Clinical trial NCT05230901: Effect of Antifibrotic Therapy on Regression of Myocardial Fibrosis After Transcatheter Aortic Valve Implantation (TAVI) in Aortic Stenosis Patients With High Fibrotic Burden
Official title: Effect of Antifibrotic Therapy on Regression of Myocardial Fibrosis After Transcatheter Aortic Valve Implantation (TAVI) in Aortic Stenosis Patients With High Fibrotic Burden
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Aortic Stenosis, Severe
Lead sponsor: University Medical Center Goettingen
Sponsor class: OTHER
First posted: 2022-02-09
Enrollment: 300
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Extracellular volume (ECV)-derived matrix volume (measured by CMR)
timeFrame: 12 months
Secondary outcomes:
measure: Left ventricular ejection fraction
timeFrame: 12 months
measure: Global longitudinal strain
timeFrame: 12 months
measure: diastolic function
timeFrame: 12 months
measure: Left ventricular myocardial tissue volumes
timeFrame: 12 months
measure: Left ventricular blood volumes
timeFrame: 12 months
measure: Kansas City Cardiomyopathy Questionnaire
timeFrame: 12 months
measure: NYHA status
timeFrame: 12 months
measure: 6min-walking test distance (6MWT)
timeFrame: 12 months
measure: NT-proBNP-levels
timeFrame: 12 months
measure: Heart failure hospitalizations
timeFrame: 12 months
measure: Total mortality
timeFrame: 12 months
measure: Cardiovascular mortality
timeFrame: 12 months
measure: Biomarker Procollagen type I carboxy-terminal propeptide (PICP)
timeFrame: 12 months
measure: Biomarker Procollagen III N-terminal propeptid (PIIINP)
timeFrame: 12 months
measure: Ratio of Increased collagen degradation (CITP) vs. matrix metalloproteinase-1 (MMP-1)
timeFrame: 12 months
measure: Methylation of Iroquois Homeobox 3 (IRX3)
timeFrame: 12 months
measure: Methylation of rfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 3 (ACAP3)
timeFrame: 12 months
measure: Methylation of Growth Arrest And DNA Damage Inducible Gamma (GADD45G)
timeFrame: 12 months
measure: Methylation of Chordin (CHRD)
timeFrame: 12 months
measure: Methylation of Klotho
timeFrame: 12 months
measure: Methylation of RAS Protein Activator Like 1 (RASAL1)
timeFrame: 12 months
measure: Methylation of ATPase Sarcoplasmic/Endoplasmic Reticulum Ca2+ Transporting 2 (ATP2A2)
timeFrame: 12 months
measure: Methylation of B9 Domain Containing 1 (B9D1)
timeFrame: 12 months
measure: Methylation of Bone Morphogenetic Protein 7 (BMP7)
timeFrame: 12 months
measure: Methylation of Latency associated peptide (LAP)
timeFrame: 12 months
measure: Serum creatinine
timeFrame: 12 months
measure: Cystatin c
timeFrame: 12 months
measure: Phosphate
timeFrame: 12 months
Other outcomes:
Locations:
city: Göttingen
country: Germany
facility: University Medical Center Göttingen
state: Lower Saxony
Study officials:
References: