Clinical Trial: Inhibition of Aldosterone to Reduce Myocardial Diffuse Fibrosis in Patients With Paroxysmal and Persistent Atrial Fibrillation in Preventing Recurrent Episodes of Atrial Fibrillation

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: Phase 3, Prospective, Randomized, Double-blinded, Placebo-controlled Study to Evaluate Efficacy of add-on Therapy With Spironolactone to Reduce Diffuse Myocardial Fibrosis Thus Preventing Recurrent Ep

Brief Summary: A randomized, double-blinded, placebo-controlled study to evaluate the effect of spironolactone in addition to conventional treatment compared with placebo in patients with paroxysmal and persistent atrial fibrillation with preserved left ventricular ejection fraction by T1 mapping, structure and function of left atrium and ventricle assessed by transthoracic echocardiography and cardiac magnetic resonance (CMR), the number of recurrent episodes of atrial fibrillation and biomarkers measured in blood.

Detailed Summary:

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. Furthermore a number of diseases which are associated with a higher prevalence of AF such as ischemic heart disease, valvular heart disease, diabetes mellitus and hypertension are also expected to increase in prevalence due to the aging population which will contribute to an increased incidence of AF. 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 atrial fibrosis. In recent years, experimental and clinical studies have demonstrated that atrial remodelling and dilation in AF depending on 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. The association of atrial 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 atrial 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
Sponsor: Svendborg Hospital

Current Primary Outcome:

• Determine change (∆) in diffuse myocardial fibrosis between groups, assessed by cardiovascular magnetic resonance (CMR) T1 mapping. [ Time Frame: Change from baseline at 12 months ]
  The study aims to non-invasively quantify extracellular volume fraction (ECV) in left atrium and ventricle as surrogate marker of diffuse myocardial fibrosis. T1 relaxation times (T1 values) will be obtained from T1 mapping. T1 values are given in [ms]. Extracellular volume fraction (ECV) will be calculated using pre-contrast and post-contrast T1 values for myocardium and blood pool (using hematocrit) using following formula: ECV = (√T1 "myocardium post-contrast" - 1 / T1 "myocardium pre-contrast") (1 / T1 "blood post-contrast" - 1 / T1 "blood pre-contrast") x (1- hematocrit). ECV is given in percentage.
• Determine difference (α) in myocardial stiffness between groups, assessed by strain analysis. [ Time Frame: At time of randomization, 6 and 12 months ]
  The study aims to characterize longitudinal changes in imaging characteristics.Strain is a dimensionless quantity and is produced by application of stress. It represents the fractional or percentage change from the original or unstressed dimension and includes both lengthening, or expansion (positive strains) and shortening, or compression (negative strains). Strain rate is the temporal derivative of strain and is a measure of the rate of deformation, with units of [1/s]. The strain rate is also equivalent to the shortening velocity per fiber length.
• Determine difference (β) in left atrial phasic function between groups, assessed by transthoracic echocardiography. [ Time Frame: At time
  
  

  Original Primary Outcome: Same as current
  
  

  Current Secondary Outcome:

  • Arrhythmic composite endpoint. [ Time Frame: 12 months from randomization ]
    Burden of atrial fibrillation, where recurrent episodes of atrial fibrillation are documented with 12-lead ECG recordings and serial Holter monitoring. AF burden assessed as cumulative AF burden, registered on 12-lead ECG recordings and serial 48-hour Holter monitoring, where a recurrent episode of AF is defined as AF ≥ 30 seconds of duration. AF burden will also include the total duration of AF, recorded on Holter monitoring.
  • Life quality, assessed by SF-12. [ Time Frame: At time of randomization and 12 months ]
  • Determine level of collagen turnover between groups, measured in blood. [ Time Frame: At time of randomization, 6 and 12 months ]

    The aims of the study are:

    • To investigate whether or not the burden of diffuse myocardial fibrosis (T1 mapping) is associated with biomarkers measured in blood.
    • To investigate whether or not left atrial volume and function is associated with biomarkers measured in blood.

    Additional biomarkers may be included as the research in those fields progresses during the conduct of this clinical trial.

  • Adverse events [ Time Frame: 15 months from randomization ]
    Adverse events (AE's) and serious adverse events (SAE's) of special interest that is hyperkalemia (serum potassium ≥ 5,5 mmol/l and serum potassium ≥ 6 mmol/l), worsening renal function (WRF) defined as a 30 % reduction in estimated glomerular filtration rate (eGFR) from baseline and gynecomastia ( Common Terminology Criteria for Adverse Events version 5.0, grade ≥ 1).
  
  
  

  Original Secondary Outcome: Same as current
  
  Information By: Svendborg Hospital
  

  Dates:
  Date Received: March 27, 2016
  Date Started: December 2013
  Date Completion: April 2017
  Last Updated: May 16, 2016
  Last Verified: May 2016