Transcatheter Aortic Valve Replacement to UNload the Left Ventricle in Patients With ADvanced Heart Failure (TAVR UNLOAD)

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to determine the safety and efficacy of transcatheter aortic valve replacement (TAVR) via a transfemoral approach in HF patients with moderate AS as compared with OHFT.

Official Title
-----------------
Transcatheter Aortic Valve Replacement to UNload the Left Ventricle in Patients With ADvanced Heart Failure: A Randomized Trial (TAVR UNLOAD)

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

Intervention / Treatment
-----------------
* Device: SAPIEN 3 THV
* Biological: Optimal Heart Failure Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria All candidates for this study must meet all of the following inclusion criteria: Age ≥18 years Heart Failure with NYHA class ≥ 2 Under appropriate and stable guideline-directed HF therapy for a minimum of 1 month prior to randomization. Note: Patients are expected to be on appropriate pharmacologic therapy and if indicated CRT for heart failure. (12, 13) Patients with aortic stenosis may not be able to tolerate maximal doses of heart failure medications and no specific guidelines exist for the medical treatment of heart failure in the setting of aortic stenosis. It is expected that the heart failure PI will review the medical therapy and confirm that it is appropriate for the patient's condition. Moderate AS confirmed by the echo core lab. Moderate AS is defined as an aortic valve area (AVA) >1.0 cm2 and ≤1.5 cm2 on rest echo or if ≤1.0 cm2 at rest and low-flow AS is suspected when the an AVA > 1.0 cm2 with low dose dobutamine stress echo (DSE). Patients with AVA<1.0 cm2 but with an indexed AVA of >0.6 cm2/m2 on either rest or DSE are also eligible. Similarly, patients with AVA >1.5 cm2 but with indexed AVA<0.9 cm2/m2 on either rest of DSE are also eligible. Note: Typically such cases will demonstrate, • Mean trans-aortic gradient (MG) ≥ 20 mmHg and < 40 mmHg at rest and aortic valve area (AVA) > 1.0 cm2 and ≤1.5 cm2 (or AVA < 1.0 cm2 but indexed AVA > 0.6 cm2) at rest OR • Mean trans-aortic gradient (MG) ≥ 20 mmHg and < 40 mmHg and aortic valve area (AVA) ≤1.0 cm2 at rest AND MG < 40 mmHg and aortic valve area (AVA) •>1.0 cm2 (or AVA < 1.0 cm2 but indexed AVA > 0.6 cm2) with low dose dobutamine stress echo (DSE). In atypical cases (for example mean gradient is below 20 mmHg but valve area is consistent with moderate AS, the final eligibility determination in regards to diagnosis of moderate AS will be made by the echocardiographic core lab. Left ventricular (LV) ejection fraction (EF) < 50% at rest Anatomically suitable for transfemoral TAVR with the SAPIEN 3 or SAPIEN 3 Ultra THV Able to provide independent informed consent (i.e., not requiring a legally authorized representative) Exclusion Criteria Candidates are excluded from the study if any of the following conditions are present: LVEF < 20% or persistent need for intravenous inotropic support Hospitalization for acute decompensated HF within 2 weeks prior to randomization Cardiac resynchronization therapy (CRT) device implantation within 1 month prior to randomization Coronary artery revascularization (PCI or CABG) within 1 month prior to randomization In need and suitable for revascularization per heart team consensus Severe aortic and/or mitral regurgitation Congenital unicuspid or congenital bicuspid aortic valve Concomitant non-aortic valvular disease with a formal indication for valve surgery per established guidelines (ESC/ACC/AHA) Previous aortic valve replacement (mechanical or bioprosthetic) Severe RV dysfunction Previous stroke with permanent disability (modified Rankin score ≥ 2) Severe lung disease as indicated by FEV1 <30% predicted or need for chronic daytime supplemental oxygen therapy Severe chronic kidney disease: glomerular filtration rate (GFR) < 30 mL/min by MDRD or need for renal replacement therapy Gastrointestinal (GI) bleeding within the past 3 months Liver cirrhosis Child-Pugh C Active systemic infection, including active endocarditis Unwilling to accept blood transfusion Evidence of intracardiac mass, thrombus or vegetation Absence of minimum amount of aortic valve calcification necessary for TAVR with the SAPIEN 3 or SAPIEN 3 Ultra THV Hypersensitivity or contraindication to clopidogrel, aspirin, or to oral anticoagulation if indicated (e.g. subject in atrial fibrillation) Sensitivity to contrast media which cannot be adequately pre-medicated Women of child-bearing potential Clinical signs of dementia Other medical, social, or psychological conditions that precludes appropriate consent and follow-up Life expectancy < 2 years due to cancer or other non-cardiac chronic diseases Unwillingness to undergo follow-up investigations Currently participating in an investigational drug or another device trial that has not reached its primary endpoint (excluding registries)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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: TAVR (with SAPIEN 3 THV) and OHFT<br>Transcatheter heart valve and Optimal Heart Failure Therapy | Device: SAPIEN 3 THV<br> <br> Biological: Optimal Heart Failure Therapy<br> <br> |
| Active Comparator: OHFT<br>Optimal Heart Failure Therapy | Biological: Optimal Heart Failure Therapy<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-Cause Death | Hierarchical occurrence within efficacy assessment time interval (EATI) of: | 12 months | 
| Disabling Stroke | Hierarchical occurrence within efficacy assessment time interval (EATI) of: | 12 months | 
| Hospitalizations related to heart failure, symptomatic aortic valve disease or non-disabling stroke -or - Clinically significant worsening of heart failure (heart failure hospitalization equivalent). | Hierarchical occurrence within efficacy assessment time interval (EATI) of: | 12 months | 
| Change in KCCQ relative to baseline | Hierarchical occurrence within efficacy assessment time interval (EATI) of: | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MACCE defined as the composite of all-cause death, all stroke, and hospitalizations for heart failure or symptomatic aortic valve disease or clinically significant worsening of heart failure within EATI. Hierarchical occurrence within EATI of: | All-cause death Disabling stroke Hospitalizations related to heart failure, symptomatic aortic valve disease or non-disabling stroke or clinically significant worsening of heart failure (heart failure event) | 12 month | 
| -All-cause death within EATI | -All-cause death within EATI | 12 month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Valve