The Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients

Rheumatic Heart Disease Clinical Trial

Official title:

Randomised Controlled Trial Into the Role of Ramipril in Fibrosis Reduction in Rheumatic Heart Disease: The RamiRHeD Trial Protocol

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03991910
• Other study ID #: RamiRHeD
• Status: Recruiting
• Phase: Phase 3
• Start date: June 27, 2019
• Est. completion date: August 8, 2024

Study information

• Verified date: August 2021
• Source: Indonesia University
• Contact: Ade Meidian Ambari, MD, FIHA
• Phone: 021-5684085
• Email: dr_ade_meidian[@]yahoo.co.id
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Objective propose: to investigate the effect of Ramipril in suppressing ST2 (suppression of tumorigenicity 2) in the cardiac mitral valve in patients with Rheumatic Heart Disease. We hypothesized that we hypothesized that ramipril will improve rheumatic mitral valve fibrosis through the downregulation of ST2.

Description:

The efficacy of secondary prevention is limited in the prevention of RHD progression. For this reason, new strategies and therapies are needed to prevent the progression of RHD. Neutralizing inflammatory cytokines or antagonizing their receptor function has been considered as a useful therapeutic strategy to treat autoimmune diseases. In this respect, new therapies targeting ST 2 and their receptors as studied in some autoimmune diseases may promise a new approach for patients with RHD. Angiotensin II induces the upregulation of Transforming growth factor β (TGF-β) and latter the binding of IL-33 to sST2 and not to the natural ligand (ST2L). The binding of IL-33 to sST2 will cause fibrogenesis even more. Thus, ACEI is hypothesized to attenuate this vicious cycle through the inhibition of Angiotensin II and consequently increase Bradykinin that furtherly inhibits fibrosis through the negative regulation of angiotensin II activity in Mitogen Activator Protein Kinase (MAPK) pathways through the suppression of the Ca2+ response and the Na+ transportACE inhibitor were agents with anti-fibrosis effects. The investigators keen to investigate the effect of Ramipril in suppressing ST2 expression as biomarkers of fibrosis in cardiac mitral valve in patients with Rheumatic Heart Disease in the National Cardiac Center Harapan Kita hospital Jakarta Indonesia. This study was designed as a randomized clinical trial. Patients with mitral stenosis valvular dysfunction due to rheumatic process planned for cardiac valve replacement surgery were given Ramipril or placebo for a minimum of 12 weeks (3 months). ST2 expression will be analyzed as the fibrosis biomarker in the mitral valve. This study will be conducted in the Department of Cardiology and Vascular Medicine, University Indonesia, National Cardiac Center Harapan Kita Hospital, Jakarta, Indonesia from June 2019

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 66
• Est. completion date: August 8, 2024
• Est. primary completion date: August 8, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Patients with mitral valve stenosis or a combination
• aged more than 18 years
• undergo cardiac valve replacement operation with or without a tricuspid valve repair,
• patients with systolic blood pressure (SBP) = 100 mmHg and diastolic blood pressure (DBP) = 60 mmHg
• passed in medication phase without side effect minimum 4 weeks until operation schedule

Exclusion Criteria:

1. Patients with congenital heart disease

2. patients with non-mitral valve surgery

3. patients with coronary artery bypass surgery

4. patients who refuse to join this study.

5. adults aged over 65 years or older

6. pregnant women

7. patients with autoimmune disease.

8. Patients with persistent hypotension (systolic blood pressure (BP) < 100 mm Hg)

9. severe aortic stenosis (aortic valve orifice < 0.75 cm2 )

10. chronic renal dysfunction with serum creatinine > 2.5 mg/ dL,

11. known ACEI intolerance.

Related Conditions & MeSH terms

• ACE Inhibitor
• Constriction, Pathologic
• Fibrosis
• Fibrosis; Heart
• Heart Diseases
• Mitral Stenosis
• Mitral Valve Stenosis
• Rheumatic Diseases
• Rheumatic Heart Disease
• Rheumatic Mitral Stenosis

Intervention

Drug:
• Placebos
the control group will be given placebo inside a capsule, so study participant won't be able to know the drug and doses inside the capsule (for masking). Placebo will be given until 5 days prior to Mitral valve replacement surgery.
• Ramipril 5Mg Oral Capsule
the treatment group will be given each Ramipril 2,5 mg inside a capsule as an initial dose, for 2 weeks. If there is no serious adverse effect in the observation period of 2 weeks, Ramipril 5 mg inside a capsule will be given for the next weeks until 5 days before the mitral valve surgery date. Study participant won't be able to know the drug and doses inside the capsule (for masking)

Locations

Country	Name	City	State
Indonesia	Ade Meidian Ambari	Jakarta	DKI Jakarta

Sponsors (1)

Lead Sponsor	Collaborator
Indonesia University

Country where clinical trial is conducted

Indonesia, 

References & Publications (4)

Ambari AM, Setianto B, Santoso A, Radi B, Dwiputra B, Susilowati E, Tulrahmi F, Doevendans PA, Cramer MJ. Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2. Front Cardiovasc Med. 2020 Jul 28;7:115. doi: 10.3389/fcvm.2020.00115. eCollection 2020. Review. — View Citation

Ciccone MM, Cortese F, Gesualdo M, Riccardi R, Di Nunzio D, Moncelli M, Iacoviello M, Scicchitano P. A novel cardiac bio-marker: ST2: a review. Molecules. 2013 Dec 11;18(12):15314-28. doi: 10.3390/molecules181215314. Review. — View Citation

Shi Q, Abusarah J, Baroudi G, Fernandes JC, Fahmi H, Benderdour M. Ramipril attenuates lipid peroxidation and cardiac fibrosis in an experimental model of rheumatoid arthritis. Arthritis Res Ther. 2012 Oct 18;14(5):R223. doi: 10.1186/ar4062. — View Citation

Wei Q, Liu H, Liu M, Yang C, Yang J, Liu Z, Yang P. Ramipril attenuates left ventricular remodeling by regulating the expression of activin A-follistatin in a rat model of heart failure. Sci Rep. 2016 Sep 19;6:33677. doi: 10.1038/srep33677. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ST2 expression in mitral valve tissue and papillary muscle	expression of ST2 in mitral valve tissue, using immunohistochemistry method	a year
Secondary	ST2 Plasma concentration	plasma level of ST2 measured by ELISA	a year
Secondary	NT-proBNP concentration (pg/ml)	concentration of NT-proBNP, plasma markers for cardiac dysfunction.	a year
Secondary	NYHA class	related symptoms will be graded in class I to IV according to NYHA.	a year
Secondary	cardiovascular mortality	Study participants will be followed up until 1 year after the surgery for any mortality that is caused by progression of the cardiac disease	1 year
Secondary	All-cause mortality	Study participants will be followed up until 1 year after the surgery for mortality of any cause.	1 year
Secondary	End diastolic dimension	The diameter across a ventricle at the end of diastole, if not else specified then usually referring to the transverse (left-to-right) internal (luminal) distance, excluding thickness of walls, although it can also be measured as the external distance.	1 year
Secondary	End systolic dimension	The diameter across a ventricle at the end of systole, if not else specified then usually referring to the transverse (left-to-right) internal (luminal) distance, excluding thickness of walls, although it can also be measured as the external distance.	1 year
Secondary	Mitral valve area	mitral valve area is the area of mitral valve, measured by the Gorlin formula MVA (cm2) = (CO ÷ DFP) ÷ (38.0 x MPG) where MVA is the mitral valve area, CO is cardiac output, DFP is the diastolic flow period, 38.0 is the constant and MPG is pressure gradient.	1 year
Secondary	Mitral valve gradient	mitralvalve graient is a echocardiographic parameters of the pressure gradient in the mitral valve	1 year
Secondary	Tricuspid maximal velocity (Vmax)	Tricuspid maximal velocity (Vmax) is the echocardiographic parameters of the maximal velocity in tricuspid valve annulus	1 year
Secondary	Tricuspid regurgitation severity	TRicuspid regurgitation severity is classified ad mild, moderate, and severe, according to European Association of Echocardiography measurement year 2010 for Tricuspid Valve regusrgitation severity.	1 year
Secondary	Ejection fraction	echocardiographic parameter to asses ventricular function	1 year
Secondary	TAPSE (tricuspid annular plane systolic excursion)	echocardiography parameter to asses right ventricular function	1 year