Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure
- Conditions
- Heart Failure
- Interventions
- Drug: Spironolacton
- Registration Number
- NCT02556450
- Lead Sponsor
- ACS Biomarker
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 528
-
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)
-
Recent wound healing/inflammation:
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Surgical procedure, coronary, cerebral or peripheral vascular events or infection in the prior 3 months
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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.
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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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Spironolacton Group Spironolacton Spironolacton Sandoz given 25mg daily oral use
- Primary Outcome Measures
Name Time Method Changes in serum concentrations of PIIINP 9 months mmol/l
- Secondary Outcome Measures
Name Time Method changes in serum plasma levels of Biomarkers 9 months PICP (synthesis), ICTP (degradation) and GAL3
Cardiac remodelling 1 9 months NT-proBNP (ELISA, central Lab), from baseline to 9 months (Certified centers and central readings).
Cardiac remodelling 3 9 months Left Atrial Volume (ml)
Adverse events screening, baseline, month1, month3, month 6, month 9 All adverse events
Cardiorespiratory performance during exercise baseline, 9 months Shuttle walk test: Distance walked in meters
Vascular function screening, baseline, month1, month3, month 6, month 9 non-invasive technologies: BP lab Audicor system
Cardiac remodelling 2 9 months Left Ventricular Mass (g/m)
heart failure or AF 9 months 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.
Worsening renal function screening, baseline, month1, month3, month 6, month 9 decline in eGFR \>20%
Hyperkalemia screening, baseline, month1, month3, month 6, month 9 rise of serum potassium to \>5.5 mmol/L
Trial Locations
- Locations (9)
Charite Universitatsmedizin Berlin, Kardiologie
🇩🇪Berlin, Germany
Hopital Sud Francilien
🇫🇷Corbeil-Essonnes, France
CHU de Nancy
🇫🇷Nancy, France
Santa Margherita Hospital
🇮🇹Cortona, Italy
Queen Elizabeth University Hospital
🇬🇧Glasgow, United Kingdom
Maastricht University Medical Center
🇳🇱Maastricht, Netherlands
St, Michaels Hospital
🇮🇪Dublin, Ireland
Central Manchester University Hospitals NHS
🇬🇧Manchester, United Kingdom
Castle Hill Hospital
🇬🇧Hull, United Kingdom