1. Vinod H. Thourani, MD on behalf of The PARTNER Trial Investigators
SAPIEN 3 Transcatheter Aortic Valve Replacement Compared with Surgery in Intermediate-Risk Patients: A Propensity Score Analysis
Vinod H. Thourani, MD on behalf of The PARTNER Trial Investigators
ACC 2016 | Chicago | April 3, 2016

2. Disclosure Statement of Financial Interest
Vinod H. Thourani, MD
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship
Company
Grant/Research Support
Consulting Fees/Honoraria
Major Stock Shareholder/Equity
Boston Scientific, Claret Medical, Edwards Lifesciences, Medtronic, St. Jude Medical
Abbott Vascular, Edwards Lifesciences, St. Jude Medical
None

3. Background
The 3rd generation SAPIEN 3 transcatheter heart valve has demonstrated improved clinical outcomes in high-risk patients at 1 year.
The 30-day outcomes in intermediate-risk patients treated with SAPIEN 3 in PARTNER 2 were…
All-cause Mortality: 1.1%
Disabling Stroke: 1.0%
PVL > Moderate: 3.8%
There is a paucity of longer-term data in intermediate-risk patients with SAPIEN 3 and there have been no rigorous comparisons with surgery in intermediate-risk patients.

4. Purpose
To evaluate the 1-year clinical and echo outcomes of SAPIEN 3 TAVR in intermediate-risk patients.
To compare these intermediate-risk patient outcomes using SAPIEN 3 TAVR with surgery results in similar intermediate-risk patients from the PARTNER 2A trial using a rigorous pre-specified propensity score analysis.

5. The PARTNER 2A and S3i Trials Study Design
Intermediate Risk Symptomatic Severe Aortic Stenosis
Intermediate Risk ASSESSMENT by Heart Valve Team
P2 S3i
n = 1078
ASSESSMENT: Optimal Valve Delivery Access
TA/TAo TAVR
SAPIEN 3
Transapical /
Transaortic (TA/TAo)
TF TAVR
Transfemoral (TF)
P2A
n = 2032
ASSESSMENT: Transfemoral Access
Transapical /
TransAortic (TA/TAo)
Transfemoral (TF)
1:1 Randomization
Yes No
TF TAVR SAPIEN XT
Surgical AVR VS
TA/Tao TAVR
SAPIEN 3

6. The PARTNER 2A and S3i Trials Study Design
Intermediate Risk Symptomatic Severe Aortic Stenosis
Intermediate Risk ASSESSMENT by Heart Valve Team
TF TAVR
SAPIEN 3
TA/TAo TAVR
P2 S3i
n = 1078
ASSESSMENT: Optimal Valve Delivery Access
Transapical /
Transaortic (TA/TAo)
Transfemoral (TF)
Surgical AVR
P2A
n = 2032
ASSESSMENT: Transfemoral Access
Transapical /
TransAortic (TA/TAo)
Transfemoral (TF)
1:1 Randomization
Yes No
TF TAVR SAPIEN XT VS
TA/Tao TAVR
SAPIEN 3
Primary Endpoint: All-Cause Mortality, All Stroke, or Mod/Sev AR at One Year (Non-inferiority Propensity Score Analysis)

7. SAPIEN Platforms in PARTNER Device Evolution
Valve
Technology
SAPIEN
SAPIEN XT
SAPIEN 3
Sheath
Compatibility
Available
Valve Sizes
23 mm
26 mm
20 mm
29 mm
22-24F
16-20F
14-16F
29 mm
23 mm
26 mm

8. The PARTNER 2A and S3i Trials Inclusion Criteria
• Severe AS: Echo-derived AVA ≤ 0.8 cm2 (or AVA index < 0.5 cm2/m2) and mean AVG > 40 mmHg or peak jet velocity > 4.0 m/s
• Cardiac Symptoms: NYHA Functional Class ≥ II
Intermediate Risk:
Determined by a multi-disciplinary Heart Team
Using a guideline STS between 4-8%*, and
Adjudicated by case review committee
* PARTNER 2A used guideline STS ≥ 4%

9. The PARTNER 2A and S3i Trials Key Exclusion Criteria
Anatomic:
Aortic annulus diameter < 18 mm or > 28 mm (echo or CT)
Bicuspid AV or predominant AR (> 3+)
Severe LV dysfunction (LVEF < 20%)
Untreated CAD requiring revascularization with either unprotected LM coronary disease or Syntax score > 32
Pre-existing surgical valve in any position
Clinical:
Serum Cr > 3.0 mg/dL or dialysis dependent
Acute MI within 1 month
CVA or TIA within 6 months
Hemodynamic instability
Life expectancy < 24 months

10. The PARTNER 2A and S3i Trials Primary Endpoint
Non-hierarchical composite of all-cause mortality, all stroke, or ≥ moderate aortic regurgitation at one year
Propensity score analysis of the valve implant (VI) populations from S3i compared to the surgical arm of the PARTNER 2A trial
All patients followed for at least 1 year
Event rates by Kaplan-Meier estimates
Non-inferiority trial design followed by superiority testing for the primary endpoint and components

11. Other Important Endpoints VARC 2 Definitions
SAFETY
EFFICACY
Cardiac mortality
Major vascular complications
All strokes and TIAs
Repeat hospitalizations
Peri-procedural MIs
Acute kidney injury
Life-threatening or disabling bleeding
New permanent pacemakers
New onset atrial fibrillation
Repeat AV intervention
Endocarditis
NYHA class
QOL instruments
6-minute walk test
Days alive out-of-hospital
ICU and index hospital LOS
ECHO VALVE PERFORMANCE
Mean AV gradient
Effective orifice area (and index)
LV function (ejection fraction)
Paravalvular AR

12. Study Methodology
Every patient reviewed (including imaging studies) by multi-disciplinary Heart Team AND case review committee
Systematic assessment by neurologists before and after index procedures for ascertainment of neurologic events
MDCT evaluation of annulus dimensions for all TAVR S3i patients (with core laboratory analyses)
In patients with CAD requiring revascularization: treatment (PCI or CABG) allowed (unless unprotected left main disease or Syntax score > 32) at the discretion of the Heart Team
CEC adjudication of major clinical events (VARC 2 definitions whenever possible)

13. Baseline Patient Characteristics Demographics (AT)
TAVR
(n = 1077)
Surgery
(n = 944)
p-value
Age - yrs
81.9 ± 6.6
81.6 ± 6.8
0.23
Male - %
61.7
55.0
0.002
BMI - kg/m2
28.7 ± 6.1
28.4 ± 6.2
0.32
Median STS Score - %
5.2 [4.3, 6.3]
5.4 [4.4, 6.7]
0.0002
NYHA Class III or IV - %
72.5
76.1
0.07
mean ± SD, median [IQR]

14. Baseline Patient Characteristics Other Co-morbidities (AT)
TAVR
(n = 1077)
Surgery
(n = 944)
p-value
CAD
69.6
66.5
0.14
Previous CABG
27.9
25.7
0.27
Cerebrovascular Disease
9.0
10.3
0.36
PVD
28.2
32.2
0.05
COPD
30.0
30.2
0.92
Cr level > 2 mg/dL
7.5
5.4
0.06
Atrial Fibrillation
36.0
34.9
0.61
Permanent Pacemaker
13.2
12.0
0.42
15 ft Walk Test > 7s
41.3
45.7

15. Statistical Analysis Plan - 1
Pre-specified propensity score analysis of SAPIEN 3 TAVR vs. P2A surgery for the composite primary endpoint (all- cause mortality, all stroke, or total AR ≥ moderate at 1 year).
The analysis incorporated 22 pre-specified baseline characteristics that were factored through a logistic regression into a propensity score.
Patient population was divided into quintiles based on propensity scores.
Quintile stratification (unlike patient matching) allows for the use of data from all patients, minimizing selection bias.

16. Statistical Analysis Plan - 2
The primary hypothesis was non-inferiority of SAPIEN 3 vs. surgery from P2A for the primary endpoint at 1 year.
Non-inferiority:
One-sided alpha: 0.05
Hypothesis testing: upper bound of the one-sided 95% CI of the primary weighted difference of proportions endpoint (weighted avg test - control) < 7.5%
Superiority:
Two-sided alpha: 0.05
Hypothesis testing: upper or lower bound of the two-sided 95% CI of the primary weighted difference of proportions endpoint (weighted avg test - control) < 0 for TAVR and > 0 for surgery

17. Quintile Propensity Score Analysis: Primary Endpoint
Surgery
TAVR
# Patients
Mortality, Stroke, AR > Mod
191
28.3%
138
13.8%
Proportional
Difference
-14.5%
Weighting
0.14
175
22.9%
171
9.9%
-12.9%
0.18
147
19.7%
197
10.7%
147
19.7%
197
10.7%
-9.1%
-9.1%
0.20
0.20
126
23.0%
219
14.6%
-8.4%
0.23
108
19.4%
238
15.1%
-4.3%
0.25
Overall weighted difference of proportions
- 9.2%
[-12.4%,-6.0%] two-sided 90% CI

18. Primary Endpoint - Non-inferiority Death, Stroke, or AR ≥ Mod at 1 Year (VI)
Weighted Difference %
Upper 1-sided 95% CI -6.0%
Non-Inferiority p-value < 0.001
Pre-specified non-inferiority margin = 7.5%
-10 -8 -6 -4 -2 2 4 6 8 10
Favors TAVR
Favors Surgery
Primary Non-Inferiority Endpoint Met

19. Weighted Difference -9.2% Superiority Testing p-value < 0.001
Primary Endpoint - Superiority Death, Stroke, or AR ≥ Mod at 1 Year (VI)
Weighted Difference %
Upper 2-sided 95.0% CI -5.4%
Superiority Testing p-value < 0.001
-10 -8 -6 -4 -2 2 4 6 8 10
Favors TAVR
Favors Surgery
Superiority Achieved

20. Superiority Analysis Components of Primary Endpoint (VI)
Favors TAVR
Favors Surgery
Weighted Difference %
Upper 2-sided 95% CI -2.4%
Superiority Testing p-value < 0.001
Mortality
-10 -8 -6 -4 -2 2 4 6 8 10
Weighted Difference %
Upper 2-sided 95% CI -1.1%
Superiority Testing p-value = 0.004
Stroke
-10 -8 -6 -4 -2 2 4 6 8 10
Weighted Difference %
Lower 2-sided 95% CI +0.2%
Superiority Testing p-value =
AR > Moderate
-10 -8 -6 -4 -2 2 4 6 8 10

21. Unadjusted Clinical Events At 30 Days and 1 Year (AT)
TAVR
Surgery
Death
All-cause
1.1
4.0
7.4
13.0
Cardiovascular
0.9
3.1
4.5
8.1
Neurological Events
Disabling Stroke
1.0
4.4
2.3
5.9
All Stroke
2.7
6.1
4.6
8.2
All-cause Death and Disabling Stroke
2.0
8.0
8.4
16.6

22. Unadjusted Time-to-Event Analysis All-Cause Mortality and All Stroke (AT)10 20 30 40
P2A Surgery
SAPIEN 3 TAVR
18.8%
All-Cause Mortality / Stroke Rate (%)
10.8%
9.7%
3.7% 3 6 9 12
Months from Procedure
Number at risk:
P2A Surgery
944
805
786
757
743
S3 TAVR
1077
1012
987
962
930

23. Unadjusted Time-to-Event Analysis All-Cause Mortality (AT)10 20 30 40
P2A Surgery
SAPIEN 3 TAVR
All-Cause Mortality (%)
13.0%
4.0%
7.4%
1.1% 3 6 9 12
Months from Procedure
Number at risk:
P2A Surgery
944
859
836
808
795
S3 TAVR
1077
1043
1017
991
963

24. Unadjusted Time-to-Event Analysis All Stroke (AT)10 20 30 40
P2A Surgery
SAPIEN 3 TAVR
All Stroke (%)
8.2%
6.1%
4.6%
2.7% 3 6 9 12
Months from Procedure
Number at risk:
P2A Surgery
944
805
786
757
743
S3 TAVR
1077
1012
987
962
930

25. Other Unadjusted Clinical Outcomes At 30 Days and 1 Year (AT)
Events (%)
30 Days
1 Year
TAVR
(n = 1077)
Surgery
(n = 944)
Re-hospitalization
4.6
6.8
11.4
15.1 MI
0.3
1.9
1.8
3.1
Major Vascular Complication
6.1
5.4
---
AKI (Stage III)
0.5
3.3
Life-Threatening/Disabling Bleeding
46.7
New Atrial Fibrillation
5.0
28.3
5.9
29.2
New Permanent Pacemaker
10.2
7.3
12.4
9.4
Re-intervention
0.1
0.0
0.6
Endocarditis
0.2
0.8
0.7

26. Paravalvular Regurgitation 3-Class Grading Scheme (VI)
≥ Moderate
1.5%
Mild
39.8%
No. of echos
30 Days
1 Year
P2A Surgery
755
610
S3i TAVR
992
875

27. The PARTNER 2A and S3i Trials Conclusions - 1
In intermediate-risk patients, SAPIEN 3 TAVR resulted in low 1-year rates of all-cause mortality (7.4%), all stroke (4.6%), and moderate or severe aortic regurgitation (1.5%)

28. The PARTNER 2A and S3i Trials Conclusions - 2
A rigorous propensity score analysis comparing SAPIEN 3 TAVR with surgery from PARTNER 2A in intermediate-risk patients at 1 year demonstrated:
Non-inferiority for the primary endpoint (composite of all-cause mortality, all stroke, or AR ≥ moderate)
Superiority of SAPIEN 3 TAVR for the primary endpoint, all-cause mortality, and all stroke
Superiority of surgery for AR ≥ moderate
Time-to-event analyses indicated that the benefits of SAPIEN 3 TAVR occurred in the first few months, suggesting procedure-related effects

29. The PARTNER 2A and S3i Trial Clinical Implications
The conclusions from the PARTNER 2A randomized trial and this propensity score analysis provide strong evidence that in intermediate-risk patients with severe aortic stenosis, SAPIEN 3 TAVR compared with surgery improves clinical outcomes and is the preferred therapy.

30. The PARTNER 2A and S3i Trial Lancet On-line
Special thanks to the PARTNER sites and patients, the clinical research teams, and the writing group!

31. The PARTNER 2A and S3i Trial Lancet On-line

32. The PARTNER 2A and S3i Trial Lancet On-line