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

NCT05230901 | Recruiting Phase 3

• 1 other identifier: 02717
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• 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

  12 months

Secondary Outcomes (28)

• Left ventricular ejection fraction

  12 months

• Global longitudinal strain

  12 months

• diastolic function

  12 months

• Left ventricular myocardial tissue volumes

  12 months

• Left ventricular blood volumes

  12 months

Study Arms (3)

Control group

OTHER

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

Other: Standard of Care

Spironolactone

EXPERIMENTAL

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

Other: Standard of Care; Drug: Spironolactone 25mg

Spironolactone + Dihydralazine

EXPERIMENTAL

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)

Other: Standard of Care; Drug: Spironolactone 25mg; Drug: Dihydralazine

Interventions

Standard of Care OTHER

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

Control group; Spironolactone; Spironolactone + Dihydralazine

Spironolactone 25mg 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; Spironolactone + Dihydralazine

Dihydralazine 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)

Spironolactone + Dihydralazine

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male, female age ≥ 60
• Diagnosis of severe symptomatic aortic stenosis
• Transcatheter aortic valve implantation (TAVI) scheduled
• Written informed consent

You may not qualify if:

• \. 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

Sponsors & Collaborators

• University Medical Center Goettingen: lead

Study Sites (1)

University Medical Center Göttingen

Göttingen, Lower Saxony, 37075, Germany

RECRUITING

MeSH Terms

Conditions

Aortic Valve Stenosis

Interventions

Standard of Care; Spironolactone; Dihydralazine

Condition Hierarchy (Ancestors)

Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Outflow Obstruction

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hydralazine; Phthalazines; Pyridazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Miriam Puls, Prof.

CONTACT

+49 551 3910958; dr.m.puls@med.uni-goettingen.de

Florian Walker, Dr.

CONTACT

+49 551 3960825; florian.walker@med.uni-goettingen.de

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Study Management on behalf of the Principal Investigator

Study Record Dates

• First Submitted: January 12, 2022
• First Posted: February 9, 2022
• Study Start: February 23, 2022
• Primary Completion: June 1, 2025
• Study Completion: March 1, 2026
• Last Updated: June 28, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)