Craig R. Smith, MDon behalf of The PARTNER Trial Investigators

Transcatheter vs. Surgical Aortic Valve Replacement in High Risk Patients with Severe Aortic Stenosis: Results From The PARTNER Trial

ACC 2011 | New Orleans | April 3, 2011

Craig R. Smith, MD

PARTNER Trial sponsor (Edwards LifeSciences) reimburses customary travel and other expenses

Presenter Disclosure Information for PARTNER at ACC April 3, 2011

Background

• Surgical aortic valve replacement (AVR) is the standard of care for treating patients with symptomatic aortic stenosis who are candidates for operation.

• Although transcatheter aortic valve replacement (TAVR) reduces mortality in patients who cannot have AVR, there have been no randomized trials comparing TAVR to AVR in patients who are at high-risk for operation.

Purpose

To compare the safety and effectiveness of TAVR (either transfemoral or transapical) to surgical AVR in high-risk, operable patients with symptomatic, severe aortic stenosis.

N = 699 N = 358High Risk Inoperable

PARTNER Study Design

Symptomatic Severe Aortic Stenosis

ASSESSMENT: High-Risk AVR Candidate3,105 Total Patients Screened

Total = 1,057 patients

2 Parallel Trials: Individually Powered

StandardTherapy

ASSESSMENT: Transfemoral

Access

Not In Study

TF TAVR

Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)

Co-Primary Endpoint: Composite of All-Cause Mortalityand Repeat Hospitalization (Superiority)

1:1 Randomization

VS

Yes No

N = 179 N = 179

Inoperable PARTNER CohortPrimary Endpoint: All-Cause Mortality

Numbers at Risk

TAVI 179 138 122 67 26 Standard Rx 179 121 83 41 12

Standard Rx

TAVI

All-

caus

e m

orta

lity

(%)

Months

∆ at 1 yr = 20.0%NNT = 5.0 pts 50.7%

30.7%

HR [95% CI] =0.54 [0.38, 0.78]

P (log rank) < 0.0001

Leon et al, NEJM 2010; 363:1597-1607

N = 179

N = 358Inoperable

StandardTherapy

ASSESSMENT: Transfemoral

Access

Not In Study

TF TAVR

Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)

Co-Primary Endpoint: Composite of All-Cause Mortalityand Repeat Hospitalization (Superiority)

1:1 Randomization

VS

Yes No

N = 179

TF TAVR AVR

Primary Endpoint: All-Cause Mortality at 1 yr(Non-inferiority)

TA TAVR AVR VS

VS

N = 248 N = 104 N = 103N = 244

PARTNER Study Design

Symptomatic Severe Aortic Stenosis

ASSESSMENT: High-Risk AVR Candidate3,105 Total Patients Screened

Total = 1,057 patients

2 Parallel Trials: Individually Powered

N = 699 High Risk

ASSESSMENT: Transfemoral

Access

Transapical (TA)Transfemoral (TF)

1:1 Randomization1:1 Randomization

Yes No

Primary Endpoint

All-cause mortality at one year

• Analysis by intent-to-treat

• Event rates by Kaplan-Meier estimates• Crossovers permitted only when assigned

therapy unsuccessful

• All patients followed for ≥ one year

Other Important Endpoints (1)

Safety:• Neurologic events

– Prospective: Stroke and stroke plus TIA (all neuro events)

– Retrospective: Major stroke (modified Rankin Score ≥ 2 @ ≥ 30 days)

• Major vascular complications (VARC definition)

• Major bleeding (modified VARC definition)

• Repeat hospitalization

• New pacemakers and new-onset atrial fibrillation (ECG core lab)

• Procedural events (assigned therapy aborted or converted to AVR, multiple valves, etc.)

• Surgical complications (re-op for bleeding, sternal infection, etc.)

Other Important Endpoints (2)

Clinical Effectiveness and Valve Performance:

• NYHA symptoms

• Six-minute walk tests

• Quality-of-life measures and cost-effectiveness (core lab)

• Echocardiography assessment of valve performance (core lab)

– Peak and mean gradients– Effective orifice area– Bioprosthetic valve regurgitation (esp. para-valvular)– Other: LV ejection fraction, MR, LV mass, evidence of structural

valve deterioration

Co-Principal Investigators

Martin B. Leon, Craig R. SmithColumbia University Medical Center

Executive Committee

Martin B. Leon, Michael Mack, D. Craig Miller, Jeffrey W. Moses,Craig R. Smith, Lars G. Svensson, E. Murat Tuzcu, John G. Webb

Data & Safety Monitoring Board

Chairman: Joseph P. CarrozzaTufts University School of Medicine

Clinical Events Committee

Chairman: John L. PetersenDuke University Medical Center

Echo Core Laboratory

Chairman: Pamela C. Douglas Duke University Medical Center

Quality of Life and Cost-Effectiveness

Chairman: David J. CohenMid America Heart Institute, Kansas City

Independent BiostatisticalCore Laboratory

Stuart Pocock, Duolao WangLondon School of Hygiene andTropical Medicine

William N. Anderson

Publications Committee

Co-Chairman: Jeffrey W. MosesLars G. Svensson

Sponsor

Edwards Lifesciences: Jodi J. Akin

Study Administration

Executive Committee

John Webb

Murat Tuzcu

Marty Leon

Jeff MosesLars Svensson Craig Miller Michael Mack

Craig Smith

Participating Study Sites

Intermountain Medical CenterSalt Lake City, UT

Emory UniversityAtlanta, GA

Univ. of MiamiMiami, FL

Univ. of Virginia Charlottesville, VA

St. Luke’s Hospital Kansas City, MO

Barnes-Jewish HospitalSt. Louis, MO

Medical City DallasDallas, TX

St. Paul's HospitalVancouver, Canada

Univ. of WashingtonSeattle, WA

Mayo ClinicRochester, MN

Stanford UniversityPalo Alto, CA

Hospital LavalQuebec City,

Canada

Ochsner FoundationNew Orleans, LA

Scripps ClinicLa Jolla, CA

Cedars-Sinai Medical CenterLos Angeles, CA

Cleveland ClinicCleveland, OH

Columbia UniversityCornell University New York, NY

Washington Hosp. CenterWash., DC

Univ. of Penn Phila., PA

Brigham & Women’sMass GeneralBoston, MA

Northwestern Univ.Chicago, IL

Toronto Gen. Hospital

Toronto, Canada

Evanston Hospital

Leipzig Heart Center Leipzig, Germany

n = 1,057 patients26 investigator sites22 USA, 3 Canada, 1 Germany

High-Risk Enrollment by Site

Cedars-Sinai Medical CtrLos Angeles, CAG. Fontana, R. Makkar

116

Columbia University New York City, NYM. Leon, C. Smith

97

Medical City DallasDallas, TXD. Brown, T. Dewey

95

Emory UniversityAtlanta, GAP. Block, R. Guyton

67

University of PennsylvaniaPhiladelphia, PAJ. Bavaria, H. Herrmann

52

Cleveland Clinic FoundCleveland, OHL. Svensson, M. Tuzcu

47

Washington Hospital CtrDistrict of ColumbiaP. Corso, A. Pichard

40

University of MiamiMiami, FLW. O’Neill, D. Williams

25

Barnes-Jewish HospitalSt. Louis, MOR. Damiano, J, Lasala

24

Stanford UniversityPalo Alto, CAC. Miller, A. Yeung

23

Northwestern UniversityChicago, ILC. Davidson, P. McCarthy

20

St. Paul's HospitalVancouver, BC, CanadaA. Cheung, J. Webb

19

Mass General Hospital Boston, MAI. Palacios, G. Vlahakis

15

St. Luke’s HospitalKansas City, MOK. Allen, D. Cohen

13

Universitaire de QuebecLaval, Quebec, CAD. Doyle, J. Rodes-Cabau

8

Scripps Clinic La Jolla, CAS. Brewster, P. Teirstein

7

Herzzentrum LeipzigLeipzig, GermanyF. Mohr, G. Schuler

7

Mayo ClinicRochester, MNC. Rihal, T. Sundt

6

Univ of WashingtonSeattle, WAM. Reisman, E. Verrier

5

Northshore Univ Health SysEvanston, ILJ. Alexander, T. Feldman

4

University of Virginia Charlottesville, VAI. Kron, S. Lim

3

Brigham & Women’s HospBoston, MAM. Davidson, A. Eisenhauer

2

Ochsner FoundationNew Orleans, LAE. Parrino, S. Ramee

2

Intermountain Med CenterSalt Lake City, UTK. Jones, B. Whisenant

1

Cornell University New York City, NYK. Krieger, C. Wong

1

Toronto General HospitalToronto, Ontario, CAC. Feindel, E. Horlick

0

High-Risk Enrollment by Site

Study Devices

Edwards SAPIEN THV23 and 26 mm valves

RetroFlex 22 and 24 F sheaths

Ascendra 24 and 26 F sheaths

Transfemoral Transapical

TAVRTransfemoral and Transapical

Inclusion Criteria

• Severe AS: Echo-derived AVA < 0.8 cm2 (or AVA index < 0.5 cm2/m2) and mean AVG > 40 mm Hg or peak jet velocity > 4.0 m/s

• Cardiac Symptoms: NYHA Functional Class ≥ II

• High surgical risk: Predicted risk of operative mortality ≥ 15% (determined by site surgeon and cardiologist); guideline = STS score ≥ 10

Key Exclusion Criteria (1)

• Bicuspid or non-calcified aortic valve

• Aortic annulus diameter (echo measurement) < 18 mm or > 25 mm

• Aortic dissection or iliac-femoral dimensions or diseaseprecluding safe sheath insertion (esp. calcification)

• Severe LV dysfunction (LVEF < 20%)

• Untreated CAD requiring revascularization

• Severe AR or MR (> 3+) or prosthetic valve (any location)

Anatomic:

Key Exclusion Criteria (2)

• Serum Cr > 3.0 mg/dL or dialysis dependent

• Acute MI within 1 month

• Upper GI bleed within 3 months

• CVA or TIA within 6 months

• Any cardiac procedure, other than BAV, within 1 month or within 6 months for DES

• Hemodynamic instability (e.g. requiring inotropic support)

Clinical:

Statistical Analysis Plan

• Primary hypothesis is non-inferiority of test (TAVR)vs. control (AVR) for all-cause mortality at 1 year

• Non-inferior if one-sided 95% upper confidence limit forthe treatment difference is < 7.5% (α =0.05)

• Primary Endpoint: All TF and TA patients– Assuming true 1-year mortality 32% after AVR and 29% after TAVR– Intended sample size = 650 patients for ≥ 85% power

• Powered Secondary Endpoint: Only TF patients– Assuming true 1-year mortality 35% after AVR and 25% after TAVR– Intended sample size = 450 patients for ≥ 85% power

Study Methodology

• Preliminary eligibility determined by site investigators

• Every case reviewed by web-based conference callbefore enrollment

• Randomized to TF-TAVR vs. AVR, or TA-TAVR vs. AVR, to be treated within 2 weeks

• Intent-to-treat (ITT) analysis for the primary and most secondary endpoints; defined as the time of randomization

• As-treated (AT) analysis for some procedural endpointsand for echo assessments; defined as thetime of procedural anesthesia induction

1 Year (189)Dead = 46Withdrawal = 1

1 Year (168)Dead = 47Withdrawal = 8

Study Flow

AVR (248)

30 Days (236)Dead = 8Withdrawal = 0

Randomized = 699 patients

TF = 492TA = 207

Transfemoraln = 492

TAVR (244)

30 Days (223)Dead = 15Withdrawal = 10

1 Year (73)Dead = 26Withdrawal = 0LTFU = 1

1 Year (68)Dead = 20Withdrawal = 3LTFU = 1

AVR (103)

30 Days (100)Dead = 4Withdrawal = 0

Transapicaln = 207

TAVR (104)

30 Days (92)Dead = 7Withdrawal = 4

42 Patients not treated as assigned

Reason TAVR (N = 348) AVR (N = 351)

Died before treatment - no. (%) 2 (0.6) 5 (1.4)

Deterioration before treatment - no. (%) 1 (0.3) 5 (1.4)

Refusal - no. (%) 1 (0.3) 17 (4.8)

Withdrawal - no. (%) 0 11 (3.1)

Total – no. (%) 4 (1.1) 38 (10.8)

Reasons for Non-treatment

ITT = 699 patients │ AT = 657 patients

NOTE: Time from randomization to treatment = TAVR 10.6 [SEM 0.7] daysvs. AVR 15.6 [SEM 1.1] days; P <0.001

Characteristic TAVR (N = 348) AVR (N = 351) p-value

Age (yr) 83.6 ± 6.8 84.5 ± 6.4 0.07

Male sex - % 57.8 56.7 0.82

STS Score 11.8 ± 3.3 11.7 ± 3.5 0.61

Logistic EuroSCORE 29.3 ± 16.5 29.2 ± 15.6 0.93

NYHAII - %

III or IV - % 94.3 94.0 0.79

CAD - % 74.9 76.9 0.59

Previous MI - % 26.8 30.0 0.40

Prior CV Intervention - % 72.1 71.6 0.93

Prior CABG - % 42.6 44.2 0.70

Prior PCI - % 34.0 32.5 0.68

Prior BAV - % 13.4 10.2 0.24

29.3 27.4 0.60

Patient Characteristics (1)

Cerebrovascular disease - %

5.7 6.0

Characteristic TAVR (N = 348) AVR (N = 351) p-value

Peripheral vascular disease - % 43.0 41.6 0.76

COPD Any 43.4

Oxygen dependent 9.2 7.1 0.34

Creatinine > 2mg/dL - % 11.1 7.0 0.06

Atrial fibrillation - % 40.8 42.7 0.75

Permanent pacemaker - % 20.0 21.9 0.58

Pulmonary hypertension - % 42.4 36.4 0.15

Frailty - % 15.6 17.6 0.58

Porcelain aorta - % 0.6 1.1 0.69

Chest wall radiation - % 0.9 0.9 1.00

Liver disease - % 2.0 2.6 0.80

Patient Characteristics (2)

43.0 0.94

Baseline Echocardiography

Echo Findings TAVR (N = 348) AVR (N = 351) p-value

AVA - cm2 0.7 ± 0.2 0.6 ± 0.2 0.13

AVG - mm Hg 42.7 ± 14.6 43.5 ± 14.3 0.45

Mean LVEF - % 52.5 ± 13.5 53.3 ± 12.8 0.45

Moderate or severe MR - % 19.8 21.3 0.63

Anesthesia time - min 330

Total procedure time - min 230

Aborted procedure - no. (%) 0

Reoperation for bleeding - no. (%) 12 (3.4)

Intra-procedural death - no. (%) 1 (0.3)

Aortic perforation - no. (%) 1 (0.3)

Aortic dissection - no. (%) 3 (0.9)

Median ICU stay (days) 5.0

Anesthesia time - min 236

Total procedure time - min 133

Aborted procedure - no. (%) 7 (2.0)

Reoperation for bleeding - no. (%) 2 (0.6)

Intra-procedural death - no. (%) 3 (0.9)

Aortic perforation - no. (%) 0

Aortic dissection - no. (%) 3 (0.9)

Median ICU stay (days) 3.0

Procedural Outcomes - TAVR vs AVR

*Converted to transapical TAVR due to porcelain aorta

AVR TAVR

3 failed access2 new TEE findings

2 diedAborted procedure - no. (%)

Sternal wound infection - no. (%) 7 (2.0)

Total cross clamp time - min 74

Pump time - min 105

Access site infection - no. (%) 7 (2.0)

Fluoroscopy time - min 31

Converted to AVR - no. (%) 9 (2.6)

Multiple (≥2) valves - no. (%) 7 (2.0)

Valve embolization - no. (%) 9 (2.6)

Procedural Outcomes - TAVR vs AVR

*Converted to transapical TAVR due to porcelain aorta

AVR TAVR

5 valve embolization3 annulus size on TEE

1 large sigmoid septumConverted to AVR - no. (%)

5 converted to AVR2 valve-in-valve

2 not treatedValve embolization - no. (%)

0

0.1

0.2

0.3

0.4

0.5

0 6 12 18 24

TAVR

AVR

Months

348 298 260 147 67

351 252 236 139 65

No. at Risk

TAVR

AVR

26.8

24.2

Primary Endpoint:All-Cause Mortality at 1 Year

HR [95% CI] =0.93 [0.71, 1.22]

P (log rank) = 0.62

Primary Endpoint:All-Cause Mortality at 1 Year

7.0-2.0 -1.0 0.0 6.03.0 4.0 5.0-3.0 1.0 2.0

Non-inferior

Upper one-sided 95% CI

8.0 %

AVR (N = 351)

26.8%

TAVR (N = 348)

24.2%

Difference -2.6%

Upper 1-sided 95% CI3.0%

Primary Non-Inferiority Endpoint Met

Non-inferiority

P value

= 0.001

Zone of non-inferiority pre-specified margin = 7.5%

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5TAVRAVR

All-Cause MortalityTransfemoral (N=492)

Months

244 215 188 119 59

248 180 168 109 56

No. at Risk

TAVR

AVR

26.4

22.2

HR [95% CI] =0.83 [0.60, 1.15]

P (log rank) = 0.25

Powered Secondary Endpoint (ITT):TF All-Cause Mortality at 1 Year

7.0-4.0 -1.0 0.0 6.03.0 4.0 5.0-5.0

Zone of non-inferiority pre-specified margin = 7.5%

1.0 2.0

Non-inferior

Upper one-sided 95% CI

Secondary TF Non-Inferiority Endpoint Met

8.0 %

Difference -4.2%

Upper 1-sided 95% CI2.3%

Non-inferiority

P value

= 0.002

-2.0-3.0

AVR (N = 244)

26.4%

TAVR (N = 248)

22.2%

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5TAVRAVR

104 83 72 28 8

103 72 68 30 9

29.0

27.9

TAVR

AVR

MonthsNo. at Risk

All-Cause MortalityTransapical (N=207)

HR [95% CI] =1.22 [0.75, 1.98]

P (log rank) = 0.41

Surgical AVR Outcomes

• Using an established predictive risk model (STS), the expected (“E”) 30-day mortality after AVR was 11.8%.

• The observed (“O”) 30-day mortality in the as-treated AVR control group was 8.0%.

• O:E = 0.68 indicates better than predicted surgical outcomes in the control AVR patients.

• There were no significant site or surgeon differences.

All-Cause Mortality at 30 DaysAll Patients

no. of patients ( %)TF Patients

no. of patients ( %)TA Patients

no. of patients ( %)

  TAVR AVR p-value TAVR AVR p-value TAVR AVR p-value

ITT 12 (3.4) 22 (6.5) 0.07 8 (3.3) 15 (6.2) 0.13 4 (3.8) 7 (7.0) 0.32

AT 18 (5.2) 25 (8.0) 0.15 9 (3.7) 18 (8.2) 0.05 9 (8.7) 7 (7.6) 0.79

All-Cause Mortality at 1 YearAll Patients

no. of patients ( %)TF Patients

no. of patients ( %)TA Patients

no. of patients ( %)

  TAVR AVR p-value TAVR AVR p-value TAVR AVR p-value

ITT 84 (24.2) 89 (26.8) 0.44 54 (22.2) 62 (26.4) 0.29 30 (29.0) 27 (27.9) 0.85

AT 81 (23.7) 78 (25.2) 0.64 51 (21.3) 55 (25.2) 0.33 30 (29.1) 23 (25.3) 0.55

All-Cause Mortality at 30 Days and 1 Year ITT and ATT by Subgroup

  30 Days 1 Year

Outcome TAVR(N = 348)

AVR(N = 351) p-value TAVR

(N = 348)AVR

(N = 351) p-value

All mortality – no. (%) 12 (3.4) 22 (6.5) 0.07 84 (24.2) 89 (26.8) 0.44

Cardiac mortality – no. (%) 11 (3.2) 10 (3.0) 0.90 47 (14.3) 40 (13.0) 0.63

Rehospitalization – no. (%) 15 (4.4) 12 (3.7) 0.64 58 (18.2) 45 (15.5) 0.38

Death or rehosp – no. (%) 25 (7.2) 33 (9.7) 0.24 120 (34.6) 119 (35.9) 0.73

MI – no. (%) 0 2 (0.6) 0.16 1 (0.4) 2 (0.6) 0.69

Acute kidney inj* – no. (%) 10 (2.9) 10 (3.0) 0.95 18 (5.4) 20 (6.5) 0.56

Clinical Outcomes at 30 Days and 1 Year All Patients (N=699)

* Renal replacement therapy

  30 Days 1 Year

Outcome TAVR(N = 348)

AVR(N = 351) p-value TAVR

(N = 348)AVR

(N = 351) p-value

Vascular complications

All – no. (%) 59 (17.0) 13 (3.8) <0.01 62 (18.0) 16 (4.8) <0.01

Major – no. (%) 38 (11.0) 11 (3.2) <0.01 39 (11.3) 12 (3.5) <0.01

Major bleeding – no. (%) 32 (9.3) 67 (19.5) <0.01 49 (14.7) 85 (25.7) <0.01

Endocarditis – no. (%) 0 (0.0) 1 (0.3) 0.32 2 (0.6) 3 (1.0) 0.63

New AF – no. (%) 30 (8.6) 56 (16.0) < 0.01 42 (12.1) 60 (17.1) 0.07

New PM – no. (%) 13 (3.8) 12 (3.6) 0.89 19 (5.7) 16 (5.0) 0.68

Clinical Outcomes at 30 Days and 1 Year All Patients (N=699)

  30 Days 1 Year

Outcome TAVR(N = 348)

AVR(N = 351)

TAVR(N = 348)

AVR(N = 351)

All Stroke or TIA – no. (%) 19 (5.5) 8 (2.4) 0.04 27 (8.3) 13 (4.3) 0.04

TIA – no. (%) 3 (0.9) 1 (0.3) 0.33 7 (2.3) 4 (1.5) 0.47

All Stroke – no. (%) 16 (4.6) 8 (2.4) 0.12 20 (6.0) 10 (3.2) 0.08

Major Stroke – no. (%) 13 (3.8) 7 (2.1) 0.20 17 (5.1) 8 (2.4) 0.07

Minor Stroke – no. (%) 3 (0.9) 1 (0.3) 0.34 3 (0.9) 2 (0.7) 0.84

Death/maj stroke – no. (%) 24 (6.9) 28 (8.2) 0.52 92 (26.5) 93 (28.0) 0.68

Neurological Events at 30 Days and 1 Year All Patients (N=699)

p-value p-value

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5TAVRAVR

Months

348 289 252 143 65

351 247 232 138 63

No. at Risk

TAVR

AVR

28.0

26.5

HR [95% CI] =0.95 [0.73, 1.23]

P (log rank) = 0.70

All-Cause Mortality or StrokeAll Patients (N=699)

NYHA Functional Class

TAVR AVR TAVR AVR TAVR AVR TAVR AVR0

20

40

60

80

100

Baseline 1 Year6 Months30 Days

Pat

ient

s S

urvi

ving

, %

I II III IV

P = 1.00 P < 0.001 P = 0.05 P = 0.75

Six-Minute Walk TestAll Patients (N=699)

Baseline 30 Days 6 Months 1 Year0

50

100

150

200

71 75

192

175

75

128

165

152

AVR TAVR

Med

ian

Dis

tanc

e, m

eter

s

P = 0.73 P = 0.002 P = 0.33 P = 0.76

SubgroupTAVR (%)

n=348AVR (%)

n=351RR

(95% CI) RR

(95% CI)P-value for

interaction

Overall 24.1 25.4 0.95(0.73-1.23)

Age<85>85

21.627.0

24.926.1

0.87(0.60-1.27)1.03(0.72-1.47)

0.52

SexMaleFemale

28.418.4

24.227.2

1.17(0.84-1.63)1.17(0.84-1.63)

0.045

BMI<26>26

27.321.0

27.423.8

0.68(0.44-1.04)0.99(0.71-1.40)

0.66

STS score<11>11

19.928.1

21.729.3

0.88(0.59-1.31)0.92(0.61-1.38)

0.87

LV ejection fraction

<55>55

26.222.4

27.722.1

0.96(0.69-1.34)1.01(0.68-1.50)

0.80

Subgroup Analyses of Treatment Effect All-Cause Mortality at 1 Year

TAVR better AVR better

0.5 1 2

SubgroupTAVR (%)

n=348AVR (%)

n=351RR

(95% CI) RR

(95% CI)P-value for

interaction

Pulmonary hypertension

NoYes

21.327.4

21.729.9

0.98(0.64-1.50)0.92(0.66-1.28)

0.80

Mitral regurgitation

NoYes

24.624.2

22.135.2

1.11(0.82-1.52)0.69(0.41-1.17)

0.12

Prior CABGNoYes

22.225.9

30.719.1

0.72(0.52-1.01)1.35(0.88-2.08)

0.02

Peripheral vasc disease

NoYes

22.426.4

25.125.4

0.89(0.63-1.27)1.04(0.70-1.54)

0.57

Cohort TA TF

28.822.1

26.225.0

1.10(0.71-1.71)0.89(0.64-1.22)

0.43

TAVR better AVR better

0.5 1 2

Subgroup Analyses of Treatment Effect All-Cause Mortality at 1 Year

Mean Gradient - AVR

Mean Gradient - TAVR

Peak Gradient - AVR

Peak Gradient - TAVR

Mea

n an

d P

eak

Gra

dien

tA

s-T

reat

ed T

rial A

rms

(mm

Hg)

50

40

30

20

60

70

10

0

80

Baseline 30 Days 6 Months 1 YearTAVR

n = 327AVR

n = 301TAVR

n = 287AVR

n = 231TAVR

n = 246AVR

n = 170TAVR

n = 227AVR

n = 159

Echo FindingsAortic Valve Gradients

Echo FindingsHemodynamic Assessments

  30 Days 1 Year

Finding TAVR AVR TAVR AVR

AVG – mmHg 9.9 ± 4.8 10.8 ± 5.0 0.04 10.2 ± 4.3 11.5 ± 5.4 0.008

AVA - cm2 1.7 ± 0.5 1.5 ± 0.4 0.001 1.6 ± 0.5 1.4 ± 0.5 0.002

LVEF - % 55.5 ± 11.4 56.0 ± 11.4 0.63 56.6 ± 10.5 57.1 ± 10.3 0.64

p-value p-value

Paravalvular Aortic Regurgitation

TAVR AVR TAVR AVR TAVR AVR0

20

40

60

80

100P < 0.001 P < 0.001 P < 0.001

1 Year6 Months30 Days

Pat

ient

s, %

None Trace Mild Moderate Severe

Study Limitations

• 8% of the control (AVR) group withdrew or refused assignedtherapy

• 5% of patients randomized to TAVR did not receiveassigned therapy (procedure aborted or converted to AVR)

• Significantly longer interval between randomization andtreatment in controls (AVR)

• An early version large TAVR delivery system was used

• Most sites had no previous TAVR experience - learningcurve impact inherent in TAVR, but not in AVR

• Insufficient statistical power to compare TA to either AVRor TF

• Long-term follow-up not available to assess TAVR durability

Conclusions (1)

• The primary endpoint of the trial was met:– In patients with aortic stenosis at high risk for operation,

TAVR was non-inferior to AVR for all-cause mortality at 1 year (24.2% vs. 26.8%, p=0.001 for non inferiority)

– Transfemoral TAVR subgroup was also non-inferior toAVR (p=0.002 for non-inferiority)

• Death at 30 days was lower than expected in botharms of the trial:

– TAVR mortality (3.4%) was the lowest reported in any series, despite an early generation device and limited previous operator experience

– AVR mortality (6.5%) was lower than the expected operative mortality (11.8%)

Conclusions (2)

• Both TAVR and AVR were associated with important but different peri-procedural hazards:

– Major strokes at 30 days (3.8 vs. 2.1%, p=0.20) and one year (5.1% vs. 2.4%, p=0.07) and major vascular complications were more frequent with TAVR (11.0% vs. 3.2%, p<0.001)

– Major bleeding (9.3% vs. 19.5%, p<0.001) and new onset atrial fibrillation (8.6% vs. 16.0%, p<0.001) were more frequent with AVR

• TAVR and AVR are both acceptable therapies in these high-risk patients; differing peri-procedural hazards should influence case-based decision-making

Conclusions (3)

• Symptom improvement (NYHA class and 6-min walkdistance) favored TAVR at 30 days and was similar to AVR at one year

• Echo findings indicate:– Small hemodynamic benefit with TAVR vs. AVR at 1 year

(mean gradient p=0.008, AVA p=0.002)– Increased para-valvular regurgitation associated with

TAVR (p<0.001)

• Preliminary subgroup analyses should be interpretedcautiously:

– Possible TAVR benefit in women and patients without prior CABG

Implications

• A multidisciplinary valve team approach benefits patients and is recommended for all future valve centers.

• TAVR is already the standard-of-care for inoperable patients with severe aortic stenosis. These results indicate that TAVR is an acceptable alternative to AVR in selected high-risk operable patients.

• Future randomized studies should focus on lower risk patients who are candidates for operation.

Back-up Slides

PARTNER Comparison of OutcomesHigh-Risk vs. Inoperable Patients

Mortality (TF) Maj Stroke Maj Vascular Maj Bleed New PM PVL (1 yr)0

5

10

15

20

25

6.4

16.216.8

3.4

11.8

3.7 3.8

9.3

3.8

6.8

Inoperable High-Risk

Per

Cen

t (%

)

5.0

11.0

  TAVR AVR

Complication With Without With Without

Stroke or TIA

All Patients – no. 31 313 16 297

Died ≤ 30 days – no. (%) 2 (6.5) 16 (5.1) 1 (6.3) 24 (8.1)

Died ≤ 1 year – no. (%) 10 (32.3) 71 (22.8) 3 (18.8) 75 (25.6)

Major Stroke

All Patients – no. 18 326 11 302

Died ≤ 30 days – no. (%) 2 (11.1) 16 (4.9) 1 (9.1) 24 (8.0)

Died ≤ 1 year – no. (%) 9 (50.0) 72 (22.2) 3 (27.3) 75 (25.1)

Neurological Events and Mortality at 30 Days and 1 Year (as treated)

  TAVR AVR

Complication With Without With Without

Major Vascular

All Patients – no. 38 306 11 302

Died ≤ 30 days – no. (%) 6 (15.8) 12 (3.9) 2 (19.2) 23 (7.6)

Died ≤ 1 year – no. (%) 14 (37.3) 67 (22.0) 5 (49.5) 73 (24.4)

Major Bleeding

All Patients – no. 52 292 88 225

Died ≤ 30 days – no. (%) 2 (3.8) 16 (5.5) 15 (17.1) 10 (4.5)

Died ≤ 1 year – no. (%) 16 (31.1) 65 (22.3) 36 (41.3) 42 (18.9)

Vascular/Bleeding Events and Mortality at 30 Days and 1 Year (as treated)

All-Cause Mortality (As Treated TAVR Trial Arm)Stratified by Major Stroke

Months

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1No Event

Event

All-Cause Mortality (As Treated TAVR Trial Arm)Stratified by Major Vascular Event

Months

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1No Event

Event

All-Cause Mortality (As Treated TAVR Trial Arm)Stratified by Major Bleed

Months

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1No Event

Event

All-Cause Mortality (As Treated AVR Trial Arm)Stratified by Major Stroke

Months

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1No Event

Event

All-Cause Mortality (As Treated AVR Trial Arm)Stratified by Major Bleed

Months

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1No Event

Event

All-Cause Mortality (As Treated AVR Trial Arm)Stratified by New Atrial fibrillation

Months

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1No Event

Event

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

AVR

TAVR

All-Cause Mortality (As Treated)Pooled Implant Approaches (N= 657)

Months

344 291 258 139 64

313 243 226 128 60

No. at Risk

TAVR

AVR

25.2

23.7

HR [95% CI] =1.02 [0.77, 1.36]

P (log rank) = 0.88

Primary Endpoint: (As Treated)All-Cause Mortality at 1 Year

7.0-2.0 -1.0 0.0 6.03.0 4.0 5.0-3.0

Zone of non-inferiority pre-specified margin = 7.5%

1.0 2.0

Non-inferior

Upper one-sided 95% CI

Primary Non-Inferiority Endpoint Met

8.0 %

Difference -1.6%

Upper 1-sided 95% CI4.0%

Non-inferiority

P value

= 0.004

AVR (N = 313)

25.2%

TAVR (N = 344)

23.6%

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

AVR

TAVR

All-Cause Mortality (As Treated)Transfemoral (N=461)

Months

240 209 186 112 58

221 172 161 100 53

No. at Risk

TAVR

AVR

25.2

21.3

HR [95% CI] =0.90 [0.64, 1.26]

P (log rank) = 0.53

Powered Secondary Endpoint (AT):TF All-Cause Mortality at 1 Year

7.0-4.0 -1.0 0.0 6.03.0 4.0 5.0-5.0

Zone of non-inferiority pre-specified margin = 7.5%

1.0 2.0

Non-inferior

Upper one-sided 95% CI

Secondary TF Non-Inferiority Endpoint Met

8.0 %

Difference -3.9%

Upper 1-sided 95% CI2.6%

Non-inferiority

P value

= 0.002

-2.0-3.0

AVR (N = 221)

25.2%

TAVR (N =240 )

21.3%

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

AVR

TAVR

All-Cause Mortality (As Treated)Transapical (N=196)

Months

104 82 72 27 6

92 71 65 28 7

No. at Risk

TAVR

AVR

25.3

29.1

HR [95% CI] =1.36 [0.82, 2.26]

P (log rank) = 0.23

All-Cause Mortality Stratified by ITT Trial Arm and Patient Gender

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

TAVR Female

AVR Female

Months

All-Cause Mortality Stratified by ITT Trial Arm and Prior CABG

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

AVR: CABG No

AVR: CABG Yes

Months

All-Cause Mortality Stratified by ITT Trial Arm and Prior CABG

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

TAVR: CABG No

AVR: CABG No

Months

All-Cause Mortality Stratified by ITT trial arm and Moderate/Severe MR

0 6 12 18 240

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

TAVR MR No

TAVR MR Yes

AVR MR No

AVR MR Yes

Months

P = 0.027 (log rank)

Echo FindingsValvular Regurgitation

  30 Days 1 Year

Finding – no. (%) TAVR AVR TAVR AVR

Transvalv. Regurg.

Mod/Severe3 (1.0) 2 (0.9) <.0001 2 (0.9) 0 (0.0) <.0001

Paravalv. Regurg.

Mod/Severe35 (12.2) 2 (0.9) <.0001 15 (6.8) 3 (1.9) <.0001

All Regurg.

Mod/Severe21 (7.7) 4 (1.7) <0.001 12 (5.5) 3 (1.9) <0.001

p-value p-value

Echo FindingsParavalvular Regurgitation

  30 Days 1 Year

Finding – no. (%) TAVR AVR TAVR AVR

None 65 (22.6) 168 (73.7) <.0001 73 (32.9) 123 (77.8) <.0001

Trace/Mild 187 (65.2) 58 (25.4) <.0001 134 (60.4) 32 (20.3) <.0001

Mod/Severe 35 (12.2) 2 (0.9) <.0001 15 (6.8) 3 (1.9) <.0001

p-value p-value

Baseline 30 Day 6 Month 1 Year 0.00

0.25

0.50

0.75

1.00

1.25

1.50

1.75

2.00

AVR

TAVR

Val

ve A

rea,

cm

2

Aortic Valve AreaAs Treated Trial Arms

TAVRn = 319

AVRn = 297

TAVRn = 279

AVRn = 228

TAVRn = 235

AVRn = 165

TAVRn = 219

AVRn = 155