Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety and efficacy of the Medtronic CoreValve® System in the treatment of symptomatic severe aortic stenosis in subjects who have a predicted high risk for aortic valve surgery and/or very high risk for aortic valve surgery.

Official Title
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Medtronic CoreValve® U.S. Pivotal Trial

Conditions
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Severe Aortic Stenosis

Intervention / Treatment
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* Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)
* Device: Surgical Aortic Valve Replacement (SAVR)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Extreme Risk Only: Subject must have comorbidities such that one cardiologist and two cardiac surgeons agree that medical factors preclude operation, based on a conclusion that the probability of death or serious morbidity exceeds the probability of meaningful improvement. Specifically, the predicted operative risk of death or serious, irreversible morbidity is ≥ 50% at 30 days. High Risk Surgical Only: Subject must have comorbidities such that one cardiologist and two cardiac surgeons agree that predicted risk of operative mortality is ≥15% (and predicted operative mortality or serious, irreversible morbidity risk of < 50%) at 30 days. Subject has senile degenerative aortic valve stenosis with: mean gradient > 40 mmHg, or jet velocity greater than 4.0 m/sec by either resting or dobutamine stress echocardiogram, or simultaneous pressure recordings at cardiac catheterization (either resting or dobutamine stress), AND an initial aortic valve area of ≤ 0.8 cm2 (or aortic valve area index ≤ 0.5 cm2/m2) by resting echocardiogram or simultaneous pressure recordings at cardiac catheterization Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater. The subject or the subject's legal representative has been informed of the nature of the trial, agrees to its provisions and has provided written informed consent as approved by the IRB 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. Exclusion Criteria: Clinical Evidence of an acute myocardial infarction ≤ 30 days before the intended treatment. Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to the intended treatment. (High Risk Surgical Only: Including bare metal stents. Additionally, any drug eluting stents placed within 6 months prior to the index procedure.) Blood dyscrasias as defined: leukopenia (WBC < 1000mm3), thrombocytopenia (platelet count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy. Untreated clinically significant coronary artery disease requiring revascularization. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support. Need for emergency surgery for any reason. Severe ventricular dysfunction with left ventricular ejection fraction (LVEF) < 20% as measured by resting echocardiogram. Recent (within 6 months) cerebrovascular accident (CVA) or transient ischemic attack (TIA). End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min. Active Gastrointestinal (GI) bleeding within the past 3 months. A known hypersensitivity or contraindication to any of the following which cannot be adequately pre-medicated: Aspirin Heparin (HIT/HITTS) Bivalirudin (Extreme Risk Only) Nitinol (titanium or nickel) Ticlopidine and clopidogrel Contrast media Ongoing sepsis, including active endocarditis. Subject refuses a blood transfusion. Life expectancy < 12 months due to associated non-cardiac co-morbid conditions. Other medical, social, or psychological conditions that in the opinion of an Investigator precludes the subject from appropriate consent. Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits). Currently participating in an investigational drug or another device trial. Symptomatic carotid or vertebral artery disease. Subject has been offered surgical aortic valve replacement but declined. (High Risk Surgical Only) Anatomical Native aortic annulus size < 18 mm or > 29 mm per the baseline diagnostic imaging. Pre-existing prosthetic heart valve any position. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation (3-4+)). Moderate to severe (3-4+) or severe (4+) mitral or severe (4+) tricuspid regurgitation. Moderate to severe mitral stenosis. Hypertrophic obstructive cardiomyopathy. New or untreated echocardiographic evidence of intracardiac mass, thrombus or vegetation. Severe basal septal hypertrophy with an outflow gradient. Aortic root angulation (angle between plane of aortic valve annulus and horizontal plane/vertebrae) > 70° (for femoral and left subclavian/axillary access) and > 30° (for right subclavian/axillary access). Ascending aorta diameter > 43 mm if the aortic annulus diameter is 23-29 mm; ascending aorta diameter > 40 mm if the aortic annulus diameter is 20-23 mm; or an ascending aorta diameter > 34 mm if the aortic annulus diameter is 18-20 mm. Congenital bicuspid or unicuspid valve verified by echocardiography. Sinus of valsalva anatomy that would prevent adequate coronary perfusion. Vascular - Transarterial access not able to accommodate an 18Fr sheath.
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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Extreme Risk: TAVI Iliofemoral<br>Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Iliofemoral Access | Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)<br>* Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)<br>|
| Experimental: Extreme Risk: TAVI Non-Iliofemoral<br>Extreme Risk Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI); Non-Iliofemoral Access | Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)<br>* Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)<br>|
| Experimental: High Risk: TAVI<br>High Risk Surgical Patients: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI) | Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)<br>* Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)<br>|
| Active Comparator: High Risk: SAVR<br>High Risk Surgical Patients: Surgical Aortic Valve Replacement (SAVR) | Device: Surgical Aortic Valve Replacement (SAVR)<br>* Surgical Aortic Valve Replacement (SAVR)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extreme Risk: All-cause Death or Major Stroke; High Risk Surgical: All-cause Mortality | All-cause Death or Major Stroke (Extreme Risk- Medtronic CoreValve® System); All-cause Mortality (High Risk Surgical- Medtronic CoreValve® System vs. Surgical Valve) | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Adverse Cardiovascular and Cerebrovascular Event (MACCE) | MACCE is defined as a composite of: All Cause Mortality Myocardial infarction (MI) All Stroke Reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve) | 30 day, 6 month, 1 year, 2 year | 
| The Occurrence of Individual MACCE Components | Individual MACCE Components Include: All Cause Mortality MI All stroke Reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve) | 30 day, 6 month, 1 year, 2 year | 
| Major Adverse Events (MAEs) | MAEs Include: MACCE Acute Kidney Injury Cardiac Tamponade Prosthetic Valve Dysfunction Cardiogenic Shock Valve Endocarditis Life-Threatening, Disabling or Major Bleeding Major Vascular Complication Cardiac Perforation Device Migration/Valve Embolism | 30 day, 6 month, 1 year, 2 year | 
| Conduction Disturbance Requiring Permanent Pacemaker Implantation |  | 30 day, 6 month, 1 year, 2 year | 
| Change in NYHA Class | Change from baseline (continuous variable). A positive number corresponds to NYHA worsening; a negative number corresponds to NYHA improvement. New York Heart Association (NYHA) Classification: Class I: Subjects with cardiac disease but without resulting limitations of physical activity. Class I: Subjects with cardiac disease resulting in slight limitation of physical activity. Class III: Subjects with cardiac disease resulting in marked limitation of physical activity. Class IV: Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. | 30 day, 6 month, 1 year, 2 year | 
| Change in Distance Walked During 6-Minute Walk Test (6MWT) | Change in distance walked during 6MWT from baseline | 30 day, 1 year | 
| Ratio of Days Alive Out of Hospital Versus Total Days Alive |  | 1 year | 
| Quality of Life (QoL) Change | QoL summary score change from baseline using the following measures: Kansas City Cardiomyopathy Questionnaire (KCCQ): Quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. 12 Item Short Form Health Survey (SF-12): Measures functional health and well-being. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. European QoL (EQ-5D): Measures 5 domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that can be converted to utilities using an algorithm. Utilities range from 0 to 1, with 1 representing perfect health, and 0 corresponding to the worst imaginable health state. | 30 day, 6 month, 1 year, 2 year | 
| Echocardiographic Assessment of Valve Performance | Using the following measures: - Effective Orifice Area (EOA) | 30 day, 6 month, 1 year, 2 year | 
| Echocardiographic Assessment of Valve Performance | Using the following measures: - Transvalvular Mean Gradient | 30 day, 6 month, 1 year, 2 year | 
| Echocardiographic Assessment of Valve Performance | Using the following measure: - Degree of Aortic Valve Regurgitation (Transvalvular and Paravalvular) | 30 day, 6 month, 1 year, 2 year | 
| Aortic Valve Hospitalizations |  | 30 day, 6 month, 1 year, 2 year | 
| Cardiovascular Deaths and Valve Related Deaths |  | 30 day, 6 month, 1 year, 2 year | 
| Strokes and Transient Ischemic Attacks (TIAs) | Strokes (of any severity) and TIAs | 30 day, 6 month, 1 year, 2 year | 
| Index Procedure Related MAEs |  | Procedure | 
| Length of Index Procedure Hospital Stay |  | Number of days from admission to discharge | 
| Device Success | Medtronic CoreValve® System subjects only. Defined as: Successful vascular access, delivery and deployment of the device, and successful retrieval of the delivery system, Correct position of the device in the proper anatomical location (placement in the annulus with no impedance on device function), Intended performance of the prosthetic valve (aortic valve area > 1.2 cm2 for 26, 29 and 31mm valves, ≥ 0.9 cm2 for 23mm valve (by echocardiography using the continuity equation) and mean aortic valve gradient < 20 mmHg or peak velocity < 3 m/sec, without moderate or severe prosthetic valve aortic regurgitation) Only one valve implanted in the proper anatomical location | Number of days from admission to discharge | 
| Procedural Success | Medtronic CoreValve® System subjects only. Defined as device success and absence of in-hospital MACCE. | Number of days from admission to discharge | 
| Prosthetic Valve Dysfunction (PVD) | PVD was defined according to VARC I using the Core Lab Echocardiography assessments including aortic regurgitation (AR) and aortic stenosis (AS) evaluations. Total AR reported as moderate or severe was considered PVD. AS was defined as significant stenosis and considered PVD if one of the following was met: Peak velocity >4 m/s Mean gradient >35 mmHg EOA < 0.8 cm2 TVIV1 / TVIV2 < 0.25 | 30 day, 6 month, 1 year, 2 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Valvular Heart Disease, Critical Aortic Stenosis, Severe Aortic Stenosis, High Risk, Aortic Valve Replacement