Determinants of the Progression and Outcome of Mitral Regurgitation (PROGRAM)
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|ClinicalTrials.gov Identifier: NCT01835054|
Recruitment Status : Recruiting
First Posted : April 18, 2013
Last Update Posted : September 5, 2017
|Condition or disease||Intervention/treatment|
|Mitral Valve Insufficiency||Other: Blood biomarkers Genetic: DNA collection Other: Echocardiography Other: Cardiopulmonary exercise testing Other: Magnetic resonance imaging (MRI) Other: Exercise stress doppler echocardiography Other: Holter ECG|
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.
|Study Type :||Observational|
|Estimated Enrollment :||440 participants|
|Official Title:||Determinants of the Progression and Outcome of Mitral Regurgitation-PROGRAM STUDY|
|Study Start Date :||December 2008|
|Estimated Primary Completion Date :||March 2018|
|Estimated Study Completion Date :||March 2018|
Patients with mitral regurgitation
At study entry, patients have 1) a clinical assessment including metabolic risk profile; 2) a blood sample for analysis of metabolic, cardiac neurohormonal blood biomarkers and DNA collection; 3) a complete rest doppler echocardiography; 4) an exercise stress doppler echocardiography; 5) a cardiopulmonary exercise testing; 6) a magnetic resonance Imaging (MRI); 7) a 24-hour Holter ECG.
At follow-up, patients have 1) a clinical events assessment; 2) a blood sample analysis; 3) a resting echocardiography every year; 4) MRI (at preop. evaluation in the subset of patients undergoing surgery); 5) a 24-hour Holter ECG (at 2-year and postop.).
Other: Blood biomarkers
Observational Study using Imaging and BiomarkersGenetic: DNA collection
Observational Study using Imaging and BiomarkersOther: Echocardiography
Observational Study using Imaging and BiomarkersOther: Cardiopulmonary exercise testing
Observational Study using Imaging and BiomarkersOther: Magnetic resonance imaging (MRI)
Observational Study using Imaging and BiomarkersOther: Exercise stress doppler echocardiography
Observational Study using Imaging and BiomarkersOther: Holter ECG
Observational Study using Imaging and Biomarkers
- Combined clinical and echocardiographic endpoint [ Time Frame: Patients will be followed for 4 years ]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.
- Progression of MR severity [ Time Frame: Patients will be followed for 4 years ]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.
- Progression of pulmonary arterial hypertension [ Time Frame: Patients will be folowed for 4 years ]The annualized progression rate of resting systolic pulmonary arterial pressure will be calculated.
- Progression of LV dysfuntion prior to surgery [ Time Frame: Patients will be followed for 4 years ]The annualized progression rate of LVEF, LV end-systolic dimension, and LV myocardial global peak systolic velocities and global longitudinal strain will be calculated.
- Maximum exercise capacity at baselin and following mitral valve surgery [ Time Frame: Patients will be followed for 4 years ]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
- Composite end-point prior to mitral valve surgery [ Time Frame: Patients will be followed for 4 years ]i.e. follow-up censored at surgery
- Composite primary end-point after mitral vale surgery [ Time Frame: Patients will be followed for 4 years ]i.e. time zero set at surgery
- Mitral valve surgery [ Time Frame: Patients will be followed for 4 years ]Motivated by the occurrence of symptoms, LV systolic dysfunction, atrial fibrillation, and/or resting pulmonary pressure > 50 mmHg.
- Arrhythmic burden [ Time Frame: Patients will be followed for 4 years ]Number and percentage of ventricular ectopic per 24 h, percent time in atrial fibrillation, or flutter per 24 h.
Biospecimen Retention: Samples With DNA
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01835054
|Contact: Philippe Pibarot, PhD, DVM||418-656-8711 ext 5938||Philippe.Pibarot@med.ulaval.ca|
|Contact: Haifa Mahjoub, MD, PhDs||418-656-8711 ext firstname.lastname@example.org|
|University Hospital of Sart Tilman||Recruiting|
|Liège, Belgium, 4000|
|Contact: Patrizio Lancellotti, MD, PhD 32(0)4/366 7194 email@example.com|
|Principal Investigator: Patrizio Lancellotti, MD, PhD|
|Sub-Investigator: Julien Magne, PhD|
|Institut Universitaire de Cardiologie et de Pneumologie de Québec||Recruiting|
|Québec, Canada, G1V4G5|
|Contact: Philippe Pibarot, PhD, DVM 418-656-8711 ext 5938 Philippe.Pibarot@med.ulaval.ca|
|Contact: Oumhani Toubal, MD, Fellow 418-656-5711 ext 2647 firstname.lastname@example.org|
|Principal Investigator: Philippe Pibarot, PhD, DVM|
|University Hospital (CHU) of Brest, Hôpital La Cavale Blanche||Recruiting|
|Brest, France, 29609|
|Contact: Florent Le Ven, MD 33298347391 email@example.com|
|Principal Investigator: Florent Le Ven, MD|
|University Hospital of Rennes||Active, not recruiting|
|Rennes, France, 35033|
|Principal Investigator:||Philippe Pibarot, PhD, DVM||Institut Universitaire de Cardiologie et de Pneumologie de Québec|