1. 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

2. Presenter Disclosure Information for PARTNER Trial, AATS May, 2011 D
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:

3. 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

4. The PARTNER Trial Study Design
Symptomatic Severe Aortic Stenosis
ASSESSMENT: High-Risk AVR Candidate
3,105 Total Patients Screened
Total = 1,057 patients
2 Parallel Trials: Individually Powered
N = 699
N = 358
High Risk
Inoperable
Standard
Therapy
ASSESSMENT: Transfemoral Access
Not In Study
TF TAVR
Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)
1:1 Randomization VS
Yes No
N = 179

5. All-cause mortality (%)
PARTNER cohort B (inoperable) All-Cause Mortality at 1 Year
HR [95% CI] = 0.54 [0.38, 0.78]
P (log rank) <
Standard Rx
TAVI
∆ at 1 yr = 20.0% NNT = 5.0 pts
50.7%
30.7%
All-cause mortality (%)
Months
Numbers at Risk
TAVR
179
138
122 67 26
Standard Rx
121 83 41 12 5

6. Neuro events at 30 days and 1 year- Inoperable cohort B
Major Stroke
P = 0.06
P = 0.18
All Stroke or TIA
P = 0.03
P = 0.04
TAVR (n=179)
Standard Rx (n=179)
per cent

7. The PARTNER Study Design
Symptomatic Severe Aortic Stenosis
ASSESSMENT: High-Risk AVR Candidate
3,105 Total Patients Screened
N = 179
N = 358
Inoperable
Standard
Therapy
ASSESSMENT: Transfemoral Access
Not In Study
TF TAVR
Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority)
1:1 Randomization VS
Yes No
Total = 1,057 patients
High Risk
N = 699
2 Parallel Trials: Individually Powered
ASSESSMENT: Transfemoral Access
Transapical (TA)
Transfemoral (TF)
1:1 Randomization
Yes No
TF TAVR
AVR
Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority)
TA TAVR VS
N = 248
N = 104
N = 103
N = 244

8. Transfemoral (TF) and Transapical (TA)
TAVR
Transfemoral (TF) and Transapical (TA)
Transfemoral
Transapical

9. PARTNER cohort A All-Cause Mortality at 1 Year
HR [95% CI] = 0.93 [0.71, 1.22]
P (log rank) = 0.62
0.5
TAVR
AVR
0.4
26.8
0.3
0.2
24.2
0.1 6 12 18 24
No. at Risk
Months
TAVR
348
298
260
147 67
351
252
236
139 65
AVR

10. All neurological events at 30 days and 1 year PARTNER Cohort A Trial (ITT)
TAVR
AVR
P=0.04
All neuro events (%)
P=0.04
Smith CR, ACC 2011, NEJM in press

11. 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)

12. Patient characteristics (AT)
Transapical Stratum
Transfemoral Stratum
Variable
AVR (n = 92)
TA-TAVR (n = 104)
AVR (n = 221)
TF-TAVR (n = 240)
Age (years) (± 1 SD)
83 ± 6
83 ± 7
85 ± 7
84 ± 7
STS risk Score (± 1 SD)
12.1 ± 3.5
11.7 ± 3.6
11.5 ± 3.3
11.9 ± 3.2
Logistic EuroSCORE (± 1 SD)
30 ± 15
30 ± 16
29 ± 15
29 ± 17
NYHA class III-IV
96%
92%
95%
Carotid endarterectomy / stent
17%
24% 6%
10%
Stroke or TIA within last 6-12 mo 7% 1% 4%
Previous CABG
56%
50%
40%
Coronary artery disease
84%
75%
Previous MI
38%
28%
26%
27%
Cerebrovascular disease
31%
43%
Peripheral vascular disease
62%
63%
35%
COPD
64%
65%
Pulmonary hypertension
42%
53%
55%
54%
Atrial fibrillation
21%
32%
23%
Mean aortic valve gradient (mmHg)
41 ± 13
42 ± 14
45 ± 15
43 ± 15
Aortic Valve Area Index (cm2/m2)
0.4 ± 0.1
0.3 ± 0.1
LV ejection fraction (%)
54 ± 11
54 ± 12
54 ± 13
52 ± 14

13. One year results (AT, n= 657)
Transapical Stratum
Transfemoral Stratum
Outcome at 1 year
AVR (n = 92)
TA-TAVR (n = 104)
AVR (n = 221)
TF-TAVR (n = 240)
P-value
All-cause mortality
25%
29%
21%
.33
All neurological events
9.7%
14.1%
1.9%
6.1%
0.03
Major stroke
5.9%
9.4%
1.4%
3.5%
.15
Minor stroke
1.1%
1.0% 0%
0.8%
.16
TIA
3.9%
3.7%
0.6%
1.8%
.25

14. Distribution of types of neurological events
47 patients, 49 neuro events
Ischemic- 72%, hemorrhagic- 0%,
ischemic evolving to hemorrhagic- 4%, unknown- 24%

15. Timing of neurological events AVR
TAVR
AVR
TAVR
AVR
TAVR
AVR
TAVR
AVR
TAVR
AVR
TAVR
AVR
TAVR
0-2
days
3-5
days
6-10
days
11-30
days
31-364
days
1-2
years
2-3
years

16. Risk Factors for Neurologic Events
Multiphase, multivariable non-proportional hazard analysis
Early high peaking hazard phase
Later constant hazard phase

17. Incremental risk factors for neurologic events
Early high peaking hazard phase
Risk Factor
Coefficient ± SD P
R (%)
Early hazard phase
TAVR
2.21±0.68
.001 59
Smaller AVA index in TAVR group
-11.8±5.1
.02 57
Atrial fibrillation not significant
in multivariable analysis
R(%) = bagging reliability

18. Early hazard of neurologic event
TAVR
%/mo
AVR
Figure 1a
Months after Procedure

19. Neurologic event- TF candidate%
7.4
TAVR
AVR
6.0
Figure 4f
2.4
3.4
Mos
54 51
106 99
TAVR AVR

20. Neurologic event- TA candidate
TAVR 12 %
AVR
Figure 4i 10
Mos
26 27
64 60
76 67
102 92
TAVR AVR

21. Neurologic event by 1 mo Influence of smaller AVA index
TAVR
Candidate % TA
Figure 5c TF
AVAI (cm2/m2)

22. Incremental risk factors for neurologic events
Late constant hazard phase
Risk Factor
Coefficient ± SD P
R (%)
Constant hazard phase
TAVR
0.40±0.43
0.4 22
(Higher) NYHA
0.95±0.40
.02 75
Stroke or TIA within 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
R(%) = bagging reliability

23. Non-TF candidate differentiation
TF stratum
TA stratum
Female
PVD
CEA
Figure 9a
CABG 20 40 60 80
100 %

24. Later hazard- assigned stratum (TAVR and AVR combined)
Candidate TA
Figure 2c TF
Months after Procedure

25. TAVR neurologic event by stratum
Candidate TA % 12 TF
Figure 4c
7.4
6.0
Mos 54
106 26
179 64
203 76
TAVR-TF
TAVR-TA

26. AVR neurologic event by stratum
Candidate % 10 TA
Figure 4d
3.4 TF
2.4
Mos 51
99 27
159 60
170 67
221 92 TF TA

27. Major Stroke Small number of events n= 29
Conservative definition (modified Rankin score ≥2)
If stroke severity unclear, categorized as major

28. Major stroke (18 TAVR, 11 AVR)
6.1
TAVR
4.8 %
4.5
2.6
Figure 7b
AVR
Mos
63 59
TAVR AVR

29. Competing Risks of Death and Neurologic Events

30. Months after Procedure
Competing risks
AVR
Alive w/o neuro event %
Death before neuro event
Figure 6c
Neuro event
Months after Procedure

31. % Neurologic event Considering competing risks AVR-TA 12 TAVR-TA 9.1
6.5
5.5
TAVR-TF
AVR-TF
2.2
2.6 67 59
114 32
106 18
179 64
160 62
202 77
170
221 92
TAVR-TF
TAVR-TA AVR-TF
AVR-TA

32. “Mortality Cost” of a Neurologic Event

33. “Mortality Cost” of neuro event
AVR
Hazard
Ratio
Observed/Expected
Figure 8c
Months after Neurologic Event

34. “Mortality Cost” of neuro event
TAVR-TF
Hazard
Ratio
Observed/Expected
Figure 8f
Months after Neurologic Event

35. “Mortality Cost” of neuro event
TAVR-TA
Hazard
Ratio
Observed/Expected
Figure 8i
Months after Neurologic Event

36. 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
TF AVR= 8.2% TAVR= 3.7% p= 0.05
Prospective, independently adjudicated 30 day neurological event rates (stroke and TIA) were low
AVR= 2.6% TAVR= 5.6% p= .05
TF AVR= 1.4% TAVR= 4.6% p= .04
Major stroke rates at 30 days were even lower
AVR= 2.3% TAVR= 3.8% p= .25
TF AVR= 1.4% TAVR= 2.5% p= .37

37. Incremental risk factors for neurological events
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

38. 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

39. 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

40. 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

41. Thank You

42. BACK-UP

43. 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)

44. Brain DWMRI after TAVR
J Am Coll Cardiol 2010;55:1427–32

45. Brain DWMRI after TAVR Valve New MRI lesions Stroke Ghanem CoreValve
73%
10%
Knipp
SAPIEN
58% 4%
Kahlert
Both
84% 0%
Astarci
91%
Rodés-Cabau, Webb
68%
3.3%

46. 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

47. The PARTNER Trial Cohort A Death and Stroke (As Treated) n= 657
Transfemoral (TF) Substrate
30 Days
1 Year
TF AVR (n=221)
TF TAVR (n=240)
P value
TF AVR (n=103)
TF TAVR n=104
Death
18 (8.2)
9 (3.7)
0.05
55 (25.2)
51 (21.3)
0.33
Stroke or TIA
All
3 (1.4)
11 (4.6)
0.04
4 (1.9)
14 (6.1)
0.03
TIA
0 (0.0)
3 (1.3)
0.08
1 (0.6)
4 (1.8)
0.25
Stroke
Minor
2 (0.8)
0.16
Major
6 (2.5)
0.37
8 (3.5)
0.15

48. The PARTNER Trial Cohort A Death and Stroke (As Treated) n= 657
Transapical (TA) Substrate
30 Days
1 Year
TA AVR (n=92)
TA TAVR (n=104)
P value
TA AVR (n=92)
TA TAVR n=104
Death
7 (7.6)
9 (8.7)
0.79
23 (25.3)
30 (29.1)
0.55
Stroke or TIA
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
Stroke
Minor
1 (1.0)
0.95
Major
4 (4.4)
7 (7.0)
0.45
5 (5.9)
9 (9.4)

49. 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.

50. % Mos Neurologic event 11 TAVR 8.0 6.7 AVR 4.5 58 58 130 125 243 218
Figure 1d
Mos
58 58
TAVR AVR

51. Neurological Events at 30 Days and 1 Year All Cohort A Patients N=699, ITT (not AT)
30 Days
1 Year
Outcome
TAVR (N = 348)
AVR (N = 351)
All Stroke or TIA – no. (%)
19 (5.5)
8 (2.4)
0.04
27 (8.3)
13 (4.3)
TIA – no. (%)
3 (0.9)
1 (0.3)
0.33
7 (2.3)
4 (1.5)
0.47
All Stroke – no. (%)
16 (4.6)
0.12
20 (6.0)
10 (3.2)
0.08
Major Stroke – no. (%)
13 (3.8)
7 (2.1)
0.20
17 (5.1)
0.07
Minor Stroke – no. (%)
0.34
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
p-value
p-value
Smith CR, ACC 2011, NEJM in press