Jeffrey W Moses, MDMarty B Leon MD

Columbia University Medical Center Cardiovascular

Research Foundation

New York City

St Francis Heart Hospital , Roslyn NY

Why Did We Do It?

PVT to Sapien

Which therapy – AVR, nothing?

92 yo man withcritical AS…

• severe COPD• creat 2.8• previous CABG(patent LIMA)

• EF 30%• Class IV CHF• STS 15.5%

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

5968 70

40

52

69

55

4132 30

6048

3145

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Bouma

1999

Iung*

2004

Pellikka

2005

Charlson

2006

Bach

2009

Spokane

(prelim)

Vannan

(Pub.

Pending)

Severe Symptomatic Aortic StenosisPercent of Cardiology Patients Treated

AVR

No AVR

Under-treatment especially

prevalent among patients

managed by Primary Care physicians

Reasons for non-treatment: 1. elderly,

2. co-morbidities, 3. patient refusal

Pre-Clinical Development

PVT to Sapien

The Andersen Stent-Valve (1989)

The Andersen Stent-Valve (1992)

DiastoleSystole

12

3

Alain Cribier Sketches (1990)

Percutaneous Valve Technologies PVT)

(1999 - 2004)

Martin Leon

Alain Cribier

Santon Rowe

Stan Rabinovich

FOUNDERS

Partner: ARAN Research & Development Ltd.

Percutaneous Valve Technologies (PVT)

Early Prototypes

PVT designed the testing equipment and crimping tools

• Different valve configurations

• Different leaflet materials,

designs and attachment means.

• Extensive hydrodynamic testing

CERA (Centre d’Experimentation et de Recherche Appliquée)Institut Monsouris, Paris, France

PVT 2000-2002: The Sheep Era

PVT - Cadaver Heart Study at AFIP

The First Case in Rouen

PVT to Sapien

Alain Cribier to Martin Leon, Stan Rowe, Stan Rabinovich, Assaf Bash

April 12, 2002

I have a fascinating case that I would like to discuss with you!

Imminent death

EF 10%

BP 60 mmHg with vasopressors

57 y/oTranseptal BAV performed

Intra-LV thrombus

Valve implantation, transseptal approach !

Dilatation of the septum required

Externalization of wire

Highest risk !..

Martin Leon to Alain CribierApril 12, 2002

High likehood of failure but… it just might work

and save his life!

You have my complete support to move ahead with the first PVT clinical placement in this desperately ill man.

Snaring the stiff wire is a good idea

IABP?

Best operator in the world!

MR

Antegrade Approach:

Guidewire Position

in LV

Antegrade Approach:

Guidewire Position

in LV

Valve Positioning

April 16, 2002; FIM-TAVI, Transseptal

April 16, 2002; FIM-TAVI, Transseptal

15 min Post-TAVI

April 16, 2002; FIM-TAVI, Transseptal

Dr. Alain CribierFirst-in-Man PIONEER

April 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, 2002Conclusions— Nonsurgical implantation of a prosthetic heart

valve can be successfully achieved with immediate and midterm

hemodynamic and clinical improvement.

Early Clinical Speedbumps

PVT to Sapien

April 16, 2002

Dr. Alain CribierFirst-in-Man PIONEER

OK, What Now?

15 min post-TAVR

• Strokes

• Aortic rupture

• Coronary occlusion

• Mitral valve injury

• Valve instability – embolization

• Para-valvular regurgitation

• Vascular complications

• Valve durability

• Technical challenges insurmountable

TAVR - The Early Skeptics

This is a crazy project that will fail!

The “Early Days” of TAVR

Paravalvular AR > Grade 2 in 25%I-REVIVE: 16 patients

Aug 2003 – July 2004

RECAST: 20 patientsDec 2003 – April 2005

24F Sheath in Femoral vein

Equine Pericardial Valve

Single size 23mm

Collaboration across the seas….

Drs. John Webb and Alain Cribier

Retrograde Trans-femoral Cribier-Edwards Aortic Valve Deployment

Rapid pacing : 200/min

108

The Heart Team - A Deal with the Devil?

Leipzig 2004

Transapical case

M. Mack F. Mohr

New Valve, New Delivery Systems, New Approaches

2004: Edwards Lifesciences Acquires PVT

J. WebbF. Mohr

M. Mack

T. Walther

Transfemoral Transapical

Edwards SAPIEN

23mm, 26mm

Cribier-Edwards, 23mm

Treated tri-leaflet Bovine Pericardial

Valve

Stainless steel stent

External cuff 50% of frame’s height

The Road toSapien

PVT to Sapien

• TAVR growth has been fueled by:

the multi-disciplinary heart team

rapid technology enhancement

commitment to evidence-based medicine

striking reduction in complications

simplification of the procedure

TAVR in 2017: Growth Drivers

The Current GenerationEdwards – 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 THV

Cobolt 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 XT

Edwards Balloon Expandable Valve Platforms

• Stainless steel frame

• Bovine pericardial tissue

• Low frame height

• Multiple access approaches

• Sizes: 23, 26 mm

• Cobalt chromium frame

• Bovine pericardial tissue

• Lower profile: 16-20F

• Complete range of sizes: 20, 23, 26, 29 mm

• Cobalt chromium frame

• Bovine pericardial tissue

• Outer sealing skirt

• Lower profile: 14/16F

• Complete range of sizes: 20, 23, 26, 29 mm

SAPIEN Valve SAPIEN XT Valve SAPIEN 3 Valve

Bovine pericardial tissue• Scalloped leaflet shape• CE ThermaFix* process is

intended to minimize the risk of calcification

Outer skirt• PET outer skirt designed to

reduce paravalvular leak

Low frame height• Respects the

cardiac anatomy

Frame design• Enhanced frame geometry

for low delivery profile• High radial strength for

circularity

Inner Skirt• Polyethylene

terephthalate (PET)

SAPIEN 3 THV

Edwards Flex CathDelivery System Evolution

Retroflex Delivery Catheter

Retroflex 2Retroflex 3

Sapien XT + NovaFlex Delivery System

18 Fr profile

SAPIEN 3 Commander Delivery SystemDistinguishing Features

• Accurate positioning

Fine control of valve positioning

Distal flex

SAPIEN 3 Valve Size 20 mm 23 mm 26 mm 29 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 alignment

Evolution of Balloon-Expandable Transcatheter Valves

2002

Cribier-Edwards

2006

SAPIEN

2009

SAPIEN XT

2013

SAPIEN 3

* Sheath compatibility for a 23 mm valve

PARTNER THV Evolution

Edwards SAPIEN XT ™ THV23 mm, 26 mm, and 29mm

PII - 2010

Edwards SAPIEN™ THV23 mm and 26 mm

PI - 2007 PII S3 - 2013

Edwards SAPIEN 3™ THV20 mm, 23 mm, 26 mm, and 29mm

PARTNER enrolled >9,000 patients in FDA studies

(including 4 RCTs) with 3 generations of

TAVR systems in ~ 7 years!

Baseline Patient Characteristics S3HR Patients (n=583 at 29 sites)

Average STS =

8.6%(Median 8.4%)

TF, 84%

TA, 10%

TAo, 6%N = 583

1,9%

34,3% 38,9%24,9%

20 mm 23 mm 26 mm 29 mm

Average Age =

82.6yrs

Male58%

Female42%

Mortality and Stroke: S3HRAt 30 Days (As Treated Patients)

2,2 1,40

20

40

60

80

100

S3HR

All-Cause Cardiovascular

% O:E = 0.26(STS 8.6%)

1,5 0,90

20

40

60

80

100

S3HR

All Stroke Disabling

Mortality Stroke

%

Baseline Patient CharacteristicsS3i Patients (n=1076 at 51 sites)

Average STS =

5.3%(Median 5.2%)

TF, 89%

TA, 7%

TAo, 4% N = 1076

4,1%

32,2%43,7%

20,0%

20 mm 23 mm 26 mm 29 mm

Average Age =

81.9yrs

Male62%

Female38%

Mortality and Stroke: S3iAt 30 Days (As Treated Patients)

1,1 0,90

20

40

60

80

100

S3i

All-Cause Cardiovascular

O:E = 0.21(STS 5.3%)

2,6 1.00

20

40

60

80

100

S3i

All Stroke Disabling

Mortality Stroke

% %

6,3%

5,2%

3,7%4,5%

3,5%

2,2%1,6%

1,1% 1,1%

0%

5%

10%

15%

20%

P1B (TF) P1A (All) P1A (TF) P2B (TF) P2B XT (TF) S3HR (All) S3HR (TF) S3i (All) S3i (TF)

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

175 344 240 271 282 583 491 1072 947

SAPIEN SXT SAPIEN 3

PARTNER 1 and 2 Trials(Overall and TF Patients)

Strokes (All) at 30 DaysEdwards SAPIEN Valves

6,7%

5,6%

4,1% 4,3%

1,5%

2,6%

0%

5%

10%

15%

20%

P1B (TF) P1A (All) P2B (TF) P2B XT (TF) S3HR (All) S3i (All)

179 344 276 284 583 1076

SAPIEN SAPIEN XT SAPIEN 3

Neurologist evaluations (pre- and post)

PARTNER 1 and 2 Trials(Overall and TF Patients)

Moderate/Severe PVL at 30 DaysEdwards SAPIEN Valves

12,0% 11,5%

16,9%

24,2%

2,9%4,2%

0%

10%

20%

30%

40%

50%

P1B (TF) P1A (Overall) P2B (TF) P2B XT (TF) S3HR (Overall) S3i (Overall)

179 344 276 284 583 1076

SAPIEN SAPIEN XT SAPIEN 3

PARTNER I and II TrialsOverall and TF Patients

Philippe

GenereuxPhilippe

Demers

Donald

Palisaitis

“Outpatient” Same-Day TAVR

Sacre-Coeur Hospital; Montreal, CN

Genereux P et al. Catheter Cardiovasc Interv 2016;87:980-2

CCI 2016

A BreakthroughTechnology

PVT to Sapien

What is a Breakthrough Technology?

• Address an unmet clinical need; penetrate an important area of clinical medicine which is not well served by current therapies

• Innovative concept and/or novel device, drug, or diagnostic technology

• Must be validated by rigorous evidence-based medicine clinical research

• Must be “generalizable” to the practicing medical community (sufficiently user-friendly)

• Rarely, elevates beyond subspecialty medicine and resonates as a significant socio-medical cultural advance (the “X” factor)

1994Post-mortem studies of intra-valvular stenting

F.I.M. THV implantation2002

F.I.M. Balloon Aortic Valvuloplasty1985

« Percutaneous Valve Technology » (prototypes)

1999

Feasibility Studies (antegrade)2002-03

Edwards Lifesciences TF & TA2004

International TF and TA

Feasibility Studies2005-07

CE mark

commercialization2007

Animal implantations(sheep)

2000

Ew PARTNER US Pivotal2008-10

Since 2007Post market registries

CoreValve

Oct 2011- FDA Approval :

Non Surgical Patients (PARTNER B)

Oct 2012- FDA Approval:

High Risks Patients (PARTNER A)