRD)).
• Intolerance or contradictions to spironolactone, i.e. latest product information on Spirix®.
• Intolerance or contradictions to dabigatran (Pradaxa®) i.e. latest product information.
• Patients who are noncompliant with.
• AF associated with an acute reversible condition, i.e. heart surgery, untreated hyperthyroidism etc.
• Geographic and social factors making follow-up difficult.

Data and biological material

Patients will be randomized to an intervention group (aldo group) or a control group (usual care). In the aldo group, patients will receive spironolactone at a fixed dose of 25 mg per day, while the control group will receive placebo. Both the aldo and control groups will be treated with the study medicine throughout 12 months and additionally follow the same therapeutic recommendations according to the Danish Society of Cardiology guidelines on treatment of AF.

Comprehensive transthoracic echocardiography, 12-lead ECG, biomarkers and Holter monitoring will be performed at the time of randomization and at 6 and 12 months, respectively. Blood samples and ECG will be collected one week after the onset of treatment, and subsequently at 1, 2, 3, 6, 9 and 12 months. During this period of 12 months, all patients will be followed for recurrence of symptomatic AF. Any relapse of symptomatic arrhythmia should be documented, if possible by 12-lead ECG or Holter monitoring.  Only documented AF-recurrence by 12-lead ECG or Holter monitoring will be taken into account. 

Collaborating researchers and departments

Internal Medicine & Emergency Department, OUH Svendborg Hospital

• PhD-student Dragana Rujic, MD
• Professor and Consultant Kenneth Egstrup, DMSc, FESC

Department of Cardiology, Copenhagen University Hospital

• Consultant Per Lav Madsen, MD, DMsc

Takeda Pharma A/S, Denmark

• Medical Advisor Palle Dahl

Siemens A/S, Denmark

• Henrik Jessen

Department of Clinical Biochemistry , OUH Svendborg Hospital

• Consultant Steen Antonsen, MD 
• Medical Laboratory Technician Leif Pennerup

Department of Clinical Biochemistry and Pharmacology, the GCP-unit, Odense University Hospital

• Unit manager and GCP-coordinator Charlotte Calov
• GCP-coordinator Tanja Busk Bidstrup

Department of Radiology, OUH Svendborg Hospital

• Consultant Inger Andersen, MD
• Radiographer Tina Juul Hansen