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

NCT ID: NCT05230901

Last Updated: 2022-06-28

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-02-23
• Study Completion Date: 2026-03-31

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.

Conditions

Aortic Stenosis, Severe

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Control group

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

Group Type: OTHER

Standard of Care

Intervention Type: OTHER

Patients with CMR-derived ECV% levels ≥25.9% will be treated with standard of care according to current guidelines (Control group).

Spironolactone

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

Group Type: EXPERIMENTAL

Standard of Care

Intervention Type: OTHER

Patients with CMR-derived ECV% levels ≥25.9% will be treated with standard of care according to current guidelines (Control group).

Spironolactone 25mg

Intervention Type: DRUG

Patients with CMR-derived ECV% levels ≥25.9% in Arm "Spironolactone" will receive spironolactone 25 mg/d in addition to standard of care medication .

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)

Group Type: EXPERIMENTAL

Standard of Care

Intervention Type: OTHER

Patients with CMR-derived ECV% levels ≥25.9% will be treated with standard of care according to current guidelines (Control group).

Spironolactone 25mg

Intervention Type: DRUG

Patients with CMR-derived ECV% levels ≥25.9% in Arm "Spironolactone" will receive spironolactone 25 mg/d in addition to standard of care medication .

Dihydralazine

Intervention Type: DRUG

Patients with CMR-derived ECV% levels ≥25.9% in arm "Spironolactone + Dihydralazine" will receive spironolactone 25 mg/d + dihydralazine (2x12.5 mg/d p.o. in slow acethylators, and 2x25mg/d p.o. in fast acethylators, confirmed by genetic testing)

Interventions

Standard of Care

Patients with CMR-derived ECV% levels ≥25.9% will be treated with standard of care according to current guidelines (Control group).

Intervention Type: OTHER

Spironolactone 25mg

Patients with CMR-derived ECV% levels ≥25.9% in Arm "Spironolactone" will receive spironolactone 25 mg/d in addition to standard of care medication .

Intervention Type: DRUG

Dihydralazine

Patients with CMR-derived ECV% levels ≥25.9% in arm "Spironolactone + Dihydralazine" will receive spironolactone 25 mg/d + dihydralazine (2x12.5 mg/d p.o. in slow acethylators, and 2x25mg/d p.o. in fast acethylators, confirmed by genetic testing)

Intervention Type: DRUG

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

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Medical Center Goettingen

OTHER

Sponsor Role: lead

Responsible Party

Karsten Gavenis

Clinical Study Management on behalf of the Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

University Medical Center Göttingen

Göttingen, Lower Saxony, Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Miriam Puls, Prof.

Role: CONTACT

dr.m.puls@med.uni-goettingen.de

+49 551 3910958

Florian Walker, Dr.

Role: CONTACT

florian.walker@med.uni-goettingen.de

+49 551 3960825

Facility Contacts

Miriam Puls, Prof. Dr.

Role: primary

dr.m.puls@med.uni-goettingen.de

Other Identifiers

02717

Identifier Type: -

Identifier Source: org_study_id