Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure

Study Overview
=================
Brief Summary
-----------------
Despite advances in care, prognosis remains poor once overt Heart Failure (HF) has developed. Prevention is most efficient when directed toward patients at risk and when mechanistically targeted to patients most likely to respond. An increase in myocardial and possibly vascular collagen content (fibrosis) may be a major determinant of the transition to HF. In patients with hypertension and diabetes, two important risk-factors for HF, changes in blood markers of fibrosis occur before clinically overt HF develops. These markers are also related to prognosis. In the general population, Galectin-3 (Gal-3), a potential marker of fibrosis, is associated with cardiovascular (CV) risk factors, and predicts development of HF. In animal models, Gal-3 is a key mediator of aldosterone-induced CV and renal fibrosis and dysfunction. The investigators hypothesize that the mineralocorticoid receptor antagonist (MRA), spironolactone, may prevent HF by acting on extracellular matrix remodelling, especially in patients with active fibrogenesis, identified by high Gal-3 levels. The benefit/risk ratio of spironolactone might be superior in patients with a higher compared to lower plasma concentrations of Gal-3. Main objective is to investigate whether spironolactone can favourably alter extra-cellular matrix remodelling, assessed by changes in the fibrosis biomarker Procollagen Type III N-Terminal Peptide (PIIINP), in patients at increased risk of developing heart failure and whether this effect is greater in patients with increased plasma concentrations of Gal-3.

Detailed Description
-----------------
The investigators hypothesize that the mineralocorticoid receptor antagonist (MRA), spironolactone, may prevent HF by acting on extracellular matrix remodelling, especially in patients with active fibrogenesis, identified by high Gal-3 levels. The benefit/risk ratio of spironolactone might be superior in patients with a higher compared to lower plasma concentrations of Gal-3.

Official Title
-----------------
Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure. A Proof of Concept Clinical Trial Within the EU FP 7 (European Union FP7) HOMAGE Programme  Heart OMics in AGing 

Conditions
-----------------
Heart Failure

Intervention / Treatment
-----------------
* Drug: Spironolacton


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent will be obtained prior to any study procedure; Age >60 years Clinical risk factors for developing heart failure, either: Coronary artery disease (h/o myocardial infarction, angioplasty or coronary artery bypass) Or At least two of the following: Diabetes Mellitus requiring Hypoglycaemic Pharmacotherapy Receiving pharmacological treatment for Hypertension Microalbuminuria Abnormal ECG (left ventricular hypertrophy, QRS >120msec, abnormal Q-waves) Biological risk: NT-pro-BNP values between 125 and 1,000 ng/L or BNP values between 35 and 280 pg/ml (consistent with ESC guidelines indicating risk of HF but helping to rule out prevalent HF or atrial fibrillation which are associated with marked increases in NT-proBNP/BNP and should be investigated) Exclusion Criteria: Recent wound healing/inflammation: Surgical procedure, coronary, cerebral or peripheral vascular events or infection in the prior 3 months Cancer Autoimmune disease Hepatic Disease Pre-existing diagnosis of clinical HF Moderate/severe LV systolic ventricular dysfunction, i.e. LVEF <45% Moderate or severe valve disease (investigators opinion) eGFR< 30ml/min Serum potassium >5.0 mmol/L Treatment with an MRA or a loop diuretic (furosemide, bumetanide, ethacrynic acid or torasemide) in the previous three months Potassium supplements or potassium-sparing diuretic at time of enrolment. Atrial fibrillation within one month prior to inclusion (AF lasting <60 seconds on ambulatory ECG monitoring is permitted) •. History of hypersensitivity to spironolactone. Requiring treatment with prohibited medication according to SmPC with exception of ACE inhibitors or angiotensin receptor blockers Patients unable to give written informed consent. Participation in another interventional trial in the preceding month Ability to walk is, in the investigators opinion, clearly limited by joint disease or other locomotor problems rather than by cardiorespiratory fitness

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Spironolacton Group<br>Spironolacton Sandoz given 25mg daily oral use | Drug: Spironolacton<br>* Administration of Spironolacton 25 mg per day<br>* Other names: Spironolacton Sandoz;|
| No Intervention: Control group<br>Only background treatment | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in serum concentrations of PIIINP | mmol/l | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in serum plasma levels of Biomarkers | PICP (synthesis), ICTP (degradation) and GAL3 | 9 months | 
| Cardiac remodelling 1 | NT-proBNP (ELISA, central Lab), from baseline to 9 months (Certified centers and central readings). | 9 months | 
| Cardiac remodelling 2 | Left Ventricular Mass (g/m) | 9 months | 
| Cardiac remodelling 3 | Left Atrial Volume (ml) | 9 months | 
| Cardiorespiratory performance during exercise | Shuttle walk test: Distance walked in meters | baseline, 9 months | 
| Vascular function | non-invasive technologies: BP lab Audicor system | screening, baseline, month1, month3, month 6, month 9 | 
| heart failure or AF | Rate of the clinical composite of development of heart failure or atrial fibrillation, non-fatal myocardial infarction or stroke or CV death from baseline to 9 months. The HOMAGE blinded clinical event committee will adjudicate all serious adverse events. | 9 months | 
| Adverse events | All adverse events | screening, baseline, month1, month3, month 6, month 9 | 
| Worsening renal function | decline in eGFR >20% | screening, baseline, month1, month3, month 6, month 9 | 
| Hyperkalemia | rise of serum potassium to >5.5 mmol/L | screening, baseline, month1, month3, month 6, month 9 |