1. Raj R. Makkar, MD On behalf of The PARTNER Trial Investigators
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

2. 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.

3. 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

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

5. All Cause Mortality (ITT) Crossover Patients Followed
HR [95% CI] = 0.57 [0.44, 0.75]
p (log rank) <
Standard Rx
TAVR
∆ at 2 yr = 24.3% NNT = 4.1 pts
67.6%
43.3%
∆ at 1 yr = 20.0% NNT = 5.0 pts
50.7%
All Cause Mortality (%)
30.7%
Point-in-time at 2 yrs: p <
Months
Numbers at Risk
TAVR
179
138
124
110 83
Standard Rx
121 85 67 51

6. All Cause Mortality (ITT) Landmark Analysis
Standard Rx
TAVR
Mortality 0-1 yr
Mortality 1-2yr
HR [95% CI] = 0.57 [0.44, 0.75]
p (log rank) <
HR [95% CI] = 0.58 [0.37, 0.92]
p (log rank) =
50.7%
All Cause Mortality (%)
35.1%
30.7%
18.2%
Months
Numbers at Risk
TAVR
179
138
124
110 83
Standard Rx
121 85 62 42

7. Cardiovascular Mortality (ITT) Crossover Patients Censored
Standard Rx
HR [95% CI] = 0.44 [0.32, 0.60]
p (log rank) <
TAVR
∆ at 2 yr = 31.4% NNT = 3.2 pts
62.4%
31.0%
∆ at 1 yr = 24.1% NNT = 4.1 pts
44.6%
Cardiovascular Mortality (%)
20.5%
Point-in-time at 2 yrs: p <
Months
Numbers at Risk
TAVR
179
138
124
110 83
Standard Rx
121 85 62 42

8. Repeat Hospitalization (ITT)
Standard Rx
HR [95% CI] = 0.41 [0.30, 0.58]
p (log rank) <
TAVR
∆ at 2 yr = 37.5% NNT = 2.7 pts
72.5%
35.0%
∆ at 1 yr = 26.9% NNT = 3.7 pts
53.9%
Repeat Hospitalization (%)
27.0%
Point-in-time at 2 yrs: p <
Months
Numbers at Risk
TAVR
179
115
100 89 64
Standard Rx 86 49 30 17

9. Hospitalization Through 2 Years
TAVR
Standard Tx
p value
Repeat Hospitalizations (No.) 78
151
<.0001
Repeat Hospitalizations (%)
35.0%
72.5%
Days Alive Out of Hospital Median [IQR]
699 [ ]
355 [ ]
.0003
This endpoint captures the total hospital days from the index procedure or randomization to one year post-procedure or randomization.
An analysis of DAOH allows for an assessment of two important objectives of the device therapy- improvement in mortality and quality of life.

10. NYHA Class Over Time Survivors
p = 0.61
p <
p <
16.9%
23.7%
57.5%
60.8%
Percent
92.2%
93.9%
Treatment Visit
Baseline
1 Year
2 Year

11. All Stroke (ITT) HR [95% CI] = 2.79 [1.25, 6.22] p (log rank) = 0.009
Standard Rx
HR [95% CI] = 2.79 [1.25, 6.22]
p (log rank) = 0.009
TAVR
Incidence (%)
∆ at 1 yr = 5.7%
∆ at 2 yr = 8.3%
5.5%
13.8%
11.2%
5.5%
Point-in-time at 2 yrs: p =
Months
Numbers at Risk
TAVR
179
128
116
105 79
Standard Rx
118 84 62 42

12. All Strokes (# pts) Events ≤ 30 Days 31 Days – 2 Years All stroke
Ischemic Stroke
p = 0.017
p = 0.437
Hemorrhagic Stroke
p = 0.316
p = 0.160

13. Days post randomization
Stroke - Hemorrhagic
ITT arm
Age
Days post randomization
Description
Trauma
Medication
Procedure related*
Device related*
TAVR 91 9
Right sided hemorrhage No
Coumadin on admission
Yes 84 53
Traumatic subarachnoid
Fall
Coumadin 85 54
Intraparenchy-mal and subdural
Not stated
124
Intracranial 88
155
Subdural hematoma
DAPT
Standard therapy (BAV)
243
"Massive cerebral hemorrhage"
n/a
*CEC adjudicated

14. Mortality or Stroke (ITT)
Standard Rx
HR [95% CI] = 0.64 [0.49, 0.84]
p (log rank) =
TAVR
∆ at 2 yr = 21.9% NNT = 4.6 pts
68.0%
46.1%
∆ at 1 yr = 16.1% NNT = 6.2 pts
51.3%
All Cause Mortality or Stroke (%)
35.2%
Months
Numbers at Risk
TAVR
179
128
116
105 79
Standard Rx
118 84 62 42

15. Mean Gradient & Valve Area
EOA
Mean Gradient
Mean Gradient (mm Hg)
AVA (cm²)
N = 158
N = 162
N = 137
N = 143
N = 84
N = 89
N = 65
N = 9
Error bars = ± 1 Std Dev 30

16. Mortality Stratified by Paravalvular Leak (ITT) Starting at Discharge
Moderate or Severe
None to Mild
p (log rank) = 0.891
Death Incidence (%)
41.2%
40.5%
35.3%
27.2%
Determination of first PV Leak starts with the discharge echo
Months
Numbers at Risk
None to Mild
147
118
107 95 72
Moderate or Severe 17 12 11 10 8

17. Mortality Stratified by STS Score (ITT)
Standard Rx
TAVR
p value (log rank) = 0.676
p value (log rank) = 0.012
Death Incidence (%)
Months
Numbers at Risk
Months 12 8 7 6 5
119 84 59 42 29 47 19 14 28 26 25 24 16
108 80 76 67 52 43 32 23 19 15

18. 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). 34

19. 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

20. 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

21. 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

22. Thank You to the Dedicated Study Teams at All PARTNER Investigational Sites38

23. BACKUP SLIDES

24. All Cause Mortality (ITT)
HR [95% CI] = 0.57 [0.44, 0.75]
p (log rank) <
Standard Rx
TAVR
∆ at 1 yr = 20.0% NNT = 5.0 pts
∆ at 2 yr = 24.7% NNT = 4.0 pts
68.0%
43.3%
50.7%
All Cause Mortality (%)
30.7%
Months
Numbers at Risk
TAVR
179
138
124
110 83 47 14
Standard Rx
121 85 62 42 19 5

25. All Cause Mortality (ITT) Cumulative Hazard
Standard Rx
TAVR
1.14
0.57
Cumulative Hazard
0.71
0.37
Months

26. Cardiovascular Mortality (ITT) Landmark Analysis
Standard Rx
TAVR
Cardiovascular Mortality 0-1 yr
Cardiovascular Mortality 1-2 yr
HR [95% CI] = 0.44 [0.32, 0.60]
p (log rank) <
HR [95% CI] = 0.48 [0.29, 0.81]
p (log rank) =
Cardiovascular Mortality (%)
44.6%
32.1%
20.5%
13.2%
Months
Numbers at Risk
TAVR
179
138
124
110 83
Standard Rx
121 85 62 42

27. All Cause Mortality (ITT) Entire Cohort vs STS Score <5
Standard Rx
TAVR
Entire Cohort
STS <5
Death Incidence (%)
Months
Months
Numbers at Risk
179
138
124
110 83 47 14
121 85 62 42 19 5 28 26 25 24 16 11 2 12 8 7 6 5 3

28. Mortality Stratified by STS Score (ITT)
Standard Rx
TAVR
STS <5
STS
STS ≥15
Death Incidence (%)
Months
Months
Months
Numbers at Risk 28 26 25 24 16 12 8 7 6 5
108 80 76 67 52
119 84 59 42 29 43 32 23 19 15 47 29 14 8

29. Mortality Stratified by STS Score (ITT) STS <15 vs STS ≥15 (out to 36 months)
Standard Rx
TAVR
STS <15
STS ≥15
Death Incidence (%)
Months
Months
Numbers at Risk
136
106
101 91 68 35 8
131 92 66 48 34 14 4 43 32 23 19 15 12 6 47 29 14 8 5 1

30. Proportional Hazards Analysis of Predictors of Death
Predictor Variable
Non-missing observations
Log hazard ratio
P value
Hazard ratio
Lower confidence limit
Upper confidence limit
Body Mass Index (lbs/in²)
179
0.0061
0.952
0.920
0.986
STS Risk Score
0.0424
0.0125
1.043
1.009
1.079
CV Conditions: Stroke or TIA within last 6-12 months
1.1563
0.0128
3.178
1.279
7.901
CV Conditions: Arrhythmia
0.4236
0.0447
1.527
1.010
2.310
CV Conditions: Peripheral vascular disease
178
0.4050
0.0586
1.499
0.985
2.281
High Risk – Oxygen dependent COPD
0.3709
0.1232
1.449
0.904
2.322
Mean Gradient -- Baseline
170
0.1713
0.989
0.974
1.005
CV Surgery: CABG
0.2006
0.746
0.477
1.168
Non-CV Conditions: Liver disease
0.5803
0.2087
1.787
0.723
4.415
CV Surgery: PCI
0.2207
0.738
0.454
1.200
NYHA Class
0.2010
0.2377
1.223
0.876
1.707
Moderate or Severe Mitral Regurgitation -- Baseline
171
0.2530
0.729
0.423
1.254
CV Surgery: Pacemaker implant
0.2759
0.2670
1.318
0.810
2.145
CV Surgery: Carotid endarterectomy / Carotid stent
0.2831
0.656
0.303
1.417
CHAD Stroke Risk Score (ignoring fibrillation)
0.1156
0.3578
1.123
0.877
1.436
CV Surgery: Prior aortic valvuloplasty
0.4040
0.764
0.405
1.439
High Risk – Porcelain Aorta
0.4138
0.799
0.466
1.369
Aortic Valve Area -- Baseline
166
0.4334
0.626
0.194
2.020
High Risk – Radiation
0.5347
0.783
0.362
1.693
High Risk – Pulmonary Hypertension
118
0.1332
0.6035
1.142
0.691
1.889
Aortic Valve Baseline: AV Annulus Diameter (cm)
150
0.6354
0.786
0.290
2.129
CV Surgery: Peripheral bypass graft
0.6843
0.664
0.093
4.770
Other vascular stent of PTA (arterial)
0.2369
0.6873
1.267
0.400
4.017
Logistic EuroSCORE
0.0022
0.7072
1.002
0.991
1.014
CV Conditions: Coronary artery Disease
0.7074
0.921
0.598
Ejection Fraction -- Baseline
172
0.7102
0.997
0.981
1.013
CV Conditions: Previous Q wave or non-Q wave MI
177
0.7281
0.911
0.538
1.543
CV Risk Factors: Diabetes Mellitus
0.0758
0.7307
0.701
1.660
Age at Screening (years)
0.0033
0.7851
1.003
0.980
1.027
Patient has Coronary Artery Stenosis> 50%?
0.0530
0.7990
1.054
1.586
CV Risk Factors: Pulmonary Hypertension
0.8383
0.958
0.635
1.446
Atrial Fibrillation -- per ecg corelab
156
0.0479
0.8606
1.049
0.615
1.791
High Risk – Renal Failure
116
0.8872
0.929
0.336
2.570
Gender
0.0229
0.9124
1.023
0.681
1.538
Baseline Creatinine
0.0198
0.9328
1.020
0.644
1.616
CV Conditions: Cerebrovascular disease
175
0.0075
0.9740
1.008
0.642
1.582

31. 95% Upper Confidence Limit 95% Lower Confidence Limit
Proportional Hazard Analysis of Predictors of Death Multivariable Analysis
Label
Parameter
Estimate p
Hazard
Ratio
95% Upper Confidence Limit
95% Lower Confidence Limit
Body Mass Index (lbs/in²)
0.0050
0.951
0.985
0.918
Stroke or TIA within last 6-12 months
0.0194
2.999
7.530
1.194
High Risk - Oxygen dependent COPD
0.0310
1.692
2.730
1.049

32. All Cause Mortality vs BAV
TAVR
Standard Rx: BAV
Standard Rx: No BAV
Death Incidence (%)
Months
Numbers at Risk
TAVR
179
138
124
110 83 47 14
Standard Rx: BAV
142
105 74 54 37 18 5
Standard RX: No BAV 39 13 10 7 2 1

33. All Stroke Plus TIA (ITT)
Standard Rx
HR [95% CI] = 3.1 [1.41, 6.83]
p (log rank) = 0.003
Point-in-Time at 2 Yrs:
p =
TAVR
Incidence (%)
∆ at 1 yr = 6.4% NNT = 15.6 pts
∆ at 2 yr = 10.7% NNT = 9.3 pts
5.5%
16.2%
11.9%
5.5%
Months
Numbers at Risk
TAVR
179
127
115
103 76
Standard Rx
118 84 62 42

34. Mortality Stratified by Stroke (ITT)
TAVR (stroke)
TAVR (no stroke)
Standard Rx (stroke)
Standard Rx (no stroke)
Death Incidence (%)
Months
Numbers at Risk
TAVR (stroke) 25 16 14 10 7
Standard Rx (stroke) 8 4 1
TAVR (no stroke)
154
122
110
100 76
Standard Rx (no stroke)
171
117 84 62 42

35. Paravalvular Regurgitation: TAVR
Slight Changes Over Time
None/Trace
Moderate
Mild
Severe

36. Cardiovascular Mortality Stratified by First PV Leak (ITT) Starting at Discharge
Moderate or Severe
Determination of first PV Leak starts with the discharge echo
None to Mild
p (log rank) = 0.381
∆ at 1 yr = 14.4% NNT = 6.9 pts
Death Incidence (%)
∆ at 2 yr = 9.7% NNT = 10.3 pts
36.7%
27.0%
30.3%
15.9%
Months
Numbers at Risk
None to Mild
147
118
107 95 72
Moderate or Severe 17 12 11 10 8

37. 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
1 Year
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
Mean LVEF (%)
57.3 ± 9.9
57.1 ± 10.2
0.8924
2 Year
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
Mean LVEF (%)
57.3 ± 8.2
56.3 ± 11.1
0.6387

38. Cross-Over Patients n = 20 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
248.0
Days from 1 year visit to
334.2
164.8
117.0
595.0
Cross-Over approved: May 28, 2010

39. 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
- 121 pts who could not have crossed over
- 116 died before
- 5 withdrew (same as from 1 year)
- 38 who could have crossed over who didn’t (out of 58 pts). Of those, 23 never crossed over.
*Days from cross-over start to death N
Mean
Std Dev
Minimum
Maximum 12
200.3
120.5
30.0
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

40. Patient Status After Cross-Over
Frequency
Percent
Alive – no implant due to access issues 2 10
Alive after implant 16 80
Died after implant
Mean follow-up as of analysis date = 197 days