Effect of Antifibrotic Therapy on Regression of Myocardial Fibrosis After Transcatheter Aortic Valve Implantation (TAVI) in Aortic Stenosis Patients With High Fibrotic Burden (Reduce-MFA)

The aim of the study is to evaluate the effect of antifibrotic therapy on regression of myocardial fibrosis after TAVI in patients with baseline high fibrotic burden. Therefore, patients will be treated with Spironolactone in addition to standard of care, Spioronolactone + Dihydralazine in addition to standard of care or according to standard of care alone without any study medication. First, differences between patients in the control arm and patients randomized to anti-fibrotic therapy will be analyzed. The second analysis will determine, whether dihydralazine medication in addition to spironolactone is able to increase a potential antifibrotic effect. Myocardial fibrosis will be assessed by cardiac magnetic resonance imaging (CMR) before TAVI and 1 year after. Quantification of potentially irreversible replacement fibrosis will be carried out by late gadolinium enhancement (LGE), and quantification of the potentially reversible diffuse interstitial fibrosis will be performed by measurement of the extracellular volume fraction (ECV), thereby deriving matrix volume and cell volume.

Study Overview

• Status: Recruiting
• Conditions: Aortic Stenosis, Severe
• Intervention / Treatment: Other: Standard of Care; Drug: Spironolactone 25mg; Drug: Dihydralazine

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Miriam Puls, Prof.; Phone Number: +49 551 3910958; Email: dr.m.puls@med.uni-goettingen.de
• Study Contact Backup: Name: Florian Walker, Dr.; Phone Number: +49 551 3960825; Email: florian.walker@med.uni-goettingen.de

Study Locations

• Germany
  • Lower Saxony
    • Göttingen, Lower Saxony, Germany, 37075
      • Recruiting
      • University Medical Center Göttingen
      • Contact: Miriam Puls, Prof. Dr.; Email: dr.m.puls@med.uni-goettingen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male, female age ≥ 60
• Diagnosis of severe symptomatic aortic stenosis
• Transcatheter aortic valve implantation (TAVI) scheduled
• Written informed consent

Exclusion Criteria:

• 1. Pre-existing dilative or ischemic heart disease with EF<35% and guideline indication for spironolactone
• Patient on current medication with spironolactone, eplerenone, or dihydralazine
• Presence of coexistent myocardial pathology such as cardiac amyloidosis, hypertrophic cardiomyopathy, or myocarditis
• Presence of coexistent severe aortic regurgitation or severe mitral stenosis
• Previous surgical valve replacement or repair
• Pacemaker or ICD implanted
• Renal impairment (serum creatinine > 1,8 mg/dl and/ or GFR < 30 ml/min/1,73 m² BSA)
• Significant hypotension (blood pressure < 90 mm Hg systolic and/or < 50 mm Hg diastolic
• Serum potassium > 5,1 mmol/l
• Contraindications for Spironolactone (anuria, acute renal failure, serum creatinine > 1.8 mg/dl, hyperkalemia, pregnancy)
• Contraindications for Dihydralazine (known allergy or hypersensitivity, systemic lupus erythematodes, adrenocortical disorders)
• Known active malignant disease with life expectancy < 1 year
• Women with child-bearing potential
• Simultaneous participation (including a waiting period of 4 weeks) in other interventional clinical trials
• Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial
• Person who is in a relationship of dependence/employment with the sponsor or the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: Control group; Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care	Other: Standard of Care; Patients with CMR-derived ECV% levels ≥25.9% will be treated with standard of care according to current guidelines (Control group).
EXPERIMENTAL: Spironolactone; Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.)	Other: Standard of Care; Patients with CMR-derived ECV% levels ≥25.9% will be treated with standard of care according to current guidelines (Control group).; Drug: Spironolactone 25mg; Patients with CMR-derived ECV% levels ≥25.9% in Arm "Spironolactone" will receive spironolactone 25 mg/d in addition to standard of care medication .
EXPERIMENTAL: Spironolactone + Dihydralazine; Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.) + Dihydralazine (2x12.5 mg/d p.o. in slow acethylators, and 2x25mg / d p.o. in fast acethylators, confirmed by genetic testing)	Other: Standard of Care; Patients with CMR-derived ECV% levels ≥25.9% will be treated with standard of care according to current guidelines (Control group).; Drug: Spironolactone 25mg; Patients with CMR-derived ECV% levels ≥25.9% in Arm "Spironolactone" will receive spironolactone 25 mg/d in addition to standard of care medication .; Drug: Dihydralazine; Patients with CMR-derived ECV% levels ≥25.9% in arm "Spironolactone + Dihydralazine" will receive spironolactone 25 mg/d + dihydralazine (2x12.5 mg/d p.o. in slow acethylators, and 2x25mg/d p.o. in fast acethylators, confirmed by genetic testing)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Extracellular volume (ECV)-derived matrix volume (measured by CMR)	Differences between treatment groups in reduction of extracellular volume (ECV)- derived matrix volume (measured by CMR) after 12 months	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular ejection fraction	Differences in recovery of left ventricular ejection fraction (EF) in % (measured by CMR) after 12 months	12 months
Global longitudinal strain	Differences in recovery of global longitudinal strain (GLS) in % (measured by CMR) after 12 months	12 months
diastolic function	Differences in recovery of diastolic function (measured by CMR) after 12 months	12 months
Left ventricular myocardial tissue volumes	Differences in reduction of left ventricular myocardial tissue volumes (measured by CMR) after 12 months	12 months
Left ventricular blood volumes	Differences in reduction of left ventricular blood volumes (measured by CMR) after 12 months	12 months
Kansas City Cardiomyopathy Questionnaire	Differences in quality of life changes according to 23-items Kansas City Cardiomyopathy Questionnaire (KCCQ) after 12 months	12 months
NYHA status	Differences in NYHA status after 12 months	12 months
6min-walking test distance (6MWT)	Differences in 6min-walking test distance (6MWT; in m) after 12 months	12 months
NT-proBNP-levels	Differences in NT-proBNP-levels (in pg/ml) after 12 months	12 months
Heart failure hospitalizations	Rate of Heart failure hospitalizations within 12 months	12 months
Total mortality	Rate of total mortality within 12 months	12 months
Cardiovascular mortality	Rate of Cardiovascular mortality within 12 months	12 months
Biomarker Procollagen type I carboxy-terminal propeptide (PICP)	Measurement of PICP in ng/ml	12 months
Biomarker Procollagen III N-terminal propeptid (PIIINP)	Measurement of PIIINP in ng/ml	12 months
Ratio of Increased collagen degradation (CITP) vs. matrix metalloproteinase-1 (MMP-1)	Measurement of CITP (in ng/l) and MMP-1 (in ng/ml)	12 months
Methylation of Iroquois Homeobox 3 (IRX3)	Measurement of Methylation of IRX3 in %	12 months
Methylation of rfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 3 (ACAP3)	Measurement of Methylation of ACAP3 in %	12 months
Methylation of Growth Arrest And DNA Damage Inducible Gamma (GADD45G)	Measurement of Methylation of GADD45G in %	12 months
Methylation of Chordin (CHRD)	Measurement of Methylation of CHRD in %	12 months
Methylation of Klotho	Measurement of Methylation of Klotho in %	12 months
Methylation of RAS Protein Activator Like 1 (RASAL1)	Measurement of Methylation of RASAL1 in %	12 months
Methylation of ATPase Sarcoplasmic/Endoplasmic Reticulum Ca2+ Transporting 2 (ATP2A2)	Measurement of Methylation of ATP2A2 in %	12 months
Methylation of B9 Domain Containing 1 (B9D1)	Measurement of Methylation of B9D1 in %	12 months
Methylation of Bone Morphogenetic Protein 7 (BMP7)	Measurement of Methylation of BMP7 in %	12 months
Methylation of Latency associated peptide (LAP)	Measurement of Methylation of LAP in %	12 months
Serum creatinine	Change in serum creatinine (in mg/dl) after 12 months	12 months
Cystatin c	Change in cystatin c (in mg/l) after 12 months	12 months
Phosphate	Change in phosphate (in mmol/l) after 12 months	12 months

Collaborators and Investigators

• Sponsor: University Medical Center Goettingen

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 23, 2022
• Primary Completion (ANTICIPATED): June 1, 2025
• Study Completion (ANTICIPATED): March 1, 2026

Study Registration Dates

• First Submitted: January 12, 2022
• First Submitted That Met QC Criteria: January 27, 2022
• First Posted (ACTUAL): February 9, 2022

Study Record Updates

• Last Update Posted (ACTUAL): June 28, 2022
• Last Update Submitted That Met QC Criteria: June 27, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis; Constriction, Pathologic; Physiological Effects of Drugs; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone; Dihydralazine
• Other Study ID Numbers: 02717

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No