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

October 27, 2021 updated by: Philippe Pibarot, Laval University

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Observational

Enrollment (Anticipated)

440

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Belgium
      • Liège, Belgium, 4000
        • Recruiting
        • University Hospital of Sart Tilman
        • Contact:
        • Principal Investigator:
          • Patrizio Lancellotti, MD, PhD
        • Sub-Investigator:
          • Julien Magne, PhD
  • Canada
      • Québec, Canada, G1V4G5
        • Recruiting
        • Institut Universitaire De Cardiologie Et De Pneumologie De Québec
        • Contact:
        • Contact:
        • Principal Investigator:
          • Philippe Pibarot, PhD, DVM
  • France
      • Brest, France, 29609
        • Recruiting
        • University Hospital (CHU) of Brest, Hôpital La Cavale Blanche
        • Contact:
        • Principal Investigator:
          • Florent Le Ven, MD
      • Rennes, France, 35033
        • Active, not recruiting
        • University Hospital of Rennes

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Cohort will be selected at primary care clinic

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
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: Echocardiography
Observational Study using Imaging and Biomarkers
Other: Blood biomarkers
Observational Study using Imaging and Biomarkers
Genetic: DNA collection
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Combined clinical and echocardiographic endpoint
Time Frame: Patients will be followed for 10 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.
Patients will be followed for 10 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression of MR severity
Time Frame: Patients will be followed for 10 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.
Patients will be followed for 10 years
Progression of pulmonary arterial hypertension
Time Frame: Patients will be folowed for 10 years
The annualized progression rate of resting systolic pulmonary arterial pressure will be calculated.
Patients will be folowed for 10 years
Progression of LV dysfuntion prior to surgery
Time Frame: Patients will be followed for 10 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.
Patients will be followed for 10 years
Maximum exercise capacity at baselin and following mitral valve surgery
Time Frame: Patients will be followed for 10 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
Patients will be followed for 10 years
Composite end-point prior to mitral valve surgery
Time Frame: Patients will be followed for 10 years
i.e. follow-up censored at surgery
Patients will be followed for 10 years
Composite primary end-point after mitral vale surgery
Time Frame: Patients will be followed for 10 years
i.e. time zero set at surgery
Patients will be followed for 10 years
Mitral valve surgery
Time Frame: Patients will be followed for 10 years
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
Arrhythmic burden
Time Frame: Patients will be followed for 10 years
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Laval University

Collaborators

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

Investigators

  • Principal Investigator: Philippe Pibarot, PhD, DVM, Institut universitaire de cardiologie et de pneumologie de Québec, University Laval

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2008

Primary Completion (ANTICIPATED)

March 1, 2024

Study Completion (ANTICIPATED)

March 1, 2024

Study Registration Dates

First Submitted

April 16, 2013

First Submitted That Met QC Criteria

April 16, 2013

First Posted (ESTIMATE)

April 18, 2013

Study Record Updates

Last Update Posted (ACTUAL)

October 28, 2021

Last Update Submitted That Met QC Criteria

October 27, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MOP#102737

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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