Hospital Israelita Albert Einstein São Paulo São Paulo SBHCI 2010 Belo Horizonte, MG; July 23, 2010 Update on TAVI Studies: Edwards SAPIEN® Transcatheter

Hospital Israelita Albert EinsteinHospital Israelita Albert Einstein São PauloSão Paulo

SBHCI 2010SBHCI 2010Belo Horizonte, MG; July 23, 2010Belo Horizonte, MG; July 23, 2010

Update on TAVI Studies:Update on TAVI Studies:Edwards SAPIEN® Edwards SAPIEN®

Transcatheter Heart Valve Transcatheter Heart Valve

Adriano Caixeta, MD, PhDAdriano Caixeta, MD, PhD

NoneNone

Disclosure Statement of Financial InterestWithin the past 12 months, I or my spouse

partner have had a financial Interest /arrangement or affiliation with the

organization (s) listed below

Dr. Alain CribierDr. Alain CribierFirst-in-Man PIONEERFirst-in-Man PIONEER

April 16, 2002April 16, 2002

Percutaneous Transcatheter Implantation of an Aortic Valve Prosthesis for Calcific Aortic Stenosis First Human Case Description Alain Cribier, MD; Helene Eltchaninoff, MD; Assaf Bash, PhD; Nicolas Borenstein, MD; Christophe Tron, MD; Fabrice Bauer, MD; Genevieve Derumeaux, MD; Frederic Anselme, MD; François Laborde, MD; Martin B. Leon, MD

AHA; Nov, 2002AHA; Nov, 2002

Lessons Learned… Lessons Learned… Lessons Learned… Lessons Learned…

TAVI in 2010TAVI in 2010

1.1. ……2.2. ……3.3. ……4.4. ……5.5. ……6.6. ……7.7. ……8.8. ……

1.1. The “high risk” severe AS patients are The “high risk” severe AS patients are “under-treated” and are excellent “under-treated” and are excellent candidates for TAVI procedurescandidates for TAVI procedures



At Least 30% of Patients with Severe At Least 30% of Patients with Severe Symptomatic AS are “Untreated”!Symptomatic AS are “Untreated”!

5968 70

4052

69

55

4132 30

6048

3145

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Bouma1999

Iung* 2004

Pellikka2005

Charlson2006

Bach Spokane(prelim)

Vannan(Pub.

Pending)

Severe Symptomatic Aortic StenosisPercent of Cardiology Patients Treated

1. Bouma B J et al. To operate or not on elderly patients with aortic stenosis: the decision and its consequences. Heart 1999;82:143-148

2. Iung B et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. European Heart Journal2003;24:1231-1243 (*includes both Aortic Stenosis and Mitral Regurgitation patients)

3. Pellikka, Sarano et al. Outcome of 622 Adults with Asymptomatic, Hemodynamically Significant Aortic Stenosis During Prolonged Follow-Up. Circulation 2005

4. Charlson E et al. Decision-making and outcomes in severe symptomatic aortic stenosis. J Heart Valve Dis2006;15:312-321

AVR

No AVR

Under-treatment especially

prevalent among patients

managed by Primary Care physicians

2.2. The Edwards technology platform has The Edwards technology platform has achieved excellent prosthetic valve achieved excellent prosthetic valve hemodynamic resultshemodynamic results

Both acute and mid-term valve performance Both acute and mid-term valve performance has surpassed expectations; equivalent to has surpassed expectations; equivalent to surgical valve implantssurgical valve implants

Striking improvements in system Striking improvements in system characteristics (and performance) over a short characteristics (and performance) over a short time! time!



The Current GenerationThe Current Generation Edwards – SAPIEN THVEdwards – SAPIEN THV

Current Skirt Height

Untreated EquineTissue

[]

Edwards-SAPIEN THV

New Skirt Height

Bovine TissueThermaFix TreatmentPericardial MappingLeaflet DeflectionProprietary Processing

Cribier-Edwards THV

Edwards Sapien XT THVEdwards Sapien XT THV

Cobalt Frame & New Leaflet Geometry Tissue Attachment

.0109 .0217 .0187 .0210 .0196 .0177 .0156 .0189 .0171 .0182 .0121

.0193 .0136 .0189 .0173 .0118 .0189 .0261 .0247 .0212 .0231 .0235 .0205 .0208 .0177 .0166 .0149 .0153 .0170 .0155

.0111 .0138 .0187 .0204 .0144 .0141 .0250 .0244 .0189 .0187 .0214 .0204 .0208 .0187 .0135 .0140 .0150 .0150 .0134

.0113 .0115 .0162 .0218 .0184 .0139 .0256 .0292 .0194 .0164 .0186 .0211 .0217 .0169 .0144 .0115 .0118 .0135 .0117

.0130 .0111 .0133 .0198 .0225 .0167 .0259 .0343 .0268 .0179 .0195 .0181 .0253 .0163 .0144 .0118 .0112 .0115 .0050

.0136 .0104 .0124 .0154 .0243 .0178 .0237 .0372 .0337 .0231 .0180 .0138 .0200 .0145 .0127 .0132 .0116 .0109 .0104

.0119 .0208 .0369 .0330 .0272 .0210 .0108 .0302 .0134 .0115 .0133 .0119 .0135 .0110

.0122 .0100 .0110 .0128 .0113 .0136 .0110

.0113 .0110 .0084 .0117

Leaflet Matching & ThermaFix

Finite ElementAnalysis

Partially Closed Design Sapien XTSapien XT

Sapien XT + NovaFlex Delivery SystemSapien XT + NovaFlex Delivery System

18 Fr profile18 Fr profile

TransfemoralTransfemoral TransapicalTransapical

Transcatheter AVITranscatheter AVITransapical Access RouteTransapical Access Route

PrePre PostPost

Mean Gradient (mm Hg)Mean Gradient (mm Hg) AVA (cm²)AVA (cm²)

p = .0076p = .0076 p = .0076p = .0076

00

1010

2020

3030

4040

5050

6060

7070

8080

00

0,20,2

0,40,4

0,60,6

0,80,8

11

1,21,2

1,41,4

1,61,6

1,81,8

22

PrePre PostPost

8.58.5

4343

0.560.56

1.691.69

Cribier – Early PHV ExperiencesCribier – Early PHV ExperiencesProcedural Results (n=16)Procedural Results (n=16)

3.3. The Edwards technology platform has also The Edwards technology platform has also achieved acceptable early and mid-term achieved acceptable early and mid-term clinical outcomesclinical outcomes

Clinical outcomes are improving, perhaps due Clinical outcomes are improving, perhaps due to better patient selection, device and to better patient selection, device and procedure enhancements, and “learning curve” procedure enhancements, and “learning curve” issues issues



Edwards TAVIEdwards TAVIClinical Data SourcesClinical Data Sources

CANADA multi-center (6) (TF=167 pts, TA=172 pts)CANADA multi-center (6) (TF=167 pts, TA=172 pts)

PARIS single center (TF=51 pts, TA=24 pts)PARIS single center

(TF=51 pts, TA=24 pts)

VANCOUVER single center (TF=164 pts, TA=86 pts)

VANCOUVER single center (TF=164 pts, TA=86 pts)

Other StudiesOther Studies

TOTAL = 664 PTSTOTAL = 664 PTSPARTNER FDA

(US/OUS, TF/TA ~1400 pts)PARTNER FDA

(US/OUS, TF/TA ~1400 pts) PIVOTAL RCTPIVOTAL RCT

POSTPOSTCE-APPROVALCE-APPROVAL

PARTNER EU (OUS, TF/TA 130 pts)SOURCE (OUS, TF/TA, 1123 pts)PARTNER EU (OUS, TF/TA 130 pts)SOURCE (OUS, TF/TA, 1123 pts)

FEASIBILITYFEASIBILITY(CE-APPROVAL)(CE-APPROVAL)

REVIVE (OUS, TF, 106 pts) TRAVERCE (OUS, TA, 172 pts) REVIVAL (US, TF/TA, 95 pts)

REVIVE (OUS, TF, 106 pts) TRAVERCE (OUS, TA, 172 pts) REVIVAL (US, TF/TA, 95 pts)

Transseptal Experience (RECAST, I-REVIVE; 36 pts)

Transseptal Experience (RECAST, I-REVIVE; 36 pts) FIRST-in-MANFIRST-in-MAN

EdwardsEdwards

TOTAL = 3062 PTSTOTAL = 3062 PTS

OVERALL TOTAL OVERALL TOTAL 3726 PTS 3726 PTS

0

0.2

0.4

0.6

0.8

1

0 6 12 18 24Months post Procedure

Su

rviv

al

Transapical

Transfemoral

At Risk: At Risk:

TA: 281 157 109 68 26TA: 281 157 109 68 26

TF: 222 176 125 46 15TF: 222 176 125 46 15

Log-Rank p-value = 0.0004Log-Rank p-value = 0.0004Hazard Ratio = 1.708Hazard Ratio = 1.708CI = 1.263 - 2.309CI = 1.263 - 2.309

POOLED* Monitored Edwards TAVIPOOLED* Monitored Edwards TAVI2-Yr Mortality2-Yr Mortality

* REVIVE, REVIVAL, TRAVERCE* REVIVE, REVIVAL, TRAVERCEand PARTNER EUand PARTNER EU

75%75%

58%58%

0%10%20%30%

40%50%60%70%

Coronaryartery

disease

MitralDisease

Peripheralvasculardisease

Prior CABG Carotiddisease

PriorPacemaker

TF TAP = <0.0001P = <0.0001 P=0.008P=0.008P=0.008P=0.008

P=0.04P=0.04

P=0.02P=0.02P = nsP = ns

TF (n=61)TF (n=61) TA (n=69)TA (n=69)

Logistic EuroSCORELogistic EuroSCORE 25.7 ± 11.5 (Range: 6-65)25.7 ± 11.5 (Range: 6-65) 33.8 ± 14.7 (Range: 5-72)33.8 ± 14.7 (Range: 5-72)

STS ScoreSTS Score 11.3 ± 6.1 (Range: 4-32)11.3 ± 6.1 (Range: 4-32) 11.8 ± 6.8 (Range: 2-41)11.8 ± 6.8 (Range: 2-41)

V. Schächinger; euroPCR 2009

PARTNER EU TrialPARTNER EU TrialRisk ProfilesRisk Profiles

POOLED* Monitored Edwards TAVIPOOLED* Monitored Edwards TAVI30-Day Mortality (vs. SOURCE)30-Day Mortality (vs. SOURCE)

0.8

0.85

0.9

0.95

1

0 5 10 15 20 25 30

Days post Procedure

Su

rviv

al

SOURCE:SOURCE:Log-Rank p-value = 0.0226Log-Rank p-value = 0.0226Hazard Ratio = 1.666Hazard Ratio = 1.666CI = 1.068 - 2.598CI = 1.068 - 2.598

POOLED:POOLED:Log-Rank p-value = 0.0589Log-Rank p-value = 0.0589Hazard Ratio = 1.608Hazard Ratio = 1.608CI = 0.974 - 2.652CI = 0.974 - 2.652 POOLED TA (n=281)POOLED TA (n=281)

SOURCE TF (n=463)SOURCE TF (n=463)

SOURCE TA (n=575)SOURCE TA (n=575)

POOLED TF (n=222)POOLED TF (n=222)


6.3%6.3%

10.3%10.3%

10.4%10.4%

16.4%16.4%

15%

19%18%

27

3436

5%

10%

15%

20%

TRAVERCE PARTNER EU REVIVAL CANADA SOURCE BERLIN

25

30

35

40

45

Clinical Trials

30d

Mor

talit

y (%

)30

d M

orta

lity

(%)

12%

TAVI in EvolutionTAVI in EvolutionTrans-apicalTrans-apical

Improved short-term outcomes!

Courtesy of Dr. Martin LeonCourtesy of Dr. Martin Leon

15%

19%18%

11%10%

6%27

3436

3029

41

5%

10%

15%

20%

TRAVERCE PARTNER EU REVIVAL CANADA SOURCE BERLIN

25

30

35

40

45

12%

Clinical Trials

30d

Mor

talit

y (%

)30

d M

orta

lity

(%)

TAVI in 2010TAVI in 2010Trans-apicalTrans-apical

Improved short-term outcomes!


62%

49%

60%

40%

50%

60%

70%

80%

TRAVERCE PARTNER EU REVIVAL CANADA BERLIN

65%


Clinical Trials

1-ye

ar s

urvi

val (

%)

1-ye

ar s

urvi

val (

%)

Improved one-year outcomes!


62%

49%

60%

78%83%

40%

50%

60%

70%

80%

TRAVERCE PARTNER EU REVIVAL CANADA BERLIN

65%


1-ye

ar s

urvi

val (

%)

1-ye

ar s

urvi

val (

%)

Clinical Trials

Improved one-year outcomes!


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Baseline 30 Days 3 Months 6 Months 1 Year 18 Months

2 Years

NY

HA

IV

III

II

I

NYHA Class

N=492 N=231 N=271 N=235 N=243 N=64 N=48

Visit

POOLED* Monitored Edwards TAVIPOOLED* Monitored Edwards TAVINYHA ClassNYHA Class


55%

Vancouver TAVI Vancouver TAVI LearningLearning Experience Experience

Courtesy of John WebbCourtesy of John Webb

Mortality @ 30 days – Trans-arterialMortality @ 30 days – Trans-arterial

56%

Courtesy of John WebbCourtesy of John Webb

Vancouver TAVI Vancouver TAVI LearningLearning Experience Experience

Mortality @ 30 days – Trans-apicalMortality @ 30 days – Trans-apical

4.4. Many TAVI complications have emerged Many TAVI complications have emerged and require further analysis and and require further analysis and clarificationclarification

Paravalvular ARParavalvular AR Conduction disturbancesConduction disturbances Vascular complicationsVascular complications StrokeStroke Coronary obstruction Coronary obstruction



Edwards TAVI Complications Edwards TAVI Complications Multiple Data Sources (TA and TF)Multiple Data Sources (TA and TF)

POOLED*POOLED*(503 pts)(503 pts)

SOURCESOURCE(1038 pts)(1038 pts)

VANCOUVERVANCOUVER(250 pts)(250 pts)

PARISPARIS(75 pts)(75 pts)

CA-MultictrCA-Multictr(339 pts)(339 pts)

Vascular (maj)** (%)Vascular (maj)** (%) 18.518.5 10.610.6 10.310.3 11.811.8 13.113.1

AR >2+ (%)AR >2+ (%) 10.910.9 4.74.7 5.05.0 5.35.3 7.77.7

Stroke (%)Stroke (%) 4.04.0 2.52.5 3.03.0 4.04.0 2.32.3

New Pacemaker (%)New Pacemaker (%) 4.44.4 7.07.0 5.55.5 5.35.3 4.94.9

Renal Failure (%)Renal Failure (%) 5.25.2 8.78.7 4.24.2 nana 2.62.6

Coronary Obstr (%)Coronary Obstr (%) 0.40.4 0.60.6 nana 00 00

** REVIVE, REVIVAL, TRAVERCE, PARTNER EUREVIVE, REVIVAL, TRAVERCE, PARTNER EU** TF Only** TF Only

Para-valvular Regurgitation Para-valvular Regurgitation

5.5. Long-term durability evaluations of TAVI Long-term durability evaluations of TAVI bioprosthetic valves are still ongoingbioprosthetic valves are still ongoing

Meticulous follow-up necessary including Meticulous follow-up necessary including echocardiograms (core lab assessments)echocardiograms (core lab assessments)

Ultimate value of TAVI will require proof of Ultimate value of TAVI will require proof of “near surgical” valve durability “near surgical” valve durability



6.6. TAVI requires a major milieu adjustment to TAVI requires a major milieu adjustment to develop an optimal programdevelop an optimal program

Hybrid cath lab - ORsHybrid cath lab - ORs Intense clinical care continuum – screening, Intense clinical care continuum – screening,

procedure, pot-procedure care, follow-upprocedure, pot-procedure care, follow-up Surgeons and interventionalists working Surgeons and interventionalists working

closely together (Heart Valve Team)!!!closely together (Heart Valve Team)!!! Strict training requirements Strict training requirements



Transcatheter AVRTranscatheter AVRHybrid OR-Cath LabHybrid OR-Cath Lab


7.7. The PARTNER trial should provide The PARTNER trial should provide valuable insights and will provide the valuable insights and will provide the evidence-based medicine justification for evidence-based medicine justification for future expansion of TAVI!future expansion of TAVI!



Medical Medical Management Management

ControlControl

PRIMARY ENDPOINTPRIMARY ENDPOINTAll-cause mortality (1 yr)All-cause mortality (1 yr)

Non-inferiorityNon-inferiority

2 Trials2 TrialsIndividually PoweredIndividually Powered

(Cohorts A & B)(Cohorts A & B)

PARTNER Trial DesignPARTNER Trial DesignFully enrolled: continued access to both patient cohorts approved by FDA

Symptomatic Severe Aortic StenosisSymptomatic Severe Aortic Stenosis

AssessmentAssessment High Risk High Risk

AVR CandidateAVR CandidateYesYes NoNo

Cohort ACohort A Cohort BCohort B

AssessmentAssessmentTransfemoral AccessTransfemoral Access


Not in StudyNot in Study

vsvsTransTrans

FemoralFemoral

Cohort A TFCohort A TF

AVRAVRControlControl vsvs

TransTransApicalApical


TransTransFemoralFemoral

1:1 Randomization1:1 Randomization


SuperioritySuperiority

YesYesYesYes NoNo

Cohort A TACohort A TA


NoNo

N=491N=491 N=203N=203

N=694N=694 N=358N=358

Total = 1,052 ptsTotal = 1,052 pts

PARTNER PARTNER Baseline Characteristics*Baseline Characteristics*

Variable %Variable %Cohort A-TFCohort A-TF(test control)(test control)

Cohort A-TACohort A-TA(test control)(test control)

Cohort B-TFCohort B-TF(test control)(test control)

Number of patientsNumber of patients 450450 182182 430430

Age (years)Age (years) 83.6 83.6 ++ 10.4 10.4 82.4 82.4 ++ 10.8 10.8 83.1 83.1 ++ 8.5 8.5

Gender (male)Gender (male) 58.158.1 57.457.4 48.748.7

DiabetesDiabetes 40.240.2 41.741.7 35.435.4

HyperlipidemiaHyperlipidemia 79.579.5 79.379.3 74.074.0

HypertensionHypertension 90.090.0 95.495.4 85.385.3

SmokingSmoking 42.642.6 56.656.6 46.946.9

Prior MIPrior MI 25.325.3 31.431.4 25.225.2

*subset of all randomized patients *subset of all randomized patients in cohort A (TF+TA) and cohort B (incl. CA)in cohort A (TF+TA) and cohort B (incl. CA)

•Preliminary snapshotPreliminary snapshot•Outcomes data blindedOutcomes data blinded

PARTNER PARTNER High Risk Co-Morbidities (1)*High Risk Co-Morbidities (1)*





Periph Vasc DiseasePeriph Vasc Disease 32.732.7 56.256.2 26.826.8

Hx CHFHx CHF 97.697.6 96.696.6 97.097.0

NYHA Class III/IVNYHA Class III/IV 94.094.0 91.691.6 93.293.2

Prior CABGPrior CABG 59.559.5 69.869.8 59.559.5

Prior PCIPrior PCI 45.745.7 48.448.4 37.237.2

Prior BAVPrior BAV 15.915.9 15.915.9 25.625.6

Severe COPD (O2 dep)Severe COPD (O2 dep) 7.17.1 9.79.7 23.823.8


PARTNER PARTNER High Risk Co-Morbidities (2)*High Risk Co-Morbidities (2)*





CNS DiseaseCNS Disease 23.023.0 32.032.0 26.926.9

Recent Stroke/TIARecent Stroke/TIA 2.52.5 3.63.6 2.42.4

CirrhosisCirrhosis 2.02.0 00 2.22.2

Porcelain aortaPorcelain aorta 0.40.4 1.01.0 15.115.1

Chest radiationChest radiation 0.60.6 1.01.0 7.87.8

Chest wall deformityChest wall deformity 00 00 6.96.9

FrailtyFrailty 18.918.9 17.617.6 27.927.9


Medical Medical Management Management

ControlControl


Non-inferiorityNon-inferiority

2 Trials2 TrialsIndividually PoweredIndividually Powered

(Cohorts A & B)(Cohorts A & B)

PARTNER Trial DesignPARTNER Trial DesignFully enrolled: continued access to both patient cohorts approved by FDA

Symptomatic Severe Aortic StenosisSymptomatic Severe Aortic Stenosis

AssessmentAssessment High Risk High Risk

AVR CandidateAVR CandidateYesYes NoNo

Cohort ACohort A Cohort BCohort B



Not in StudyNot in Study

vsvsTransTrans

FemoralFemoral

Cohort A TFCohort A TF


TransTransApicalApical


TransTransFemoralFemoral



SuperioritySuperiority

YesYesYesYes NoNo

Cohort A TACohort A TA


NoNo

N=491N=491 N=203N=203

N=694N=694 N=358N=358

Total = 1,052 ptsTotal = 1,052 pts

First Presentation of First Presentation of PARTNER Data PARTNER Data

at TCT 2010!at TCT 2010!

8.8. The future is exciting – TAVI procedure The future is exciting – TAVI procedure device enhancements and expanded device enhancements and expanded clinical indications!clinical indications! New valve designs, lower profile systems, New valve designs, lower profile systems,



New TAVI TechnologiesNew TAVI Technologies Direct FlowDirect Flow

SadraSadra

AorTx AorTx

Jena ValveJena Valve

HLTHLT

ABPS PercValveABPS PercValve

EndoTechEndoTech

Ventor EmbracerVentor Embracer

SymetisSymetis

Next Clinical TargetsNext Clinical TargetsNext Clinical TargetsNext Clinical Targets

• Valve-in-valve for bio-prosthetic aortic Valve-in-valve for bio-prosthetic aortic and mitral valve failureand mitral valve failure

• Lower risk AS patientsLower risk AS patients• Mixed AS and CAD patientsMixed AS and CAD patients• Asymptomatic severe ASAsymptomatic severe AS• Low flow - low gradient AS – impedance Low flow - low gradient AS – impedance

mismatchmismatch• Aortic regurgitationAortic regurgitation


Transcatheter AVITranscatheter AVIEndless Possibilities!Endless Possibilities!

Trans-apicalTrans-apicalAVRAVR

Courtesy of Dr. John WebbCourtesy of Dr. John Webb

Trans-apicalTrans-apicalMVRMVR

(valve-in-valve)(valve-in-valve)

Edwards-SapienEdwards-Sapien

In the next 5-10 years, many (? most) patients with severe AS requiring AVR

will be treated using transcatheter lesser-invasive modalities!

Martin Leon

Documents

Hospital Israelita Albert Einstein São Paulo São Paulo SBHCI 2010 Belo Horizonte, MG; July 23, 2010 Update on TAVI Studies: Edwards SAPIEN® Transcatheter