Feasibility of Transcatheter Aortic Valve Replacement in Low-Risk Patients With Symptomatic, Severe Aortic Stenosis

Trial Objectives: To assess the safety and feasibility of Transcatheter Aortic Valve
Replacement (TAVR) with commercially available bioprostheses in patients with severe,
symptomatic aortic stenosis (AS) who are low‐risk (STS score ≤3%) for surgical aortic valve
replacement (SAVR).

Methodology: This is a multicenter, prospective trial of TAVR in low-risk patients at up to
twelve sites in the United States. The trial will have three arms. The first will comprise
200 patients undergoing transfemoral TAVR. The second arm will comprise200 closely matched
historical controls who underwent isolated bioprosthetic SAVR.

Historical controls will be selected from among patients at the same site who have undergone
isolated bioprosthetic SAVR within the previous 36 months. TAVR patients will then be matched
to SAVR patients using STS database variables to perform propensity matching, including (but
not limited to) age, gender, race, ethnicity, STS score, and valve prosthesis size. Once the
historical matched controls are identified, detailed chart review will abstract in-hospital
and 30-day outcomes for the SAVR cohort.

The third arm of the trial will comprise a registry of TAVR in up to 100 low-risk patients
with bicuspid aortic valve. The results from the registry arm will be analyzed independently.

Primary Efficacy Endpoint: All-cause mortality at 30 days following transfemoral TAVR vs.
bioprosthetic SAVR.

Primary Safety Endpoint: Defined as the composite of major adverse events at 30 days:

a. all-cause mortality c. spontaneous myocardial infarction (MI) d. reintervention: defined
as any cardiac surgery or percutaneous reintervention that repairs, alters, or replaces a
previously implanted aortic valve e. VARC life-threatening bleeding f. Increase in serum
creatinine to ≥300% (>3x increase compared to baseline) OR serum creatinine ≥4.0 mg/dL with
an acute increase ≥0.5 mg/dL OR new requirement for dialysis g. coronary artery obstruction
requiring percutaneous or surgical intervention h. VARC major vascular complication i.
cardiac tamponade j. cardiac perforation k. pericarditis l. mediastinitis m. hemolysis n.
infective endocarditis o. moderate or severe aortic insufficiency p. significant aortic
stenosis q. permanent pacemaker implantation r. new-onset atrial fibrillation

Secondary Endpoints (TAVR Cohort):

1. Major adverse cardiovascular and cerebrovascular events (MACCE) at 30 days, 6 months, 12
months, and 2, 3, 4 and 5 years, defined as the composite of:

1. all-cause mortality

2. stroke

3. spontaneous MI

4. reintervention

2. The occurrence of the individual components of MACCE at 30 days, 6 months, 12 months,
and 2, 3, 4, and 5 years (including stoke).

3. The composite of major adverse device events post-procedure, and at 6 months, 1 year,
and 2, 3, 4, 5 years

4. VARC major vascular complications, at 30 days and 1 year

5. VARC life-threatening or disabling bleeding, at 30 days and 1 year

6. Technical success upon exit from the operating room or catheterization laboratory,
defined as all of the following:

1. alive

2. successful access, delivery, and retrieval of the device and/or delivery system

3. correct positioning and successful deployment of the valve

4. no need for unplanned or emergency surgery or reintervention related to the device
or access procedure, including reinstitution of cardiopulmonary bypass post-weaning
for SAVR patients

7. Device success at 30 days and 1 year, defined as all of the following:

1. absence of procedural mortality

2. correct positioning of a single prosthetic heart valve in the proper anatomical
location

3. device performing as intended:

1. No migration, erosion, embolization, detachment, fracture, hemolysis requiring
transfusion, thrombosis, or endocarditis 2. Intended performance of the heart valve: no
prosthesis-patient mismatch, mean aortic valve gradient <20 mm Hg OR peak velocity <3 m/s,
AND no moderate or severe bioprosthetic valve regurgitation 8. Procedural success at 30 days,
defined as device success AND no major adverse device events 9. Bioprosthetic valve
regurgitation, defined as either moderate or severe aortic regurgitation OR moderate or
severe paravalvular leak, at hospital discharge, 12 months, and 2, 3, 4, and 5 years 10.
Incidence of new-onset atrial fibrillation at hospital discharge, and at 30 days, 12 months,
and 2, 3, 4, and 5 years.

11. Conduction disturbance requiring permanent pacemaker implantation at hospital discharge,
12 months, and 2, 3, 4, and 5 years.

12. Change in NYHA class from baseline to 30 days, baseline to 6 months, baseline to 12
months, and baseline to 2-5 years.

13. Change in distance walked during 6-minute walk test from baseline to 12 months.

14. Change in responses to the short form Kansas City Cardiomyopathy Questionnaire (KCCQ-12)
from baseline to 12 months.

15. Echocardiographic assessment of the bioprosthetic valve post-procedure, at 12 months, and
at years 2-5, including (but not limited to):

a. aortic valve mean gradient, maximum gradient, and peak velocity b. calculated aortic valve
area c. degree of bioprosthetic valve regurgitation 16. Assessment for subclinical leaflet
thrombosis with multislice computed tomography, or transesophageal echocardiography if GFR
<50 mL/min/m2, at 1 to 2 months.

17. Individual patient level Success all of the following and device success:

1. No re-hospitalizations or re-interventions for the underlying condition (e.g., HF)

2. Return to prior living arrangement (or equivalent)

3. Improvement vs. baseline in symptoms (NYHA Class decrease ≥ 1)

4. Improvement vs. baseline in functional status (6MWT increase ≥ 50 meters)

5. Improvement vs. baseline in QoL (KCCQ increase ≥ 10)

Number of Trial Sites: 12

Sample Size: 200 consecutive patients and 200 historical controls, and an additional 100 (up
to) patients with bicuspid aortic valve

Patient Population: Patients with severe, symptomatic AS who are determined by the Heart Team
to be at low surgical risk (STS score ≤3%).

Inclusion Criteria:

1. Severe, degenerative AS, defined as:

1. mean aortic valve gradient ≥40 mm Hg OR Vmax ≥4 m/sec AND

2. calculated aortic valve area ≤1.0 cm2 OR aortic valve area index ≤0.6 cm2/m2

2. Symptomatic AS, defined as a history of at least one of the following:

1. dyspnea that qualifies at New York Heart Association (NYHA) class II or greater

2. angina pectoris

3. cardiac syncope

3. The Heart Team, including at least one cardiothoracic surgeon and one interventional
cardiologist, deem the patient to be reasonable for transfemoral TAVR with a
commercially available bioprosthetic valve

4. The Heart Team agrees that the patient is low-risk, quantified by an estimated risk of
≤3% by the calculated STS score for operative mortality at 30 days; AND agrees that
SAVR would be an appropriate therapy if offered.

5. The Heart Team agrees that transfemoral TAVR is anatomically feasible, based upon
multislice CT measurements

6. Procedure status is elective

7. Expected survival is at least 24 months

For the bicuspid cohort only:

8. Aortic Stenosis of a bicuspid aortic valve

Exclusion Criteria:

1. Concomitant disease of another heart valve or the aorta that requires either
transcatheter or surgical intervention

2. Any condition that is considered a contraindication for placement of a bioprosthetic
aortic valve (e.g. patient requires a mechanical aortic valve)

3. Aortic stenosis secondary to a bicuspid aortic valve (except for the bicuspid valve
cohort)

4. Prior bioprosthetic surgical aortic valve replacement

5. Mechanical heart valve in another position

6. End-stage renal disease requiring hemodialysis or peritoneal dialysis, or a creatinine
clearance <20 cc/min

7. Left ventricular ejection fraction <20%

8. Recent (<6 months) history of stroke or transient ischemic attack

9. Symptomatic carotid or vertebral artery disease, or recent (<6 weeks) surgical or
endovascular treatment of carotid stenosis

10. Any contraindication to oral antiplatelet or anticoagulation therapy following the
procedure, including recent or ongoing bleeding, or HASBLED score >3

11. Severe coronary artery disease that is unrevascularized

12. Recent (<30 days) acute myocardial infarction

13. Patient cannot undergo transfemoral TAVR for anatomic reasons (as determined by
supplemental imaging studies); this would include inadequate size of iliofemoral
access vessels or an aortic annulus size that is not accommodated by the commercially
available valves

14. Any comorbidity not captured by the STS score that would make SAVR high risk, as
determined by a cardiothoracic surgeon who is a member of the heart team; this
includes:

1. porcelain or severely atherosclerotic aorta

2. frailty

3. hostile chest

4. IMA or other conduit either crosses midline of sternum or is adherent to sternum

5. severe pulmonary hypertension (PA systolic pressure > 2/3 of systemic pressure)

6. severe right ventricular dysfunction

15. Ongoing sepsis or infective endocarditis

16. Recent (<30 days) or ongoing bleeding that would preclude treatment with anticoagulant
or antiplatelet therapy, including recent gastrointestinal bleeding

17. Uncontrolled atrial fibrillation (resting heart rate >120 beats per minute)

18. Severe chronic obstructive pulmonary disease, as demonstrated by forced expiratory
volume (FEV1) <750 cc

19. Liver failure with Childs class C or D

20. Pre-procedure shock, inotropes, mechanical assist device, or cardiac arrest

21. Pregnancy or intent to become pregnant prior to completion of all protocol follow-up
procedures

22. Known allergy to warfarin or aspirin