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)

University Medical Center Goettingen

Status and phase: Enrolling; Phase 3

Conditions: Aortic Stenosis, Severe

Treatments: Drug: Dihydralazine; Drug: Spironolactone 25mg; Other: Standard of Care

Study type: Interventional

Funder types: Other

Identifiers

NCT05230901

02717

Details and patient eligibility

About

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.

Enrollment: 300 estimated patients

Sex: All

Ages: 60+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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300 participants in 3 patient groups

Control group

Other group

Description:

Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care

Treatment:

Other: Standard of Care

Spironolactone

Experimental group

Description:

Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.)

Treatment:

Other: Standard of Care

Drug: Spironolactone 25mg

Spironolactone + Dihydralazine

Experimental group

Description:

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)

Treatment:

Other: Standard of Care

Drug: Spironolactone 25mg

Drug: Dihydralazine