Clinical trial NCT03991910: The Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients
Official title: Randomised Controlled Trial Into the Role of Ramipril in Fibrosis Reduction in Rheumatic Heart Disease: The RamiRHeD Trial Protocol
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Rheumatic Heart Disease
Mitral Stenosis
Rheumatic Mitral Stenosis
Fibrosis; Heart
ACE Inhibitor
Keywords: Rheumatic Heart Disease
Mitral Stenosis
Rheumatic Mitral Stenosis
Valve Fibrosis
ramipril
ST2
Lead sponsor: Indonesia University
Sponsor class: OTHER
First posted: 2019-06-19
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: pre post test design with placebo control
Primary purpose: TREATMENT

Brief 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.

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: ST2 expression in mitral valve tissue and papillary muscle
timeFrame: a year
Secondary outcomes:
measure: ST2 Plasma concentration
timeFrame: a year
measure: NT-proBNP concentration (pg/ml)
timeFrame: a year
measure: NYHA class
timeFrame: a year
measure: cardiovascular mortality
timeFrame: 1 year
measure: All-cause mortality
timeFrame: 1 year
measure: End diastolic dimension
timeFrame: 1 year
measure: End systolic dimension
timeFrame: 1 year
measure: Mitral valve area
timeFrame: 1 year
measure: Mitral valve gradient
timeFrame: 1 year
measure: Tricuspid maximal velocity (Vmax)
timeFrame: 1 year
measure: Tricuspid regurgitation severity
timeFrame: 1 year
measure: Ejection fraction
timeFrame: 1 year
measure: TAPSE (tricuspid annular plane systolic excursion)
timeFrame: 1 year
Other outcomes:
Locations:
city: Jakarta
country: Indonesia
facility: Ade Meidian Ambari
state: DKI Jakarta
Study officials:
affiliation: Universitas Indonesia, RSPJN harapan kita
name: Ade Meidian Ambari, MD,FIHA
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
citation: 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.
citation: Ambari AM, Setianto B, Santoso A, Radi B, Dwiputra B, Susilowati E, Tulrahmi F, Wind A, Cramer MJM, Doevendans P. Randomised controlled trial into the role of ramipril in fibrosis reduction in rheumatic heart disease: the RamiRHeD trial protocol. BMJ Open. 2021 Sep 13;11(9):e048016. doi: 10.1136/bmjopen-2020-048016.