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Determinants of the Progression and Outcome of Mitral Regurgitation (PROGRAM)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by Laval University
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
Heart and Stroke Foundation of Canada
University Hospital, Brest
Information provided by (Responsible Party):
Philippe Pibarot, Laval University
ClinicalTrials.gov Identifier:
NCT01835054
First received: April 16, 2013
Last updated: August 31, 2016
Last verified: August 2016

April 16, 2013
August 31, 2016
December 2008
March 2017   (final data collection date for primary outcome measure)
Combined clinical and echocardiographic endpoint [ Time Frame: Patients will be followed for 4 years ] [ Designated as safety issue: No ]
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.
Combined clinical and echocardiographic endpoint [ Time Frame: Patients will be followed for 4 years ] [ Designated as safety issue: No ]
Development of symptoms, left ventricular (LV) dysfunction (LV Ejection Fraction<60% and/or LV end diastolic diameter >40mm), atrial fibrillation or flutter, pulmonary arterial hypertension (resting systolic pressure >50mmHg), occurence of pulmonary oedema, congestive heart failure or cardiovascular death
Complete list of historical versions of study NCT01835054 on ClinicalTrials.gov Archive Site
  • Progression of MR severity [ Time Frame: Patients will be followed for 4 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    i.e. follow-up censored at surgery
  • Composite primary end-point after mitral vale surgery [ Time Frame: Patients will be followed for 4 years ] [ Designated as safety issue: No ]
    i.e. time zero set at surgery
  • Mitral valve surgery [ Time Frame: Patients will be followed for 4 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Number and percentage of ventricular ectopic per 24 h, percent time in atrial fibrillation, or flutter per 24 h.
  • Progression of MR severity [ Time Frame: Patients will be followed for 4 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    The annualized progression rate of resting systolic pulmonary arterial pressure will be calculated.
  • Progression of LV dysfuntion [ Time Frame: Patients will be followed for 4 years ] [ Designated as safety issue: No ]
    The annualized progression rate of LVEF, LV end-systolic dimension, and LV myocardial global peak systolic velocities and strain will be calculated.
  • Maximum exercise capacity at baseline [ Time Frame: Patients will be followed for 4 years ] [ Designated as safety issue: No ]
    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
Not Provided
Not Provided
 
Determinants of the Progression and Outcome of Mitral Regurgitation
Determinants of the Progression and Outcome of Mitral Regurgitation-PROGRAM STUDY
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.

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.

Observational
Observational Model: Cohort
Time Perspective: Prospective
Not Provided
Retention:   Samples With DNA
Description:
Fasting blood sample (serum, lithium-heparin, EDTA) and white cells - Tissue (explanted mitral valves)
Probability Sample
Cohort will be selected at primary care clinic
Mitral Valve Insufficiency
  • 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
  • Other: Cardiopulmonary exercise testing
    Observational Study using Imaging and Biomarkers
  • Other: Magnetic resonance imaging (MRI)
    Observational Study using Imaging and Biomarkers
  • Other: Exercise stress doppler echocardiography
    Observational Study using Imaging and Biomarkers
  • Other: Holter ECG
    Observational Study using Imaging and Biomarkers
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.).

Interventions:
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
440
March 2018
March 2017   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Age > 18 or 21 years (Legal age according to the countries involved in this study)
  • Presence of at least moderate chronic OMR defined as an ERO ≥20mm2 and/or a regurgitant volume ≥30mL

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 II indication for mitral valve operation according to the 2006-2007 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)
Both
21 Years and older   (Adult, Senior)
No
Contact: Philippe Pibarot, PhD, DVM 418-656-8711 ext 5938 Philippe.Pibarot@med.ulaval.ca
Contact: Haifa Mahjoub, MD, PhDs 418-656-8711 ext 2647 haifa.mahjoub@criucpq.ulaval.ca
Belgium,   Canada,   France
 
NCT01835054
MOP#102737
No
Not Provided
Not Provided
Philippe Pibarot, Laval University
Laval University
  • Canadian Institutes of Health Research (CIHR)
  • Heart and Stroke Foundation of Canada
  • University Hospital, Brest
Principal Investigator: Philippe Pibarot, PhD, DVM Institut Universitaire de Cardiologie et de Pneumologie de Québec
Laval University
August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP