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

Inclusion Criteria:

Patients to be included in the study must meet the following inclusion criteria:

1. Age ≥18 years

2. NYHA class ≥ 2

3. NT-proBNP > 1500 pg/mL (or BNP > 400 pg/mL) or hospitalization for HF within the last
year

4. Under appropriate guideline-directed HF therapy (including cardiac resynchronization
therapy) for a minimum of 3 months.

-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.

5. 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 an AVA > 1.0 cm2 with low dose dobutamine stress echo (DSE). Patients
with AVA<1.0 cm2 but with an indexed AVA of >0.6cm2 on either rest or 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.

6. Left ventricular (LV) ejection fraction (EF) < 50% at rest

7. Anatomically suitable for transfemoral TAVR with the SAPIEN 3 THV

8. 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:

1. LVEF < 20% or persistent need for intravenous inotropic support

2. Hospitalization for acute decompensated HF within 2 weeks prior to randomization

3. Cardiac resynchronization therapy (CRT) device implantation within 3 months prior to
randomization

4. Coronary artery revascularization (PCI or CABG) within 3 months prior to randomization

5. In need and suitable for revascularization per heart team consensus

6. Severe aortic and/or mitral regurgitation

7. Congenital unicuspid or congenital bicuspid aortic valve

8. Concomitant non-aortic valvular disease with a formal indication for valve surgery per
established guidelines (ESC/ACC/AHA)

9. Previous aortic valve replacement (mechanical or bioprosthetic)

10. Severe RV dysfunction

11. Previous stroke with permanent disability (modified Rankin score ≥ 2)

12. Chronic obstructive pulmonary disease (COPD) GOLD 4 (FEV1 <30% predicted, <50%
predicted with chronic respiratory failure present (long-term oxygen therapy), or
FEV1/FVC <0.70)

13. Severe chronic kidney disease: glomerular filtration rate (GFR) < 30 mL/min by MDRD or
need for renal replacement therapy

14. Gastrointestinal (GI) bleeding within the past 3 months

15. Liver cirrhosis Child-Pugh C

16. Active systemic infection, including active endocarditis

17. Unwilling to accept blood transfusion

18. Evidence of intracardiac mass, thrombus or vegetation

19. Absence of minimum amount of aortic valve calcification necessary for TAVR with the
SAPIEN 3 THV

20. Hypersensitivity or contraindication to clopidogrel, aspirin, or to oral
anticoagulation if indicated (e.g. subject in atrial fibrillation)

21. Sensitivity to contrast media which cannot be adequately pre-medicated

22. Women of child-bearing potential

23. Clinical signs of dementia

24. Other medical, social, or psychological conditions that precludes appropriate consent
and follow-up

25. Life expectancy < 2 years due to cancer or other non-cardiac chronic diseases

26. Unwillingness to undergo follow-up investigations

27. Currently participating in an investigational drug or another device trial that has
not reached its primary endpoint (excluding registries)