History and Future

of

Aortic Valve Implantation

OTTAVIO ALFIERI

S.Raffaele University Hospital

Milano

Aetiologies of Single Valvular

Heart Diseases in the Euro Heart

Survey

0%

20%

40%

60%

80%

100%

AS AR MR MS

Other

Ischemic

Congenital

Inflammatory

Endocarditis

Rheumatic

Degenerative

(Iung. Eur Heart J 2003;24:1244-53)

43% 13% 32% 12%

Aortic Stenosis: Survival

NEJM 1997;337;32-41 and UK Heart Valve Registry

Years

% S

urv

ival

3 15

45% alive

97.2% alive

Onset of symptoms

Surgery

Failure

Syncope

Angina

Age

(years)

70 years

(%)

1 comorbidity

(%)

AS 69±12 56 36

AR 58±16 25 26

MS 58±13 18 22

MR 65±14 44 42

Patient Characteristics

in the Euro Heart Survey

(Iung. Eur Heart J 2003;24:1244-53)

Surgical Risk vs. Benefit

Poor value:

•Patient

•Purchaser

•Physician

Optimum

Value

Surgical Risk

Clinical Benefit

Limited

Value

Increasing age

?

22 centres, 67,764 patients, 4,743

octogenarians

0

2

4

6

8

10

12

50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-90

Age (years)

Co

mp

lic

ati

on

s (

%).

.

Mortality

Renal failure

Stroke

Central Cardiac Audit Database, UK

Survival after Isolated Aortic Surgery

in patients aged 80+:

Influence of pulmonary disease

No lung

disease COPD/emphysema/asthma

Discharge 96.7% 75.7%

1 year 90.6% 69.6%

2 years 88.9% 54.9%

5 years 63.6% 20.0%

Central Cardiac Audit Database, UK

Survival after Isolated Aortic Surgery in

patients aged 80+:

Influence of peripheral vascular

disease

No PVD PVD

Discharge 96.0% 79.6%

1 year 90.2% 68.2%

2 years 88.3% 52.3%

5 years 57.8% 28.5%

Central Cardiac Audit Database, UK

One third of patients did not undergo surgery

because of age, comorbidities or LV dysfunction

Not surprisingly….

Severe AS : Valve Area ≤ 0.6 cm²/m² BSA or Mean Gradient 50 mmHg

Symptomatic AS : NYHA Class III or IV or Angina

Aortic Stenosis 75 years

N=408

No Severe AS

(n=114)

Severe AS

(n=284)

No Symptoms

N=68

Symptoms

N=216

Intervention

N=144 (67%)

No Intervention

N=72 (33%)

NYHA III :106

NYHA IV : 36

Angina : 148

Severe symptomatic AS

(Iung. Eur Heart J 2005;26:2714-20)

At least 30-40% of Cardiologists’

AS Patients Go Untreated

59

41

68

32

70

30

40

60

52

48

69

31

55

45

0

10

20

30

40

50

60

70

80

90

100

Bouma 1999 Iung* 2004 Pellikka 2005 Charlson 2006 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 Journal

2003;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 Decision-making and outcomes in severe symptomatic aortic stenosis al.. J Heart Valve Dis2006;15:312-321

No AVR

AVR

Under-treatment

especially

prevalent among

patients

managed by

Primary Care

physicians

Aortic Valve Implantation

The Evolving Process

Conventional midline sternotomy

Surgical through Minimal Incision

On pump, arrested heart sutureless valve replacement

Transaortic, beating heart delivery

Transapical delivery

Percutaneous - antegrade or retrograde

Inva

siveness

F.I.M. Balloon Aortic Valvuloplasty

1985

0

100

200

First attempt of treating non surgical AS patients

Thousand of cases performed worldwide

Hemodynamic / symptomatic improvement

No effect on patient’s survival

ONE MAIN LIMITATION

Early valve restenosis: 80% at one year

BAV

THE LANCET, JANUARY 11, 1986

F.I.M.: 20mm Balloon

Sept 1985

THE GOAL….

F.I.M. Balloon Aortic Valvuloplasty

1985Concept of« stented valve », to rule out post-BAV valvular restenosis

1987

1989

First animal implantation (balloon exp) in pig

Post mortem studies of intra-valvular stenting

« Percutaneous Valve Technology » (prototypes)

1999 First animal implantation(self exp)

2000Large series of animal implantation

2000-02 F.I.M. PHV implantation2002

Feasibility Studies (antegrade)2002-03

First in ManCorevalve 25 F

2004

International TF Feasibility Studies2005-07

CE markcommercialization2007

The pioneers

Henning Andersen (May 1st 1989)

First successful pig implant

Granted with 2 patents

Alain Cribier (April 16, 2002)

Parallel research and proof of concept

Implanted first percutaneous aortic valve on a patient via an antegrade approach

8 days post-implantation

F.I.M Alain Cribier 2002

F.I.M. and Feasibility Studies

pre CE approval

RESULTS

Procedural success about 90%

Mortality at 30 days ranges from 5 to 18%

Acute myocardial infarction in 2 to 11%

Severe AR in about 5%

Vascular complications in 10 to 15%

Stroke in 3 to 9%

AV bock in 4 to 20%

Survival :70 to 80% at 2 y.

Edwards SAPIENCore Valve

CE-MARKED DEVICES

(Transfemoral / Transaxillary) (Transfemoral / Transapical)

Generation 1

25FrEndovascular

Generation 2

21FrEndovascular

Generation 3

18FrPercutaneous

14 patients

65 patients

>3000 patients

*

CoreValve evolution

General anesthesiaSurgical cutdown/repairVentricular assistance

• Pre-closing with ProStar™ • Local Anesthesia• Beating heart • Valve delivery without rapid pacing• No cardiac assistance

18 French Procedural Progress

Evolution to a « real cath lab procedure »

within the first 40 Patients of 18 Fr study

Developments and Improvments

Untreated

Equine Tissue

Cribier-Edwards™ THV

23mm

Edwards SAPIEN™ THV

23mm, 26mm

Treated

Bovine Tissue

DurabilityHeamodynamic Performance

Profile – Ease of Use

Edwards SAPIEN™ THV II

23mm, 26mm

Low profile

Cobalt-chrome

Ascendra Introducer Sheath 26Fr.

RetroFlex II

Edwards SAPIEN

RETROFLEX DELIVERY SYSTEM

Stainless Steel Braid – BETTER TORQUE

Front end rotational grip – SINGLE HANDED ARTICULATION

Edwards SAPIEN evolution

Joint Task Force Positioning Paper:‟Transcatheter valve implantations for patients with Aortic Stenosis”

TAVI is reserved to pts. with

severe AS and symptoms who

are inoperable or at high risk

for surgery

INDICATION

STEPS OF PTS. SELECTION

-Confirmation of severity of AS

-Evaluation of symptoms-QoL

-Analysis of surgical risk

-Evaluation of life expectancy

-Assessment of feasibility and

exlusion of contraindications

Gradients and Valve Area

ECHO TT and TEE

Hemodynamics

CT

MRI

Dobutamine testing

Pouleur AC , et al, Radiology, 2007;244: 745-754

MDCT MRI TEE

Analysis of surgical risk

Logistic Euroscore > 20

STS Score > 10 (new M & M)

Parsonnet

Ambler

Mini Nutritional Assesment

(Geriatric Version)

Contraindicatios (general)

Aortic annulus (too small or to large)

Bicuspid valve ( ? )

Asymmetric heavy valvular calcification

Aortic root dilatation (for self-expandable)

Presence of LV thrombus

TT<TEE<CT

Risk of embolism

Risk of coronary

occlusion

Prosthesis selection

Contraindications for TF approach

Iliac arteries severe calcification

tortuosity,small diameter;previous ao-

fem.by-pass

Aorta:severe atheroma of the

arch,coartation,aneurysm with protruding

thrombus….

Bulky atherosclerosis of the asc. aorta

Transverse asc.aorta

Size

Calcifications

Tortuosity

Stenosis

Degree

lenght

Atheromatous

disease

Insertion ofAmplatz Ultra stiff0,35 CookWire

Contraindications for TA approach

Previous surgery of the LV (Dor)

Calcified pericardium

Severe respiratory insufficiency

Dislocated LV apex

Teamwork

anesthesiologist

Surgeon

cardiologist

others

Interventionalist

40

The procedure requires the close cooperation of a team of specialists in valve disease, including clinical cardiologists, echocardiographists, interventional cardiologists, cardiac surgeons, and anaesthesiologists.

Appropriate environment

Hybrid room

Cath lab

Operating room

NO COMPROMISES

Imaging quality

Sterility

Instrumentation

Ergonomics

Device availability

POST CE MARK RESULTS

(from registries)

Edwards THV Clinical Studies

Program

Methods

34 Centres Initially Participating

in Commercial Launch

1123 patients

Included:

32 Centres

1038 Patients

The SOURCE Registry has

100% procedure data

98% 30 day data

All consecutively enrolled

Excluded:

2 Centres / 85 Patients• Unable to obtain Ethic Cte approval

• Unable to secure administrative support

• One missing patient due to admin. error

Source Registry

Baseline Demographics and Risk

FactorsTF

(n=463)

TA

(n=575) P-value

Age (yrs) 81.7 80.7 NS

Female 55.2% 56% NS

Pulmonary Disease 25.4% 29.4% NS

Renal Failure 26.3% 32.9% 0.024

Logistic EuroSCORE 25.7 29.2 <0.005

Peripheral Vascular

Disease

10.9% 27.5% <0.001

Carotid Artery Stenosis

(>50%)

7.6% 17.1% <0.001

Incidence of CAD 47.4% 56.0% <0.006

Porcelain Aorta 4.6% 11.5% <0.001

Prior CABG 17.6% 26.9% <0.001

Mitral Valve Disease 16.1% 32.8% <0.001

Risk Analysis: Logistic

EuroSCORE

0

10

20

30

40

50

Pe

rce

nt

of

Pa

tie

nts

< 20 20 - 40 41 - 60 > 60

Baseline EuroSCORE - The SOURCE Registry

Transapical

Transfemoral

6% 3%

16%

12%

49%48%

30%

37%

As EuroSCORE gets higher, ratio of TA to

TF is greater

TF (n=459) TA (n=571)

30 day 93.7% 89.7%

EuroSCORE <20 94.6%

(Mean 12.5)

93.4%

(Mean 12.4)

EuroSCORE >20 93.3%

(Mean 33.7)

63% of pts

88.1%

(Mean 36.3)

70% of pts

Survival

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Fraction of Months post Procedure

Su

rviv

al

< 20 >= 20

SOURCE 30 Day All Cause Mortality -- Transfemoral Approach

Stratified by Logistic EuroSCORE SOURCE 30 Day All Cause Mortality -- Transapical Approach

Stratified by Logistic EuroSCORE

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Fraction of Months post Procedure

Su

rviv

al

< 20 >= 20

p=0.068

Survival of TA pts with ES< and >20 are significantly different (93.4 vs. 88.1) (p=0.067)

Procedure Complications (<30 Days)

TF (n=463) TA (n=575) Total (n=1038)

Acute procedure

success

436/95.6%n=456

523/92.9%n=563

959/94.1%n=1019

Device Success

Comp

428/92.4% 522/90.8% 950/91.5%

Conversion to

sAVR

8/1.7% 20/3.5% 28/2.7%

AR >+2** 15 (3.2%) 34 (5.9%) 49 (4.7%)

Valve Migration 0(0.0%) 3(0.5%) 3(0.3%)

Valve Malposition 8(1.7%) 8 (1.4%) 16(1.5%)

Coronary

Obstruction

3(0.7%) 3(0.5%) 6 (0.6%)

Major Complications (< 30 Days)

TF (n=463) TA (n=575) Total (n=1038)

Death 29 (6.3%) 59(10.3%) 88(8.5%)

Stroke 11 (2.4%) 16 (2.6%) 27(2.5%)

Renal Failure

Requiring

Dialysis

23(5.0%) 69 (11.7%) 92 (8.7%)

Permanent

Pacemaker

31 (6.7%) 42 (7.3%) 73 (7.0%)

Major Vascular / Access Complications

TF : 10.6 % (not significant predictor of 30 d. survival)

TA: 2.4 % (significant predictor of 30 d. survival)

Native Aortic Valve Disease

Severe AS: AVAI ≤0.6 cm2/m2

27mm ≥AV annulus ≥20mm

Sino-tubular Junction ≤43mm

Age ≥80 y (21F)≥75 y (18F)

Logistic EuroSCORE ≥20% (21F)

≥15% (18F)

Age ≥65 y

Liver cirrhosis (Child A or B)

Pulmonary insufficiency: FEV1<1L

Previous cardiac surgery

PHT (PAP>60mmHg)

Recurrent P.E’s

RV failure

Hostile thorax (radiation, burns,etc)

Severe connective tissue disease

Cachexia

+1 or more

Primary Endpoints:

• Procedural success

• 30-Day outcomes

• Long term outcomes

CoreValve post CE mark experience

CLINICAL INDICATIONS

18 F Expanded Evaluation Registry(EER)

Patient Demographics

52

In-Training Solo Total EER

Mean ± SD or % N = 918 N = 565 N = 1483

Age (years) 80.8 6.7 81.7 5.9 81.2 6.4

Logistic EuroSCORE (%) 22.2 13.6 23.2 13.7 22.6 13.7

Female 55.8% 54.7% 55.4%

NYHAI-II: 17.2%

III-IV: 82.8%

I-II: 14.4%

III-IV: 85.6%

I-II: 16.1%

III-IV: 83.9%

Aortic Valve Area (cm2) 0.65 0.18 0.61 0.17 0.64 0.18

Peak gradient (mm Hg) 78.3 26.1 81.3 25.8 79.5 26.1

Mean gradient (mm Hg) 48.4 16.4 50.4 16.0 49.2 16.3

LVEF(%) 52.9 13.8 51.4 13.7 52.3 13.8

±

±

±

±

±

±

±

±

±

±

±

±

±

±

±

±

±

±

Age (years)

Logistic Euro SCORE

Female

NYHA I-II

NYHA III-IV

Aortic Valve Area (cm2)

Peak Gradient (mmHg)

Mean Gradient (mmHg)

LVEF (%)

Procedural Results

In-Training

(N = 867)

Solo

(N = 511)

Total EER

(N = 1378)

97.7% 98.4% 98.0%

0%

20%

40%

60%

80%

100%

Procedural Success

131.2120.5

127.2

0

20

40

60

80

100

120

140

160

180

200

Procedure Mean Time SD (minutes)

Mortality Rate

2.6%1.9%

2.4%

0%

2%

4%

6%

8%

10%

12%

In-Training

(N = 918)

Solo

(N = 565)

Total EER

(N = 1483)

24-Hour

10.7%9.7%

10.3%

0%

2%

4%

6%

8%

10%

12%

In-Training (N = 918)

Solo (N = 565)

Total EER (N = 1483)

30-Day

24 - Hour

30- Day

In Training Solo Total EER In Training Solo Total EER

0%

6%

12%

0%

6%

12%

≤ 30-Day Adverse Events*

In-Training Certified Both

CARDIAC Deaths†5.4% 3.9% 4.9%

Aortic Dissection 0.7% 0.2% 0.6%Cardiac Tamponade 3.5% 2.2% 3.0%Cardiac Perforation 2.3% 1.8% 2.1%

Access Site Complication 2.5% 0.7% 1.8%Major Bleeding 5.1% 3.3% 4.4%

Conversion to Surgery 0.6% 0.9% 0.7%Myocardial Infarction 0.9% 0.4% 0.7%

Major Arrhythmia 9.1% 4.6% 7.5%Pacemaker 18.8% 17.8% 18.4%

Renal Failure 1.9% 1.5% 1.7%Stroke 2.2% 2.2% 2.2%

TIA 0.2% 0.4% 0.3%Structural Valve Dysfunction 0.0% 0.0% 0.0%

Valve Migration 0.0% 0.0% 0.0%

* Multiple events in same patients = data not cumulative† Includes deaths where cause is not known

CONSIDERATIONS

Multidisciplinary approach and team work essential

Both systems and different access routes should be available to increase the spectrum of treatable pts.

The “real world” post commercialization experience shows a high procedure success with a relatively low 30-day mortality

A relatively low rate of complications is documented

Experience in managing complications improves the outcome

Expanded indications are expected

Pts. selection remains critical

Advances and refinements in technology are ongoing and will facilitate the procedure and improve outcome

My Wish List (P.Block,June 2009)

True percutaneous insertion

No need of general anesthesia

Multiple valve sizes

Smallest size possible < 16 Fr

Smooth outer surface to pass through aorta

Easy transition over arch

Easy transit through valve

“Self seating”

Adequate radial strength

Repositionable and retrivable if needed

No valve gradient

Conforms to annulus without AR

Long term durability

PERSPECTIVES

Progress in delivery systems and valve manufacturing will lead to lower profile,repositionable,retrievable and more durable devices, as well as a wider range of prosthetic dimensions

Improved imaging, such as on-line 3-D reconstruction and stereotaxis could facilitate valve implantation

Indications will be expanded, but randomized trials are highy desirable