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
Disclosures
Raj R. Makkar is a principal site investigator for The
PARTNER Trial (US) for Edwards Lifesciences and
is national principal investigator for the St Jude
TAVR study. He has received consulting fees, grant
support and lecture fees from Medtronic, equity from
Entourage Medical Technologies and grant support
from St Jude Medical.
• Transcatheter Aortic Valve Replacement (TAVR) is the
standard of care for inoperable patients with severe
aortic stenosis (AS), demonstrating 1-year outcomes
of the PARTNER Trial, offering reduced mortality and
improved quality of life.
Published October 2010
4
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
8
All Cause Mortality (ITT)
Crossover Patients Followed
Standard Rx
All Cause Mortality (%)
TAVR
HR [95% CI] =
0.57 [0.44, 0.75]
p (log rank) < 0.0001
67.6%
∆ at 1 yr = 20.0%
NNT = 5.0 pts
50.7%
43.3%
30.7%
∆ at 2 yr = 24.3%
NNT = 4.1 pts
Months
Numbers at Risk
TAVR
Standard Rx
13
179
179
138
121
124
85
110
67
83
51
All Cause Mortality (ITT)
Landmark Analysis
All Cause Mortality (%)
Standard Rx
TAVR
Mortality 0-1 yr
Mortality 1-2yr
HR [95% CI] =
0.57 [0.44, 0.75]
p (log rank) < 0.0001
HR [95% CI] =
0.58 [0.37, 0.92]
p (log rank) = 0.0194
50.7%
35.1%
30.7%
18.2%
Months
Numbers at Risk
TAVR
Standard Rx
15
179
179
138
121
124
85
110
62
83
42
Cardiovascular Mortality (ITT)
Crossover Patients Censored
Cardiovascular Mortality (%)
Standard Rx
TAVR
∆ at 1 yr = 24.1%
NNT = 4.1 pts
HR [95% CI] =
0.44 [0.32, 0.60]
p (log rank) < 0.0001
62.4%
44.6%
20.5%
∆ at 2 yr = 31.4%
NNT = 3.2 pts
31.0%
Months
Numbers at Risk
TAVR
Standard Rx
16
179
179
138
121
124
85
110
62
83
42
Repeat Hospitalization (ITT)
Repeat Hospitalization (%)
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
72.5%
53.9%
27.0%
∆ at 2 yr = 37.5%
NNT = 2.7 pts
35.0%
Months
Numbers at Risk
TAVR
Standard Rx
18
179
179
115
86
100
49
89
30
64
17
Hospitalization Through 2 Years
Repeat Hospitalizations (No.)
Repeat Hospitalizations (%)
Days Alive Out of Hospital
Median [IQR]
19
TAVR
Standard Tx
p value
78
151
<.0001
35.0%
72.5%
<.0001
699 [201-720]
355 [116-712]
.0003
NYHA Class Over Time
Survivors
p = 0.61
p < 0.0001
p < 0.0001
16.9%
23.7%
57.5%
Percent
60.8%
Treatment Visit
20
93.9%
92.2%
Baseline
1 Year
2 Year
All Stroke (ITT)
Standard Rx
Incidence (%)
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%
13.8%
11.2%
5.5%
5.5%
Months
Numbers at Risk
TAVR
Standard Rx
21
179
179
128
118
116
84
105
62
79
42
All Strokes (# pts)
14
1
12
Hemorrhagic
Events
10
Ischemic
8
4
6
12
1
4
2
5
4
3
0
Standard Rx
TAVR
Standard Rx
≤ 30 days
24
TAVR
31 days- 2 years
≤ 30 Days
31 Days – 2 Years
All stroke
p=0.010
p=0.319
Ischemic Stroke
p = 0.017
p = 0.437
Hemorrhagic Stroke
p = 0.316
p = 0.160
Stroke - Hemorrhagic
ITT arm Age
Days post
Description Trauma
randomization
Medication
Procedure Device
related* related*
TAVR
91
9
Right sided
hemorrhage
No
Coumadin on
admission
Yes
No
TAVR
84
53
Traumatic
subarachnoid
Fall
Coumadin
No
No
Intraparenchymal and
subdural
Fall
Not stated
No
No
Fall
Not stated
No
No
Not stated
DAPT
No
No
Not stated
No
n/a
TAVR
85
54
TAVR
84
124
TAVR
88
155
Standard
therapy
(BAV)
91
*CEC adjudicated
25
243
Intracranial
Subdural
hematoma
"Massive
cerebral
Not stated
hemorrhage"
All Cause Mortality or Stroke (%)
Mortality or Stroke (ITT)
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
68.0%
51.3%
46.1%
35.2%
∆ at 2 yr = 21.9%
NNT = 4.6 pts
Months
Numbers at Risk
TAVR
Standard Rx
26
179
179
128
118
116
84
105
62
79
42
Mean Gradient & Valve Area
30
Mean Gradient
AVA (cm²)
Mean Gradient (mm Hg)
EOA
N = 158
N = 137
N = 84
N = 65
N=9
N = 162
N = 143
N = 89
N = 65
N=9
Error bars = ± 1 Std Dev
Mortality Stratified by Paravalvular Leak (ITT)
Starting at Discharge
Moderate or Severe
Death Incidence (%)
None to Mild
p (log rank) = 0.891
41.2%
35.3%
40.5%
27.2%
Months
Numbers at Risk
None to Mild
Moderate or Severe
31
147
17
118
12
107
11
95
10
72
8
Mortality Stratified by STS Score (ITT)
STS <5
STS ≥15
STS 5-14.9
TAVR
Standard Rx
p value (log rank) = 0.676
Death Incidence (%)
p value (log rank) = 0.012
Months
Numbers at Risk
33
Months
12
119
8
84
7
59
6
42
5
29
47
29
19
14
8
28
108
43
26
80
32
25
76
23
24
67
19
16
52
15
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…
34

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.
35
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.
36
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.
37
Thank You to the Dedicated Study
Teams at All PARTNER
Investigational Sites
BACKUP SLIDES
All Cause Mortality (ITT)
HR [95% CI] =
0.57 [0.44, 0.75]
p (log rank) < 0.0001
Standard Rx
All Cause Mortality (%)
TAVR
∆ at 1 yr = 20.0%
NNT = 5.0 pts
50.7%
68.0%
43.3%
30.7%
∆ at 2 yr = 24.7%
NNT = 4.0 pts
Months
Numbers at Risk
TAVR
Standard Rx
40
179
179
138
121
124
85
110
62
83
42
47
19
14
5
All Cause Mortality (ITT)
Cumulative Hazard
Cumulative Hazard
Standard Rx
TAVR
1.14
0.71
0.37
Months
41
0.57
Cardiovascular Mortality (ITT)
Landmark Analysis
Standard Rx
TAVR
Cardiovascular Mortality 1-2 yr
HR [95% CI] =
0.44 [0.32, 0.60]
p (log rank) < 0.0001
HR [95% CI] =
0.48 [0.29, 0.81]
p (log rank) = 0.0043
Cardiovascular Mortality (%)
Cardiovascular Mortality 0-1 yr
44.6%
32.1%
20.5%
13.2%
Months
Numbers at Risk
TAVR
Standard Rx
42
179
179
138
121
124
85
110
62
83
42
All Cause Mortality (ITT)
Entire Cohort vs STS Score <5
Standard Rx
Death Incidence (%)
Entire Cohort
TAVR
STS <5
Months
Months
Numbers at Risk
179
179
43
138
121
124
85
110
62
83
42
47
19
14
5
28
12
26
8
25
7
24
6
16
5
11
3
2
0
Mortality Stratified by STS Score (ITT)
TAVR
Standard Rx
STS 5-14.9
STS ≥15
Months
Months
Months
Death Incidence (%)
STS <5
Numbers at Risk
44
28
12
26
8
25
7
24
6
16
5
108
119
80
84
76
59
67
42
52
29
43
47
32
29
23
19
19
14
15
8
Mortality Stratified by STS Score (ITT)
STS <15 vs STS ≥15 (out to 36 months)
Death Incidence (%)
Standard Rx
STS <15
STS ≥15
Months
Months
TAVR
Numbers at Risk
136
131
45
106
92
101
66
91
48
68
34
35
14
8
4
43
47
32
29
23
19
19
14
15
8
12
5
6
1
Proportional Hazards Analysis of
Predictors of Death
Predictor Variable
46
Body Mass Index (lbs/in²)
STS Risk Score
CV Conditions: Stroke or TIA within last 6-12 months
CV Conditions: Arrhythmia
CV Conditions: Peripheral vascular disease
High Risk – Oxygen dependent COPD
Mean Gradient -- Baseline
CV Surgery: CABG
Non-CV Conditions: Liver disease
CV Surgery: PCI
NYHA Class
Moderate or Severe Mitral Regurgitation -- Baseline
CV Surgery: Pacemaker implant
CV Surgery: Carotid endarterectomy / Carotid stent
CHAD Stroke Risk Score (ignoring fibrillation)
CV Surgery: Prior aortic valvuloplasty
High Risk – Porcelain Aorta
Aortic Valve Area -- Baseline
High Risk – Radiation
High Risk – Pulmonary Hypertension
Aortic Valve Baseline: AV Annulus Diameter (cm)
CV Surgery: Peripheral bypass graft
Other vascular stent of PTA (arterial)
Logistic EuroSCORE
CV Conditions: Coronary artery Disease
Ejection Fraction -- Baseline
CV Conditions: Previous Q wave or non-Q wave MI
CV Risk Factors: Diabetes Mellitus
Age at Screening (years)
Patient has Coronary Artery Stenosis> 50%?
CV Risk Factors: Pulmonary Hypertension
Atrial Fibrillation -- per ecg corelab
High Risk – Renal Failure
Gender
Baseline Creatinine
CV Conditions: Cerebrovascular disease
Non-missing
observations
Log hazard
ratio
P value
179
179
179
179
178
179
170
179
178
179
179
171
179
179
179
179
179
166
179
118
150
179
179
179
179
172
177
179
179
179
179
156
116
179
179
175
-0.0489
0.0424
1.1563
0.4236
0.4050
0.3709
-0.0108
-0.2927
0.5803
-0.3039
0.2010
-0.3166
0.2759
-0.4219
0.1156
-0.2697
-0.2248
-0.4680
-0.2441
0.1332
-0.2411
-0.4089
0.2369
0.0022
-0.0826
-0.0030
-0.0935
0.0758
0.0033
0.0530
-0.0429
0.0479
-0.0737
0.0229
0.0198
0.0075
0.0061
0.0125
0.0128
0.0447
0.0586
0.1232
0.1713
0.2006
0.2087
0.2207
0.2377
0.2530
0.2670
0.2831
0.3578
0.4040
0.4138
0.4334
0.5347
0.6035
0.6354
0.6843
0.6873
0.7072
0.7074
0.7102
0.7281
0.7307
0.7851
0.7990
0.8383
0.8606
0.8872
0.9124
0.9328
0.9740
Hazard ratio
Lower
confidence
limit
Upper
confidence
limit
0.952
1.043
3.178
1.527
1.499
1.449
0.989
0.746
1.787
0.738
1.223
0.729
1.318
0.656
1.123
0.764
0.799
0.626
0.783
1.142
0.786
0.664
1.267
1.002
0.921
0.997
0.911
1.079
1.003
1.054
0.958
1.049
0.929
1.023
1.020
1.008
0.920
1.009
1.279
1.010
0.985
0.904
0.974
0.477
0.723
0.454
0.876
0.423
0.810
0.303
0.877
0.405
0.466
0.194
0.362
0.691
0.290
0.093
0.400
0.991
0.598
0.981
0.538
0.701
0.980
0.701
0.635
0.615
0.336
0.681
0.644
0.642
0.986
1.079
7.901
2.310
2.281
2.322
1.005
1.168
4.415
1.200
1.707
1.254
2.145
1.417
1.436
1.439
1.369
2.020
1.693
1.889
2.129
4.770
4.017
1.014
1.417
1.013
1.543
1.660
1.027
1.586
1.446
1.791
2.570
1.538
1.616
1.582
Proportional Hazard Analysis of
Predictors of Death
Multivariable Analysis
Label
Parameter
Estimate
p
Hazard
Ratio
95% Upper 95% Lower
Confidence Confidence
Limit
Limit
Body Mass Index (lbs/in²)
-0.05032
0.0050
0.951
0.985
0.918
Stroke or TIA within last 6-12 months
1.09824
0.0194
2.999
7.530
1.194
High Risk - Oxygen dependent COPD
0.52611
0.0310
1.692
2.730
1.049
47
All Cause Mortality vs BAV
Standard Rx: BAV
Standard Rx: No BAV
Death Incidence (%)
TAVR
Months
Numbers at Risk
TAVR
Standard Rx: BAV
179
142
138
105
124
74
110
54
83
37
47
18
14
5
Standard RX: No BAV
39
18
13
10
7
2
1
48
All Stroke Plus TIA (ITT)
Standard Rx
Incidence (%)
TAVR
HR [95% CI] =
3.1 [1.41, 6.83]
p (log rank) = 0.003
∆ at 1 yr = 6.4%
NNT = 15.6 pts
Point-in-Time at 2 Yrs:
p = 0.0029
∆ at 2 yr = 10.7%
NNT = 9.3 pts
16.2%
11.9%
5.5%
5.5%
Months
Numbers at Risk
TAVR
Standard Rx
49
179
179
127
118
115
84
103
62
76
42
Mortality Stratified by Stroke (ITT)
TAVR (no stroke)
Standard Rx (no stroke)
Death Incidence (%)
TAVR (stroke)
Standard Rx (stroke)
Months
Numbers at Risk
TAVR (stroke)
Standard Rx (stroke)
TAVR (no stroke)
25
8
154
16
4
122
14
1
110
10
0
100
7
0
76
Standard Rx (no stroke)
171
117
84
62
42
50
Paravalvular Regurgitation: TAVR
Slight Changes Over Time
1%
0%
4%
1%
12%
11%
35%
30%
46%
42%
66%
52%
30 Day
51
1 Year
2 Year
None/Trace
Moderate
Mild
Severe
Cardiovascular Mortality Stratified by First
PV Leak (ITT)
Starting at Discharge
Moderate or Severe
Determination of first PV Leak
starts with the discharge echo
Death Incidence (%)
None to Mild
p (log rank) = 0.381
∆ at 1 yr = 14.4%
NNT = 6.9 pts
36.7%
30.3%
15.9%
∆ at 2 yr = 9.7%
NNT = 10.3 pts
27.0%
Months
Numbers at Risk
None to Mild
Moderate or Severe
52
147
17
118
12
107
11
95
10
72
8
Echocardiography
Baseline
TAVR
n = 179
Standard Rx
n = 179
p value
Aortic valve area (cm2)
0.6 ± 0.2
0.7 ± 0.2
0.6077
Mean AV gradient (mm Hg)
44.2 ± 14.9
43.0 ± 15.1
0.4608
Mean LVEF (%)
53.7 ± 13.1
51.3 ± 14.2
0.1135
Aortic valve area (cm2)
1.6 ± 0.5
0.7 ± 0.3
<0.0001
Mean AV gradient (mm Hg)
10.9 ± 5.5
44.4 ± 15.7
<0.0001
Mean LVEF (%)
57.3 ± 9.9
57.1 ± 10.2
0.8924
Aortic valve area (cm2)
1.6 ± 0.5
0.7 ± 0.2
<0.0001
Mean AV gradient (mm Hg)
10.6 ± 4.4
41.9 ± 20.7
<0.0001
Mean LVEF (%)
57.3 ± 8.2
56.3 ± 11.1
0.6387
1 Year
2 Year
53
Cross-Over Patients
Mean
Std
Dev.
Min
Max
Days from ITT to cross-over
699.5
166.5
462.0
979.0
Days from cross-over start to
cross-over
73.9
72.6
0
248.0
Days from 1 year visit to
cross-over
334.2
164.8
117.0
595.0
n = 20
54
Cross-Over approved: May 28, 2010
Patients Status
Did Not Cross-Over
Frequency Percent
Died after cross-over process started*
12
7.55
Died before cross-over process started
116
72.96
No cross-over – still alive
23
14.47
Withdrew after cross-over process started
3
1.89
Withdrew before cross-over process started
5
3.14
*Days from cross-over start to death
N
Mean
Std Dev
12
200.3
120.5
55
Minimum
30.0
Maximum
388.0
121 patients could not cross over (116 died, 5 withdrawn)
38/58 (65%) who could have crossed over did not of which 23 (39.6%) are alive
Patient Status
After Cross-Over
Frequency
Percent
Alive – no implant due to access issues
2
10
Alive after implant
16
80
Died after implant
2
10
56
Mean follow-up as of analysis date = 197 days