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

 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

 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

Aortic stenosis is life threatening and progresses rapidly
Onset Severe Symptoms
100
80
60
40
20
Latent Period
(Increasing Obstruction,
Myocardial Overload)
Angina
Syncope
Failure
0 2 4
Average Survival, y
6
0 40 50 60
Age, y
70 80
– Survival after onset of symptoms is 50% at 2 years and 20% at 5 years 1
– “Surgical intervention [for severe AS] should be performed promptly once even…minor symptoms occur” 1

At least 40% of patients with severe aortic stenosis (AS) do not have an AVR
2-8
74
No AVR
52 100
80
60
40
20
0
54
46
Aortic Valve Replacement (AVR)
43 60 61
57
40 39
26
48
69
31
1999 2005 2006 2006 2009 2009 2010

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

 Multidisciplinary in all aspects:
 Patient selection
 Procedure planning
 Patient treatment
 Post-operative care

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

September 22, 2010 on NEJM.org

Absolute Reduction in Mortality Continues to Diverge at 2 Years
100
HR [95% CI] = 0.57 [0.44, 0.75]
P (log rank) < .0001
Edwards SAPIEN THV
Standard Therapy
80
60
∆ at 1 yr = 20.0%
NNT = 5.0 pts
50.7%
67.6%
40
20
Numbers at Risk
Edwards
SAPIEN THV
Standard
Therapy
0
0
179
179
6
138
121
30.7%
12
Months
124
85
18
110
67
43.3%
∆ at 2 yr = 24.3%
NNT = 4.1 pts
24
83
51

100
MCID = 5 points Edwards SAPIEN THV
Standard Therapy
80
Improvement in quality of life
60
40
20
∆ = 13.9
P < .001
0
0
MCID, minimum clinically important difference.
2 4 6
Months
8 10
∆ = 24.5
P < .001
12

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 <
.0001
 Bleeding events, 16.2% vs 2.2%, P < .0001

5-Year Survival
35
30
25
20
23
30
28
15
10 12
5
4 3
0
Breast
Cancer
*
Lung Cancer Colorectal
*
Cancer
*
Prostate
Cancer
*
Ovarian
Cancer
*
Severe
Inoperable
AS
†
* National Institutes of Health. National Cancer Institute. Surveillance Epidemiology and End Results. Cancer Stat Fact Sheets.http://seer.cancer.gov/statfacts/.
Accessed November 16, 2010.
† Using constant hazard ratio. Data on file, Edwards Lifesciences LLC. Analysis courtesy of Murat Tuczu.

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

 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.

 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.

 Severe calcific aortic stenosis defined as echo derived valve area of < 0.8 cm 2 (EOA index < 0.5 cm 2 ), 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!


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

n = 358
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
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

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

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

Crossover Patients Followed
Standard Rx
TAVR
HR [95% CI] =
0.57 [0.44, 0.75] p (log rank) < 0.0001
∆ at 1 yr = 20.0%
NNT = 5.0 pts
50.7%
30.7%
67.6%
43.3%
∆ at 2 yr = 24.3%
NNT = 4.1 pts
Numbers at Risk
TAVR
Standard Rx
179
179
138
121
Months
124
85
110
67
83
51

All Cause Mortality (ITT)
Landmark Analysis
Standard Rx
Mortality 0-1 yr
TAVR
Mortality 1-2yr
HR [95% CI] =
0.57 [0.44, 0.75] p (log rank) < 0.0001
50.7%
HR [95% CI] =
0.58 [0.37, 0.92] p (log rank) = 0.0194
35.1%
30.7%
18.2%
Numbers at Risk
TAVR
Standard Rx
179
179
138
121
Months
124
85
110
62
83
42

Cardiovascular Mortality (ITT)
Crossover Patients Censored
Standard Rx
TAVR
HR [95% CI] =
0.44 [0.32, 0.60] p (log rank) < 0.0001
∆ at 1 yr = 24.1%
NNT = 4.1 pts 44.6%
20.5%
62.4%
∆ at 2 yr = 31.4%
NNT = 3.2 pts
31.0%
Numbers at Risk
TAVR
Standard Rx
179
179
138
121
Months
124
85
110
62
83
42

Standard Rx
TAVR
∆ at 1 yr = 26.9%
NNT = 3.7 pts
HR [95% CI] =
0.41 [0.30, 0.58] p (log rank) < 0.0001
53.9%
27.0%
72.5%
∆ at 2 yr = 37.5%
NNT = 2.7 pts
35.0%
Numbers at Risk
TAVR
Standard Rx
179
179
115
86
Months
100
49
89
30
64
17

TAVR Standard Tx p value
Repeat Hospitalizations (No.) 78 151 <.0001
Repeat Hospitalizations (%)
Days Alive Out of Hospital
Median [IQR]
35.0% 72.5% <.0001
699 [201-720] 355 [116-712] .0003

Survivors p = 0.61
p < 0.0001
16.9%
23.7% p < 0.0001
60.8%
92.2% 93.9%
57.5%
Treatment Visit Baseline 1 Year 2 Year

Standard Rx
TAVR
HR [95% CI] =
2.79 [1.25, 6.22] p (log rank) = 0.009
∆ at 1 yr = 5.7% ∆ at 2 yr = 8.3%
Numbers at Risk
TAVR
Standard Rx
179
179
128
118
11.2%
5.5%
Months
116
84
105
62
13.8%
5.5%
79
42

8
7
6
5
0,6
Hemorrhagic CVA
Ischemic CVA
TIA
4
3
6,7
0,6
2,2
2
1
0
1,7
Standard Rx TAVR
≤ 30 days
2,2 1,1
0,6
Standard Rx TAVR
31 days- 365 days
1,7
1,1
Standard Rx TAVR
366- 730 days
Note: Percents are of patients in the trial (n/179).
≤ 30 Days
All CVA
Ischemic Stroke
Hemorrhagic Stroke p = 0.010
p = 0.017
p = 0.316
31 Days – 1 Year p = 0.387
p = 0.155
p = 0.121
1 Year – 2 Years p = 0.028
p = 0.083
p = 0.415

Standard Rx
TAVR
∆ at 1 yr = 16.1%
NNT = 6.2 pts
HR [95% CI] =
0.64 [0.49, 0.84] p (log rank) = 0.0009
51.3%
35.2%
68.0%
46.1%
∆ at 2 yr = 21.9%
NNT = 4.6 pts
Numbers at Risk
TAVR
Standard Rx
179
179
128
118
Months
116
84
105
62
79
42

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

EOA
Mean Gradient
N = 158
N = 162
N = 137
N = 143
N = 84
N = 89
N = 65
N = 65
N = 9
N = 9
Error bars = ± 1 Std Dev

Mortality Stratified by Paravalvular Leak (ITT)
Starting at Discharge
Moderate or Severe
None to Mild p (log rank) = 0.891
35.3%
27.2%
41.2%
40.5%
Numbers at Risk
None to Mild
Moderate or Severe
147
17
118
12
Months
107
11
95
10
72
8

Mortality Stratified by STS Score (ITT)
STS <5
Standard Rx
STS 5-14.9
STS ≥15
TAVR p value (log rank) = 0.676
p value (log rank) = 0.012
Numbers at Risk
12
119
47
8
84
29
Months
7
59
19
6
42
14
5
29
8
28
108
43
26
80
32
Months
25
76
23
24
67
19
16
52
15

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).

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.

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.

• 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.