Medtronic Evolut Transcatheter Aortic Valve Replacement in Low Risk Patients

Study Overview
=================
Brief Summary
-----------------
The study objective is to demonstrate that the safety and effectiveness of the Medtronic TAVR system as measured by rates of all-cause mortality or disabling stroke at two years is noninferior to SAVR in the treatment of severe aortic stenosis in subjects who have a low predicted risk of operative mortality for SAVR. The purpose of the expanded use addendum to the Medtronic TAVR in Low Risk Patients Trial protocol is to conclude the randomized phase of the trial and initiate the single-arm, non-randomized, continued access phase of the trial.

Detailed Description
-----------------
Multi-center, international, prospective, randomized, interventional, pre-market. Subjects will be randomized on 1:1 basis to either TAVR with the Medtronic TAVR system or to SAVR. Patients will be seen at pre and post-procedure, discharge, 30 days, 6 months, 1 year, 18 months, and annually through 10 years. The expanded use addendum is a multi-center, prospective, non-randomized continued access trial. All heart team approved subjects will be assigned to TAVR with the Medtronic TAVR system. Patients will be seen at pre and post-procedure, discharge, 30 days, and annually through 10 years. Enrollment is expected not to exceed 3660 attempted implants in the United States.

Official Title
-----------------
Transcatheter Aortic Valve Replacement With the Medtronic Transcatheter Aortic Valve Replacement System In Patients at Low Risk for Surgical Aortic Valve Replacement

Conditions
-----------------
Aortic Valve Stenosis

Intervention / Treatment
-----------------
* Device: Medtronic Transcatheter Aortic Valve Replacement Systems
* Device: Surgical Aortic Valve Replacement (SAVR)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Severe aortic stenosis, defined as follows: For symptomatic patients: Aortic valve area ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), OR mean gradient ≥40 mmHg, OR Maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at rest For asymptomatic patients: Very severe aortic stenosis with an aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND maximal aortic velocity ≥5.0 m/sec , or mean gradient ≥60 mmHg by transthoracic echocardiography at rest, OR Aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND a mean gradient ≥40 mmHg or maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at rest, AND an exercise tolerance test that demonstrates a limited exercise capacity, abnormal BP response, or arrhythmia OR Aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND mean gradient ≥40 mmHg, or maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at rest, AND a left ventricular ejection fraction <50%. Documented heart team agreement of low risk for SAVR, where low risk is defined as predicted risk of mortality for SAVR <3% at 30 days per multidisciplinary local heart team assessment. The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits. Exclusion Criteria: Any condition considered a contraindication for placement of a bioprosthetic valve (eg, subject is indicated for mechanical prosthetic valve). A known hypersensitivity or contraindication to any of the following that cannot be adequately pre-medicated: aspirin or heparin (HIT/HITTS) and bivalirudin ticlopidine and clopidogrel Nitinol (titanium or nickel) contrast media Blood dyscrasias as defined: leukopenia (WBC <1000 mm3), thrombocytopenia (platelet count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy, or hypercoagulable states. Ongoing sepsis, including active endocarditis. Any percutaneous coronary or peripheral interventional procedure with a bare metal stent within 30 days prior to randomization, or drug eluting stent performed within 180 days prior to randomization. Multivessel coronary artery disease with a Syntax score >22 and/or unprotected left main coronary artery. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within 10 weeks of Heart Team assessment. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support. Recent (within 2 months of Heart Team assessment) cerebrovascular accident (CVA) or transient ischemic attack (TIA). 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). Estimated life expectancy of less than 24 months due to associated non-cardiac co-morbid 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 trial procedure due to unstable coronary artery disease (WHO criteria). Need for emergency surgery for any reason. Subject is pregnant or breast feeding. Subject is less than legal age of consent, legally incompetent, or otherwise vulnerable Pre-existing prosthetic heart valve in any position. Severe mitral regurgitation amenable to surgical replacement or repair. Severe tricuspid regurgitation amenable to surgical replacement or repair. Moderate or severe mitral stenosis amenable to surgical replacement or repair. Hypertrophic obstructive cardiomyopathy with left ventricular outflow gradient. Bicuspid aortic valve verified by echocardiography, MDCT, or MRI. Prohibitive left ventricular outflow tract calcification. Sinus of Valsalva diameter unsuitable for placement of the self-expanding bioprosthesis. Aortic annulus diameter of <18 or >30 mm. Significant aortopathy requiring ascending aortic replacement. For transfemoral or transaxillary (subclavian) access: Access vessel mean diameter <5.0 mm for Evolut 23R, 26R, or 29R mm TAV, or access vessel mean diameter <5.5 mm for Evolut 34R mm or Evolut PRO TAV. However, for transaxillary (subclavian) access in patients with a patent LIMA, access vessel mean diameter <5.5mm for Evolut 23R, 26R, or 29R mm TAV, or access vessel mean diameter <6.0 mm for the Evolut 34R or Evolut PRO TAV.
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 Transcatheter Aortic Valve Replacement Systems<br>Treatment of Aortic Stenosis with the Medtronic CoreValve System Transcatheter Aortic Valve Implantation (TAVI) device or the Medtronic Corevalve Evolut R System Transcatheter Aortic Valve Implantation (TAVI) | Device: Medtronic Transcatheter Aortic Valve Replacement Systems<br>* Treatment of severe aortic stenosis in subjects who have a low predicted risk of operative mortality for SAVR with Medtronic TAVR Systems<br>|
| Active Comparator: Surgical Aortic Valve Replacement (SAVR)<br>Treatment of Aortic Stenosis with commercial Surgical Aortic Valve Replacement (SAVR) | Device: Surgical Aortic Valve Replacement (SAVR)<br>* Treatment of severe aortic stenosis in subjects who have a low predicted risk of operative mortality for SAVR with a commercially approved surgical bioprothesis<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: All Cause Mortality or Disabling Stroke Rate at 24 Months, Randomized Controlled Trial Safety: All Cause Mortality or All Stroke Rate at 12 Months, Continued Access Study | Assessment of procedural safety by: All-cause mortality: all deaths from any cause after valve intervention. This includes all cardiovascular and non-cardiovascular deaths. Disabling stroke: a modified rankin score (mRS) of 2 or more at 90 days post-stroke and an increase of at least one mRS category from an individual's pre-stroke baseline. All stroke: any stroke after valve intervention (ischemic, hemorrhagic, or undetermined stroke). | Randomized Controlled Trial - 24 months Continued Access Study - 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RCT: Composite of Death, Disabling Stroke, Life-threatening Bleed, Major Vascular Complication, or AKI (II or III) at 30 Days CAS: Composite of Death, All Stroke, Life-threatening Bleed, or Major Vascular Complication at 30 Days | Randomized Controlled Trial: Combined clinical efficacy after 30 days was defined as the composite of all-cause mortality, disabling stroke, life-threatening bleed, major vascular complication, or AKI (II or III) Continued Access Study: Combined clinical efficacy after 30 days was defined as the composite of all-cause mortality, all stroke, life-threatening bleed, or major vascular complication | 30 days | 
| New Pacemaker Implantation at 30 Days | The rate of new permanent pacemaker implant at 30 days | 30 days | 
| Prosthetic Valve Endocarditis at 1 Year | The rate of prosthetic valve endocarditis at 1 year | 1 year | 
| Prosthetic Valve Thrombosis at 1 Year | The rate of prosthetic valve thrombosis at 1 year | 1 year | 
| All Stroke (Disabling and Non-disabling) at 1 Year | The rate of all stroke (disabling and non-disabling) at 1 year | 1 year | 
| Life-threatening Bleeding at 1 Year | The rate of life-threatening bleeding at 1 year | 1 year | 
| Valve-related Dysfunction Requiring Repeat Procedure at 1 Year | The rate of valve-related dysfunction requiring repeat procedure at 1 year | 1 year | 
| Valve-related Dysfunction (Moderate or Severe Stenosis or Regurgitation) at 1 Year, Randomized Controlled Trial | Stenosis (moderate or severe) Any of the following: Peak aortic velocity >4 m/s OR mean aortic gradient >40 mmHg, AND EOA <0.8 cm2 Peak aortic velocity >4 m/s OR mean aortic gradient >40 mmHg, AND EOA ≥0.8 cm2, and DVI <0.25 Peak aortic velocity ≤4 m/s and mean aortic gradient ≤ 40 mmHg, AND EOA <0.8 cm2, and DVI <0.25 Regurgitation (moderate or severe) Any of the following: Moderate or Severe Total Regurgitation Moderate or Severe Paravalvular Regurgitation Moderate or Severe Transvalvular Regurgitation | 1 year | 
| Randomized Controlled Trial - Health-related Quality of Life as Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) at 30 Days and 1 Year Continued Access Study - Health-related Quality of Life as Assessed by KCCQ at 1 Year | Quality of life summary scores and change from baseline using the following measures: 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. | Randomized Controlled Trial - 30 days and 1 year Continued Access Study - 1 year | 
| Repeat Hospitalization for Aortic Valve Disease at 1 Year, Randomized Controlled Trial | The rate of repeat hospitalization for aortic valve disease at 1 year | 1 year |