Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Severe, Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI).

Study Overview
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Brief Summary
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The purpose of the study is to investigate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with severe, symptomatic Aortic Stenosis (AS) at intermediate surgical risk by randomizing patients to either Surgical Aortic Valve Replacement (SAVR) or TAVI with the Medtronic CoreValve® System. Single Arm: The purpose of this trial is to evaluate the safety and effectiveness of transcatheter aortic valve implementation (TAVI) in patients with severe symptomatic Aortic Stenosis (AS) at intermediate surgical risk with TAVI. This is a non-randomized phase of the pivotal clinical trial.

Official Title
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Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI)

Conditions
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Severe Aortic Stenosis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have co-morbidities such that Heart Team agrees predicted risk of operative mortality is ≥3% and <15% at 30 days (Intermediate Clinical Risk classification). Heart team evaluation of clinical surgical mortality risk for each patient includes the calculated STS score for predicted risk of surgical mortality augmented by consideration of the overall clinical status and co-morbidities unmeasured by the STS risk calculation; Heart Team unanimously agree on treatment proposal and eligibility for randomization* based on their clinical judgement (including anatomy assessment, risk factors, etc.); Subject has severe aortic stenosis presenting with; Critical aortic valve area defined as an initial aortic valve area of ≤1.0cm2 or aortic valve area index < 0.6cm2/m2 AND Mean gradient > 40mmHg or Vmax > 4m/sec by resting echocardiogram or simultaneous pressure recordings at cardiac catherization [or with dobutamine stress, if subject has left ventricular ejection fraction (LVEF) <55%] or velocity ratio < 0.25; Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater; Subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits; Subject meets the legal minimum age to provide informed consent based on local regulatory requirements; Exclusion Criteria: Subject has refused surgical aortic valve replacement (SAVR) as a treatment option; (not applicable for Single Arm) Any condition considered a contraindication for placement of a bioprosthetic valve (i.e., subject requires a mechanical valve); A known hypersensitivity or contraindication to all anticoagulation/antiplatelet regimens (or inability to be anticoagulated for the index procedure), nitinol, or sensitivity to contrast media which cannot be adequately pre-medicated; Blood dyscrasias as defined: leukopenia (WBC <1000mm3), thrombocytopenia (platelet count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy; Ongoing sepsis, including active endocarditis; Any condition considered a contraindication to extracorporeal assistance; Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to randomization* (Subjects with recent placement of drug eluting stent(s) should be assessed for ability to safely proceed with SAVR within the protocol timeframe); Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within six weeks of randomization*; Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support; Recent (within 6 months of randomization*) cerebrovascular accident (CVA) or transient ischemic attack (TIA); Active gastrointestinal (GI) bleeding that would preclude anticoagulation; Subject refuses a blood transfusion; 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); Multivessel coronary artery disease with a Syntax score >22 and/or unprotected left main coronary artery (Syntax score calculation is not required for patients with history of previous revascularization if repeat revascularization is not planned); Estimated life expectancy of less than 24 months due to associated non-cardiac comorbid conditions; Other medical, social, or psychological conditions that in the opinion of the Investigator precludes the subject from appropriate consent or adherence to the protocol required follow-up exams; Currently participating in an investigational drug or another device trial (excluding registries); Evidence of an acute myocardial infarction ≤30 days before the index procedure; Need for emergency surgery for any reason; True porcelain aorta (i.e. Heart Team agrees the aorta is not clampable for SAVR); Extensive mediastinal radiation; Liver failure (Child-C); Reduced ventricular function with left ventricular ejection fraction (LVEF) <20% as measured by resting echocardiogram; Uncontrolled atrial fibrillation (e.g. resting heart rate > 120 bpm); Pregnancy or intent to become pregnant prior to completion of all protocol follow-up requirements; End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min; Pulmonary Hypertension (systolic pressure> 80mmHg); Severe Chronic Obstructive Pulmonary Disease (COPD) demonstrated by Forced Expiratory Volume (FEV1) < 750cc; Frailty assessments identify: Subject is < 80 years of age and three or more of the following apply Subject is ≥ 80 years of age and two or more of the following apply Wheelchair bound Resides in an institutional care facility (e.g., nursing home, skilled care center) Body Mass Index < 20 kg/m2 Grip Strength < 16 kg Katz Index Score ≤ 4 Albumin < 3.5 g/dL; Marfan syndrome or other known connective tissue disease that would necessitate aortic root replacement/intervention; (Not applicable for Single Arm) Note: Additional anatomical and vascular exclusion criteria may apply. Note: * For purposes of the single arm phase of the trial, randomization will refer to trial enrollment.
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: Medtronic CoreValve® System TAVI<br>Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI) | Device: Medtronic CoreValve® System Transcatheter Aortic Valve Implantation (TAVI)<br> <br> Device: Medtronic CoreValve® Evolut R System Transcatheter Aortic Valve Implantation (TAVI)<br> <br> |
| Active Comparator: SAVR<br>Surgical Aortic Valve Replacement (SAVR) | Procedure: Surgical Aortic Valve Replacement (SAVR)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause Mortality or Disabling Stroke Rate Expressed as a Posterior Probability | All-cause mortality: all deaths from any cause after valve intervention. This includes all cardiovascular and non-cardiovascular deaths. Disabling Stroke: a modified rankin (mRS) score of 2 or more at 90 days and an increase in at least one mRS category from an individual's pre-strike baseline. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) | MACCE is defined as a composite of: All-cause death Myocardial infarction (MI) All stroke, and Reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve) | 30 days, 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is complete. | 
| Percentage of Participants With Individual MACCE Components | MACCE is defined as a composite of: All-cause death Myocardial infarction (MI) All stroke, and Reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve) | 30 days, 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is complete. | 
| Percentage of Participants With Major Adverse Events (MAE) | Major Adverse Events (MAE) include all death, MI, all stroke, reintervention, cardiac perforation, cardiac tamponade, cardiogenic shock, valve malpositioning, prosthetic valve dysfunction, acute kidney injury, major vascular complication, life threatening or disabling bleed, major bleed, and valve endocarditis. | 30 days, 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is complete. | 
| Percentage of Participants With Conduction Disturbance Requiring Permanent Pacemaker Implantation |  | 30 day, 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is complete. | 
| Change in NYHA Class From Baseline | 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. | Baseline to 30 days, 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is complete. | 
| Change in Distance Walked During 6-minute Walk Test (6MWT) | Change in distance walked during 6MWT from baseline | From baseline to 30 days, baseline to 12 months, and baseline to 24 months | 
| Ratio of Days Alive Out of Hospital Versus Total Days Alive |  | 12 and 24 months | 
| Quality of Life (QoL) Change From Baseline | 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. 36 Item Short Form Health Survey (SF-36): 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. | Baseline, 30 days, 3 months, 6 months, 12 months, and 24 months. Data for 3-5 years will be posted once data is complete. | 
| Transvalvular Mean Gradient (in mmHg) as an Assessment of Prosthetic Valve Performance | Using the following measure: -Transvalvular mean gradient | discharge, 6 months, 12 months, and 24 months. Data for 3-5 years will be posted once data is complete | 
| Effective Orifice Area as an Assessment of Prosthetic Valve Performance | Using the following measure: -Effective Orifice Area (cm^2) | discharge, 6 months, 12 months, and 24 months. Data for 3-5 years will be posted once data is complete | 
| Degree of Aortic Valve Regurgitation as an Assessment of Prosthetic Valve Performance | Using the following measure: - Degree of Aortic Valve Regurgitation (Transvalvular and Paravalvular) | discharge, 6 months, 12 months, and 24 months. Data for 3-5 years will be posted once data is complete | 
| Percentage of Participants With Aortic Valve Disease Related Hospitalizations |  | 30 days, 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is complete. | 
| Percentage of Participants With Cardiovascular Deaths and Valve-Related Deaths |  | 30 days, 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is complete | 
| Percentage of Participants With Stroke and TIAs | Strokes (of any severity) and Transient Ischemic Attacks (TIAs) | 30 days, 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is complete. | 
| Peri-procedural Neurological Injury | Neurological injury (stroke, TIA, or encephalopathy) | discharge or 7 days post index procedure (whichever occurred first) | 
| Index Procedure Related Major Adverse Events (MAEs) | Index procedure related MAEs were defined as events occurring during, or as a direct result of, the index procedure. | Procedure through 30 day visit | 
| Length of Index Procedure Hospital Stay |  | Number of days from admission to discharge (expected average of 7 days) | 
| Presence of Atrial Fibrillation |  | post-procedure, discharge, 30 days, 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is complete. | 
| Device Success (Medtronic CoreValve® System Subjects Only) | Absence of procedural mortality Correct positioning of a single prosthetic heart valve into the proper anatomical location Intended performance of the prosthetic heart valve (no prosthesis-patient mismatch and mean aortic valve gradient <20 mmHg or peak velocity <3 m/s, AND no moderate or severe prosthetic valve regurgitation) | Number of days from admission to discharge (expected average of 7 days) | 
| Procedural Success (Medtronic CoreValve® System Subjects Only) | Defined by device success and absence of in-hospital major adverse cardiovascular and cerebrovascular events (MACCE) | Number of days from admission to discharge (expected average of 7 days) | 
| Evidence of Prosthetic Valve Dysfunction (Medtronic CoreValve® System Subjects Only) | Prosthetic Valve Dysfunction (PVD) was defined according to Valve Academic Research Consortium (VARC) II using the Core Lab Echocardiography assessments including aortic regurgitation (AR) and aortic stenosis (AS) evaluations. Total aortic regurgitation (AR) reported as moderate or severe was considered PVD defined as: Mean aortic valve gradient ≥20 mmHg AND ((EOA ≤0.9 cm2 if BSA <1.6 or ≤1.1 cm2 if BSA ≥1.6) OR DVI <0. 35 m/s) OR moderate or severe total AR | 6 months, 12 months, and 24 months. Data for 3-5 years will be posted once data is complete. | 
| Percentage of Participants With Early Safety Endpoint | Percentage of participants with VARC II early safety composite at 30 days | 30 Days | 
| Percentage of Participants With Clinical Efficacy (After 30 Days) | Combined clinical efficacy after 30 days was defined as the composite of all-cause mortality, all strokes (disabling and non-disabling), hospitalization for valve-related symptoms or worsening congestive heart failure, NYHA III or IV, and valve-related dysfunction. | 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is complete | 
| Percentage of Participants With Time-Related Safety | The VARC II time-related valve safety composite was defined as the rate of valve-related dysfunction (mean aortic valve gradient ≥ 20 mm Hg, EOA ≤ 0.9-1.1 cm2 depending on body surface area and/or DVI <0.35, AND/ OR moderate or severe prosthetic valve regurgitation), aortic valve reintervention, prosthetic valve endocarditis, prosthetic valve thrombosis, thromboembolic events, and VARC II bleeding events. | 30 days, 6 months, 12 months, 18 months, and 24 months. Data for 3-5 years will be posted once data is available. | 
| Resheath and Recapture Success (Evolut R Only) | The Evolut™ R system provides operators with the ability to resheath or recapture the valve before it is completely deployed in the event of initial suboptimal positioning. Successful resheath was defined as successfully retrieving a portion of the valve into the capsule of the delivery catheter, and successful recapture was defined as successfully recapturing the entirety of the valve into the capsule of the delivery catheter. | Procedure |