Transcript Two-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in “Inoperable” Patients With Severe Aortic Stenosis: The PARTNER Trial Raj R.

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.
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.
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Background (2)
• 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
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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.
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PARTNER Study Design
Symptomatic Severe Aortic Stenosis
ASSESSMENT: High-Risk AVR Candidate
3,105 Total Patients Screened
Total = 1,057 patients
n = 699
High-Risk
ASSESSMENT:
Transfemoral
Access
Transfemoral
Access
1:1 Randomization
AVR
VS
n = 358
High-Risk TA
1:1 Randomization
TA TAVR
AVR
VS
Primary Endpoint: All-Cause Mortality (1 yr)
(Non-inferiority)
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Inoperable
ASSESSMENT:
High-Risk TF
TF TAVR
2 Parallel Trials:
Individually Powered
1:1 Randomization
TF TAVR
n = 179
VS
Standard
Therapy
n = 179
Primary Endpoint: All-Cause Mortality
Over Length of Trial (Superiority)
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!
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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
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Study Flow
Inoperable Cohort
n = 358
Randomized Inoperable
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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
Statistical Method
• Primary analysis was by “intention-to-treat” (ITT).
• Mortality was estimated by ITT, both with and
without censoring of the cross-over patients
(n = 11 cross-over patients from 1-2 years).
• Clinical outcomes were analyzed by ITT with
censoring of Standard Rx cross-over patients.
• Event rates are given as Kaplan-Meier estimates.
• Core lab echo results are presented from the “as
treated” (AT) cohort.
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Patient Characteristics (1)
TAVR
Standard Rx
n = 179
n = 179
83.1 ± 8.6
83.2 ± 8.3
0.95
45.8
46.9
0.92
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
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
Characteristic
Age – yr
Male sex (%)
STS Score
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p value
Patient Characteristics (2)
TAVR
Standard Rx
n = 179
n = 179
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
0.04
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 (%)
8.4
5.0
0.29
Liver disease (%)
3.4
3.4
1.00
Characteristic
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p value
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
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All Cause Mortality (ITT)
Crossover Patients Censored
Standard Rx
All Cause Mortality (%)
TAVR
HR [95% CI] =
0.56 [0.43, 0.73]
p (log rank) < 0.0001
68.0%
∆ at 1 yr = 20.0%
NNT = 5.0 pts
50.7%
43.3%
30.7%
∆ at 2 yr = 24.7%
NNT = 4.0 pts
Months
Numbers at Risk
TAVR
Standard Rx
14
179
179
138
121
124
85
110
62
83
42
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
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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
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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
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Hospitalization Through 2 Years
Repeat Hospitalizations (No.)
Repeat Hospitalizations (%)
Days Alive Out of Hospital
Median [IQR]
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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 Cerebrovascular Events (%)
8
7
Hemorrhagic CVA
0.6
Ischemic CVA
6
TIA
Events
5
4
6.7
3
2.2
0.6
2
1
1.7
1.1
2.2
1.7
1.1
0.6
0
Standard
Rx
TAVR
Standard
Rx
≤ 30 days
TAVR
31 days- 365 days
Standard
Rx
366- 730 days
Note: Percents are of patients in the trial (n/179).
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TAVR
≤ 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
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
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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
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Clinical Outcomes
1 Year and 2 Year (ITT)
Outcome
1 Year
2 Year
n = 179
n = 179
TAVR
Standard
Rx
P value
0.8 (1)
0.7 (1)
0.906
1.1 (2)
2.3 (4)
2.8 (5)
4.7 (7)
0.449
0.257
TAVR
Standard
Rx
P value
Myocardial infarction
All, % (n)
1.6 (2)
2.5 (2)
0.694
2.8 (5)
7.6 (9)
0.449
0.149
Acute kidney injury
Creatinine > 3 mg/dL, % (n)
Renal failure (CEC), % (n)
Bleeding – major, % (n)
24.2 (42) 14.9 (21)
0.038
1.1 (2)
3.2 (5)
28.9 (48) 20.1 (25)
0.093
Cardiac re-intervention
BAV, % (n)
1.1 (2)
82.3 (138)
<.0001
2.8 (4)
85.3 (140)
<.0001
Re-TAVR, % (n)
1.7* (3)
NA
-
1.7* (3)
NA
-
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)
0.8 (1)
0.316
New pacemaker, % (n)
4.7 (8)
8.6 (14)
0.149
6.4 (10)
8.6 (14)
0.469
AVR, % (n)
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All Cause Mortality (ITT)
Control Patients Alive on First Crossover Date
All Cause Mortality (%)
Crossed-Over
Not Crossed-Over
∆ at 1 yr = 11.0%
21.0%
10.0%
Months past first cross-over
Numbers at Risk
Not Crossed-Over
Crossed-Over
29
38
20
32
19
24
18
17
17
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
Echo Analysis PV Leak Changes
30 Days Compared to 2 Years
Patients With Data at Both Time Points
2 Year
Mild
Moderate
30 Day
None
Trace
Severe
None
10
3
0
0
0
Trace
7
5
6
0
0
Mild
4
7
10
1
0
Moderate
0
4
3
0
0
Severe
0
0
1
0
0
Of the 61 patients alive with data at 2 years:
42.6% Improved
32
41.0% Unchanged
16.4% Progressed
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
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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).
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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.
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Thank You to the Dedicated Study
Teams at All PARTNER
Investigational Sites