Determinants of the Progression and Outcome of Mitral Regurgitation

Mitral Valve Insufficiency Clinical Trial

— PROGRAM  

Official title:

Determinants of the Progression and Outcome of Mitral Regurgitation-PROGRAM STUDY

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01835054
• Other study ID #: MOP#102737
• Status: Recruiting
• Start date: December 2008
• Est. completion date: March 2024

Study information

• Verified date: October 2021
• Source: Laval University
• Contact: Philippe Pibarot, PhD, DVM
• Phone: 418-656-8711
• Email: Philippe.Pibarot[@]med.ulaval.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Mitral regurgitation (MR) is one of the most frequent valve lesions, both in North America and in Europe, and its prevalence is increasing with the aging of the population. Organic Mitral Regurgitation (OMR) and Ischemic Mitral Regurgitation are the 2 main categories of MR. Organic or primary MR is caused by an anatomic alteration of the valvular or subvalvular mitral apparatus and refers to rheumatic MR and degenerative MR that includes mitral leaflet prolapse and flail leaflet. In the past 20 years, degenerative MR has become, by far, the most frequent cause of severe MR leading to surgery in the western world. However, the best current treatment for OMR remains uncertain and controversial. We have obtained preliminary data showing that OMR is a dynamic lesion. Hence, the echocardiographic evaluation of MR at rest, as generally performed during routine clinical exam, does not necessarily reflect the status of MR during patient's daily activities and thereby does not adequately assess the risk of rapid progression and poor outcome in these patients. The objective of this study is to identify the independent predictors of disease progression and outcome in patients with asymptomatic chronic OMR and to develop and validate novel imaging and circulating biomarkers to improve risk stratification and therapeutic decision-making process in patients with chronic asymptomatic primary OMR.

Description:

Mitral regurgitation (MR) is one of the most frequent valve lesions, both in North America and in Europe, and its prevalence is increasing owing to the aging of the population. There are 2 main categories of MR: Organic Mitral Regurgitation (OMR) and Ischemic Mitral Regurgitation. Organic or primary MR is caused by an anatomic alteration of the valvular or subvalvular mitral apparatus and refers to rheumatic MR and degenerative MR that includes mitral leaflet prolapse and flail leaflet. In the past 20 years, degenerative MR has become, by far, the most frequent cause of severe MR leading to surgery in the western world. However, the best current treatment for OMR remains uncertain and controversial. This is, in large part, due to the lack of prospective data on the determinants of OMR progression and outcome. Furthermore, we have obtained preliminary data showing that OMR is a dynamic lesion. Hence, the echocardiographic evaluation of MR at rest, as generally performed during routine clinical exam, does not necessarily reflect the status of MR during patient's daily activities and thereby does not adequately assess the risk of rapid progression and poor outcome in these patients.

The general objective of this study is thus: to identify the independent predictors of disease progression and outcome in patients with asymptomatic chronic OMR and to develop and validate novel imaging and circulating biomarkers to improve risk stratification and therapeutic decision-making process in patients with chronic asymptomatic primary OMR.

The specific aims of the study are: (1) To obtain and analyze: a) the dynamic changes in MR severity, pulmonary arterial pressure, and LV function during exercise; b) the maximum exercise capacity; c) the metabolic profile; d) the plasma natriuretic peptides, e) the degree and localization of myocardial fibrosis measured by cardiac magnetic resonance Imaging (MRI); f) the blood markers of myocardial extracellular matrix (ECM) turnover; g) the progression of MR severity and LV dysfunction during follow-up; and h) the occurrence of adverse clinical outcomes (i.e. symptoms, LV dysfunction, atrial fibrillation (Holter ECG), pulmonary hypertension, heart failure, cardiovascular death) during follow-up in a series of 440 patients with at least moderate OMR and no symptoms at baseline. (2) To analyze the valve tissue samples explanted from the patients who will undergo mitral valve repair with quadrangular resection during follow-up in order to document the presence of lipids, inflammation, and expression of metalloproteinases (MMPs). (3) To obtain and analyze the postoperative changes in LV geometry and function, pulmonary arterial pressure, symptoms, and exercise capacity in the subset of patients who will undergo mitral valve surgery during follow-up. (4) To evaluate the usefulness of the exercise induced changes in MR severity, pulmonary arterial pressure, and LV function (i.e. contractile reserve), and of the blood levels of natriuretic peptides and ECM biomarkers for the prediction of rapid progression to LV dysfunction and adverse events. (5) To examine the relationship between the metabolic abnormalities linked to visceral obesity and the progression and outcome of OMR. (6) To determine, among the baseline clinical, echocardiographic, MRI, metabolic, and biomarkers variables, those which are independently associated with the progression of MR severity and LV dysfunction, and the occurrence of adverse clinical outcomes in patients with OMR.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 440
• Est. completion date: March 2024
• Est. primary completion date: March 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

Inclusion Criteria:

• Age > 18 or 21 years (Legal age according to the countries involved in this study)

• Presence of at least mild chronic OMR defined as an ERO =10mm2 and/or a regurgitant volume =20mL

Exclusion Criteria:

• MR due to ischemic heart disease or cardiomyopathy

• > mild mitral stenosis, aortic regurgitation, aortic stenosis or pulmonary stenosis

• previous valve operation

• history of myocardial infarction or angiographycally documented coronary stenosis

• congenital or pericardial heart disease

• endocarditis

• contra-indication or inability to exercise

• pregnancy

• Class I or IIa indication for mitral valve operation according to the 2014 ACC/AHA/ESC guidelines

• Typical contraindications to contrast-enhanced MRI (surgery in the last 3 months, defibrillator, pericardial electrodes, brain surgery, aneurysm clipping, neurostimulator, electric stimulation device or magnetically activated, cochlear implant, insulin pump or medication delivery device, Swan-Ganz catheter)

Related Conditions & MeSH terms

• Mitral Valve Insufficiency

Intervention

Other:
• Blood biomarkers
Observational Study using Imaging and Biomarkers

Genetic:
• DNA collection
Observational Study using Imaging and Biomarkers

Other:
• Echocardiography
Observational Study using Imaging and Biomarkers
• Cardiopulmonary exercise testing
Observational Study using Imaging and Biomarkers
• Magnetic resonance imaging (MRI)
Observational Study using Imaging and Biomarkers
• Exercise stress doppler echocardiography
Observational Study using Imaging and Biomarkers
• Holter ECG
Observational Study using Imaging and Biomarkers

Locations

Country	Name	City	State
Belgium	University Hospital of Sart Tilman	Liège
Canada	Institut Universitaire de Cardiologie et de Pneumologie de Québec	Québec
France	University Hospital (CHU) of Brest, Hôpital La Cavale Blanche	Brest
France	University Hospital of Rennes	Rennes

Sponsors (4)

Lead Sponsor	Collaborator
Laval University	Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada, University Hospital, Brest

Countries where clinical trial is conducted

Belgium,  Canada,  France, 

References & Publications (15)

Clemenceau A, Bérubé JC, Bélanger P, Gaudreault N, Lamontagne M, Toubal O, Clavel MA, Capoulade R, Mathieu P, Pibarot P, Bosse Y. Deleterious variants in DCHS1 are prevalent in sporadic cases of mitral valve prolapse. Mol Genet Genomic Med. 2018 Jan;6(1):114-120. doi: 10.1002/mgg3.347. Epub 2017 Dec 10. — View Citation

Donal E, Mascle S, Brunet A, Thebault C, Corbineau H, Laurent M, Leguerrier A, Mabo P. Prediction of left ventricular ejection fraction 6 months after surgical correction of organic mitral regurgitation: the value of exercise echocardiography and deformation imaging. Eur Heart J Cardiovasc Imaging. 2012 Nov;13(11):922-30. doi: 10.1093/ehjci/jes068. Epub 2012 Apr 14. — View Citation

Dupuis M, Mahjoub H, Clavel MA, Côté N, Toubal O, Tastet L, Dumesnil JG, O'Connor K, Dahou A, Thébault C, Bélanger C, Beaudoin J, Arsenault M, Bernier M, Pibarot P. Forward Left Ventricular Ejection Fraction: A Simple Risk Marker in Patients With Primary Mitral Regurgitation. J Am Heart Assoc. 2017 Oct 27;6(11). pii: e006309. doi: 10.1161/JAHA.117.006309. — View Citation

Lancellotti P, Magne J. Stress testing for the evaluation of patients with mitral regurgitation. Curr Opin Cardiol. 2012 Sep;27(5):492-8. doi: 10.1097/HCO.0b013e3283565c3b. Review. — View Citation

Magne J, Lancellotti P, O'Connor K, Van de Heyning CM, Szymanski C, Piérard LA. Prediction of exercise pulmonary hypertension in asymptomatic degenerative mitral regurgitation. J Am Soc Echocardiogr. 2011 Sep;24(9):1004-12. doi: 10.1016/j.echo.2011.04.003. Epub 2011 May 17. — View Citation

Magne J, Lancellotti P, Piérard LA. Exercise pulmonary hypertension in asymptomatic degenerative mitral regurgitation. Circulation. 2010 Jul 6;122(1):33-41. doi: 10.1161/CIRCULATIONAHA.110.938241. Epub 2010 Jun 21. — View Citation

Magne J, Lancellotti P, Piérard LA. Exercise-induced changes in degenerative mitral regurgitation. J Am Coll Cardiol. 2010 Jul 20;56(4):300-9. doi: 10.1016/j.jacc.2009.12.073. — View Citation

Magne J, Mahjoub H, Dulgheru R, Pibarot P, Pierard LA, Lancellotti P. Left ventricular contractile reserve in asymptomatic primary mitral regurgitation. Eur Heart J. 2014 Jun 21;35(24):1608-16. doi: 10.1093/eurheartj/eht345. Epub 2013 Sep 7. — View Citation

Magne J, Mahjoub H, Pibarot P, Pirlet C, Pierard LA, Lancellotti P. Prognostic importance of exercise brain natriuretic peptide in asymptomatic degenerative mitral regurgitation. Eur J Heart Fail. 2012 Nov;14(11):1293-302. doi: 10.1093/eurjhf/hfs114. Epub 2012 Jul 10. — View Citation

Magne J, Mahjoub H, Pierard LA, O'Connor K, Pirlet C, Pibarot P, Lancellotti P. Prognostic importance of brain natriuretic peptide and left ventricular longitudinal function in asymptomatic degenerative mitral regurgitation. Heart. 2012 Apr;98(7):584-91. doi: 10.1136/heartjnl-2011-301128. Epub 2012 Feb 18. — View Citation

Magne J, Mathieu P, Dumesnil JG, Tanné D, Dagenais F, Doyle D, Pibarot P. Impact of prosthesis-patient mismatch on survival after mitral valve replacement. Circulation. 2007 Mar 20;115(11):1417-25. Epub 2007 Mar 5. — View Citation

Mascle S, Schnell F, Thebault C, Corbineau H, Laurent M, Hamonic S, Veillard D, Mabo P, Leguerrier A, Donal E. Predictive value of global longitudinal strain in a surgical population of organic mitral regurgitation. J Am Soc Echocardiogr. 2012 Jul;25(7):766-72. doi: 10.1016/j.echo.2012.04.009. Epub 2012 May 19. — View Citation

Sénéchal M, Michaud N, Machaalany J, Bernier M, Dubois M, Magne J, Couture C, Mathieu P, Bertrand OF, Voisine P. Relation of mitral valve morphology and motion to mitral regurgitation severity in patients with mitral valve prolapse. Cardiovasc Ultrasound. 2012 Jan 27;10:3. doi: 10.1186/1476-7120-10-3. — View Citation

Toubal O, Mahjoub H, Thébault C, Clavel MA, Dahou A, Magne J, O'Connor K, Beaudoin J, Bernier M, Le Ven F, Pibarot P. Increasing Pulmonary Arterial Pressure at Low Level of Exercise in Asymptomatic, Organic Mitral Regurgitation. J Am Coll Cardiol. 2018 Feb 13;71(6):700-701. doi: 10.1016/j.jacc.2017.11.062. — View Citation

Van de Heyning CM, Magne J, Vrints CJ, Piérard L, Lancellotti P. The role of multi-imaging modality in primary mitral regurgitation. Eur Heart J Cardiovasc Imaging. 2012 Feb;13(2):139-51. doi: 10.1093/ejechocard/jer257. Epub 2011 Nov 29. Review. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Combined clinical and echocardiographic endpoint	The primary outcome is the time to occurrence of the first composite end-point: development of symptoms, left ventricular (LV) dysfunction (LV Ejection Fraction<60% and/or LV end diastolic diameter >40mm), ventricular arrhytmia requiring hospitalization, mediaction and/or implantation of defibrillator, atrial fibrillation or flutter, pulmonary arterial hypertension (resting systolic pressure >50mmHg), occurence of pulmonary oedema, congestive heart failure or cardiovascular death.	Patients will be followed for 10 years
Secondary	Progression of MR severity	The annualized progression rate of MR severity will be calculated as the difference between effective regurgitant orifice, regurgitant volume, and vena contracta width measured at baseline and those measured at the last follow-up divided by the time between the first and last examinations.	Patients will be followed for 10 years
Secondary	Progression of pulmonary arterial hypertension	The annualized progression rate of resting systolic pulmonary arterial pressure will be calculated.	Patients will be folowed for 10 years
Secondary	Progression of LV dysfuntion prior to surgery	The annualized progression rate of LVEF, LV end-systolic dimension, and LV myocardial global peak systolic velocities and global longitudinal strain will be calculated.	Patients will be followed for 10 years
Secondary	Maximum exercise capacity at baselin and following mitral valve surgery	Maximum exercise capacity at baseline as measured by the percentage of age and gender predicted VO2max. We will determine which are, among the clinical and Doppler-echocardiographic variables, the independent determinants of maximum exercise capacity at baseline. The baseline exercise capacity will also be used as an independent variable, i.e. we will determine if it is an independent predictor of the primary end-point and of the other secondary end-points	Patients will be followed for 10 years
Secondary	Composite end-point prior to mitral valve surgery	i.e. follow-up censored at surgery	Patients will be followed for 10 years
Secondary	Composite primary end-point after mitral vale surgery	i.e. time zero set at surgery	Patients will be followed for 10 years
Secondary	Mitral valve surgery	Motivated by the occurrence of symptoms, LV systolic dysfunction, atrial fibrillation, and/or resting pulmonary pressure > 50 mmHg.	Patients will be followed for 10 years
Secondary	Arrhythmic burden	Number and percentage of ventricular ectopic per 24 h, percent time in atrial fibrillation, or flutter per 24 h.	Patients will be followed for 10 years