Transcript Neurologic Events

Transcatheter (TAVR) versus Surgical (AVR)
Aortic Valve Replacement: Incidence, hazard,
determinants, and consequences of neurological
events in the PARTNER Trial
The PARTNER Stroke Substudy Writing Group*
On behalf of The PARTNER Trial Investigators and Patients
* Miller DC, Mack MJ, Svensson LG, Kodali SK, Kapadia S, Anderson WN,
Rajeswaran J, Blackstone EH
Presenter Disclosure Information
for PARTNER Trial, AATS May, 2011
D. Craig Miller , M.D.
Affiliation/Financial Relationship Company
Grant/ Research Support:
NHLBI research grant RO1 HL67025
Consulting Fees/Honoraria:
•The PARTNER U.S. Pivotal Trial Executive Committee, Edwards Lifesciences
(uncompensated)
•Stanford PI – The PARTNER Trial, Edwards Lifesciences (uncompensated)
•Consultant, Abbott Vascular (MitraClip)
•Consultant, Medtronic CardioVascular Division
•Consultant, St. Jude Medical
Major Stock Shareholder/Equity Interest:
Royalty Income:
Ownership/Founder:
Salary:
Intellectual Property Rights:
Other Financial Benefit:
Background
 Surgical AVR is the standard of care for
symptomatic aortic stenosis
 Survival after TAVR is superior compared to
medical therapy in inoperable patients, and is
non-inferior to that after AVR in high-risk
operative candidates, but neurological
complications occur more frequently after TAVR
 No randomized trial comparing TAVR and AVR
focusing on neurological events has been
performed
The PARTNER Trial
Study Design
Symptomatic Severe Aortic Stenosis
ASSESSMENT: High-Risk AVR Candidate
3,105 Total Patients Screened
N = 699
High
Risk
Total = 1,057 patients
Inoperable N =
358
2 Parallel Trials:
Individually Powered
ASSESSMENT:
Transfemoral
Access
Yes
No
1:1 Randomization
N = 179
N = 179
TF TAVR
Standard
Therapy
Not In Study
VS
Primary Endpoint: All-Cause Mortality
Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality
and Repeat Hospitalization (Superiority)
PARTNER cohort B (inoperable)
All-Cause Mortality at 1 Year
HR [95% CI] =
0.54 [0.38, 0.78]
P (log rank) < 0.0001
∆ at 1 yr = 20.0%
NNT = 5.0 pts
Standard Rx
All-cause mortality
(%)
TAVI
50.7%
30.7%
Months
Numbers at Risk
TAVR
Standard Rx
179
179
138
121
122
83
67
41
26
12
Neuro events at 30 days and 1
year- Inoperable cohort B
per cent
Major Stroke
P = 0.06
P = 0.18
All Stroke or TIA
P = 0.03
P = 0.04
10.6
6.7
1.7
30 Days
TAVR (n=179)
Standard Rx (n=179)
4.5
1 Year
The 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
Inoperable
2 Parallel Trials:
Individually Powered
ASSESSMENT:
Yes
Transfemoral
Access
Transfemoral (TF)
1:1 Randomization
ASSESSMENT:
No
Transfemoral
Access
Transapical (TA)
1:1 Randomization
Yes
No
1:1 Randomization
N = 244
N = 248
N = 104
N = 103
N = 179
N = 179
TF TAVR
AVR
TA TAVR
AVR
TF TAVR
Standard
Therapy
VS
N = 358
VS
Primary Endpoint: All-Cause Mortality at 1 yr
(Non-inferiority)
Not In Study
VS
Primary Endpoint: All-Cause Mortality
Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality
and Repeat Hospitalization (Superiority)
TAVR
Transfemoral (TF) and Transapical (TA)
Transfemoral
Transapical
PARTNER cohort A
All-Cause Mortality at 1 Year
0.5
HR [95% CI] =
0.93 [0.71, 1.22]
P (log rank) = 0.62
26.8
TAVR
AVR
0.4
0.3
0.2
24.2
0.1
0
0
6
No. at Risk
12
18
24
Months
TAVR
348
298
260
147
67
AVR
351
252
236
139
65
All neurological events
at 30 days and 1 year
PARTNER Cohort A Trial (ITT)
All neuro events (%)
20
TAVR
10
5.5
P=0.04
AVR
8.3
P=0.04
4.3
2.4
0
30 Days
1 Year
Smith CR, ACC 2011, NEJM in press
Purpose
• Analyze stroke and TIA after TAVR and surgical AVR
in high-risk (≈15%, floor= STS 8-9%), operable patients
with symptomatic, severe aortic stenosis in the
PARTNER Trial
• “As Treated” (AT) patients n= 657 (vs. ITT)
• Captured all neurological events at all times
• Prospective, independent, blinded adjudication of
adverse neurological events by CEC, supplemented by
CEC retrospective assessment of stroke severity
• Unblinded re-review of all CEC summaries and source
documents by 2 investigators (DCM, MJM)
Patient characteristics (AT)
Transapical Stratum
Variable
Age (years) (± 1 SD)
STS risk Score (± 1 SD)
Logistic EuroSCORE (± 1 SD)
NYHA class III-IV
Carotid endarterectomy / stent
Stroke or TIA within last 6-12 mo
Previous CABG
Coronary artery disease
Previous MI
Cerebrovascular disease
Peripheral vascular disease
COPD
Pulmonary hypertension
Atrial fibrillation
Mean aortic valve gradient
(mmHg)
Aortic Valve Area Index (cm2/m2)
LV ejection fraction (%)
Transfemoral Stratum
AVR
TA-TAVR
AVR
TF-TAVR
(n = 92)
83 ± 6
12.1 ± 3.5
30 ± 15
96%
17%
7%
56%
84%
38%
31%
62%
64%
42%
21%
(n = 104)
83 ± 7
11.7 ± 3.6
30 ± 16
92%
24%
1%
50%
75%
28%
43%
63%
64%
53%
32%
(n = 221)
85 ± 7
11.5 ± 3.3
29 ± 15
95%
6%
1%
40%
75%
26%
26%
35%
65%
55%
26%
(n = 240)
84 ± 7
11.9 ± 3.2
29 ± 17
95%
10%
4%
40%
75%
27%
24%
35%
63%
54%
23%
41 ± 13
42 ± 14
45 ± 15
43 ± 15
0.4 ± 0.1
54 ± 11
0.4 ± 0.1
54 ± 12
0.3 ± 0.1
54 ± 13
0.4 ± 0.1
52 ± 14
One year results (AT, n= 657)
Outcome at 1 year
All-cause mortality
All neurological
events
Major stroke
Minor stroke
TIA
Transapical
Stratum
Transfemoral
Stratum
AVR
TA-TAVR
AVR
TF-TAVR
(n = 92)
25%
(n = 104)
29%
(n = 221)
25%
(n = 240)
21%
P-value
.33
9.7%
14.1%
1.9%
6.1%
0.03
5.9%
1.1%
3.9%
9.4%
1.0%
3.7%
1.4%
0%
0.6%
3.5%
0.8%
1.8%
.15
.16
.25
Distribution of types of
neurological events
47 patients, 49 neuro events
Ischemic- 72%, hemorrhagic- 0%,
ischemic evolving to hemorrhagic- 4%, unknown- 24%
Timing of neurological events
AVR
14
TIA
12
Minor Stroke
10
Major Stroke
8
6
4
AVR
TAVR
6-10
days
AVR
TAVR
3-5
days
AVR
TAVR
AVR
TAVR
0-2
days
AVR
TAVR
AVR
TAVR
0
AVR
TAVR
2
11-30 31-364 1-2 2-3
days days years years
Risk Factors for
Neurologic Events
Multiphase, multivariable non-proportional
hazard analysis
 Early high peaking hazard phase
 Later constant hazard phase
Incremental risk factors for
neurologic events
Early high peaking hazard phase
Coefficient ±
SD
P
R
(%)
TAVR
2.21±0.68
.001
59
Smaller AVA index in
TAVR group
-11.8±5.1
.02
57
Risk Factor
Early hazard phase
Atrial fibrillation not significant
in multivariable analysis
R(%) = bagging reliability
Early hazard of neurologic event
80
TAVR
60
%/mo
40
20
0
AVR
.25
.50
.75
1.0
Months after Procedure
Neurologic event- TF candidate
30
TF Candidate
25
20
% 15
10
AVR
6.0
TAVR
7.4
5
0
3.4
2.4
Mos
TAVR 242
AVR 221
6
12
18
24
203
170
179
159
106
99
54
51
Neurologic event- TA candidate
30
TA Candidate
25
TAVR
20
12
% 15
AVR
10
10
5
0
Mos
TAVR 102
AVR
92
6
12
18
76
67
64
60
26
27
24
Neurologic event by 1 mo
Influence of smaller AVA index
20
TAVR
15
Candidate
% 10
TA
5
TF
0.2
0.3
0.4
0.5
AVAI (cm2/m2)
0.6
Incremental risk factors for
neurologic events
Late constant hazard phase
Coefficient ± SD
P
R (%)
0.40±0.43
0.4
22
(Higher) NYHA
0.95±0.40
.02
75
Stroke or TIA within 6-12 mo
1.93±0.64
.002
60
Non-TF TAVR candidate
2.3±0.45
<.0001
96
History of PCI (less risk)
-1.60±0.63
.01
77
COPD (less risk)
-1.06±0.47
.03
79
Risk Factor
Constant hazard phase
TAVR
R(%) = bagging reliability
Non-TF candidate differentiation
TF stratum
TA stratum
Female
PVD
CEA
CABG
0
20
40
60
%
80
100
Later hazard- assigned stratum
(TAVR and AVR combined)
4
3
%/m 2
1
Candidate
TA
TF
0
6
12
18
Months after Procedure
24
TAVR neurologic event
by stratum
30
TAVR
25
Candidate
TA
20
% 15
12
10
TF
5
0
7.4
6.0
Mos
TAVR-TF 242
TAVR-TA 102
6
12
18
203
76
179
64
106
26
24
54
AVR neurologic event
by stratum
30
AVR
25
Candidate
20
10
TA
2.4
TF
6
12
18
24
170
67
159
60
99
27
51
% 15
10
5
0
TF
TA
Mos
221
92
3.4
Major Stroke
Small number of events n= 29
Conservative definition (modified Rankin score ≥2)
If stroke severity unclear, categorized as major
Major stroke (18 TAVR, 11 AVR)
10
8
%
6
4.8
4
4.5
2.6
2
0
TAVR
6.1
AVR
Mos
TAVR 344
AVR 313
6
12
18
24
284
239
252
222
137
128
63
59
Competing Risks of
Death and Neurologic Events
Competing risks
100
Alive w/o neuro event
AVR
80
%
60
40
20
0
Death before neuro event
Neuro event
6
12
18
Months after Procedure
24
Neurologic event
25 Considering
20 competing risks
%
15
TAVR-TA
10
5
0
TAVR-TF
TAVR-TA
AVR-TF
240
104
221
AVR-TA
12
9.1
6.5
TAVR-TF
5.5
AVR-TF
2.6
2.2
6
202
12
179
77
170
64
160
18
114
32
106
18
24
67
59
“Mortality Cost” of a Neurologic
Event
“Mortality Cost” of neuro event
8
AVR
6
Hazard
Ratio
4
Observed/Expected
2
0
3
6
9
12
Months after Neurologic Event
“Mortality Cost” of neuro event
8
TAVR-TF
6
Hazard
Ratio
4
Observed/Expected
2
0
3
6
9
12
Months after Neurologic Event
“Mortality Cost” of neuro event
8
TAVR-TA
6
Hazard
Ratio
4
Observed/Expected
2
0
3
6
9
12
Months after Neurologic Event
Conclusions
• Remarkably low 30 day mortality rates in these
elderly, very high-risk AS patients in both arms of study
AVR= 8% (O:E= 0.68) TAVR= 5.2% (O:E= 0.42) p= .15
TFAVR= 8.2%
TAVR= 3.7% p= 0.05
• Prospective, independently adjudicated 30 day
neurological event rates (stroke and TIA) were low
TF-
AVR= 2.6%
AVR= 1.4%
TAVR= 5.6% p= .05
TAVR= 4.6% p= .04
• Major stroke rates at 30 days were even lower
TF-
AVR= 2.3%
AVR= 1.4%
TAVR= 3.8%
TAVR= 2.5%
p= .25
p= .37
Conclusions
Incremental risk factors for neurological events
• Early peaking high hazard phase:
TAVR
Smaller AVA index (TAVR group only)
• Later constant hazard phase:
Generalized heavy arteriosclerotic burden
(“non-TF TAVR candidate”)
Stroke/TIA within 6-12 months
Higher NYHA class
Conclusions
• Higher observed incidence of neurological
events in the “non-TF candidate” stratum
reflected the patient substrate, and was not
related to the TA-TAVR or AVR procedures per
se
Conclusions
• Taking competing hazard of death into
consideration, the likelihood of a neurologic event
was lowest in AVR patients and highest in TA-TAVR
group
• A neurologic event raised the risk of mortality
• In AVR group: High peak, quickly returning to
baseline hazard
• In TAVR groups: After initial peak, risk remained
elevated throughout the 24 months of follow-up,
particularly in TA stratum
Limitations
• These results can only be interpreted within the
constraints of the PARTNER Trial protocol:
• Carefully controlled patient selection
• Regimented training and proctoring
• Critical case monitoring and review
• Dedicated multi-disciplinary “Heart Valve Team”
in these 26 centers
• “TF first” protocol philosophy and TAVR sheath
sizes available
• Learning curve, first generation TAVR device
• Not adequately powered for TF vs. TA comparison
Thank You
BACK-UP
Inferences
Can TAVR stroke rate be lowered?
EARLY HIGH HAZARD PHASE
• Peri-procedural anticoagulation management
• Clopidogrel load, + dual antiplatelet Rx
• Warfarin or dabigatran Rx
• No protamine reversal (TF)
• Bridge AF patients with heparin
• Cerebral embolic prevention devices
• Newer low profile THV deployment systems
• Carotid compression during BAV, THV deployment
LATE CONSTANT HAZARD PHASE
• More rigorous patient selection (TA)
Brain DWMRI after TAVR
J Am Coll Cardiol
2010;55:1427–32
Brain DWMRI after TAVR
Valve
New MRI
lesions
Stroke
CoreValve
73%
10%
SAPIEN
58%
4%
Kahlert
Both
84%
0%
Astarci
Both
91%
0%
SAPIEN
68%
3.3%
Ghanem
Knipp
Rodés-Cabau,
Webb
Embrella® Embolic Deflector
Initial Vancouver
experience in 4 patients, 3
with TAVI and 1 with BAV
Effectiveness?
Safety?
Nietlispach et al., J Am Coll Cardiol Intv 2010;3:1133– 8
The PARTNER Trial Cohort A
Death and Stroke (As Treated) n= 657
Transfemoral (TF) Substrate
30 Days
TF
AVR
TF TAVR
(n=221) (n=240)
1 Year
P value
TF AVR
(n=103)
TF TAVR
n=104
P
value
Death 18 (8.2)
Stroke or
TIA
All 3 (1.4)
TIA 0 (0.0)
9 (3.7)
0.05
55 (25.2)
51 (21.3)
0.33
11 (4.6)
3 (1.3)
0.04
0.08
4 (1.9)
1 (0.6)
14 (6.1)
4 (1.8)
0.03
0.25
Stroke
Minor 0 (0.0)
Major 3 (1.4)
2 (0.8)
6 (2.5)
0.16
0.37
0 (0.0)
3 (1.4)
2 (0.8)
8 (3.5)
0.16
0.15
The PARTNER Trial Cohort A
Death and Stroke (As Treated) n= 657
Transapical (TA) Substrate
30 Days
TA AVR
(n=92)
P value
TA AVR
(n=92)
TA TAVR
n=104
P value
9 (8.7)
0.79
23 (25.3)
30 (29.1)
0.55
All 5 (5.5)
8 (7.9)
0.50
8 (9.7)
13 (14.1)
0.37
TIA 1 (1.1)
0 (0.0)
0.31
3 (3.9)
3 (3.7)
0.97
Minor 1 (1.1)
1 (1.0)
0.95
1 (1.1)
1 (1.0)
0.95
Major 4 (4.4)
7 (7.0)
0.45
5 (5.9)
9 (9.4)
0.37
Death 7 (7.6)
TA TAVR
(n=104)
1 Year
Stroke or TIA
Stroke
Stroke Definition- The Modified
Rankin Scale
Minor
• 0- No Symptoms
• 1- No significant disability. Able to carry out all
usual activities, despite some symptoms
Major
• 2- Slight disability. Able to look after own affairs
without assistance, but unable to carry out all
previous activities.
• 3- Moderate disability. Requires some help, but
able to walk unassisted.
• 4- Moderately severe disability. Unable to attend to
own bodily needs without assistance, and unable
to walk unassisted.
• 5- Severe disability. Requires constant nursing
care and attention, bedridden, incontinent.
• 6- Dead.
Neurologic event
15
TAVR
10
8.0
%
AVR
6.7
4.5
5
0
11
Mos
TAVR 344
AVR 313
6
12
18
24
278
251
243
218
130
125
58
58
Neurological Events at 30 Days
and 1 Year All Cohort A Patients
N=699, ITT (not AT)
30 Days
TAVR
(N = 348)
Outcome
1 Year
AVR
p-value TAVR
(N = 351)
(N = 348)
AVR
p-value
(N = 351)
All Stroke or TIA – no. (%)
19 (5.5)
8 (2.4)
0.04
27 (8.3)
13 (4.3)
0.04
TIA – no. (%)
3 (0.9)
1 (0.3)
0.33
7 (2.3)
4 (1.5)
0.47
All Stroke – no. (%)
16 (4.6)
8 (2.4)
0.12
20 (6.0)
10 (3.2)
0.08
Major Stroke – no. (%)
13 (3.8)
7 (2.1)
0.20
17 (5.1)
8 (2.4)
0.07
Minor Stroke – no. (%)
3 (0.9)
1 (0.3)
0.34
3 (0.9)
2 (0.7)
0.84
Death/maj stroke – no. (%)
24 (6.9)
28 (8.2)
0.52
92 (26.5)
93 (28.0)
0.68
Smith CR, ACC 2011, NEJM in press