Effect of Antifibrotic Therapy on Regression of Myocardial Fibrosis After Transcatheter Aortic Valve Implantation (TAVI) in Aortic Stenosis Patients With High Fibrotic Burden
- Conditions
- Aortic Stenosis, Severe
- Interventions
- Registration Number
- NCT05230901
- Lead Sponsor
- University Medical Center Goettingen
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 300
- Male, female age ≥ 60
- Diagnosis of severe symptomatic aortic stenosis
- Transcatheter aortic valve implantation (TAVI) scheduled
- Written informed consent
-
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control group Standard of Care Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care Spironolactone Standard of Care Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.) Spironolactone + Dihydralazine Standard of Care 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) Spironolactone + Dihydralazine Spironolactone 25mg 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) Spironolactone Spironolactone 25mg Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.) Spironolactone + Dihydralazine 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)
- Primary Outcome Measures
Name Time Method Extracellular volume (ECV)-derived matrix volume (measured by CMR) 12 months Differences between treatment groups in reduction of extracellular volume (ECV)- derived matrix volume (measured by CMR) after 12 months
- Secondary Outcome Measures
Name Time Method Methylation of rfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 3 (ACAP3) 12 months Measurement of Methylation of ACAP3 in %
Left ventricular blood volumes 12 months Differences in reduction of left ventricular blood volumes (measured by CMR) after 12 months
Kansas City Cardiomyopathy Questionnaire 12 months Differences in quality of life changes according to 23-items Kansas City Cardiomyopathy Questionnaire (KCCQ) after 12 months
NT-proBNP-levels 12 months Differences in NT-proBNP-levels (in pg/ml) after 12 months
Left ventricular ejection fraction 12 months Differences in recovery of left ventricular ejection fraction (EF) in % (measured by CMR) after 12 months
Global longitudinal strain 12 months Differences in recovery of global longitudinal strain (GLS) in % (measured by CMR) after 12 months
diastolic function 12 months Differences in recovery of diastolic function (measured by CMR) after 12 months
Left ventricular myocardial tissue volumes 12 months Differences in reduction of left ventricular myocardial tissue volumes (measured by CMR) after 12 months
6min-walking test distance (6MWT) 12 months Differences in 6min-walking test distance (6MWT; in m) after 12 months
Biomarker Procollagen III N-terminal propeptid (PIIINP) 12 months Measurement of PIIINP in ng/ml
NYHA status 12 months Differences in NYHA status after 12 months
Total mortality 12 months Rate of total mortality within 12 months
Cardiovascular mortality 12 months Rate of Cardiovascular mortality within 12 months
Methylation of Iroquois Homeobox 3 (IRX3) 12 months Measurement of Methylation of IRX3 in %
Methylation of Klotho 12 months Measurement of Methylation of Klotho in %
Methylation of RAS Protein Activator Like 1 (RASAL1) 12 months Measurement of Methylation of RASAL1 in %
Methylation of B9 Domain Containing 1 (B9D1) 12 months Measurement of Methylation of B9D1 in %
Methylation of Latency associated peptide (LAP) 12 months Measurement of Methylation of LAP in %
Heart failure hospitalizations 12 months Rate of Heart failure hospitalizations within 12 months
Biomarker Procollagen type I carboxy-terminal propeptide (PICP) 12 months Measurement of PICP in ng/ml
Ratio of Increased collagen degradation (CITP) vs. matrix metalloproteinase-1 (MMP-1) 12 months Measurement of CITP (in ng/l) and MMP-1 (in ng/ml)
Methylation of Growth Arrest And DNA Damage Inducible Gamma (GADD45G) 12 months Measurement of Methylation of GADD45G in %
Methylation of Chordin (CHRD) 12 months Measurement of Methylation of CHRD in %
Methylation of ATPase Sarcoplasmic/Endoplasmic Reticulum Ca2+ Transporting 2 (ATP2A2) 12 months Measurement of Methylation of ATP2A2 in %
Methylation of Bone Morphogenetic Protein 7 (BMP7) 12 months Measurement of Methylation of BMP7 in %
Serum creatinine 12 months Change in serum creatinine (in mg/dl) after 12 months
Cystatin c 12 months Change in cystatin c (in mg/l) after 12 months
Phosphate 12 months Change in phosphate (in mmol/l) after 12 months
Trial Locations
- Locations (1)
University Medical Center Göttingen
🇩🇪Göttingen, Lower Saxony, Germany