EVEREST II Pivotal Study High Risk Registry (HRR)

Study Overview
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Brief Summary
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Prospective, multi-center, single arm registry. Clinical follow-up at discharge, 30 days, 6, 12, 18 and 24, months, and 3, 4 and 5 years. Concurrent Control (CC) group identified retrospectively from the patients screened for the HRR who did not enroll; patient survival determined at 12 months. NCT00209274 (EVEREST II RCT) Intended use Percutaneous reduction of clinically significant mitral regurgitation in symptomatic patients who are considered to be high risk for operative mortality (high surgical risk).

Detailed Description
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The EVEREST II HRR is a single-arm prospective, multicenter clinical trial enrolling high surgical risk patients of the EVEREST II study (NCT00209274). Patients were considered high surgical risk if either their Society of Thoracic Surgery (STS) predicted operative mortality risk was ≥ 12%, or the surgeon investigator determined the patient to be high risk (≥ 12% predicted operative mortality risk) due to the presence of, at a minimum, one of the following pre-specified risk factors: Porcelain aorta or mobile ascending aortic atheroma Post-radiation mediastinum Previous mediastinitis Functional MR with ejection fraction (EF) < 40% Over 75 years old with EF < 40% Prior re-operation with patent grafts Two or more prior chest surgeries Hepatic cirrhosis Three or more of the following STS high risk factors: i. Creatinine > 2.5 mg/dL ii. Prior chest surgery iii. Age over 75 iv. EF < 35% Upon completion of enrollment in the HRR, a process was initiated to ensure patient consent to participate in a Concurrent Control (CC) group was in place. Patients were identified to determine survival through 12 months with current standard of care treatment.CC patients were derived from a cohort of patients screened for enrollment in the HRR,yet did not enroll. All patients had moderate-to-severe (3+) or severe (4+) MR based on transthoracic echocardiography (TTE). To be considered eligible for inclusion in the CC group, the patient had to be classified as high surgical risk using the same criteria used for the HRR. Upon follow-up with the clinical sites, it was determined that some of the initially identified patients with moderate-to-severe (3+) or severe (4+) MR met the criteria for high surgical risk. Of these patients, some were not included due to; lack of Institutional Review Board (IRB) approval at the site, lack of informed consent and unable to be contacted. The remaining patients make up the CC group.

Official Title
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A Study of the Evalve® Cardiovascular Valve Repair (MitraClip®) System Endovascular Valve Edge-to-Edge REpair STudy (EVEREST II) EVEREST II High Risk Registry

Conditions
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Mitral Valve Insufficiency, Mitral Valve Regurgitation, Mitral Valve Incompetence, Mitral Regurgitation, Mitral Insufficiency

Intervention / Treatment
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* Device: Percutaneous mitral valve repair using MitraClip implant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Candidates for the high risk arm of the study must meet all of the following inclusion criteria: Predicted procedural mortality risk calculated using the STS surgical risk calculator of ≥ 12% or in the judgment of the surgeon investigator the patient is considered a high risk surgical candidate due to the presence of one of the following indications: Porcelain aorta or mobile ascending aortic atheroma Post-radiation mediastinum Previous mediastinitis Functional MR with EF<40 Over 75 years old with EF<40 Re-operation with patent grafts Two or more prior chest surgeries Hepatic cirrhosis i Three or more of the following STS high risk factors: i) Creatinine > 2.5 mg/dL ii) Prior chest surgery iii) Age over 75 iv) EF<35 Age 18 years or older. Symptomatic moderate to severe (3+) or severe (4+) chronic mitral regurgitation (MR) and in the judgment of the investigator intervention to reduce MR is likely to provide symptomatic relief for the patient. MR is determined as defined in Appendix A of the EVEREST II study protocol. American Society of Anesthesiologists (ASA) physical status classification of ASA IV or lower. The primary regurgitant jet originates from malcoaptation of the A2 and P2 scallops of the mitral valve. Male or Female. Female subjects of childbearing potential must have a negative pregnancy test within seven (7) days before the procedure. The subject or the subject's legal representative has been informed of the nature of the study and agrees to its provisions and has provided written informed consent as approved by the Institutional Review Board of the respective clinical site. The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits. Transseptal catheterization is determined to be feasible by the treating physician. Exclusion Criteria: Candidates will be excluded from the study if any of the following conditions are present: Evidence of an acute myocardial infarction in the prior 2 weeks of the intended treatment (defined as: Q wave or non-Q wave infarction having creatine kinase (CK) enzymes ≥ two times (2X) the upper laboratory normal limit with the presence of a Creatine Kinase MB Isoenzyme (CKMB) elevated above the institution's upper limit of normal). In the judgment of the Investigator, the femoral vein cannot accommodate a 24 F catheter or presence of ipsilateral deep vein thrombosis (DVT). Ejection fraction < 20%, and/or end-systolic dimension > 60 mm as defined in Appendix A of the EVEREST II protocol. Mitral valve orifice area < 4.0 cm2 as defined in Appendix A of the EVEREST II protocol. If leaflet flail is present: Flail Width: the width of the flail segment is greater than or equal to 15 mm, as defined in Section 4.3 and Appendix A, or Flail Gap: the flail gap is greater than or equal to 10 mm, as defined in Section 4.3 and Appendix A. If leaflet tethering is present: a). Coaptation Length: the vertical coaptation length is less than 2 mm, as defined in Section 4.3 and Appendix A. Leaflet anatomy which may preclude clip implantation, proper clip positioning on the leaflets or sufficient reduction in MR. This may include: Evidence of calcification in the grasping area of the A2 and/or P2 scallops Presence of a significant cleft of A2 or P2 scallops More than one anatomic criteria dimensionally near the exclusion limits Bileaflet flail or severe bileaflet prolapse Lack of both primary and secondary chordal support Hemodynamic instability defined as systolic pressure < 90 mmHg without after load reduction or cardiogenic shock or the need for inotropic support or intra-aortic balloon pump. Need for emergent or urgent surgery for any reason. Prior mitral valve leaflet surgery or any currently implanted mechanical prosthetic mitral valve. Echocardiographic evidence of intracardiac mass, thrombus or vegetation. Active endocarditis or active rheumatic heart disease or leaflets degenerated from rheumatic diseased (i.e. noncompliant, perforated). History of bleeding diathesis or coagulopathy or subject will refuse blood transfusions. Active infections requiring current antibiotic therapy (if temporary illness, patients may enroll 2 weeks after discontinuation of antibiotics). Patients must be free from infection prior to treatment. Any required dental work should be completed a minimum of 3 weeks prior to treatment. Intravenous drug abuse or suspected inability to adhere to follow-up. Patients in whom transesophageal echocardiography (TEE) is contraindicated. A known hypersensitivity or contraindication to study or In the judgment of the Investigator, patients in whom the presence of a permanent pacemaker or pacing leads would interfere with placement of the test device or the placement of the test device would disrupt the leads. Currently participating in an investigational drug or another device study that has not completed the primary endpoint or that clinically interferes with the current study endpoints. [Note: Trials requiring extended follow-up for products that were investigational, but have since become commercially available, are not considered investigational trials].

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Risk Registry Arm<br>Includes patients with a predicted procedural mortality of 12% or higher. The high risk registry arm of the study is powered to show superiority of safety of treatment with the MitraClip compared to mitral valve surgery. The patients who are enrolled in this arm will undergo percutaneous mitral valve repair using MitraClip implant. | Device: Percutaneous mitral valve repair using MitraClip implant<br>* Procedure/Surgery: Mitral valve repair or replacement surgery Repair or replacement of mitral valve<br>* Other names: MitraClip Implant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Functional and Structural Measures - Freedom From Death | Defined as all causes of death for the primary safety Major Adverse Event (MAE) Endpoint. Death is further divided into 2 categories: A. Cardiac death is defined as death due to any of the following: Acute myocardial infarction. Cardiac perforation/pericardial tamponade. Arrhythmia or conduction abnormality. Stroke within 30 days of the procedure or stroke suspected of being related to the procedure. Death due to any complication of the procedure, including bleeding, vascular repair, transfusion reaction, or bypass surgery. Any death for which a cardiac cause cannot be excluded. B. Non-cardiac death is defined as a death not due to cardiac causes (as defined above). | 12 months | 
| Percentage of Participants With Freedom From Death and Mitral Regurgitation (MR) >2+ | Kaplan-Meier estimated percentage of patients who are alive and have a mitral regurgitation severity grade of 2+ or less | 12 months | 
| Number of Participants With Clinical Measures of Benefit-New York Heart Association (NYHA) Class | The major effectiveness endpoint is an assessment of multiple functional and structural measures of benefit including New York Heart Association (NYHA) Class. Class I: Patients with cardiac disease but without resulting limitations of physical activity. Class II: Patients with cardiac disease resulting in slight limitation of physical activity. Patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation dyspnea, or anginal pain. Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 30 days | 
| Number of Participants With New York Heart Association (NYHA) Class | Class I: Patients with cardiac disease but without resulting limitations of physical activity. Class II: Patients with cardiac disease resulting in slight limitation of physical activity. Patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation dyspnea, or anginal pain. Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 12 months | 
| Clinical Measures of Benefit-Quality of Life (QOL) as Measured by Short Form (SF) 36 | Standardized quality of life surveys allow physicians to evaluate the effectiveness of different treatment methods and the physical and psychological benefits a patient is likely to receive from a particular treatment.In the EVEREST II HRR,the patients were asked to complete the SF-36 QOL survey at baseline, 30 days and 12 months. The physical & mental function were assessed by the Physical Component Summary (PCS) score & Mental Component Summary (MCS) score. The PCS & MCS norms for 65-75 year olds are 44 and 52 respectively; and 31 & 46 for congestive heart failure (CHF) patients respectively. Each scale from the SF-36 is an algebraic sum of responses for all items in that scale.For ease of analysis each scale is then transformed to a 0-100 scale using a formula that converts the lowest & highest possible scores to 0 & 100 respectively.The scoring of the SF-36 indicates that 0% in a domain represents the poorest possible QoL & 100% indicates full QoL. | 12 months | 
| Left Ventricular End Diastolic Volume (LVEDV) | Left Ventricular End Diastolic Volume (LVEDV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 12 months | 
| Left Ventricular End Systolic Volume (LVESV) | Left Ventricular End Systolic Volume (LVESV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 12 months | 
| Left Ventricular (LV) Function - Internal Dimension | Left Ventricular Internal Dimension in diastole (LVIDd) and Left Ventricular Internal Dimension in systole (LVIDs) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 12 months | 
| Number of Patients With CHF Having Hospitalization During Discharge Through 12 Months | Number of patients with incidence of re-hospitalizations for CHF in the 12-months after the MitraClip implant procedure. | 12 months | 
| Number of CHF Events Leading to Hospitalizations During Discharge Through 12 Months | Incidence of re-hospitalizations for CHF in the 12-months after the MitraClip implant procedure. | 12 months | 
| Left Ventricular End Diastolic Volume (LVEDV) | Left Ventricular End Diastolic Volume (LVEDV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | Discharge or 30 days | 
| Left Ventricular End Systolic Volume (LVESV) | Left Ventricular End Systolic Volume (LVESV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | Discharge or 30 days | 
| Left Ventricular (LV) Function - Internal Dimension | Left Ventricular Internal Dimension in diastole (LVIDd) and Left Ventricular Internal Dimension in systole (LVIDs) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | Discharge or 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Major Adverse Events (MAE) | Combined clinical endpoint of death, myocardial infarction, reoperation for failed surgical repair or replacement, nonelective cardiovascular surgery for adverse events, stroke, renal failure, deep wound infection, ventilation for greater than 48 hours, GI complication requiring surgery, new onset of permanent atrial fibrillation, septicemia, and transfusion of 2 or more units of blood. | 30 days | 
| Number of Participants Experiencing Major Adverse Events | Combined clinical endpoint of death, myocardial infarction, reoperation for failed surgical repair or replacement, nonelective cardiovascular surgery for adverse events, stroke, renal failure, deep wound infection, ventilation for greater than 48 hours, GI complication requiring surgery, new onset of permanent atrial fibrillation, septicemia, and transfusion of 2 or more units of blood. | 12 months | 
| Procedural Freedom From In-hospital MAE | Percutaneous Clip procedure or surgery with no occurrence of in-hospital MAE. | 30 Days | 
| Number of Participants Over 75 Years of Age With MAE | Combined clinical endpoint of death, myocardial infarction, reoperation for failed surgical repair or replacement, nonelective cardiovascular surgery for adverse events, stroke, renal failure, deep wound infection, ventilation for greater than 48 hours, GI complication requiring surgery, new onset of permanent atrial fibrillation, septicemia, and transfusion of 2 or more units of blood. | 30 days | 
| Number of Participants Over 75 Years of Age With MAE | Combined clinical endpoint of death, myocardial infarction, reoperation for failed surgical repair or replacement, nonelective cardiovascular surgery for adverse events, stroke, renal failure, deep wound infection, ventilation for greater than 48 hours, GI complication requiring surgery, new onset of permanent atrial fibrillation, septicemia, and transfusion of 2 or more units of blood. | 12 months | 
| Number of Participants Experiencing Major Vascular Complications | Defined as the occurrence of any of the following resulting from the index procedure: Hematoma at access site >6 cm; Retroperitoneal hematoma; Arterial-venous fistula; Symptomatic peripheral ischemia/ nerve injury with clinical signs or symptoms lasting >24 hours; Vascular surgical repair at catheter access sites; Pulmonary embolism; Ipsilateral deep vein thrombus; or Access site-related infection requiring intravenous antibiotics and/or extended hospitalization. | 30 days | 
| Number of Participants Experiencing Major Vascular Complications | Defined as the occurrence of any of the following resulting from the index procedure: Hematoma at access site >6 cm; Retroperitoneal hematoma; Arterial-venous fistula; Symptomatic peripheral ischemia/ nerve injury with clinical signs or symptoms lasting >24 hours; Vascular surgical repair at catheter access sites; Pulmonary embolism; Ipsilateral deep vein thrombus; or Access site-related infection requiring intravenous antibiotics and/or extended hospitalization. | 12 months | 
| Number of Participants With Major Bleeding Complications | Defined as procedure related bleeding that requires a transfusion of ≥2 units of blood and/or surgical intervention. | 30 days | 
| Number of Participants With Major Bleeding Complications | Defined as procedure related bleeding that requires a transfusion of ≥2 units of blood and/or surgical intervention. | 12 months | 
| Number of Participants With Non-cerebral Thromboembolism | Defined as any mural thrombus or thromboembolism in the vasculature (excluding central nervous system events) confirmed by standard clinical and laboratory testing and which requires intervention. | 30 days | 
| Number of Participants With Non-cerebral Thromboembolism | Defined as any mural thrombus or thromboembolism in the vasculature (excluding central nervous system events) confirmed by standard clinical and laboratory testing and which requires intervention. | 12 months | 
| Number of Participants With Thrombosis | Evidence of formation of an independently moving thrombus on any part of the Clip or any commercially available implant used during surgery by echocardiography or fluoroscopy. If Clip is explanted or an autopsy is performed this diagnosis should be confirmed. | 30 days | 
| Number of Participants With Thrombosis | Evidence of formation of an independently moving thrombus on any part of the Clip or any commercially available implant used during surgery by echocardiography or fluoroscopy. If Clip is explanted or an autopsy is performed this diagnosis should be confirmed. | 12 months | 
| Number of Participants With Hemolysis | Defined as new onset of anemia associated with laboratory evidence of red cell destruction. Diagnosed when plasma free hemoglobin is greater than 40 mg/dL on two measures within 24 hours or on one measure if intervention is initiated based on other clinical symptoms | 30 days | 
| Number of Participants With Hemolysis | Defined as new onset of anemia associated with laboratory evidence of red cell destruction. Diagnosed when plasma free hemoglobin is greater than 40 mg/dL on two measures within 24 hours or on one measure if intervention is initiated based on other clinical symptoms. | 12 months | 
| Number of Participants With Dysrhythmias | Includes all new onset atrial fibrillation and heart block requiring placement of a permanent pacemaker. | 30 days | 
| Number of Participants With Dysrhythmias | Includes all new onset atrial fibrillation and heart block requiring placement of a permanent pacemaker. | 12 months | 
| Number of Participants With Endocarditis | Using Duke Criteria, endocarditis can be confirmed by: Pathological criteria: Endocarditis is confirmed if microorganisms are identified by culture or histology in a vegetation, embolized vegetation, or an intracardiac abscess; or if pathological lesions are observed & histologically confirmed showing active endocarditis. Clinical criteria: Endocarditis is confirmed by the presence of 2 major criteria, 1 major plus 3 minor criteria, or 5 minor criteria. Major criteria include persistently +ve blood cultures with the presence of typical organisms for endocarditis; persistent bacteremia; evidence of endocardial involvement with positive echocardiogram with signs of oscillating vegetation, abscesses, valve perforation, new partial dehiscence of prosthetic valve or new valvular regurgitation. Minor criteria include predisposing heart condition, fever, vascular phenomena, immunologic phenomena, & positive blood culture or echocardiogram not meeting major criteria. | 30 days | 
| Number of Participants With Endocarditis | Using Duke Criteria, endocarditis can be confirmed by: Pathological criteria: Endocarditis is confirmed if microorganisms are identified by culture or histology in a vegetation, embolized vegetation, or an intracardiac abscess; or if pathological lesions are observed & histologically confirmed showing active endocarditis. Clinical criteria: Endocarditis is confirmed by the presence of 2 major criteria, 1 major plus 3 minor criteria, or 5 minor criteria. Major criteria include persistently +ve blood cultures with the presence of typical organisms for endocarditis; persistent bacteremia; evidence of endocardial involvement with positive echocardiogram with signs of oscillating vegetation, abscesses, valve perforation, new partial dehiscence of prosthetic valve or new valvular regurgitation. Minor criteria include predisposing heart condition, fever, vascular phenomena, immunologic phenomena, & positive blood culture or echocardiogram not meeting major criteria. | 12 months | 
| Number of Participants With Atrial Septal Defect (ASD) | Occurrence of clinically significant ASD as a result of the procedure requiring intervention. | 30 days | 
| Number of Participants With Atrial Septal Defect (ASD) | Occurrence of clinically significant ASD as a result of the procedure requiring intervention. | 12 months | 
| Number of Participants With Mitral Valve Stenosis | Mitral stenosis associated with a total mitral valve orifice area less than 1.5 cm2. | 30 days | 
| Number of Participants With Mitral Valve Stenosis | Mitral stenosis associated with a total mitral valve orifice area less than 1.5 cm2. | 12 months | 
| Number of Participants With Mitral Valve Stenosis | Mitral stenosis associated with a total mitral valve orifice area less than 1.5 cm2. | 24 months | 
| Number of Participants With Mitral Valve Stenosis | Mitral stenosis associated with a total mitral valve orifice area less than 1.5 cm2. | 36 months | 
| Number of Participants With Mitral Valve Stenosis | Mitral stenosis associated with a total mitral valve orifice area less than 1.5 cm2. | 48 months | 
| Mitral Valve Area: By Planimetry | Mitral valve area as measured by core lab echocardiography. | 30 days | 
| Mitral Valve Area: By Planimetry | Mitral valve area as measured by core lab echocardiography. | 12 months | 
| Mitral Valve Area: By Planimetry | Mitral valve area as measured by core lab echocardiography. | 24 months | 
| Mitral Valve Area: By Planimetry | Mitral valve area as measured by core lab echocardiography. | 36 months | 
| Mitral Valve Area: By Planimetry | Mitral valve area as measured by core lab echocardiography. | 48 months | 
| Mitral Valve Area: By Planimetry | Mitral valve area as measured by core lab echocardiography. | 60 months | 
| Mitral Valve Area: By Pressure Half-time | Mitral valve area as measured by core lab echocardiography. | 30 days | 
| Mitral Valve Area: By Pressure Half-time | Mitral valve area as measured by core lab echocardiography. | 12 months | 
| Mitral Valve Area: By Pressure Half-time | Mitral valve area as measured by core lab echocardiography. | 24 months | 
| Mitral Valve Area: By Pressure Half-time | Mitral valve area as measured by core lab echocardiography. | 36 months | 
| Mitral Valve Area: By Pressure Half-time | Mitral valve area as measured by core lab echocardiography. | 48 months | 
| Mitral Valve Area: By Pressure Half-time | Mitral valve area as measured by core lab echocardiography. | 60 months | 
| Mitral Valve Area Index : By Planimetry | Mitral valve area as measured by core lab echocardiography by planimetry and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 30 days | 
| Mitral Valve Area Index : By Planimetry | Mitral valve area as measured by core lab echocardiography by planimetry and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 12 months | 
| Mitral Valve Area Index : By Planimetry | Mitral valve area as measured by core lab echocardiography by planimetry and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 24 months | 
| Mitral Valve Area Index : By Planimetry | Mitral valve area as measured by core lab echocardiography by planimetry and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 36 months | 
| Mitral Valve Area Index : By Planimetry | Mitral valve area as measured by core lab echocardiography by planimetry and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 48 months | 
| Mitral Valve Area Index : By Planimetry | Mitral valve area as measured by core lab echocardiography by planimetry and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 60 months | 
| Mitral Valve Area (MVA) Index: by Pressure-Half Time Formula | Mitral valve area as measured by core lab echocardiography using the pressure half-time formula and indexed to Body surface area (BSA). [MVA Index = MVA (cm^2)/BSA (m^2)] | 30 days | 
| Mitral Valve Area Index : By Pressure Half-time Formula | Mitral valve area as measured by core lab echocardiography using the pressure half-time formula and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 12 months | 
| Mitral Valve Area Index : By Pressure Half-time Formula | Mitral valve area as measured by core lab echocardiography using the pressure half-time formula and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 24 months | 
| Mitral Valve Area Index : By Pressure Half-time Formula | Mitral valve area as measured by core lab echocardiography using the pressure half-time formula and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 36 months | 
| Mitral Valve Area Index : By Pressure Half-time Formula | Mitral valve area as measured by core lab echocardiography using the pressure half-time formula and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 48 months | 
| Mitral Valve Area Index : By Pressure Half-time Formula | Mitral valve area as measured by core lab echocardiography using the pressure half-time formula and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)]. | 60 months | 
| Transvalvular Mitral Valve Gradient | Defined as the mean pressure gradients across the mitral valve as measured by echocardiography. | 30 days | 
| Transvalvular Mitral Valve Gradient | Defined as the mean pressure gradients across the mitral valve as measured by echocardiography. | 12 months | 
| Transvalvular Mitral Valve Gradient | Defined as the mean pressure gradients across the mitral valve as measured by echocardiography. | 24 months | 
| Transvalvular Mitral Valve Gradient | Defined as the mean pressure gradients across the mitral valve as measured by echocardiography. | 36 months | 
| Transvalvular Mitral Valve Gradient | Defined as the mean pressure gradients across the mitral valve as measured by echocardiography. | 48 months | 
| Transvalvular Mitral Valve Gradient | Defined as the mean pressure gradients across the mitral valve as measured by echocardiography. | 60 months | 
| Mitral Valve Index | Mitral valve area as measured by core lab echocardiography and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)] | 30 days | 
| Mitral Valve Index | Mitral valve area as measured by core lab echocardiography and indexed to body surface area [MVA Index = MVA (cm^2)/BSA (m^2)] | 12 months | 
| Number of Participants With New Coumadin Use | New onset use of Coumadin or warfarin to treat a potential thrombus on a defibrillator lead. | 30 days | 
| Number of Participants With New Coumadin Use | New onset use of Coumadin or warfarin to treat a potential thrombus on a defibrillator lead. | 6 months | 
| Number of Participants With New Coumadin Use | New onset use of Coumadin or warfarin to treat a potential thrombus on a defibrillator lead. | 12 months | 
| Number of Participants Discharged to a Nursing Home or Skilled Nursing Facility or Hospital | Discharge to a nursing home or skilled nursing facility following discharge from the hospital after definitive treatment. | 30 Days | 
| Post-procedure Length of Hospital Stay | Defined as the number of days from the end of the procedure until the patient is discharged from the hospital. This does not include time in a nursing or skilled care facility. | Length of Hospital Stay, assessed at 30 days | 
| Post-procedure Intensive Care Unit (ICU)/ Critical Care Unit (CCU) Time | Number of hours patients are in an intensive care unit or step down unit before discharge or moving to a standard care unit. | Length of ICU/CCU stay, assessed at 30 Days | 
| Number of Participants With Successful Clip Implant | Rate of successful delivery and deployment of Clip implants with echocardiographic evidence of leaflet approximation and retrieval of the investigational delivery catheter. | 30 Days | 
| Number of Participants With High Risk Procedural Success | Successful implantation of the Clip (s) with resulting MR severity of 2+ of less at discharge or a 1 grade MR reduction at discharge accompanied by a 1 level reduction in NYHA. | 30 days | 
| Number of Participants With MR Severity | MR Severity: Site-assessed mitral regurgitation severity using echocardiography. MR severity is graded on a scale of 0+ to 4+ where 0+ means absence of mitral regurgitation, 1+ is mild, 1+ to 2+ is mild-to-moderate, 2+ to 3+ is moderate to moderate-to-Severe, 3+ is moderate-to-severe, 3+ to 4+ is moderate-to-severe to severe, 4+ is severe. | Discharge or 30 days | 
| Number of Participants With MR Severity | MR Severity: Site-assessed mitral regurgitation severity using echocardiography. MR severity is graded on a scale of 0+ to 4+ where 0+ means absence of mitral regurgitation, 1+ is mild, 1+ to 2+ is mild-to-moderate, 2+ to 3+ is moderate to moderate-to-Severe, 3+ is moderate-to-severe, 3+ to 4+ is moderate-to-severe to severe, 4+ is severe. | 12 months | 
| Number of Participants With MR Severity | MR Severity: Site-assessed mitral regurgitation severity using echocardiography. MR severity is graded on a scale of 0+ to 4+ where 0+ means absence of mitral regurgitation, 1+ is mild, 1+ to 2+ is mild-to-moderate, 2+ to 3+ is moderate to moderate-to-Severe, 3+ is moderate-to-severe, 3+ to 4+ is moderate-to-severe to severe, 4+ is severe. | 24 months | 
| Number of Participants With MR Severity | MR Severity: Site-assessed mitral regurgitation severity using echocardiography. MR severity is graded on a scale of 0+ to 4+ where 0+ means absence of mitral regurgitation, 1+ is mild, 1+ to 2+ is mild-to-moderate, 2+ to 3+ is moderate to moderate-to-Severe, 3+ is moderate-to-severe, 3+ to 4+ is moderate-to-severe to severe, 4+ is severe. | 36 months | 
| Number of Participants With MR Severity | MR Severity: Site-assessed mitral regurgitation severity using echocardiography. MR severity is graded on a scale of 0+ to 4+ where 0+ means absence of mitral regurgitation, 1+ is mild, 1+ to 2+ is mild-to-moderate, 2+ to 3+ is moderate to moderate-to-Severe, 3+ is moderate-to-severe, 3+ to 4+ is moderate-to-severe to severe, 4+ is severe. | 48 months | 
| Number of Participants With MR Severity | MR Severity: Site-assessed mitral regurgitation severity using echocardiography. MR severity is graded on a scale of 0+ to 4+ where 0+ means absence of mitral regurgitation, 1+ is mild, 1+ to 2+ is mild-to-moderate, 2+ to 3+ is moderate to moderate-to-Severe, 3+ is moderate-to-severe, 3+ to 4+ is moderate-to-severe to severe, 4+ is severe. | 60 months | 
| Number of Participants With Treatment Durability | Defined as the proportion of Acute Procedural Success patients with MR severity grade of 2+ or less that have not required surgery for valve dysfunction. | 12 months | 
| Number of Participants With Treatment Durability | Defined as the proportion of Acute Procedural Success patients with MR severity grade of 2+ or less that have not required surgery for valve dysfunction. | 24 months | 
| Number of Participants With Clinical Durability | Proportion of patients who have an acute reduction in MR severity of at least one grade (as measured by the discharge echocardiogram) that have not required surgery for valve dysfunction and meet either of the following: 1) MR severity grade of 2+ or less or 2) a one grade reduction in MR severity compared to baseline accompanied by at least a one level reduction in NYHA. | 12 months | 
| Number of Participants With Clinical Durability | Proportion of patients who have an acute reduction in MR severity of at least one grade (as measured by the discharge echocardiogram) that have not required surgery for valve dysfunction and meet either of the following: 1) MR severity grade of 2+ or less or 2) a one grade reduction in MR severity compared to baseline accompanied by at least a one level reduction in NYHA. | 24 months | 
| Number of Participants With Composite Functional and Structural Measures - Clinical Measures of Benefit-New York Heart Association (NYHA) Class | Class I: Patients with cardiac disease but without resulting limitations of physical activity. Class II: Patients with cardiac disease resulting in slight limitation of physical activity. Patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation dyspnea, or anginal pain. Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 24 months | 
| Number of Participants With Composite Functional and Structural Measures - Clinical Measures of Benefit-New York Heart Association (NYHA) Class | Class I: Patients with cardiac disease but without resulting limitations of physical activity. Class II: Patients with cardiac disease resulting in slight limitation of physical activity. Patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation dyspnea, or anginal pain. Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 36 months | 
| Number of Participants With Composite Functional and Structural Measures - Clinical Measures of Benefit-New York Heart Association (NYHA) Class | Class I: Patients with cardiac disease but without resulting limitations of physical activity. Class II: Patients with cardiac disease resulting in slight limitation of physical activity. Patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation dyspnea, or anginal pain. Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 48 months | 
| Number of Participants With New York Heart Association (NYHA) Class | Class I: Patients with cardiac disease but without resulting limitations of physical activity. Class II: Patients with cardiac disease resulting in slight limitation of physical activity. Patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation dyspnea, or anginal pain. Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 60 months | 
| Left Ventricular End-diastolic Volume (LVEDV). | Left Ventricular End Diastolic Volume (LVEDV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 24 months | 
| Left Ventricular End-diastolic Volume (LVEDV). | Left Ventricular End Diastolic Volume (LVEDV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 36 months | 
| Left Ventricular End-diastolic Volume (LVEDV). | Left Ventricular End Diastolic Volume (LVEDV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 48 months | 
| Left Ventricular End-diastolic Volume (LVEDV). | Left Ventricular End Diastolic Volume (LVEDV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 60 months | 
| Left Ventricular End-systolic Volume (LVESV). | Left Ventricular End Systolic Volume (LVESV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 24 months | 
| Left Ventricular End-systolic Volume (LVESV). | Left Ventricular End Systolic Volume (LVESV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 36 months | 
| Left Ventricular End-systolic Volume (LVESV). | Left Ventricular End Systolic Volume (LVESV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 48 months | 
| Left Ventricular End-systolic Volume (LVESV). | Left Ventricular End Systolic Volume (LVESV) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 60 months | 
| Left Ventricular Measurement: Left Ventricular Internal Dimension Diastole (LVIDd), Left Ventricular Internal Dimension Systole (LVIDs) | Left Ventricular Internal Dimension in diastole (LVIDd) and Left Ventricular Internal Dimension in systole (LVIDs) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 24 months | 
| Left Ventricular Measurement: Left Ventricular Internal Dimension Diastole (LVIDd), Left Ventricular Internal Dimension Systole (LVIDs) | Left Ventricular Internal Dimension in diastole (LVIDd) and Left Ventricular Internal Dimension in systole (LVIDs) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 36 months | 
| Left Ventricular Measurement: Left Ventricular Internal Dimension Diastole (LVIDd), Left Ventricular Internal Dimension Systole (LVIDs) | Left Ventricular Internal Dimension in diastole (LVIDd) and Left Ventricular Internal Dimension in systole (LVIDs) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 48 months | 
| Left Ventricular Measurement: Left Ventricular Internal Dimension Diastole (LVIDd), Left Ventricular Internal Dimension Systole (LVIDs) | Left Ventricular Internal Dimension in diastole (LVIDd) and Left Ventricular Internal Dimension in systole (LVIDs) as determined by the core echocardiography laboratory from a transthoracic echocardiogram (TTE). | 60 months | 
| Number of Days Re-hospitalized for CHF | Defined as the number of days hospitalized for CHF in the 12-months prior to the Clip implant procedure date compared to the number of days re-hospitalized for CHF in the 12-months after Clip implant. | 12 months | 
| Number of Hospital Re-Admissions for Congestive Heart Failure (CHF) | Defined as the number of hospital admissions (i.e. events) for which the primary diagnosis for hospitalization is congestive heart failure, in the 12-months post-discharge following the MitraClip procedure. | 12 months | 
| Regurgitant Volume | Regurgitant volume as measured by the core echocardiographic laboratory at follow-up. | 30 days | 
| Regurgitant Volume | Regurgitant volume as measured by the core echocardiographic laboratory at follow-up. | 12 months | 
| Regurgitant Volume | Regurgitant volume as measured by the core echocardiographic laboratory at follow-up. | 24 months | 
| Regurgitant Fraction (RF) | RF is defined as the percentage of the left ventricular (LV) stroke volume that regurgitates into the left atrium. | 30 days | 
| Regurgitant Fraction | RF is defined as the percentage of the left ventricular (LV) stroke volume that regurgitates into the left atrium. | 12 months | 
| Regurgitant Fraction | RF is defined as the percentage of the left ventricular (LV) stroke volume that regurgitates into the left atrium. | 24 months | 
| Cardiac Output (CO) | CO is defined as the volume of blood pumped by the left ventricle per unit time (L/min). | 30 Days | 
| Cardiac Output | CO is defined as the volume of blood pumped by the left ventricle per unit time (L/min) | 12 months | 
| Cardiac Output | CO is defined as the volume of blood pumped by the left ventricle per unit time (L/min) | 24 months | 
| Cardiac Index | Cardiac index (cardiac output divided by body surface area) as measured by core lab echocardiography. | 30 Days | 
| Cardiac Index | Cardiac index (cardiac output divided by body surface area) as measured by core lab echocardiography. | 12 months | 
| Cardiac Index | Cardiac index (cardiac output divided by body surface area) as measured by core lab echocardiography. | 24 months | 
| Left Ventricular Ejection Fraction (LVEF) | Left Ventricular Ejection Fraction (LVEF) as determined by the core echocardiography laboratory. | Discharge or 30 days | 
| Left Ventricular Ejection Fraction (LVEF) | Left Ventricular Ejection Fraction (LVEF) as determined by the core echocardiography laboratory. | 12 months | 
| Left Ventricular Ejection Fraction (LVEF) | Left Ventricular Ejection Fraction (LVEF) as determined by the core echocardiography laboratory. | 24 months | 
| Left Ventricular Ejection Fraction (LVEF) | Left Ventricular Ejection Fraction (LVEF) as determined by the core echocardiography laboratory. | 36 months | 
| Left Ventricular Ejection Fraction (LVEF) | Left Ventricular Ejection Fraction (LVEF) as determined by the core echocardiography laboratory. | 48 months | 
| Left Ventricular Ejection Fraction (LVEF) | Left Ventricular Ejection Fraction (LVEF) as determined by the core echocardiography laboratory. | 60 months | 
| Percentage of Participants With Freedom From Mitral Valve Surgery | Percentage of patients who did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | Baseline | 
| Percentage of Participants With Freedom From Mitral Valve Surgery | Percentage of patients who did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | 12 months | 
| Percentage of Participants With Freedom From Mitral Valve Surgery | Percentage of patients who did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | 24 months | 
| Percentage of Participants With Freedom From Mitral Valve Surgery | Percentage of patients who did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | 36 months | 
| Percentage of Participants With Freedom From Mitral Valve Surgery | Percentage of patients who did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | 48 months | 
| Percentage of Participants With Freedom From Mitral Valve Surgery | Percentage of patients who did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | 60 months | 
| Number of Participants With Mitral Valve Repair Success | Mitral Valve Repair Success defined as freedom from mitral valve replacement surgery for valve dysfunction, death, re-operation and MR > 2+ at 12 months. | 12 months | 
| Number of Participants With Mitral Valve Repair Success | Freedom from mitral valve replacement surgery for Valve Dysfunction, death, re-operation, and MR > 2+. | 24 months | 
| Composite Functional and Structural Measures - Percentage of Participants With Freedom From Death | Defined as all causes of death for the primary safety Major Adverse Event (MAE) Endpoint. Death is further divided into 2 categories: A. Cardiac death is defined as death due to any of the following: Acute myocardial infarction. Cardiac perforation/pericardial tamponade. Arrhythmia or conduction abnormality. Stroke within 30 days of the procedure or stroke suspected of being related to the procedure. Death due to any complication of the procedure, including bleeding, vascular repair, transfusion reaction, or bypass surgery. Any death for which a cardiac cause cannot be excluded. B. Non-cardiac death is defined as a death not due to cardiac causes (as defined above). | 24 months | 
| Percentage of Participants With Composite Functional and Structural Measures - Freedom From Death and MR >2+ | Kaplan-Meier estimated proportion of patients who are alive and have a mitral regurgitation severity grade of 2+ or less. | 24 months | 
| Number of Participants With Device Embolization or Single Leaflet Device Attachment | Device embolization is defined as bilateral Clip detachment resulting in Clip embolization. Reasons for Clip embolization include leaflet tearing, Clip unlocking, Clip fracture or inadequate Clip placement (i.e., malposition). Not included are any fractures or other failures of the Clip that do not result in Clip detachment from both leaflets. A single leaflet device attachment (SLDA) is defined as attachment of one mitral valve leaflet to the MitraClip device. | 0 to 12 months | 
| Number of Participants With Device Embolization or Single Leaflet Device Attachment | Device embolization is defined as bilateral Clip detachment resulting in Clip embolization. Reasons for Clip embolization include leaflet tearing, Clip unlocking, Clip fracture or inadequate Clip placement (i.e., malposition). Not included are any fractures or other failures of the Clip that do not result in Clip detachment from both leaflets. A single leaflet device attachment (SLDA) is defined as attachment of one mitral valve leaflet to the MitraClip device. | 24 months | 
| Number of Participants With Device Embolization or Single Leaflet Device Attachment | Device embolization is defined as bilateral Clip detachment resulting in Clip embolization. Reasons for Clip embolization include leaflet tearing, Clip unlocking, Clip fracture or inadequate Clip placement (i.e., malposition). Not included are any fractures or other failures of the Clip that do not result in Clip detachment from both leaflets. A single leaflet device attachment (SLDA) is defined as attachment of one mitral valve leaflet to the MitraClip device. | 48 months | 
| Number of Participants With Device Embolization or Single Leaflet Device Attachment | Device embolization is defined as bilateral Clip detachment resulting in Clip embolization. Reasons for Clip embolization include leaflet tearing, Clip unlocking, Clip fracture or inadequate Clip placement (i.e., malposition). Not included are any fractures or other failures of the Clip that do not result in Clip detachment from both leaflets. A single leaflet device attachment (SLDA) is defined as attachment of one mitral valve leaflet to the MitraClip device. | 36 months | 
| Number of Participants With Device Embolization or Single Leaflet Device Attachment | Device embolization is defined as bilateral Clip detachment resulting in Clip embolization. Reasons for Clip embolization include leaflet tearing, Clip unlocking, Clip fracture or inadequate Clip placement (i.e., malposition). Not included are any fractures or other failures of the Clip that do not result in Clip detachment from both leaflets. A single leaflet device attachment (SLDA) is defined as attachment of one mitral valve leaflet to the MitraClip device. | 60 months | 
| Number of Participants With Mitral Valve Surgery Post-MitraClip Procedure | Number of patients who underwent surgical mitral valve repair or replacement after the index MitraClip procedure. | 60 months | 
| Number of Participants With Second MitraClip Device Implanted | It is a summary of re-interventions to place an additional MitraClip Device. | 0 to 5 years | 
| Percentage of Participants With Freedom From All-Cause Mortality and Mitral Valve Surgery | Kaplan-Meier estimate of the percentage of patients who are alive and did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | 12 months | 
| Percentage of Participants With Freedom From All-Cause Mortality and Mitral Valve Surgery | Kaplan-Meier estimate of the percentage of patients who are alive and did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | 24 months | 
| Percentage of Participants With Freedom From All-Cause Mortality and Mitral Valve Surgery | Kaplan-Meier estimate of the percentage of patients who are alive and did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | 36 months | 
| Percentage of Participants With Freedom From All-Cause Mortality and Mitral Valve Surgery | Kaplan-Meier estimate of the percentage of patients who are alive and did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | 48 months | 
| Percentage of Participants With Freedom From All-Cause Mortality and Mitral Valve Surgery | Kaplan-Meier estimate of the percentage of patients who are alive and did not undergo surgical mitral valve repair or replacement after the index MitraClip procedure | 60 months | 
| Number of Participants With Mitral Valve Replacement | Defined as how often patients receiving surgery required replacement of the mitral valve. | 12 months | 
| Number of Participants With Mitral Valve Replacement | Defined as how often patients receiving surgery required replacement of the mitral valve. | 24 months | 
| Number of Participants With Mitral Valve Replacement | Defined as how often patients receiving surgery required replacement of the mitral valve. | 36 months | 
| Number of Participants With Mitral Valve Replacement | Defined as how often patients receiving surgery required replacement of the mitral valve. | 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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REALISM, Mitral Valve Insufficiency, Mitral Valve Regurgitation, Mitral Valve Incompetence, Mitral Regurgitation, Mitral Insufficiency, Mitral Valve, MR, Mitral Valve Prolapse, Edge to Edge (E2E), Alfieri Technique, MitraClip, Functional MR, Degenerative MR, Echocardiogram, Coronary Artery Disease (CAD), Heart Failure, Heart Attack, EVEREST, EVEREST I, EVEREST II