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

University Medical Center Goettingen300 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

300

Conditions

Aortic Stenosis, Severe

Interventions

Eligibility

Sex: ALLMin age: 60 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

Time frame: 12 months

Secondary Outcomes

Left ventricular ejection fraction

Differences in recovery of left ventricular ejection fraction (EF) in % (measured by CMR) after 12 months

Time frame: 12 months

Global longitudinal strain

Differences in recovery of global longitudinal strain (GLS) in % (measured by CMR) after 12 months

Time frame: 12 months

diastolic function

Differences in recovery of diastolic function (measured by CMR) after 12 months

Time frame: 12 months

Left ventricular myocardial tissue volumes

Differences in reduction of left ventricular myocardial tissue volumes (measured by CMR) after 12 months

Time frame: 12 months

Left ventricular blood volumes

Differences in reduction of left ventricular blood volumes (measured by CMR) after 12 months

Time frame: 12 months

Kansas City Cardiomyopathy Questionnaire

Differences in quality of life changes according to 23-items Kansas City Cardiomyopathy Questionnaire (KCCQ) after 12 months

Time frame: 12 months

NYHA status

Differences in NYHA status after 12 months

Time frame: 12 months

6min-walking test distance (6MWT)

Differences in 6min-walking test distance (6MWT; in m) after 12 months

Time frame: 12 months

NT-proBNP-levels

Differences in NT-proBNP-levels (in pg/ml) after 12 months

Time frame: 12 months

Heart failure hospitalizations

Rate of Heart failure hospitalizations within 12 months

Time frame: 12 months

Total mortality

Rate of total mortality within 12 months

Time frame: 12 months

Cardiovascular mortality

Rate of Cardiovascular mortality within 12 months

Time frame: 12 months

Biomarker Procollagen type I carboxy-terminal propeptide (PICP)

Measurement of PICP in ng/ml

Time frame: 12 months

Biomarker Procollagen III N-terminal propeptid (PIIINP)

Measurement of PIIINP in ng/ml

Time frame: 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)

Time frame: 12 months

Methylation of Iroquois Homeobox 3 (IRX3)

Measurement of Methylation of IRX3 in %

Time frame: 12 months

Methylation of rfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 3 (ACAP3)

Measurement of Methylation of ACAP3 in %

Time frame: 12 months

Methylation of Growth Arrest And DNA Damage Inducible Gamma (GADD45G)

Measurement of Methylation of GADD45G in %

Time frame: 12 months

Methylation of Chordin (CHRD)

Measurement of Methylation of CHRD in %

Time frame: 12 months

Methylation of Klotho

Measurement of Methylation of Klotho in %

Time frame: 12 months

Methylation of RAS Protein Activator Like 1 (RASAL1)

Measurement of Methylation of RASAL1 in %

Time frame: 12 months

Methylation of ATPase Sarcoplasmic/Endoplasmic Reticulum Ca2+ Transporting 2 (ATP2A2)

Measurement of Methylation of ATP2A2 in %

Time frame: 12 months

Methylation of B9 Domain Containing 1 (B9D1)

Measurement of Methylation of B9D1 in %

Time frame: 12 months

Methylation of Bone Morphogenetic Protein 7 (BMP7)

Measurement of Methylation of BMP7 in %

Time frame: 12 months

Methylation of Latency associated peptide (LAP)

Measurement of Methylation of LAP in %

Time frame: 12 months

Serum creatinine

Change in serum creatinine (in mg/dl) after 12 months

Time frame: 12 months

Cystatin c

Change in cystatin c (in mg/l) after 12 months

Time frame: 12 months

Phosphate

Change in phosphate (in mmol/l) after 12 months

Time frame: 12 months

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts