ACC 2015 | San Diego | March 15, 2015ACC 2015 | San Diego | March 15, 2015

Susheel Kodali, MDSusheel Kodali, MDon behalf of The PARTNER Trial Investigatorson behalf of The PARTNER Trial Investigators

Clinical and Echocardiographic Clinical and Echocardiographic Outcomes at 30 Days with the SAPIEN 3 Outcomes at 30 Days with the SAPIEN 3 TAVR System in Inoperable, High-Risk TAVR System in Inoperable, High-Risk and Intermediate-Risk AS Patientsand Intermediate-Risk AS Patients

Susheel Kodali, MDSusheel Kodali, MD

Within the past 12 months, I or my spouse/partner have had a financial Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.interest/arrangement or affiliation with the organization(s) listed below.

• Grant/Research SupportGrant/Research Support

• Steering CommitteeSteering Committee

• SAB (Equity)SAB (Equity)

• HonorariaHonoraria

• Edwards Lifesciences, Medtronic, Edwards Lifesciences, Medtronic, Boston Scientific, Claret MedicalBoston Scientific, Claret Medical

• Edwards Lifesciences, Claret Edwards Lifesciences, Claret Medical, MerilMedical, Meril

• Thubrikar Aortic Valve, IncThubrikar Aortic Valve, Inc

• St. Jude Medical, Claret MedicalSt. Jude Medical, Claret Medical

Affiliation/Financial RelationshipAffiliation/Financial Relationship CompanyCompany

Disclosure Statement of Financial InterestDisclosure Statement of Financial Interest

BackgroundBackground

• Based on randomized trials with first generation devices, Based on randomized trials with first generation devices, transcatheter aortic valve replacement (TAVR) has been transcatheter aortic valve replacement (TAVR) has been incorporated into the treatment strategy for high-risk and incorporated into the treatment strategy for high-risk and inoperable patients with severe AS.inoperable patients with severe AS.

• Procedural complications remain a concern with TAVR, Procedural complications remain a concern with TAVR, including stroke, vascular complications, paravalvular leak including stroke, vascular complications, paravalvular leak (PVL) and conduction disturbances.(PVL) and conduction disturbances.

• Addressing these limitations will support TAVR use in Addressing these limitations will support TAVR use in lower risk populations.lower risk populations.

Evolution of the Edwards Balloon-Evolution of the Edwards Balloon-Expandable Transcatheter ValvesExpandable Transcatheter Valves

* Sheath compatibility for a 23 mm valve

2002

Cribier-Edwards

2006

SAPIEN

2009

SAPIEN XT

2013

SAPIEN 3

SAPIEN 3 Transcatheter Heart ValveSAPIEN 3 Transcatheter Heart ValveDistinguishing Features Distinguishing Features

Bovine pericardial Bovine pericardial tissuetissue

Outer skirt to reduce PVLOuter skirt to reduce PVL

Low frame heightLow frame height

Enhanced frame geometry for Enhanced frame geometry for ultra-low delivery profileultra-low delivery profile

SAPIEN 3 Commander Delivery SystemSAPIEN 3 Commander Delivery SystemDistinguishing Features Distinguishing Features

• Accurate positioningAccurate positioning

Fine control of valve positioning Distal flex

SAPIEN 3 Valve Size 20 mm20 mm 23 mm23 mm 26 mm26 mm 29 mm29 mm

Expandable Sheath 14F 14F 14F 16F

Minimum Access Vessel Diameter 5.5 mm 5.5 mm 5.5 mm 6.0 mm

• Improved coaxial alignmentImproved coaxial alignment

The PARTNER II S3 TrialThe PARTNER II S3 TrialPurposePurpose

To evaluate the safety and efficacy of the SAPIEN 3 To evaluate the safety and efficacy of the SAPIEN 3 transcatheter heart valve system at 30 days in transcatheter heart valve system at 30 days in inoperable, high-risk, and intermediate-risk patients.inoperable, high-risk, and intermediate-risk patients.

Intermediate Risk Operable

(PII S3i)

Intermediate Risk Operable

(PII S3i)

High Risk Operable / Inoperable

(PII S3HR)

High Risk Operable / Inoperable

(PII S3HR)

Symptomatic Severe Aortic Stenosis

ASSESSMENT by Heart Valve Team

n = 1076 Patients

n = 583Patients

ASSESSMENT: Optimal Valve

Delivery Access

ASSESSMENT: Optimal Valve

Delivery Access

SAPIEN 32 Single Arm Non-RandomizedHistorical-Controlled Studies

Transfemoral (TF)

TF TAVRSAPIEN 3

TAA TAVRSAPIEN 3

Transapical /Transaortic (TA/TAo)

TF TAVRSAPIEN 3

PI A SAPIEN

PII A SAVR

Transfemoral (TF)

TAA TAVRSAPIEN 3

Transapical /Transaortic (TA/TAo)

The PARTNER II S3 TrialThe PARTNER II S3 TrialStudy DesignStudy Design

Key Inclusion CriteriaKey Inclusion Criteria

• Risk determined by STS score and heart team:Risk determined by STS score and heart team:– High Risk / Inoperable (S3HR): High Risk / Inoperable (S3HR): STS score > 8 or heart team STS score > 8 or heart team

determinationdetermination

– Intermediate Risk (S3i): Intermediate Risk (S3i): STS score between 4 and 8 or heart STS score between 4 and 8 or heart team determinationteam determination

• Severe aortic stenosis determined by echocardiography:Severe aortic stenosis determined by echocardiography:– Valve area < 0.8 cmValve area < 0.8 cm22 or Valve area index < 0.5 cm or Valve area index < 0.5 cm22/m/m22 and and mean mean

gradient > 40mmHg or peak velocity > 4 m/sgradient > 40mmHg or peak velocity > 4 m/s

Key Exclusion CriteriaKey Exclusion Criteria

Study MethodologyStudy Methodology

• All patients presented on a screening call for approval prior to All patients presented on a screening call for approval prior to implant.implant.

• 3D imaging of annulus (CT or 3D TEE) recommended for S3HR and 3D imaging of annulus (CT or 3D TEE) recommended for S3HR and required for majority of S3i with core lab analysis prior to implant.required for majority of S3i with core lab analysis prior to implant.

• All patients evaluated by a neurologist at baseline and at follow-up All patients evaluated by a neurologist at baseline and at follow-up time points.time points.

• Primary Analysis: Primary Analysis: As treated patientsAs treated patients

• S3HR and S3i combined for echocardiographic analyses (valve S3HR and S3i combined for echocardiographic analyses (valve implant patients).implant patients).

The PARTNER II S3 Trial: The PARTNER II S3 Trial: S3HRS3HRParticipating SitesParticipating Sites

583 Patients Enrolled at 583 Patients Enrolled at 29 US Participating Sites29 US Participating Sites

The PARTNER II S3 Trial: The PARTNER II S3 Trial: S3iS3iParticipating SitesParticipating Sites

1076 Patients Enrolled at 1076 Patients Enrolled at 51 US Participating Sites51 US Participating Sites

The PARTNER II S3 Trial: The PARTNER II S3 Trial: S3HR & S3iS3HR & S3iTop 10 Enrollment SitesTop 10 Enrollment Sites

S3HRS3HR S3iS3iCedars-Sinai Medical Ctr.Cedars-Sinai Medical Ctr.Los Angeles, CALos Angeles, CA

7373 Cedars-Sinai Medical Ctr.Cedars-Sinai Medical Ctr.Los Angeles, CALos Angeles, CA

106106

Columbia University Medical Ctr.Columbia University Medical Ctr.New York, NYNew York, NY

6565 University of PennsylvaniaUniversity of PennsylvaniaPhiladelphia, PAPhiladelphia, PA

6666

Emory UniversityEmory UniversityAtlanta, GAAtlanta, GA

6363 Emory UniversityEmory UniversityAtlanta, GAAtlanta, GA

6262

University of PennsylvaniaUniversity of PennsylvaniaPhiladelphia, PAPhiladelphia, PA

4343 University of Texas, HoustonUniversity of Texas, HoustonHouston, TXHouston, TX

5252

Heart Hospital Baylor PlanoHeart Hospital Baylor PlanoPlano, TXPlano, TX

3030 Columbia University Medical Ctr.Columbia University Medical Ctr.New York, NYNew York, NY

4848

Ochsner HospitalOchsner HospitalNew Orleans, LANew Orleans, LA

2626 Heart Hospital Baylor PlanoHeart Hospital Baylor PlanoPlano, TXPlano, TX

4646

University of Texas, HoustonUniversity of Texas, HoustonHouston, TXHouston, TX

2525 Cleveland Clinic FoundationCleveland Clinic FoundationCleveland, OHCleveland, OH

4141

Stanford University Medical Ctr.Stanford University Medical Ctr.Stanford, CAStanford, CA

2424 Newark Beth Israel Medical Ctr.Newark Beth Israel Medical Ctr.Newark, NJNewark, NJ

3838

Newark Beth Israel Medical Ctr.Newark Beth Israel Medical Ctr.Newark, NJNewark, NJ

2121 The Christ HospitalThe Christ HospitalCincinnati, OHCincinnati, OH

3838

Washington Hospital Ctr.Washington Hospital Ctr.Washington, DCWashington, DC

1919 Mayo ClinicMayo ClinicRochester, MNRochester, MN

3535

Co-Principal InvestigatorsCo-Principal Investigators

Susheel KodaliSusheel KodaliColumbia University, NYColumbia University, NY

Vinod ThouraniVinod ThouraniEmory University, GAEmory University, GA

Case Review Board ChairmenCase Review Board Chairmen

Scott LimScott LimUniversity of Virginia, VAUniversity of Virginia, VA

S. Chris MalaisrieS. Chris MalaisrieNorthwestern, ILNorthwestern, IL

Data & Safety Monitoring BoardData & Safety Monitoring Board

Chairman:Chairman: Joseph P. CarrozzaJoseph P. CarrozzaSt. Elizabeth Med. Ctr., BostonSt. Elizabeth Med. Ctr., Boston

Clinical Events CommitteeClinical Events Committee

Chairman:Chairman: Sagar KalahastiSagar KalahastiCleveland Clinic, C5 ResearchCleveland Clinic, C5 Research

Echo Core Laboratory ConsortiumEcho Core Laboratory Consortium

Rebecca T. HahnRebecca T. HahnColumbia University/CRF, NYColumbia University/CRF, NY

Philippe PibarotPhilippe PibarotQuebec Heart & Lung Inst., Laval, QCQuebec Heart & Lung Inst., Laval, QC

Neil J. WeissmanNeil J. WeissmanMedstar Health Res. Inst., Wash DCMedstar Health Res. Inst., Wash DC

ECG Core LaboratoryECG Core Laboratory

Jose M. DizonJose M. DizonColumbia University/CRF, NYCColumbia University/CRF, NYC

CT Core LaboratoryCT Core Laboratory

Jonathan LeipsicJonathan LeipsicSt. Paul’s Hospital, Vancouver, BCSt. Paul’s Hospital, Vancouver, BC

Study AdministrationStudy Administration

Study Flow: Study Flow: S3HR & S3iS3HR & S3i30 Day Patient Status30 Day Patient Status

0 Withdrawal

3 LTFU

13 Deaths

0 Withdrawal

5 LTFU

12 Deaths

S3HRS3HR S3iS3i

n = 583n = 583n = 583n = 583

n = 570n = 570SAPIEN 3SAPIEN 3n = 570n = 570

SAPIEN 3SAPIEN 3

567 / 570 or 99.5% follow-up567 / 570 or 99.5% follow-upvisits performed at 30 Days visits performed at 30 Days 567 / 570 or 99.5% follow-up567 / 570 or 99.5% follow-upvisits performed at 30 Days visits performed at 30 Days

n = 1076n = 1076n = 1076n = 1076

n = 1064n = 1064SAPIEN 3SAPIEN 3n = 1064n = 1064

SAPIEN 3SAPIEN 3

1059 / 1064 or 99.5% follow-up1059 / 1064 or 99.5% follow-upvisits performed at 30 Days visits performed at 30 Days

1059 / 1064 or 99.5% follow-up1059 / 1064 or 99.5% follow-upvisits performed at 30 Days visits performed at 30 Days

Baseline Patient CharacteristicsBaseline Patient CharacteristicsS3HR PatientsS3HR Patients

Average STS =Average STS =

8.6%8.6%(Median 8.4%)(Median 8.4%)

N = 583N = 583Average Age =Average Age =

82.6yrs82.6yrs

Baseline Patient CharacteristicsBaseline Patient CharacteristicsS3i PatientsS3i Patients

Average STS =Average STS =

5.3%5.3%(Median 5.2%)(Median 5.2%)

N = 1076N = 1076Average Age =Average Age =

81.9yrs81.9yrs

Baseline Patient CharacteristicsBaseline Patient CharacteristicsDemographicsDemographics

Characteristic Characteristic (%)(%)S3HRS3HR(n=583)(n=583)

S3iS3i(n=1076)(n=1076)

NYHA Class NYHA Class III or IVIII or IV 90.190.1 72.672.6

Previous CABGPrevious CABG 33.133.1 28.028.0

Previous CVAPrevious CVA 11.011.0 8.98.9

Peripheral Vascular DiseasePeripheral Vascular Disease 35.235.2 28.328.3

DiabetesDiabetes 34.534.5 34.134.1

COPD - OCOPD - O22 Dependent Dependent 11.711.7 5.05.0

CKD - Creat. ≥ 2mg/dLCKD - Creat. ≥ 2mg/dL 12.012.0 7.57.5

Atrial FibrillationAtrial Fibrillation 43.743.7 36.036.0

Permanent PacemakerPermanent Pacemaker 16.316.3 13.213.2

FrailtyFrailty 30.930.9 8.68.6

Baseline EchocardiographyBaseline Echocardiography

CharacteristicCharacteristicS3HRS3HR(n=583)(n=583)

S3iS3i(n=1076)(n=1076)

AV Area - cmAV Area - cm22 (mean ± SD)(mean ± SD) 0.67 ± 0.180.67 ± 0.18 0.70 ± 0.170.70 ± 0.17

Annulus Diam. - cm Annulus Diam. - cm (mean ± SD)(mean ± SD) 2.2 ± 0.22.2 ± 0.2 2.2 ± 0.22.2 ± 0.2

AV Gradient - mmHg AV Gradient - mmHg (mean ± SD)(mean ± SD) 45.5 ± 14.345.5 ± 14.3 46.3 ± 12.746.3 ± 12.7

LV Ejection Fraction LV Ejection Fraction (%)(%) 56.4 ± 14.856.4 ± 14.8 58.6 ± 13.358.6 ± 13.3

Mod-Severe MR Mod-Severe MR (%)(%) 3.03.0 2.32.3

Procedural FactorsProcedural Factors

S3HRS3HR(n=583)(n=583)

S3iS3i(n=1076)(n=1076)

Post-Dilatation Post-Dilatation (%)(%) 14.814.8 11.311.3

>1 Valve Implanted >1 Valve Implanted (%)(%) 0.90.9 0.40.4

Valve Embolization Valve Embolization (%)(%) 0.20.2 0.10.1

IABP During Procedure IABP During Procedure (%)(%) 0.50.5 0.40.4

Cardiopulmonary BypassCardiopulmonary Bypass (%) (%) 1.21.2 0.60.6

Conscious Sedation Conscious Sedation (%)(%) 1313 1717

Median LOS – Median LOS – Days (Min, Max)Days (Min, Max) 5 (1, 33)5 (1, 33) 4 (1, 64)4 (1, 64)

Mortality and Stroke: Mortality and Stroke: S3HRS3HRAt 30 Days (As Treated Patients)At 30 Days (As Treated Patients)

% O:E = 0.26O:E = 0.26(STS 8.6%)(STS 8.6%)

MortalityMortality StrokeStroke

%

Mortality and Stroke: Mortality and Stroke: S3iS3iAt 30 Days (As Treated Patients)At 30 Days (As Treated Patients)

O:E = 0.21O:E = 0.21(STS 5.3%)(STS 5.3%)

MortalityMortality StrokeStroke

% %

TransfemoralTransfemoral Transapical / TransaorticTransapical / Transaortic

%

Mortality: Mortality: S3HR & S3iS3HR & S3iAt 30 Days (As Treated Patients)At 30 Days (As Treated Patients)

491 947 92 125

All-Cause Mortality at 30 DaysAll-Cause Mortality at 30 DaysEdwards SAPIEN Valves (As Treated Patients) Edwards SAPIEN Valves (As Treated Patients)

175 344 240 271 282 583 491 1072 947

SAPIEN SXT SAPIEN 3

PARTNER I and II TrialsOverall and TF Patients

104 125 94 92 125

SAPIEN SAPIEN XT SAPIEN 3

Nested Registries

All-Cause Mortality at 30 DaysAll-Cause Mortality at 30 DaysEdwards SAPIEN Valves (As Treated Patients) Edwards SAPIEN Valves (As Treated Patients)

PARTNER I and II TrialsTA/TAo Patients

StrokesStrokesAt 30 Days (As Treated Patients)At 30 Days (As Treated Patients)

Events Events (%)(%)

S3HRS3HROverallOverall(n=583)(n=583)

S3HRS3HRTFTF

(n=491)(n=491)

S3HRS3HRTA/TAoTA/TAo

(n=92)(n=92)

S3iS3iOverallOverall(n=1076)(n=1076)

S3iS3iTFTF

(n=951)(n=951)

S3iS3iTA/TAoTA/TAo(n=125)(n=125)

AllAll 1.541.54 1.631.63 1.091.09 2.602.60 2.422.42 4.004.00

Disabling*Disabling* 0.860.86 0.810.81 1.091.09 1.021.02 0.950.95 1.601.60

Non-DisablingNon-Disabling 0.690.69 0.810.81 00 1.581.58 1.471.47 2.402.40

TIATIA 0.690.69 0.610.61 1.091.09 0.370.37 0.420.42 00

*CEC adjudicated or Modified Rankin Score ≥ 2 at 30 days

All Strokes at 30 DaysAll Strokes at 30 DaysEdwards SAPIEN Valves Edwards SAPIEN Valves

SAPIEN SAPIEN XT SAPIEN 3

PARTNER I and II Trials

Neurologist evaluations (pre- and post)

Other Clinical EventsOther Clinical EventsAt 30 Days (As Treated Patients)At 30 Days (As Treated Patients)

Events Events (%)(%)

S3HRS3HROverallOverall(n=583)(n=583)

S3HRS3HRTFTF

(n=491)(n=491)

S3HRS3HRTA/TAoTA/TAo

(n=92)(n=92)

S3iS3iOverallOverall(n=1076)(n=1076)

S3iS3iTFTF

(n=951)(n=951)

S3iS3iTA/TAoTA/TAo(n=125)(n=125)

Major Vascular Comps.Major Vascular Comps. 5.05.0 5.35.3 3.33.3 5.65.6 5.95.9 3.23.2

Bleeding - Life ThreateningBleeding - Life Threatening 6.36.3 5.55.5 10.910.9 5.45.4 4.44.4 12.912.9

Annular RuptureAnnular Rupture 0.30.3 0.20.2 1.11.1 0.20.2 0.20.2 00

Myocardial InfarctionsMyocardial Infarctions 0.50.5 0.40.4 1.11.1 0.30.3 0.30.3 00

Coronary ObstructionCoronary Obstruction 0.20.2 00 1.11.1 0.40.4 0.40.4 00

Acute Kidney InjuryAcute Kidney Injury 1.01.0 0.80.8 2.22.2 0.50.5 0.30.3 1.61.6

New Permanent PacemakerNew Permanent Pacemaker 13.013.0 13.213.2 12.012.0 10.110.1 10.410.4 7.27.2

Aortic Valve Re-interventionAortic Valve Re-intervention 1.01.0 0.80.8 2.22.2 0.70.7 0.80.8 00

EndocarditisEndocarditis 0.20.2 0.20.2 00 0.10.1 0.10.1 00

%

Baseline 30 Days

90%

73%

13%6%

583 10495501075

I

II

III

IV

NYHA Functional ClassNYHA Functional ClassAt 30 Days (As Treated Patients)At 30 Days (As Treated Patients)

Echo Findings: Echo Findings: S3HR & S3iS3HR & S3iAortic Valve Area (Valve Implant Patients)Aortic Valve Area (Valve Implant Patients)

No. of EchosOverall 1546 1461

No. of EchosOverall 1546 1461

Echo Findings: Echo Findings: S3HR & S3iS3HR & S3iAortic Valve Area (Valve Implant Patients)Aortic Valve Area (Valve Implant Patients)

No. of EchosOverall 1602 1531

Echo Findings: Echo Findings: S3HR & S3iS3HR & S3iMean Gradients (Valve Implant Patients)Mean Gradients (Valve Implant Patients)

No. of Echos

Echo Findings: Echo Findings: S3HR & S3iS3HR & S3iMean Gradients (Valve Implant Patients)Mean Gradients (Valve Implant Patients)

Overall 1602 1531

Paravalvular Leak: Paravalvular Leak: S3HR & S3iS3HR & S3i(Valve Implant Patients)(Valve Implant Patients)

1504No. of Echos

0.1%

Moderate/Severe PVL at 30 DaysModerate/Severe PVL at 30 DaysEdwards SAPIEN Valves Edwards SAPIEN Valves

PARTNER I and II Trials

SAPIEN SAPIEN XT SAPIEN 3

Conclusions (1)Conclusions (1)

• In high-risk and inoperable patients (S3HR), the SAPIEN 3 In high-risk and inoperable patients (S3HR), the SAPIEN 3 TAVR system demonstrated low mortality and stroke and TAVR system demonstrated low mortality and stroke and excellent clinical outcomes at 30 days:excellent clinical outcomes at 30 days:– Mortality: Mortality: 2.2% (TF 1.6%, TA/TAo 5.4%)2.2% (TF 1.6%, TA/TAo 5.4%)

– Disabling Stroke: Disabling Stroke: 0.9%0.9%

• In intermediate-risk patients (S3i), SAPIEN 3 was In intermediate-risk patients (S3i), SAPIEN 3 was associated with strikingly low mortality and strokes at 30 associated with strikingly low mortality and strokes at 30 days:days:– Mortality:Mortality: 1.1% (TF 1.1%, TA/TAo 1.6%) 1.1% (TF 1.1%, TA/TAo 1.6%)

– Disabling Stroke: Disabling Stroke: 1.0%1.0%

Conclusions (2)Conclusions (2)

• Other important clinical findings with SAPIEN 3 Other important clinical findings with SAPIEN 3 (both S3HR & S3i) include:(both S3HR & S3i) include:– Major vascular complications: Major vascular complications: ~5%~5%

– Annular rupture: Annular rupture: ~0.2%~0.2%

– Coronary obstruction: Coronary obstruction: ~0.3% ~0.3%

– New pacemakers: New pacemakers: ~10%~10%

• Significant paravalvular regurgitation with SAPIEN 3 (both Significant paravalvular regurgitation with SAPIEN 3 (both S3HR & S3i) was rare:S3HR & S3i) was rare:– Severe: Severe: 0.1%0.1%

– Moderate: Moderate: 3.7%3.7%

ImplicationsImplications

• The rapid evolution of balloon-expandable TAVR, The rapid evolution of balloon-expandable TAVR, both procedural developments and technical both procedural developments and technical enhancements, represented in the SAPIEN 3 clinical enhancements, represented in the SAPIEN 3 clinical and echo results, indicates at least parity with the and echo results, indicates at least parity with the best surgical outcomes in comparable patients.best surgical outcomes in comparable patients.

• SAPIEN 3 TAVR should now be considered as an SAPIEN 3 TAVR should now be considered as an alternative to surgery, even in lower risk patients with alternative to surgery, even in lower risk patients with aortic stenosis. aortic stenosis.

Dedicated to the Memory of Mike Davidson,Dedicated to the Memory of Mike Davidson,a Cherished Member of Our PARTNER Teama Cherished Member of Our PARTNER Team

Backup SlidesBackup Slides

Primary Endpoint: Primary Endpoint: S3HR S3HR

• Primary Endpoint: Primary Endpoint: Non-Hierarchical composite of Death + Non-Hierarchical composite of Death + All Stroke + Total AR ≥ ModerateAll Stroke + Total AR ≥ Moderate

• Patients in S3HR cohort are confirmed to be comparable Patients in S3HR cohort are confirmed to be comparable to patients in P1A SAPIEN group via propensity modeling to patients in P1A SAPIEN group via propensity modeling on baseline characteristics.on baseline characteristics.

• Overall treatment effect is adjusted for propensity quintiles Overall treatment effect is adjusted for propensity quintiles defined by propensity scores.defined by propensity scores.

• Patients that received SAPIEN 3 have 9% lower event rate Patients that received SAPIEN 3 have 9% lower event rate than patients that received SAPIEN.than patients that received SAPIEN.

Primary Endpoint: Primary Endpoint: S3HRS3HR

8.08.0-10.0-10.0 -8.0-8.0 -6.0-6.0 6.06.000 2.02.0 4.04.0-12.0-12.0 -4.0-4.0 -2.0-2.0

Non-inferiorNon-inferior

Two-sided 95% CITwo-sided 95% CI

10.010.0%%

Proportion Difference between SAPIEN 3 and SAPIEN: -9.0%*Proportion Difference between SAPIEN 3 and SAPIEN: -9.0%*

Two-sided 95% Stratified Newcombe CI: [-13.9%, -4.5%]Two-sided 95% Stratified Newcombe CI: [-13.9%, -4.5%]

Proportion Difference between SAPIEN 3 and SAPIEN: -9.0%*Proportion Difference between SAPIEN 3 and SAPIEN: -9.0%*

Two-sided 95% Stratified Newcombe CI: [-13.9%, -4.5%]Two-sided 95% Stratified Newcombe CI: [-13.9%, -4.5%]

Primary Non-Inferiority Endpoint Met: Primary Non-Inferiority Endpoint Met: p < 0.001p < 0.001Sequential Superiority Endpoint Met: Sequential Superiority Endpoint Met: p < 0.01p < 0.01

Primary Non-Inferiority Endpoint Met: Primary Non-Inferiority Endpoint Met: p < 0.001p < 0.001Sequential Superiority Endpoint Met: Sequential Superiority Endpoint Met: p < 0.01p < 0.01

Zone of non-inferiorityZone of non-inferioritypre-specified pre-specified margin = 7.5%margin = 7.5%-4.5-4.5-13.9-13.9

-14.0-14.0

*Weighted*WeightedPrimary Endpoint: Primary Endpoint: Non-Hierarchical Composite ofNon-Hierarchical Composite ofDeath + All Stroke + Total AR ≥ ModerateDeath + All Stroke + Total AR ≥ Moderate

7.57.5