Effect of Antifibrotic Therapy on Regression of Myocardial Fibrosis After Transcatheter Aortic Valve Implantation (TAVI) in Aortic Stenosis Patients With High Fibrotic Burden
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 300
- 试验地点
- 1
- 主要终点
- Extracellular volume (ECV)-derived matrix volume (measured by CMR)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male, female age ≥ 60
- •Diagnosis of severe symptomatic aortic stenosis
- •Transcatheter aortic valve implantation (TAVI) scheduled
- •Written informed consent
排除标准
- •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
研究组 & 干预措施
Control group
Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care
干预措施: Standard of Care (Other)
Spironolactone
Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.)
干预措施: Standard of Care (Other)
Spironolactone
Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.)
干预措施: Spironolactone 25mg (Drug)
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)
干预措施: Standard of Care (Other)
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)
干预措施: Spironolactone 25mg (Drug)
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)
干预措施: Dihydralazine (Drug)
结局指标
主要结局
Extracellular volume (ECV)-derived matrix volume (measured by CMR)
时间窗: 12 months
Differences between treatment groups in reduction of extracellular volume (ECV)- derived matrix volume (measured by CMR) after 12 months
次要结局
- Left ventricular blood volumes(12 months)
- Kansas City Cardiomyopathy Questionnaire(12 months)
- NT-proBNP-levels(12 months)
- Left ventricular ejection fraction(12 months)
- Global longitudinal strain(12 months)
- diastolic function(12 months)
- Left ventricular myocardial tissue volumes(12 months)
- 6min-walking test distance (6MWT)(12 months)
- Biomarker Procollagen III N-terminal propeptid (PIIINP)(12 months)
- Methylation of Latency associated peptide (LAP)(12 months)
- NYHA status(12 months)
- Total mortality(12 months)
- Cardiovascular mortality(12 months)
- Methylation of Iroquois Homeobox 3 (IRX3)(12 months)
- Methylation of Klotho(12 months)
- Methylation of RAS Protein Activator Like 1 (RASAL1)(12 months)
- Methylation of B9 Domain Containing 1 (B9D1)(12 months)
- Heart failure hospitalizations(12 months)
- Biomarker Procollagen type I carboxy-terminal propeptide (PICP)(12 months)
- Ratio of Increased collagen degradation (CITP) vs. matrix metalloproteinase-1 (MMP-1)(12 months)
- Methylation of Growth Arrest And DNA Damage Inducible Gamma (GADD45G)(12 months)
- Methylation of rfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 3 (ACAP3)(12 months)
- Methylation of Chordin (CHRD)(12 months)
- Methylation of ATPase Sarcoplasmic/Endoplasmic Reticulum Ca2+ Transporting 2 (ATP2A2)(12 months)
- Methylation of Bone Morphogenetic Protein 7 (BMP7)(12 months)
- Serum creatinine(12 months)
- Cystatin c(12 months)
- Phosphate(12 months)
研究者
Karsten Gavenis
Clinical Study Management on behalf of the Principal Investigator
University Medical Center Goettingen