Transcatheter Aortic Valve Implantation. SSVQ November 23, 2012 Centre Mont-Royal 15:40

Transcatheter Aortic Valve Implantation SSVQ November 23, 2012 Centre Mont-Royal 15:40 Nicolo Piazza MD, PhD, FRCPC, FESC, FACC McGill University Health Center German Heart Center Munich 1

First-in-Human Cribier-Edwards Cribier et al. Circulation 2002;106:3006-3008

Dr. Jean-Claude Laborde 1 st generation CoreValve

January 2008 350 November 2012 95 000

Carotid artery Ascending aorta Subclavian artery Left ventricular apex Femoral artery

Austria Belgium Denmark France Germany Italy Netherlands Portugal Spain Switzerland United Kingdom

Registry data

35 TAVI implants/million

Registry data

53 TAVI centers/country

Approximately 1 TAVI center/million

51 TAVI implants/ center

400 350 Mechanical SAVR Biological SAVR 300 250 200 150 100 50 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2111 2012

400 350 300 Mechanical SAVR Biological SAVR TAVI 250 200 150 100 50 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2111 2012

400 350 300 Mechanical SAVR Biological SAVR TAVI 250 200 150 100 50 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2111 2012

1990 - Crossing of fortunes

400 350 300 Mechanical SAVR Biological SAVR TAVI Total numbers 250 200 150 100 50 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2111 2012

TAVI SAVR % mortality 12 10 8 6 4 2 0 11.4 9.9 8.3 2.3 2.4 4.3 3.4 2.5 1.5 3.8 1.3 2.1 2007 2008 2009 2010 2011 2012

STS database 2006-2010 33% 66% Extreme risk/inoperable (STS >15%) High risk (STS > 10-15%) Intermediate risk (STS 4-10%) Low risk (STS <4%)

June 2007 June 2010 1st 2nd 3rd 4th N=105 N=105 N=105 N=105 n = 420 patients Change in baseline characteristics Impact on 30-day and 6-month mortality

Q1 Q2 Q3 Q4 Age (yrs.) 81 81 80 78 Logistic ES (%) 25 19 18 17 STS (%) 7 6 5 4

11.4% Q1 4-fold reduction 3.8% Q4 Lange et al. JACC 2012

23.5% Q1 2-fold reduction Q4 12.4% Lange et al. JACC 2012

TAVI vs. SAVR Intermediate Risk Foundation for the SURTAVI trial Manuscript in submission

3666 patients enrolled TAVI 782 SAVR 2884 784 matched patients TAVI 392 SAVR - 392 510 matched patients (STS scores 3-8%) 2882 patients excluded based on propensity scores 274 patients excluded based on STS score <3% and >8% TAVI 255 patients analyzed SAVR 255 patients analyzed

Bern-Rotterdam-Munich Study

1-year Mortality (STS 3-8%) Bern-Rotterdam-Munich Study

CoreValve SURTAVI Trial Study Design

Symptomatic Severe Aortic Stenosis ASSESSMENT by Heart Valve Team n=2000 Randomized Patients Yes Operable (STS 4) ASSESSMENT: Transfemoral Access No Two Parallel Randomized Trials +3 Nested Registries Inoperable ASSESSMENT: Transfemoral Access n=500 Randomized Patients Transfemoral (TF) Transapical (TA) Yes >7mm Yes 6-7mm No 1:1 Randomization 1:1 Randomization 1:1 Randomization 6-7mm Registry TF TAVR SAPIEN XT VS Surgical AVR TAVR: TA / TAO VS Surgical AVR TF TAVR SAPIEN XT VS TF TAVR SAPIEN TA Registry TAO Registry Primary Endpoint: All-Cause Mortality + Major Stroke at Two Years (Non-inferiority) Primary Endpoint: All-Cause Mortality + Major Stroke + Repeat Hospitalization at One Year (Non-inferiority) Transcatheter Valve-in-Surgical Valve Registry

Patient characteristics Access route Valve type and size

Echocardiography Coronary angiography CT imaging

Function Anchoring Sealing

Annular rupture Coronary obstruction Embolization Paravalvular leaks Conduction abnormalities Patient-prosthesis mismatch

Perimeter Area Diameters

Prosthesis dimension Annulus dimension Annulus dimension X 100 Prosthesis dimension = annulus perimeter

Edwards SAPIEN - PARTNER 1 RCT - PARTNER Continued Access Program - Source and Source XT registry Medtronic CoreValve - Advance Registry - National Registries

Stainless Steel Frame Bovine Pericardial Cribier-Edwards THV 23mm Edwards SAPIEN THV 23 mm and 26 mm Edwards SAPIEN XT THV 23 mm, 26 mm, and 29mm

PARTNER Trial Timelines 2006 2012 May 07 Aug 09 Mar 09 Aug 09 Mar 11 Dec 11 PARTNER IB - TF Randomized continued access Cohort B - TF PARTNER IA - TF PARTNER IA - TA Transapical approach not available at start of PARTNER I Trial PARTNER continued access TA and TF PARTNER IIB - TF PARTNER IIA

Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened N = 699 High Risk Total = 1,057 patients 2 Parallel Trials: Individually Powered Inoperable N = 358 ASSESSMENT: Transfemoral Access Yes No 1:1 Randomization Not In Study N = 179 TF TAVR VS N = 179 Standard Therapy Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)

Standard Rx TAVR HR [95% CI] = 0.53 [0.41, 0.68] p (log rank) < 0.0001 80.9% All Cause Mortality (%) 50.8% 20.1% 30.7% NNT = 5.0 pts 68.0% 25.0% 43.0% NNT = 4.0 pts 54.1% 26.8% NNT = 3.7 pts Months

STS <5 STS 5-14.9 STS 15 Cohort C Futile 100% 100% Death Incidence (%) 80% 60% 40% 20% p value (log rank) = 0.676 80% 60% 40% 20% p value (log rank) = 0.012 0% 0 6 12 18 24 Months 0% 0 6 12 18 24 Months 47

Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened N = 699 High Risk Total = 1,057 patients 2 Parallel Trials: Individually Powered Inoperable N = 358 Yes ASSESSMENT: Transfemoral Access No ASSESSMENT: Transfemoral Access Transfemoral (TF) Transapical (TA) Yes No 1:1 Randomization 1:1 Randomization 1:1 Randomization Not In Study N = 244 N = 248 N = 104 N = 103 N = 179 N = 179 TF TAVR VS AVR TA TAVR VS AVR TF TAVR VS Standard Therapy Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)

49

Goal of the registry was to allow investigators to maintain proficiency with the procedure and to continue to gather data - Over 2000 patients were enrolled between completion of the PARTNER trial in Aug 09 and initiation of the PARTNER IIA trial in Dec 11 All patients were treated with the Edwards Sapien valve from either the transapical or transfemoral approach depending on access Retroflex 3 catheter was used for all transfemoral cases Enrollment was limited by the FDA (39 patients/month initially) This allowed for 1-2 cases per site per month

PARTNER RCT n = 1057 PARTNER NRCA n = 2068 Cohort A TF Arm Cohort A TA Arm Cohort B TF Transfemoral n=1080 Transapical n = 988 TA TAVR (n=104) SAVR (n=103) NRCA TF n = 1080 TF TAVR (n=244) SAVR (n=248) TF TAVR (n=179) Medical (n=179) PMA TF n = 423

Characteristic PMA Cohort TF-TAVR (n=423) NRCA Cohort TF-TAVR (n=1080) p-value Age yr 83.59 ± 7.58 84.75 ± 7.75 <0.001 STS Score 11.54 ± 4.49 10.93 ± 3.84 0.001 Logistic EuroSCORE 28.03 ± 16.87 24.38 ± 15.14 <0.001 NYHA Class III - % 44.7 47.4 0.33 Class IV - % 48.9 48.1 0.77 CAD - % 72.1 75.9 0.13 Previous MI - % 23.3 23.5 0.96 Prior PCI - % 31.1 37.9 0.01 Prior CABG - % 36.9 37.5 0.04 Prior BAV - % 13.7 24.1 <0.0001 Cerebrovascular Disease - % 26.1 21.4 0.06 Peripheral Vascular Disease - % 33.3 27.4 0.02

Surgical Cutdown - % 76.8 48.6 <0.0001 Total procedure time (skin-to-skin) (min) 145.24 ± 82.32 118.91 ± 58.28 <0.0001 Post-Dilatation 36.6 9.2 <0.0001

All mortality no. (%) 24 (5.7) 53 (4.9) 0.54 Cardiac mortality no. (%) 18 (4.3) 36 (3.3) 0.39 Rehospitalization no. (%) 23 (5.4) 63 (5.8) 0.77 Death or rehosp no. (%) 44 (10.4) 114 (10.6) 0.93 Stroke or TIA no. (%) 26 (6.1) 41 (3.8) 0.05 Stroke 23 (5.4) 36 (3.3) 0.06

All mortality % 25.8 18.0 0.001 Cardiac mortality % 11.7 8.5 0.07 Stroke % 7.3 4.8 0.05 Death or major stroke - % 27.7 19.7 0.001

PARTNER 1 RCT vs. NRCA All-cause mortality TF-TAVR 2-Yr Death (%) 50 40 30 20 10 0 PMA NRCA HR: 1.31 [95% CI: 1.07, 1.62] Log-Rank p= 0.010 0 4 8 12 16 20 24 35.9% 29.5% Time in Months Number at risk PMA NRCA 423 368 338 313 292 278 265 1080 948 767 604 304 272 183 * Events adjudicated to one year

Registry Enrollment Time Cohort 1 N=1038 SOURCE Cohort 2 N=1269 SOURCE XT N=2681 Nov 07- Jan 09 Feb 09 Dec 09 Dec 10 Jun 11 THV SAPIEN SAPIEN XT TF Delivery System TA Delivery System Retroflex Novaflex Ascendra Ascendra 2

THV SAPIEN SAPEIN XT Centers 37 94 Countries 14 17 Access TF, TA TF, TA, TAO, SC THV SAPIEN 23mm, 26mm SAPIEN XT 23mm, 26mm, 29mm AE Definitions Non VARC VARC AE Adjudication Principal Investigators CEC Monitoring No Yes Follow-up 30 Days, annually to 2 Years 30 Days, annually to 5 Years

SOURCE Cohort 1 Cohort 2 SOURCE XT Nov 07- Jan 09 Feb 09 Dec 09 Jul 10 Oct 11 TF RetroFlex NovaFlex NovaFlex+ esheath 22/24 Fr. 18/19Fr 16/18Fr Ascendra Ascendra 2 TA 33/26 Fr 24/24 Fr

SOURCE SOURCE XT 3.7% 0.3% 62.7% 39.9% 33.3% 62.7% TF TA TAO Subclavian

All-cause Mortality (%) 9.6 6.3 <0.0001 Cardiac mortality (%) 4.0 2.6 0.0072 Any Stroke (%) 4.7 2.2 <0.0001 Vascular Complication Major (%)* 5.0 14.5 <0.0001 Major Bleeding (%) * 3.6 8.0 <0.0001 Ventricular Injury (%) 0.3 0.2 0.2453 MI (%) 0.7 0.6 0.7896 New pacemaker 7.2 9.5 0.0027 * Different definitions for SOURCE and SOURCE XT

Major Bleeding Major Vascular Complications (%) (%) P=0.0145 P=0.0003

CoreValve ADVANCE Methods

CoreValve ADVANCE Baseline Characteristics

CoreValve ADVANCE Procedural Results

CoreValve ADVANCE 30-day Outcomes

CoreValve ADVANCE 6-month Survival

CoreValve ADVANCE 6-month Stroke

Paravalvular aortic regurgitation Stroke Conduction disturbances

PARTNER 1A ADVANCE Registry Mild AR associated with mortality? Moderate AR associated with mortality?

PARTNER 1 NRCA Only Mortality & Paravalvular leak 2-Year Death (%) 60 50 40 30 20 NRCA-TF - None or Trace PVL at 30D NRCA-TF - Mild PVL at 30D NRCA-TF - Mod or Sev PVL at 30D 37.8% 21.7% 20.2% 10 Log Rank P= <.001 0 0 60 120 180 240 300 360 420 480 540 600 660 720 Time in Days Number At Risk None or Trace PVL 388 373 339 300 238 127 119 112 76 Mild PVL 400 388 350 303 247 125 114 106 74 Mod or Sev PVL 120 113 97 81 66 37 34 32 23 * Events adjudicated to one year

PARTNER 1 RCT TAVR vs. AVR 2-year Stroke p=0.12

PARTNER 1 RCT vs. NRCA 2-year Stroke TF-TAVR 2-Yr Stroke (%) 10 8 6 4 2 0 PMA NRCA HR: 1.58 [95% CI: 1.03, 2.43] Log-Rank p= 0.036 9.0% 5.8% 0 4 8 12 16 20 24 Time in Months Number at risk PMA NRCA 423 349 321 299 279 267 254 1080 916 743 580 292 264 177 * Events adjudicated to one year

CoreValve ADVANCE Freedom from Stroke

CoreValve National Registries Stroke 30-days

ADVANCE Registry Italian Registry No association between new-onset LBBB and mortality at 6-months, 1, and 2 years Urena et al. J Am Coll Cardiol 2012

CoreValve National Registries Pacemaker Implantation

CoreValve Advance Registry Impact of PPM

Introduction of new devices: head to head randomized trials or registries? Phase 1 Phase 2 Phase 3 Setting with no other US legally marketed transcatheter valve RCT TAVI vs. SAVR TAVI vs. medical treatment After transcatheter valve is on the US market for the same indications being sought RCT TAVI old vs. TAVI new Significant long-term data about transcatheter valves is available OPC can be developed Registry Single arm clinical trial

TAVI CANDIDATES 2012 Low Risk Intermediate Risk High Risk Inoperable SAVR PATIENTS? PARTNER II SURTAVI TAVI POPULATION