1. Types of AVR
Examples of replacement aortic valves: a) shows an aortic homograft, b) and c) show a xenograft, d) shows a ball and cage valve, e) shows a tilting-disk valve, f) shows a bi-leaflet valve

2. Elderly Patients Pts >80years, operative mortality as high as 30%.
Percutaneous aortic balloon valvuloplasty is an alternative to valve replacement introduced in ‘80s.
Inflating one or more large balloons across the aortic valve from a percutaneous route, a modest decrease in gradient and improvement in symptoms

3. Balloon Valvuloplasty
Follow-up has demonstrated a high rate of re-stenosis (>60% at 6 months and nearly 100% at 2 years), with no decrease in mortality rate after procedure
Therefore, now only has a role in critically ill elderly pts who are not candidates for surgery or as a “bridge” in critically ill pts before AV replacement

4. Building on 50 Years of Proven Valve Expertise

5. Helping to Solve a Grave Problem
Aortic stenosis is life threatening and progresses rapidly
Survival after onset of symptoms is 50% at 2 years and 20% at 5 years1
“Surgical intervention [for severe AS] should be performed promptly once even…minor symptoms occur”1
Latent Period
(Increasing Obstruction,
Myocardial Overload)
Survival, %
100 80 60 40 20 50 70
Age, y
Onset Severe Symptoms
Angina
Syncope
Average Survival, y
Failure 2 4 6

6. Addressing a Serious Unmet Need
At least 40% of patients with severe aortic stenosis (AS) do not have an AVR2-8
1999
2006
2009
2005
2010
Patients, %
Aortic Valve Replacement (AVR)
No AVR 46 57 40 39 26 48 31 54 43 60 61 74 52 69 20 80
100
Bouma
Pellikka
Charlson
Varadarajan
Jan
Bach
Freed

7. Edwards SAPIEN Transcatheter Heart Valve With the RetroFlex 3 Transfemoral System
For inoperable patients with severe symptomatic native aortic valve stenosis

8. Patient-Focused Multidisciplinary Heart Team Approach
Multidisciplinary in all aspects:
Patient selection
Procedure planning
Patient treatment
Post-operative care

9. The PARTNER Trial Protocol
Not in Study
Assessment
Transfemoral Access
Yes No
Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) TF
TAVR
(n = 179)
Standard Therapy
(Control) vs
1:1 Randomization
(n = 492) TA
(n = 207)
Primary Endpoint: All-Cause Mortality (1 yr) (Non-inferiority)
(n = 244)
AVR
(n = 248)
(n = 104)
(n = 103)
Cohort A
(n = 699)
Cohort B
(n = 358)
2 Cohorts
Individually Powered
(N = 1,057)
TA, transapical; TF, transfemoral.
Operability
Severe Symptomatic Native Aortic Valve Stenosis

10. A Seminal Date in Cardiovascular Medicine
September 22, 2010 on NEJM.org

11. Absolute Reduction in Mortality Continues to Diverge at 2 Years
HR [95% CI] = 0.57 [0.44, 0.75]
P (log rank) < .0001
Edwards SAPIEN THV
Standard Therapy 20 40 60 80
100
∆ at 1 yr = 20.0% NNT = 5.0 pts
67.6%
50.7%
All-Cause Mortality, %
43.3%
30.7%
∆ at 2 yr = 24.3% NNT = 4.1 pts
Months
Numbers at Risk
Edwards SAPIEN THV
179
138
124
110 83
Standard
Therapy
121 85 67 51

12. Edwards SAPIEN THV Delivered QOL Benefits60 40 20 80
100 4 6 8 10 12 2
Standard Therapy
Edwards SAPIEN THV
∆ = 13.9 P < .001
∆ = 24.5 P < .001
KCCQ Score (Mean)
MCID = 5 points
Months
Improvement in quality of life
MCID, minimum clinically important difference.

13. Peri-procedural Hazards
At 30 days, TAVR resulted in more frequent strokes, major vascular complications, and bleeding events than standard therapy
All strokes, 7.3% vs 1.7%, P = .02
Major vascular complications, 16.8% vs 1.1%, P <
Bleeding events, 16.2% vs 2.2%, P < .0001

14. Sobering Perspective 5-Year Survival Survival, % * 23 4 12 30 28 3† * 23 4 12 30 28 3 5 10 15 20 25 35
Breast
Cancer
Lung Cancer
Colorectal
Prostate
Ovarian
Severe
Inoperable AS
* National Institutes of Health. National Cancer Institute. Surveillance Epidemiology and End Results. Cancer Stat Fact Sheets. Accessed November 16, 2010.
† Using constant hazard ratio. Data on file, Edwards Lifesciences LLC. Analysis courtesy of Murat Tuczu.

15. Advancing the Science of TAVR

16. Raj R. Makkar, MD On behalf of The PARTNER Trial Investigators
Two-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in “Inoperable” Patients With Severe Aortic Stenosis: The PARTNER Trial
Raj R. Makkar, MD On behalf of The PARTNER Trial Investigators
TCT 2011 | San Francisco, CA | November 10, 2011

17. Background (1)
Transcatheter aortic valve replacement (TAVR) is the recommended treatment for “inoperable” patients with severe aortic stenosis (AS), based upon 1-year results of The PARTNER Trial which demonstrated reduced mortality and improved quality of life.
However, whether clinical benefit and valve performance are sustained beyond one year is unknown and longer term outcomes will importantly alter clinical practice decisions. 17

18. Objectives
To evaluate the clinical outcomes of TAVR compared to standard therapy at 2 years in “inoperable” aortic stenosis patients.
To assess valve hemodynamics and durability using echocardiography.
To perform subgroup analyses to better define the impact of co-morbidities on outcomes. 18

19. Inclusion Criteria
Severe calcific aortic stenosis defined as echo derived valve area of < 0.8 cm2 (EOA index < 0.5 cm2), and mean gradient > 40 mmHg or jet velocity > 4.0 m/s.
NYHA functional class II or greater.
Risk of death or serious irreversible morbidity of AVR as assessed by cardiologist and two surgeons must exceed 50%.
Surgeons must agree and attest that before PARTNER these patients would not have received AVR treatment! 19

20. Key End-Points for 2 Year Analysis
All cause mortality
Cardiac mortality
Rehospitalization
Stroke
NYHA functional class
Days alive and out of hospital
Echo-derived valve areas, transvalvular gradients, paravalvular aortic regurgitation
Mortality outcomes stratified by STS score 20

21. Study Flow - Inoperable Cohort
Randomized Inoperable
n = 179
Standard therapy
n = 179
TAVR
85/85 patients
100% followed at 1 Yr
124/124 patients
100% followed at 1 Yr
Note: The follow-up compliance is with regard to protocol defined windows. At 2 and 3 years the start of the window is 45 days before the nominal time point.
The death counts agree with the counts in the death tables, where crossover patients are followed past crossover.
The followed counts are greater than the at risk numbers in the Kaplan-Meier plots, because this flow diagram is based on windows. In contrast, the KM at risk numbers reflect the exact time points.
56/56 patients
100% followed at 2 Yr
99/102 patients*
97.1% followed at 2 Yr
5 withdrawals in the first year in Standard Rx arm
*3 patients followed outside of protocol window in TAVR group
No patients were lost to follow-up 21

22. Patient Characteristics (1)
TAVR
n = 179
Standard Rx
p value
Age – yr
83.1 ± 8.6
83.2 ± 8.3
0.95
Male sex (%)
45.8
46.9
0.92
STS Score
11.2 ± 5.8
12.1 ± 6.1
0.14
NYHA
I or II (%)
III or IV (%)
7.8
92.2
6.1
93.9
0.68
CAD (%)
67.6
74.3
0.20
Prior MI (%)
18.6
26.4
0.10
Prior CABG (%)
37.4
45.6
0.17
Prior PCI (%)
30.5
24.8
0.31
Prior BAV (%)
16.2
24.4
0.09
CVD (%)
27.4
27.5
1.00

23. Patient Characteristics (2)
TAVR n = 179
Standard Rx n = 179
p value
PVD (%)
30.3
25.1
0.29
COPD
Any (%)
O2 dependent (%)
41.3
21.2
52.5
25.7
0.04
0.38
Creatinine > 2 mg/dL (%)
5.6
9.6
0.23
Atrial fibrillation (%)
32.9
48.8
Perm. pacemaker (%)
22.9
19.5
0.49
Pulmonary HTN (%)
42.4
43.8
0.90
Frailty (%)
18.1
28.0
0.09
Porcelain aorta (%)
19.0
11.2
0.05
Chest wall radiation (%)
8.9
8.4
1.00
Chest wall deformity (%)
5.0
Liver disease (%)
3.4

24. All Cause Mortality (ITT) Crossover Patients Followed
HR [95% CI] = 0.57 [0.44, 0.75]
p (log rank) <
Standard Rx
TAVR
∆ at 2 yr = 24.3% NNT = 4.1 pts
67.6%
43.3%
∆ at 1 yr = 20.0% NNT = 5.0 pts
50.7%
All Cause Mortality (%)
30.7%
Point-in-time at 2 yrs: p <
Months
Numbers at Risk
TAVR
179
138
124
110 83
Standard Rx
121 85 67 51

25. All Cause Mortality (ITT) Landmark Analysis
Standard Rx
TAVR
Mortality 0-1 yr
Mortality 1-2yr
HR [95% CI] = 0.57 [0.44, 0.75]
p (log rank) <
HR [95% CI] = 0.58 [0.37, 0.92]
p (log rank) =
50.7%
All Cause Mortality (%)
35.1%
30.7%
18.2%
Numbers at Risk
TAVR
179
138
124
110 83
Standard Rx
121 85 62 42
Months

26. Cardiovascular Mortality (ITT) Crossover Patients Censored
Standard Rx
HR [95% CI] = 0.44 [0.32, 0.60]
p (log rank) <
TAVR
∆ at 2 yr = 31.4% NNT = 3.2 pts
62.4%
31.0%
∆ at 1 yr = 24.1% NNT = 4.1 pts
44.6%
Cardiovascular Mortality (%)
20.5%
Point-in-time at 2 yrs: p <
Months
Numbers at Risk
TAVR
179
138
124
110 83
Standard Rx
121 85 62 42

27. Cardiovascular Mortality (ITT) Landmark Analysis
Standard Rx
TAVR
Cardiovascular Mortality 0-1 yr
Cardiovascular Mortality 1-2 yr
HR [95% CI] = 0.44 [0.32, 0.60]
p (log rank) <
HR [95% CI] = 0.48 [0.29, 0.81]
p (log rank) =
Cardiovascular Mortality (%)
44.6%
32.1%
20.5%
13.2%
Months
Numbers at Risk
TAVR
179
138
124
110 83
Standard Rx
121 85 62 42

28. Repeat Hospitalization (ITT)
Standard Rx
HR [95% CI] = 0.41 [0.30, 0.58]
p (log rank) <
TAVR
∆ at 2 yr = 37.5% NNT = 2.7 pts
72.5%
35.0%
∆ at 1 yr = 26.9% NNT = 3.7 pts
53.9%
Repeat Hospitalization (%)
27.0%
Point-in-time at 2 yrs: p <
Months
Numbers at Risk
TAVR
179
115
100 89 64
Standard Rx 86 49 30 17

29. Hospitalization Through 2 Years
TAVR
Standard Tx
p value
Repeat Hospitalizations (No.) 78
151
<.0001
Repeat Hospitalizations (%)
35.0%
72.5%
Days Alive Out of Hospital Median [IQR]
699 [ ]
355 [ ]
.0003
This endpoint captures the total hospital days from the index procedure or randomization to one year post-procedure or randomization.
An analysis of DAOH allows for an assessment of two important objectives of the device therapy- improvement in mortality and quality of life.

30. NYHA Class Over Time Survivors
p = 0.61
p <
p <
16.9%
23.7%
57.5%
60.8%
Percent
92.2%
93.9%
Treatment Visit
Baseline
1 Year
2 Year

31. All Stroke (ITT) HR [95% CI] = 2.79 [1.25, 6.22] p (log rank) = 0.009
Standard Rx
HR [95% CI] = 2.79 [1.25, 6.22]
p (log rank) = 0.009
TAVR
Incidence (%)
∆ at 1 yr = 5.7%
∆ at 2 yr = 8.3%
5.5%
13.8%
11.2%
5.5%
Point-in-time at 2 yrs: p =
Months
Numbers at Risk
TAVR
179
128
116
105 79
Standard Rx
118 84 62 42

32. All Cerebrovascular Events (%)
Note: Percents are of patients in the trial (n/179).
≤ 30 Days
31 Days – 1 Year
1 Year – 2 Years
All CVA
p = 0.010
p = 0.387
p = 0.028
Ischemic Stroke
p = 0.017
p = 0.155
p = 0.083
Hemorrhagic Stroke
p = 0.316
p = 0.121
p = 0.415

33. Mortality or Stroke (ITT)
Standard Rx
HR [95% CI] = 0.64 [0.49, 0.84]
p (log rank) =
TAVR
∆ at 2 yr = 21.9% NNT = 4.6 pts
68.0%
46.1%
∆ at 1 yr = 16.1% NNT = 6.2 pts
51.3%
All Cause Mortality or Stroke (%)
35.2%
Months
Numbers at Risk
TAVR
179
128
116
105 79
Standard Rx
118 84 62 42

34. Clinical Outcomes 1 Year and 2 Year (ITT)
TAVR
Standard Rx
P value
 2 Year
n = 179
TAVR
Standard Rx
P value
Myocardial infarction
All, % (n)
0.8 (1)
0.7 (1)
0.906
1.6 (2)
2.5 (2)
0.694
Acute kidney injury
Creatinine > 3 mg/dL, % (n)
1.1 (2)
2.8 (5)
0.449
Renal failure (CEC), % (n)
2.3 (4)
4.7 (7)
0.257
3.2 (5)
7.6 (9)
0.149
Bleeding – major, % (n)
24.2 (42)
14.9 (21)
0.038
28.9 (48)
20.1 (25)
0.093
Start with MI
Check reTAVR
Is this censored or ITT
Cardiac re-intervention
BAV, % (n)
1.1 (2)
82.3 (138)
<.0001
2.8 (4)
85.3 (140)
Re-TAVR, % (n)
1.7* (3) NA -
AVR, % (n)
0 (0)
7.6 (10)
0.002
0.9 (1)
8.9 (11)
0.005
Endocarditis, % (n)
1.4 (2)
0.8 (1)
0.618
2.3 (3)
0.316
New pacemaker, % (n)
4.7 (8)
8.6 (14)
0.149
6.4 (10)
0.469 34

35. Mean Gradient & Valve Area
EOA
Mean Gradient
Mean Gradient (mm Hg)
AVA (cm²)
N = 158
N = 162
N = 137
N = 143
N = 84
N = 89
N = 65
N = 9
Error bars = ± 1 Std Dev 35

36. Mortality Stratified by Paravalvular Leak (ITT) Starting at Discharge
Moderate or Severe
None to Mild
p (log rank) = 0.891
Death Incidence (%)
41.2%
40.5%
35.3%
27.2%
Determination of first PV Leak starts with the discharge echo
Months
Numbers at Risk
None to Mild
147
118
107 95 72
Moderate or Severe 17 12 11 10 8

37. Mortality Stratified by STS Score (ITT)
Standard Rx
TAVR
p value (log rank) = 0.676
p value (log rank) = 0.012
Death Incidence (%)
Months
Numbers at Risk
Months 12 8 7 6 5
119 84 59 42 29 47 19 14 28 26 25 24 16
108 80 76 67 52 43 32 23 19 15

38. Conclusions (1)
At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery…
TAVR remained superior to standard therapy with incremental benefit from 1 to 2 years, markedly reducing the rates of…
All cause mortality
Cardiovascular mortality
Repeat hospitalization
TAVR improved NYHA functional status and decreased Class III/IV symptoms compared to standard therapy (17% vs 64%; p < 0.001). 38

39. Conclusions (2)
At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery…
There were more neurologic events in TAVR patients vs Standard Rx (16.2% vs 5.5%; p = 0.003) with 5 new events (3 strokes and 2 TIAs) between 1-2 years in TAVR patients.
After 30 days, differences in stroke frequency were largely due to increased hemorrhagic strokes in TAVR patients.
A subgroup analysis according to surgical risk score suggests that the most pronounced benefit of TAVR is in patients without extreme clinical co-morbidities. 39

40. Conclusions (3)
At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery…
TAVR hemodynamics by echo showed durable improvements in AVA and mean gradients up to 3 years after implantation.
Moderate or severe paravalvular AR in the TAVR patients did not influence 2-year survival and there was a trend towards reduced paravalvular AR between 1 and 2 years. 40

41. Clinical Implications
Two year data continues to support the role of TAVR as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates.
The ultimate value of TAVR in “inoperable” patients will depend on careful selection of patients who are not surgical candidates, and yet do not have extreme co-morbidities that overwhelm the benefits of TAVR and render the intervention futile. 41

42. QUESTIONS?