THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial

• Freedom from death (Cohort A: Edwards Sapien Valve{Transfemoral or Transapical} vs. other surgical valve) [ Time Frame: 1 year ]
• Freedom from Death (Cohort B: Edwards Sapien Valve{transfemoral} vs. medical therapy) [ Time Frame: duration of study ]

• Freedom from death (Cohort A: Edwards Sapien Valve vs. other surgical valve) [ Time Frame: 1 year ]
• Freedom from Death (Cohort B: Edwards Sapien Valve vs. medical therapy) [ Time Frame: duration of study ]

• Functional Improvement from baseline per NYHA functional classification (Cohort A and Cohort B) [ Time Frame: 30 days, 6 months, 1 year ]
• Freedom from MACCE and expanded safety composite events. [ Time Frame: 30 days, 6 months, 1 year ]
• Evidence of prosthetic valve dysfunction (hemolysis, infection, thrombosis, severe paravalvular leak, or migration) (Cohort A) [ Time Frame: 30 days, 6 months, 1 year ]
• Length of index hospital stay (Cohort A) [ Time Frame: number of days hospitalized ]
• Total hospital days from the index procedure to one year post procedure. (Cohort A) [ Time Frame: 1 year ]
• Improved Quality of Life (QOL) from baseline to 30 days, 6 months, and annually through year 5 (Cohort A and Cohort B) [ Time Frame: 30 days, 6 months, years 1 - 5 ]
• Improved valve function demonstrated by a responder analysis showing the percentage of patients in each treatment group who have a greater than 50% improvement in AVA at 30 days, 6 months, and 12 months. (Cohort A and Cohort B) [ Time Frame: 30 days, 6 months, 1 year ]
• Total hospital days from the index procedure or randomization in to control arm for medical management patients to 1 year post procedure or randomization (Cohort B) [ Time Frame: 1 year ]
• Composite of survival, recurrent hospitalization and NYHA class.

• Functional Improvement from baseline per NYHA functional classification (Cohort A and Cohort B) [ Time Frame: 30 days, 6 months, 1 year ]
• Freedom from MACCE defined as death, myocardial infarction, stroke, or aortic valve reintervention (Cohort A and Cohort B) [ Time Frame: 30 days, 6 months, 1 year ]
• Evidence of prosthetic valve dysfunction (hemolysis, infection, thrombosis, sever paravalvular leak, or migration) (Cohort A) [ Time Frame: 30 days, 6 months, 1 year ]
• Length of index hospital stay (Cohort A) [ Time Frame: number of days hospitalized ]
• Total hospital days from the index procedure to one year post procedure. (Cohort A) [ Time Frame: 1 year ]
• Improved Quality of Life (QOL) from baseline to 30 days, 6 months, and 1 year (Cohort A and Cohort B) [ Time Frame: 30 days, 6 months, 1 year ]
• Improved valve function demonstrated by a responder analysis showing the percentage of patients in each treatment group who have a greater than 50% improvement in AVA at 30 days, 6 months, and 12 months. (Cohort A and Cohort B) [ Time Frame: 30 days, 6 months, 1 year ]
• Total hospital days from the index procedure or randomization in to control arm for medical management patients to 1 year post procedure or randomization (Cohort B) [ Time Frame: 1 year ]

The purpose of this study is to determine the safety and effectiveness of the device and delivery systems (transfemoral and transapical) in high risk, symptomatic patients with severe aortic stenosis.

Subjects will undergo a physical exam and screening tests will be performed to determine if they are either A) a patient with a high surgical risk or B) not a candidate for surgery. They will then be randomized (like the flip of a coin) to have the investigational device implanted or to receive the current surgical or medical management available.

• Device: Edwards SAPIEN Transcatheter Heart Valve
• Device: Surgical Valve Replacement
• Other: medical management and/or balloon aortic valvuloplasty

• Experimental: 1
  Cohort A: Sapien Valve
  Intervention: Device: Edwards SAPIEN Transcatheter Heart Valve
• Active Comparator: 2
  Cohort A: other surgical valve
  Intervention: Device: Surgical Valve Replacement
• Experimental: 3
  Cohort B: Sapien Valve
  Intervention: Device: Edwards SAPIEN Transcatheter Heart Valve
• Active Comparator: 4
  Cohort B: Medical therapy
  Intervention: Other: medical management and/or balloon aortic valvuloplasty

• Reynolds MR, Magnuson EA, Lei Y, Wang K, Vilain K, Li H, Walczak J, Pinto DS, Thourani VH, Svensson LG, Mack MJ, Miller DC, Satler LE, Bavaria J, Smith CR, Leon MB, Cohen DJ; PARTNER Investigators. Cost-effectiveness of transcatheter aortic valve replacement compared with surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results of the PARTNER (Placement of Aortic Transcatheter Valves) trial (Cohort A). J Am Coll Cardiol. 2012 Dec 25;60(25):2683-92. doi: 10.1016/j.jacc.2012.09.018. Epub 2012 Nov 1.
• Green P, Woglom AE, Genereux P, Daneault B, Paradis JM, Schnell S, Hawkey M, Maurer MS, Kirtane AJ, Kodali S, Moses JW, Leon MB, Smith CR, Williams M. The impact of frailty status on survival after transcatheter aortic valve replacement in older adults with severe aortic stenosis: a single-center experience. JACC Cardiovasc Interv. 2012 Sep;5(9):974-81. doi: 10.1016/j.jcin.2012.06.011. PubMed PMID: 22995885.
• Reynolds MR, Magnuson EA, Wang K, Thourani VH, Williams M, Zajarias A, Rihal CS, Brown DL, Smith CR, Leon MB, Cohen DJ; PARTNER Trial Investigators. Health-related quality of life after transcatheter or surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results from the PARTNER (Placement of AoRTic TraNscathetER Valve) Trial (Cohort A). J Am Coll Cardiol. 2012 Aug 7;60(6):548-58. Epub 2012 Jul 18.
• Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, Fontana GP, Dewey TM, Thourani VH, Pichard AD, Fischbein M, Szeto WY, Lim S, Greason KL, Teirstein PS, Malaisrie SC, Douglas PS, Hahn RT, Whisenant B, Zajarias A, Wang D, Akin JJ, Anderson WN, Leon MB; PARTNER Trial Investigators. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med. 2012 May 3;366(18):1686-95. Epub 2012 Mar 26.
• Makkar RR, Fontana GP, Jilaihawi H, Kapadia S, Pichard AD, Douglas PS, Thourani VH, Babaliaros VC, Webb JG, Herrmann HC, Bavaria JE, Kodali S, Brown DL, Bowers B, Dewey TM, Svensson LG, Tuzcu M, Moses JW, Williams MR, Siegel RJ, Akin JJ, Anderson WN, Pocock S, Smith CR, Leon MB; PARTNER Trial Investigators. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med. 2012 May 3;366(18):1696-704. Epub 2012 Mar 26.
• Miller DC, Blackstone EH, Mack MJ, Svensson LG, Kodali SK, Kapadia S, Rajeswaran J, Anderson WN, Moses JW, Tuzcu EM, Webb JG, Leon MB, Smith CR; PARTNER Trial Investigators and Patients; PARTNER Stroke Substudy Writing Group and Executive Committee. Transcatheter (TAVR) versus surgical (AVR) aortic valve replacement: occurrence, hazard, risk factors, and consequences of neurologic events in the PARTNER trial. J Thorac Cardiovasc Surg. 2012 Apr;143(4):832-843.e13.
• Reynolds MR, Magnuson EA, Lei Y, Leon MB, Smith CR, Svensson LG, Webb JG, Babaliaros VC, Bowers BS, Fearon WF, Herrmann HC, Kapadia S, Kodali SK, Makkar RR, Pichard AD, Cohen DJ; Placement of Aortic Transcatheter Valves (PARTNER) Investigators. Health-related quality of life after transcatheter aortic valve replacement in inoperable patients with severe aortic stenosis. Circulation. 2011 Nov 1;124(18):1964-72. Epub 2011 Oct 3.
• Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S, Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC, Akin JJ, Anderson WN, Wang D, Pocock SJ; PARTNER Trial Investigators. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011 Jun 9;364(23):2187-98. Epub 2011 Jun 5.
• Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Brown DL, Block PC, Guyton RA, Pichard AD, Bavaria JE, Herrmann HC, Douglas PS, Petersen JL, Akin JJ, Anderson WN, Wang D, Pocock S; PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010 Oct 21;363(17):1597-607.

Inclusion Criteria Cohort A

1. Patients must have co-morbidities such that the surgeon and cardiologist Co-PIs concur that the predicted risk of operative mortality is ≥15% and/or a minimum STS score of 10
2. Patient has senile degenerative aortic valve stenosis with echocardiographically derived criteria: mean gradient >40 mmHg or jet velocity greater than 4.0 m/s or an initial aortic valve area of < 0.8 cm2
3. Patient is symptomatic from his/her aortic valve stenosis, as demonstrated by NYHA Functional Class II or greater
4. The subject or the subject'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 IRB of the respective clinical site

5. The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits

   Cohort B All candidates for Cohort B of this study must meet #2, 3, 4, 5 of the above criteria and

6. The subject, after formal consults by a cardiologist and two cardiovascular surgeons agree 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 should exceed 50%.

Exclusion Criteria

1. Evidence of an acute myocardial infarction ≤ 1month before the intended treatment
2. Aortic valve is a congenital unicuspid or bicuspid valve; or is non-calcified
3. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+)
4. Any therapeutic invasive cardiac procedure performed within 30 days of the index procedure, (or 6 months if the procedure was a drug eluting coronary stent implantation)
5. Pre-existing prosthetic heart valve in any position, prosthetic ring, or severe (greater than 3+) mitral insufficiency
6. Blood dyscrasias as defined: Leukopenia, acute anemia, thrombocytopenia, history of bleeding diathesis or coagulopathy
7. Untreated clinically significant coronary artery disease requiring revascularization
8. Hemodynamic instability requiring inotropic support or mechanical heart assistance.
9. Need for emergency surgery for any reason
10. Hypertrophic cardiomyopathy with or without obstruction
11. Severe ventricular dysfunction with LVEF <20
12. Echocardiographic evidence of intracardiac mass, thrombus or vegetation
13. Active peptic ulcer or upper GI bleeding within the prior 3 months
14. A known hypersensitivity or contraindication to aspirin, heparin, ticlopidine, or clopidogrel, or sensitivity to contrast media, which cannot be adequately pre-medicated
15. Native aortic annulus size < 16mm or > 24mm per the baseline echo as estimated by the LVOT
16. Patient has been offered surgery but has refused surgery.
17. Recent (within 6 months) CVA or a TIA
18. Renal insufficiency and/or end stage renal disease requiring chronic dialysis
19. Life expectancy < 12 months due to non-cardiac co-morbid conditions.
20. Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal luminal diameter 5cm or greater; marked tortuosity (hyperacute bend), aortic arch atheroma or narrowing (especially with calcification and surface irregularities) of the abdominal or thoracic aorta, severe "unfolding" and tortuosity of the thoracic aorta(applicable for transfemoral patients only).
21. Iliofemoral vessel characteristics that would preclude safe placement of 22F or 24F introducer sheath such as severe obstructive calcification, severe tortuosity or vessels size less than 7 mm in diameter(applicable for transfemoral patients only).
22. Currently participating in an investigational drug or another device study