The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves

• Cohort A: Time to death, major stroke and repeat hospitalization assessed at 2 year [ Time Frame: Cohort A: Time frame 2 Years ] [ Designated as safety issue: Yes ]
  •Cohort A: Non-hierarchical composite of all cause mortality and major stroke (Cohort A: Edwards SAPIEN Valve {Transfemoral or Transapical} vs. other surgical valve)
• Cohort B: Time to death, major stroke and repeat hospitalization assessed at 1 year [ Time Frame: Cohort B time frame 1 year ] [ Designated as safety issue: Yes ]

  Cohort B: Non-hierarchical composite of all cause mortality, major stroke and repeat hospitalization assessed at 1 year.

  A non-hierarchical composite; primary endpoint composed of time to 1) death, and 2) major stroke, and 3) repeat hospitalization (for valve-related decompensation or procedure-related complications)

• Freedom from other secondary events assessed at 30 days, or hospital discharge, 2 years. [ Time Frame: Cohort A 30 days or hospital discharge, 2 years ] [ Designated as safety issue: Yes ]

  Cohort A: Functional Improvement from baseline per NYHA, mRS, and Barthel index functional classification

  o Freedom from Stroke/MI/Major Vascular complication/Life threatening bleed/reoperation or catheter based interventionNalve related complication (valve thrombus, displacement, or procedure related valve complication)/pericarditis/hemolysis/mediastinitis/endocarditis/moderate or severe aortic insufficiency/possible or significant aortic stenosis, permanent pacemaker insertion, new mitral valve dysfunction, acute kidney injury

• Freedom from other secondary events assessed at 30 days, 6 months and 1 year [ Time Frame: Cohort B: 30 days, 6 months and 1 year ] [ Designated as safety issue: Yes ]

  Cohort B: Freedom from other secondary events assessed at 30 days, 6 months and 1 year

  Freedom from Stroke/MI/Major Bleeding/Acute Renal Injury/Major Vascular Complication/Valve Related Complication/Aortic PVL/Severe Conduction Defect

The purpose of this trial is to determine the safety and effectiveness of the Edwards SAPIEN XT transcatheter heart valve and delivery systems: NovaFlex (transfemoral access) and Ascendra2 (transapical access) in patients with symptomatic, calcific, severe aortic stenosis.

A prospective randomized, multi-center trial with two population cohorts: 1) patients who are designated to have intermediate risk for surgical aortic valve replacement (Cohort A - operable) and 2) patients who are not suitable for aortic valve surgery (Cohort B - inoperable). Enrollment will consist of up to 2000 patients in Cohort A, up to 500 patients in Cohort B, up to 100 patients each in NR1, NR2, NR3, and NR4 and up to 50 patients each in NR5 and NR6. Study patients will undergo clinical follow-up at discharge, 30 days, 6 months, 1 year and then annually for a minimum of 5 years.

• Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
  Inoperable subjects randomized to test or control
  Other Name: Implantation of the Transcatheter Aortic Valve Prosthesis
• Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
  Operable subjects randomized to test or control
  Other Name: Implantation of the Transcatheter Aortic Valve Prosthesis
• Device: AVR with a surgical heart valve
  Operable subjects randomized to test or control
  Other Name: Aortic valve replacement surgery
• Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
  Inoperable subjects without eligible transfemoral access.
  Other Name: Implantation of the Transcatheter Aortic Valve Prosthesis (Inoperable Transapical/Transaortic Registry)
• Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
  Inoperable subjects (Cohort B) with transfemoral vessels 6-7 mm
  Other Name: Implantation of the Transcatheter Aortic Valve Prosthesis (small vessel registry)
• Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
  Patients with structural valve deterioration of a previously implanted bioprosthetic surgical valve requiring redo valve implantation
  Other Name: Implantation of the Transcatheter Aortic Valve Prosthesis (Valve in Valve registry)
• Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
  Inoperable subjects without eligible transfemoral access.
  Other Name: Implantation of the Transcatheter Aortic Valve Prosthesis (Inoperable Transaortic Registry)
• Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
  Inoperable subjects (Cohort B) requiring transfemoral 29 mm valve procedure
  Other Name: Implantation of the Transcatheter Aortic Valve Prosthesis (inoperable TF 29 mm registry)
• Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
  Inoperable subjects (Cohort B) requiring transapical 29 mm valve procedure
  Other Name: Implantation of the Transcatheter Aortic Valve Prosthesis (inoperable TA 29 mm registry)

• Experimental: Inoperable subjects (Cohort B) - Test
  Test: SAPIEN XT™ valve with the NovaFlex or NovaFlex+ delivery system
  Intervention: Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
• Active Comparator: Inoperable subjects (Cohort B) - Control
  Control: SAPIEN® valve with the RetroFlex3™ delivery system
  Intervention: Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
• Experimental: Operable subjects (Cohort A -Transfemoral) - Test
  Test: SAPIEN XT™ valve with the NovaFlex or NovaFlex+ delivery system
  Intervention: Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
• Active Comparator: Operable subjects (Cohort A -Transfemoral) - Control
  Control: AVR with a surgical bioprosthetic heart valve
  Intervention: Device: AVR with a surgical heart valve
• Experimental: Operable subjects (Cohort A -Transapical) - Test
  Test: SAPIEN XT™ valve with the Ascendra2 or Ascendra+ delivery system
  Intervention: Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
• Active Comparator: Operable subjects (Cohort A -Transapical) - Control
  Control: AVR with a surgical bioprosthetic heart valve
  Intervention: Device: AVR with a surgical heart valve
• Experimental: Registry 1
  Registry 1: SAPIEN XT™ valve with the Ascendra2 or Ascendra+ delivery system
  Intervention: Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
• Experimental: Registry 2
  Registry 2: SAPIEN XT™ valve with the NovaFlex or NovaFlex+ delivery system
  Intervention: Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
• Experimental: Registry 3
  Registry 3: SAPIEN XT™ valve with the Ascendra2 or Ascendra+ delivery system
  Intervention: Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
• Experimental: Registery 4
  Registry 4: SAPIEN XT™ valve with the Ascendra2 or Ascendra+ delivery system
  Intervention: Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
• Experimental: Registry 5
  Registry 5: SAPIEN XT™ valve with the NovaFlex or NovaFlex+ delivery system
  Intervention: Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis
• Experimental: Registry 6
  Registry 6: SAPIEN XT™ valve with the Ascendra2 or Ascendra+ delivery system
  Intervention: Device: TAVR Implantation of the Transcatheter Aortic Valve Prosthesis

Eligibility:

All Candidates for this study (Cohorts A and B) must meet the following criteria:

1. Patient has senile degenerative aortic valve stenosis with echocardiographically derived criteria: mean gradient >40 mmHg or jet velocity greater than 4.0 m/s and an initial aortic valve area (AVA) of ≤0.8 cm2 or indexed EOA < 0.5 cm2/m2. Qualifying echo must be within 45 days of the date of the procedure.
2. Patient is symptomatic from his/her aortic valve stenosis, as demonstrated by NYHA Functional Class II or greater.
3. The heart team agrees (and verified in the case review process) that valve implantation will likely benefit the patient.
4. The study patient or the study patient's legal representative has been informed of the nature of the study, agrees to its provisions and has provided written informed consent as approved by the Institutional Review Board (IRB) of the respective clinical site.
5. The study patient agrees to comply with all required post-procedure follow-up visits including annual visits through 5 years and analysis close date visits, which will be conducted as a phone follow-up.

Once eligibility in accordance to the above criteria is established, patients are assessed for operability. Patients who are candidates for AVR must meet the criteria specific to Cohort A (intermediate risk patients) and patients who are deemed not to be candidates for surgery must meet the criteria specific to Cohort B (inoperable patients). All candidates must meet the above criteria in order to be stratified into Cohort A or Cohort B.

Additional Eligibility Criteria Specific to Cohort A

Inclusion Criteria:

1. STS ≥ 4
2. Heart team (including examining cardiac surgeon) agrees on eligibility including assessment that TAVR or AVR is appropriate
3. Heart team agrees (a priori) on treatment strategy for concomitant coronary disease (if present)
4. Study patient agrees to undergo surgical aortic valve replacement (AVR) - if randomized to control treatment

Additional Eligibility Criteria Specific to Cohort B

Inclusion Criteria:

1. The heart team agrees that medical factors preclude operation, based on a conclusion that the probability of death or serious, irreversible morbidity exceeds the probability of meaningful improvement. Specifically, the probability of death or serious, irreversible morbidity is ≥ 50%.
2. The heart team agrees the patient is likely to benefit from valve replacement.

Exclusion Criteria for Cohort A and Cohort B:

1. Evidence of an acute myocardial infarction ≤ 1 month (30 days) before the intended treatment [defined as: Q wave MI, or non-Q wave MI with total CK elevation of CK-MB ≥ twice normal in the presence of MB elevation and/or troponin level elevation (WHO definition)].
2. Aortic valve is a congenital unicuspid or congenital bicuspid valve, or is non-calcified.
3. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+).
4. Preexisting mechanical or bioprosthetic valve in any position (NR3)
5. Any therapeutic invasive cardiac procedure resulting in a permanent implant that is performed within 30 days of the index procedure (unless part of planned strategy for treatment of concomitant coronary artery disease). Implantation of a permanent pacemaker is not excluded.
6. Any patient with a balloon valvuloplasty (BAV) within 30 days of the procedure (unless BAV is a bridge to procedure after a qualifying ECHO).
7. Patient with planned concomitant surgical or transcatheter ablation for Atrial Fibrillation
8. Leukopenia (WBC < 3000 cell/mL), acute anemia (Hgb < 9 g/dL), Thrombocytopenia (Pit < 50,000 cell/mL).
9. Hypertrophic cardiomyopathy with or without obstruction (HOCM).
10. Severe ventricular dysfunction with LVEF < 20%.
11. Echocardiographic evidence of intracardiac mass. thrombus or vegetation.
12. Active upper GI bleeding within 3 months (90 days) prior to procedure.
13. A known contraindication or hypersensitivity to all anticoagulation regimens, or inability to be anticoagulated for the study procedure.
14. Clinically (by neurologist) or neuroimaging confirmed stroke or transient ischemic attack (TIA) within 6 months (180 days) of the procedure.
15. Renal insufficiency (creatinine> 3.0 mg/dL) and/or renal replacement therapy at the time of screening.
16. Estimated life expectancy < 24 months (730 days) due carcinomas, chronic liver disease, chronic renal disease or chronic end stage pulmonary disease.
17. Expectation that patient will not improve despite treatment of aortic stenosis.
18. Currently participating in an investigational drug or another device study. Note: Trials requiring extended follow-up for products that were investigational, but have since become commercially available, are not considered investigational trials.
19. It is known that the patient is currently enrolled in The PARTNER Trial or was withdrawn from The PARTNER Trial prior to endpoint analysis.

Exclusion Criteria Specific to Cohort A:

1. Heart Team assessment of inoperability (including examining cardiac surgeon).

2. Complex coronary artery disease:

   • Unprotected left main coronary artery
   • Syntax score> 32 (in the absence of prior revascularization)
3. Native aortic annulus size < 18 mm or> 27 mm as measured by echocardiogram.
4. Active bacterial endocarditis within 6 months (180 days) of procedure.
5. Patient refuses aortic valve replacement surgery.

Exclusion Criteria Specific to Cohort B:

1. Untreated clinically significant coronary artery disease requiring revascularization.
2. Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation or mechanical heart assistance within 30 days of screening evaluation.
3. Need for emergency surgery for any reason.
4. Native aortic annulus size < 18 mm or > 25 mm as measured by echocardiogram.
5. Significant aortic disease, including marked tortuosity (hyperacute bend), aortic arch atheroma [especially if thick (> 5 mm), protruding or ulcerated] or narrowing (especially with calcification and surface irregularities) of the abdominal or thoracic aorta, severe "unfolding" and tortuosity of the thoracic aorta.
6. Iliofemoral vessel characteristics that would preclude safe placement of 22F or 24F introducer sheath such as severe obstructive calcification. Severe tortuosity or minimum average vessel size less than 7 mm.

Specific Criteria for Registry 1 (NR1) and Registry 4 (NR4)

Inclusion: Same criteria as Cohort B Including non-femoral access.

Exclusion: Same criteria as Cohort B.

Specific Criteria for Registry 2 (NR2)

Inclusion: Same criteria as Cohort B Including non-femoral access

Exclusion: Same criteria as Cohort B, except for exclusion 22 which is modified (italicized) for NR2 as follows.

• Iliofemoral vessel characteristics that would preclude safe placement of 22F or 24F introducer sheath such as severe obstructive calcification, severe tortuosity or minimum average vessel size less than 6 mm.

Specific Criteria for Registry 3 (NR3)

Inclusion:

1. Stenosed or insufficient surgically implanted bioprosthetic valve in the aortic position.
2. NYHA class > II.
3. Heart team consensus that the risk of surgical mortality or major morbidity ≥ 50%.

Exclusion:

1. Bioprosthetic valve labeled external diameter < 21mm.
2. Surgical or transcatheter valve in another position on the same side of the heart (mitral and tricuspid rings are not an exclusion).
3. Hemodynamic instability defined as requiring inotropic, pressor, or mechanical support.
4. Infectious endocarditis within 6 months.
5. Bacteremia within 1 month.
6. Intra-cardiac thrombus or vegetation.
7. Acute myocardial infarction ≤ 1 month (30 days) before the intended treatment [defined as: Q wave MI, or non-Q wave MI with total CK elevation ≥ twice normal in the presence of MB elevation and/or troponin level elevation (WHO definition)].
8. Percutaneous coronary intervention or implantation of a permanent pacemaker within 7 days of the index procedure.
9. Leukopenia (WBC < 3000 cell/mL), acute anemia (Hgb < 9 g/dL), thrombocytopenia (Plt < 50,000 cell/mL).
10. Hypertrophic cardiomyopathy with obstruction (HOCM).
11. Severe ventricular dysfunction with LVEF < 20%.
12. Active upper GI bleeding within 3 months (90 days) prior to procedure requiring transfusion.
13. Inability to be anticoagulated for the study procedure.
14. Stroke or transient ischemic attack within 6 months (180 days).
15. Insufficiency (creatinine > 3.0 mg/dL) and/or renal replacement therapy at the time of screening.
16. Estimated life expectancy < 24 months.
17. Participating in an investigational drug or another device study. Note: Trials requiring extended follow-up for products that were investigational, but have since become commercially available, are not considered investigational trials.
18. The patient requires emergency surgery for any reason.
19. Xenograft or THV in another position.
20. Index valve has moderate or severe paravalvular regurgitation.
21. Index valve is unstable or rocking.
22. Extensive, severe non-revascularized coronary disease.
23. Increased risk of coronary obstruction by prosthetic leaflets (non-stented or internally stented valve which might extend above a coronary ostium).
24. Increased risk of embolization (non-stented and non-calcified valve).

Specific Criteria for Registry 5 (NR5) and Registry 6 (NR6)

Inclusion: Same criteria as Cohort B including non-femoral access

Exclusion: Same criteria as Cohort B except "Native aortic annulus size <18mm or >27mm as measured by echocardiogram