1. CRT 2011
Washington DC, February 27th – March 1st
Review of the Data from the Femoral Approach Clinical Trials: CoreValve®
Eberhard Grube, MD, FACC, FSCAI
University Hospital, Dept of Medicine II, Bonn, Germany
Hospital Alemaõ Oswaldo Cruz, Saõ Paulo, Brazil
Stanford University, School of Medicine, Palo Alto, CA

2. Disclosure Statement of Financial Interest
Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Physician Name Company/Relationship
Eberhard Grube, MD Medtronic, CoreValve: C, SB, AB, OF
Sadra Medical: E, C, SB, AB
Direct Flow: C, SB, AB
Mitralign: AB, SB, E
Boston Scientific: C, SB, AB
Biosensors: E, SB, C, AB
Cordis: AB
Abbott Vascular: AB
Capella: SB, C, AB
Embrella, SB
Claret, SB
Key
G – Grant and or Research Support E – Equity Interests S – Salary, AB – Advisory Board
C – Consulting fees, Honoraria R – Royalty Income I – Intellectual Property Rights
SB – Speaker’s Bureau O – Ownership OF – Other Financial Benefits‘ 2

3. Caveat
Some of the studies presented here contain both different devices and different approaches.
The data presented her is specific to the CoreValve device.
The data is made up for the vast majority of transfemoral cases, with, in certain cases (e.g. Italian Registry) a minority of Subclavian cases

4. TAVI
Currently available devices and
access routes

5. Overview on Current Publications on TAVI
Year of publication
Type of TAVI
Study Design
Device
Total patients
Age
Logistic EuroScore
Procedural success
Procedural mortality
30 day mortality
30 day stroke
Lichtenstein et al.
2006 TA
Single center
Edwards 7
80±7 35
100 - 14
Cribier et al. TF 36
~27 75
7.4
22.2
3.7
Webb et al. 18
26.2±13.1
77.8
11.1
Grube et al.
TF/TS
CoreValve 25 11 84 20 12
Walther et al.
2007
Multi center 59 27
93.2
13.6
3.4 50
82±7 28 86 2 4
Multi center (2)
82±6
21.7±12.6 88 6 10
Svensson et al.
2008 40
35.5 90
22.5
17.5
Piazza et al.
646
81±7
23.1±13.8 97
1.5 8
1.9
136
10.8
2.9
82±5
27.6±12.2 94
2009
TF/TA
168
28.6
94.1
1.2
11.3
4.2
Himbert et al.
82±8
26±13
93.3
Osten et al. 46
25.3 91
2.2
6.5
Thielmann et al. 39
81±5
44.2±12.6
2.6
17.9
Bleiziffer et al.
TF/TA/TS
Edwards/CoreValve
203
22±14
11.2
Buellesfeld et al.
2010
23.8±15.4
90.5
11.9*
Thomas et al.
Multi center (34)
1038
25.7 (TF)/29.1 (TA)
93.8
8.5
2.5
Rodés-Cabau et al.
Multi center (6)
339
1.7
10.4
2.3
Petronio et al.
Multi center (13)
514 83
20.1
98.6
0.8
5.4
1.8
Tchetche et al. 45
81.8±4.2
25.2±8.4
97.8
4.4
*in-hospital

6. Complementary Role of Edwards Sapien and CoreValve Transcatheter Aortic Valve Prostheses
Anatomic TAVI Suitability
TAVI Device Selection %
Jilaihawi Het al. JACC Interv 2010;3:859-66

7. CoreValve Experience: Over 13,000 Patients in Over 42 Countries since 2006

8. CoreValve Clinical Experience
Study
Study Size
Number of Centers
Follow-up to Date
Status
18 Fr Safety and Efficacy
126 9
2 years
Enrollment complete
Australia-New Zealand Study
380
6 months
Enrolling
REDO 18 4
30 days
Advance Study
1000
Up to 50 NA
CoreValve US Pivotal Trial
>1,300 40
Italian Registry
772 14
1 year
Enrollment Complete
Belgian Registry
328 (141 CoreValve)
13 (6 CoreValve)
Spanish Registry
108 3
French Registry
244 (78 CoreValve) 16
UK Registry
872 (460 CoreValve) 25
German Registry
697 (588 CoreValve) 22
Medtronic Sponsored Studies
Independent Studies

9. Baseline Patient Characteristics
18 Fr S&E1
ANZ2
Spanish Registry3
French Registry4
Belgian Registry6
German Registry8
UK Registry7
Italian Registry8 N
126
118
108 66
141
588
460
772
Age (years)
81.9 ± 6.4
82.3 ± 7.7
78.6 ± 6.7
82.5 ± 5.9
82 ± 6
81.4 ± 6.4 83
Female
57.1%
40.7%
54.6%
51.5%
56%
55.8%
48%
Logistic EuroSCORE (%)
23.4 ± 13.8
18.4 ± 11.9
16 ± 13.9
24.7 ± 11.2
25 ± 15
20.8 ± 13.3
20.3
22.9 ± 13.5
NYHA Class III and IV
74.6%
83.9%
58.4% –
78%
88.2%
74%
70.6%
LVEF %
51.6 ± 13.1
57.8 ± 13.0
51 ± 15
59 ± 13
52.1 ± 15
51 ± 13
Mean Pressure Gradient (mmHg)
46.8 ± 15.9
50.6 ± 16.2
55 ± 14.3
46 ± 15
49 ± 16
48.7 ± 17.2
52 ± 17
Aortic Valve Area (cm2)
0.72 ± 0.17
0.71 ± 0.21
0.63 ± 0.2
0.71 ± 0.16
0.63 ± 0.13
0.64 ± 0.18
0.71
Severe Aortic Stenosis in the elderly Patient >75 years
with high surgical risk and log Euroscore >20%
See Reference slide for sources. 9

10. Short-Term Clinical Outcomes

11. Consistently High Procedural Success
98.1%
97.0%
98.0%
98.7%
99.0%
98.1%
100%
95.8%
83.1%*
80%
60%
Percent of Patients (%)
40%
20% 0%
18 Fr S&E1
ANZ2
Spain3
French4
Belgian5
Germany6
UK7
Italian8
N = 126
N = 118
N = 108
N = 78
N = 141
N = 588
N = 460
N = 772 11

12. Consistent Haemodynamic Improvement Across Studies
Peak Gradient (mmHg)
Mean Gradient (mmHg)
120
120
18 Fr S&E1
18 Fr S&E1
100
ANZ2
100
ANZ2
83.8
Spanish3
Spanish3 84 80
81.9
Italian4 80
Italian4
72.5
Gradient (mmHg) 60
Gradient (mmHg) 52 55 60
50.7 40 40
46.8
18.9 18
9.7 20 20
8.5 9
12.6
16.8
2.4
Baseline
30 Days
Baseline
30 Days 12

13. Improvement in Functional Status
Paired 30-Day NYHA Classification
60%
18 Fr S&E1, N = 89
53.9%
ANZ2, N = 89
50%
46.1%
40%
30%
23.6%
21.3%
20%
16.9%
14.6%
9.0%
10%
4.5%
4.5%
4.5%
0.0%
0.0%
1.1%
0.0% 0%
Worsened 3 Levels
Worsened 2 Levels
Worsened 1 Level
No Change
Improved 1 Level
Improved 2 Levels
Improved 3 Levels
Approximately 80% of patients improved at least 1 NYHA class post-implant 13

14. Longer-Term Clinical Outcomes

15. Sustained Hemodynamic Performance at 2 Years
EOA
Mean Gradient 2 50
46.8
1.8 45
1.81
1.6
1.76
1.77
1.74 40
1.71
1.4 35
1.2
P < 0.001 30
Effective Orifice Area (cm2) 1
Mean Gradient (mmHg) 25
0.8 20
0.6
0.72
10.5
10.1 15
9.8
8.5 9
0.4 10
0.2 5
Baseline n = 109
Discharge n = 73
30-Day n = 60
6 Months n = 47
1 Year n = 52
2 Years n = 37 15

16. Sustained Functional Improvement at 2 Years
NYHA Classification
100% 6% 4% 7% 6% 7%
90%
16%
21%
18%
80%
27%
29%
Improved 3 levels
70%
Improved 2 levels
60%
Improved 1 level
Percentage of Patients
50%
59%
49%
54%
No Change
40%
49%
47%
Worsened 1 level
30%
Worsened 2 levels
Worsened 3 levels
20%
16%
15%
15%
10%
14%
13% 1% 3%
10% 5% 4% 5% 0%
Discharge n = 102
1 Month n = 89
6 Months n = 88
1 Year n = 83
2 Years n = 61
74% of patients sustained improvement of at least one functional class at 2 years (P < 0.01).

17. Aortic Regurgitation at 2 Years
100% 6% 6% 6% 3% 9%
90%
80%
37%
34%
32%
39%
42%
70%
Grade 4
52%
Grade 3
60%
Grade 2
Percentage of Patients
50%
Grade 1
40%
None (0)
30%
63%
63%
59%
55%
52%
20%
42%
10% 0%
Procedure N = 33
Discharge N = 84
30 Days N = 75
6 Months N = 69
1 Year N = 62
2 Years N = 43 17

18. Two Year Safety Results
Valve migrations
0 (0%)
Frames fractures
Structural valve deterioration*
Paravalvular leak adverse events
1 (0.8%)†
* Change in NYHA function resulting from intrinsic valve abnormality resulting in stenosis or regurgitation.
† Grade 2 Aortic insufficiency post-implant; treated on day 127 for symptomatic paravalvular leak with percutaneous Amplatzer plug.

19. Complications

20. Peri-procedural Complications
Vascular Complications
CoreValve
Edwards Sapien %
N=103
Bleiziffer
EurJCVSurg
2009
N=646
Piazza
EuroInterv
2008
N=514
Petronio
Circ Interv
2010
Avanzas
Rev Esp
Card2010
N=108
Zahn
EHJ
In press
N=588
v.Mieghem
EuroInt
2010
N=99
Tchetche
EuroInt
2010
N=21
Eltchaninoff
EHJ
in press
N=21
N=113
Webb
Circulation
2009
N=51
Himbert
JACC
2009
N=463
Thomas
Circulation
2010
Rodés-Cabau
Circulation
2010
N=168 20

21. 30-Day Stroke Rate 20% 15% 9.6% 10% 5% 4.5% 4.0% 4.0% 2.6% 1.9% 1.7%
18 Fr S&E1* N = 125
ANZ2 N = 118
French3 N = 66
Belgian4 N = 119
German5 N = 588
UK6 N = 460
Italian7 N = 772
Stroke is not defined consistently across all studies.
* Stroke is defined as permanent neurologic defects, included patients who had reversible neurologic events if there was structural
evidence of an intracranial event. . 21 21

22. Post-Procedure Aortic Regurgitation0% 0% 0% 2%
0.2%
100% 6%
90%
15.5%
24.1%
80%
AR grade 4
70%
52%
AR grade 3
60%
55%
AR grade 2
46.3%
Percent of Patients (%)
50%
AR grade 1
40%
None
30%
20%
42%
27.8%
27%
10% 0%
18 Fr S&E1 N = 84
Spanish2* N = 108
German3† N = 697
* Measured with angiography.
† German registry data includes both patients treated with CoreValve, 84.5%, and EDW Sapien, 15.5%.

23. Survival

24. All Cause Mortality at 30 Days%
Medtronic CoreValve
Edwards Sapien THV
N=126
Büllesfeld
submitted
N=136
Grube
Circ Interv
2008
N=646
Piazza
EuroInterv
2008
N=514
Petronio
Circ Interv
2010
Avanzas
RevEspCard
2010
N=108
N=18
Webb
Circulation
2006
N=50
Webb
Circulation
2007
N=113
Webb
Circulation
2009
N=463
Thomas
Circulation
2010
Rodés-Cabau
Circulation
2010
N=168 24

25. 30-Day All-Cause Mortality
25%
20%
15.2%
15.1%
15%
12.4% %
10%
9.0%
7.4%
7.2%
5.5% 5%
5.6% 0%
18 Fr S&E1 N = 125
ANZ2 N = 118
Spain3 N = 108
French4 N = 66
Belgian5 N = 119
German6 N = 588
UK7 N = 460
Italian8 N = 772 25

26. Percent of Patients (%)
One Year Survival
Survival rates comparable with octogenarians who have had sAVR or sAVR+CABG5
100%
90%
85.1%
81.6%
79.0%
80%
71.9%
70%
60%
Percent of Patients (%)
50%
40%
30%
20%
10% 0%
18 Fr S&E1 N = 126
Belgian2 N = 141
UK3 N = 460
Italian4 N = 772 26

27. Percent of Patients (%)
Two Year Survival
100%
90%
77.6%
80%
70%
59.7%
60%
Percent of Patients (%)
50%
40%
30%
20%
10% 0%
18 Fr S&E1 N = 126
UK2 N = 460 27

28. Distribution of Mortality Over Time in the Italian Registry8
Early mortality
Late mortality
Cumulative mortality 16 7 14 6 12 5 10
Number of Patients
Cumulative Events (%) 4 8 3 6 2 4 1 2 2 4 9 11 14 16 22 24 26 30 33 37 43 52 60 63 69 78 85 91 93 96
112
118
122
125
166
173
190
208
223
238
250
267
302
336
349
Days after TAVI
Incidence and Predictors of Early and Late Mortality After Transcatheter Aortic Valve Implantation in 663 Patients With Severe Aortic Stenosis – Corrado Tamburino et al. Circulation 2011;123;

29. Learning Curve Across Study Periods in the Italian Registry
0.93
I Tertile (n = 221)
II Tertile (n = 221)
III Tertile (n = 221)
98.2
97.7
98.2
100 90
P-value 80 70 60
Cumulative Incidence (%) 50
0.34 40
0.04 30
17.6
13.1
14.2 20
7.9 10
3.6
5.0
Procedural Success
Death at 30 Days
Death at 1 Year
Incidence and Predictors of Early and Late Mortality After Transcatheter Aortic Valve Implantation in 663 Patients With Severe Aortic Stenosis – Corrado Tamburino et al. Circulation 2011;123;

30. Italian Registry Multivariate Analysis on Mortality
Hazard Ratio
95% LCL
95% UCL
P Value
Overall mortality
Intraprocedural stroke
15.76
3.27
75.90
0.001
Pre-procedural mitral regurgitation 3+ or 4+
4.62
1.66
12.87
0.003
Systolic pulmonary artery pressure >60 mm Hg
3.21
1.19
8.71
0.02
Prior acute pulmonary edema
2.75
1.32
5.72
0.007
Diabetes mellitus
2.45
5.07
Odds Ratio
Early mortality
Conversion to open heart surgery
38.68
2.86
522.59
0.006
Cardiac tamponade
10.97
1.59
75.61
Major access site complications
8.47
1.67
42.82
0.01
Left ventricular ejection fraction <40%
3.51
1.62
7.62
0.002
Prior balloon aortic valvuloplasty
2.87
1.24
6.65
2.66
1.26
5.56
Late mortality
Prior stroke
5.468
1.47
20.39
Post-procedural paravalvular leak ≥2+
3.785
1.57
9.10
2.696
1.09
6.68
0.03
Chronic kidney disease
2.532
1.01
6.35
0.048
LCL indicates lower confidence limit; UCL indicates upper confidence limit
Incidence and Predictors of Early and Late Mortality After Transcatheter Aortic Valve Implantation in 663 Patients With Severe Aortic Stenosis – Corrado Tamburino et al. Circulation 2011;123;

31. Conclusions on Mortality causes from the Italian Registry
Early mortality is strongly associated with procedural complications
Late mortality is generally associated with baseline clinical comobidities:
Early mortality was predicted by conversion to surgery, cardiac tamponade, major access site complications, as well as LVEF <40%, prior valvuloplasty, and diabetes.
Predictors of late mortality (30-day to 1 year) included prior stroke, post-procedural AR of 2+, prior acute pulmonary edema, and chronic kidney disease.
Permanent pacemaker implant is not a predictor of mortality.
Incidence and Predictors of Early and Late Mortality After Transcatheter Aortic Valve Implantation in 663 Patients With Severe Aortic Stenosis – Corrado Tamburino et al. Circulation 2011;123;

32. Conclusion

33. In Summary
Consistent, positive clinical outcomes demonstrated in multiple trials and registries
Positive survival in target patient population
Significant acute and medium-term hemodynamic and clinical benefits
Prospective studies are underway to assess the long-term outcomes of TAVI with CoreValve
Refinements in device and implantation technique are expected to:
Reduce learning curve
Improve patient outcomes
Expand target patient population

34. Backup

35. Potential Complications With CoreValve
Death including all cause and cardiovascular mortality
Myocardial infarction including coronary occlusion
Stroke including permanent stroke and TIA
Re-intervention including sAVR and repeat valve placement
Aortic regurgitation
Permanent pacemaker placement
Pericardial tamponade (wire perforations)
Vascular and bleeding complications
Valve migration or fracture
For complete list of adverse events, warnings
and contraindications reference CoreValve IFU 35

36. Proper Implant Location Results in Less ParaValvular Leak35
P = 0.19
P = 0.05 30
P = 0.10 25 20
Good
Grade >1 Paravalvular Leak (%)
Suboptimal 15 10 5
1 Month
3 Months
6 Months
12 Months
N = 326
Proper implant location defined as 4 to 8 mm below annulus
De Carlo. Serial Echocardiographic Evaluation of the CoreValve Aortic Bioprosthesis:
Italian Registry EuroPCR 2010.

37. Pacemaker Implantation Varies Between Studies
Procedural variability, anatomical
differences and clinical practice
variation impact pacemaker
implant rates9,10:
Depth of implant may induce conduction disturbances11
Valvuloplasty balloon size may impact conduction system11
Anatomical and patient-related factors may impact conduction disturbances12
Inter-hospital variability due to physician subjectivity, country-based healthcare norms and reimbursement strategies9
New Pacemaker Implants
Weighted Average 28.5%
60%
50%
42.5%
40%
40%
35.2%
31.3%
Percent of Patients (%)
30%
26.9%
26%
23%
18.5%
20%
10% 0%
18 Fr S&E1 N = 125
ANZ2 N = 99
Spain3 N = 108
French4 N = 66
Belgian5 N = 119
German6 N = 588
UK7 N = 460
Italian8 N = 772
See Reference slide for sources 1-8
9. N. Piazza, “AV-Block and Pacemaker Requirements Associated with Medtronic CoreValve TAVI: Incidence, Outcomes and Treatment Strategies”, TCT 2009.
10. Latsios et al. Device Landing Zone” Calcification, Assessed by MSCT, as Predictive Factor for Pacemaker Implantation after TAVI. Catheter Cardiovasc Interv [Epub ahead of print].
11. N. Piazza, “AV-Block and Pacemaker Requirements Associated with Medtronic CoreValve TAVI: Incidence, Outcomes and Treatment Strategies”, TCT 2009.
N. Piazza, “Persistent Conduction Abnormalities and Requirments
for Pacemaking 6 Months after TAVI”, PCR 2010. 37 37

38. Pacemaker Implantation Varies by Center
Italian Registry – Pacemaker Implantation Rate by Center
Average Pacemaker Implantation Rate 18.5%
50%
45%
40%
36.2%
35.7%
35.0%
35%
32.3%
30%
24.1%
Pacemaker Implantation Rate (%)
25%
21.4%
18.6%
18.2%
20%
14.7%
15.4%
14.9%
15%
11.1%
10%
3.7% 5% 0%
Legnano
Mirano
Pisa, University
Brescia, H. Civile
Milano, Niguarda
Firenze, Careggi
Padova, University
Roma, S. Camillo
Catania, University
Milano, S. Ambrogio
Firenze, University
Milano, S. Raffaele
Bologna, University
Petronio, AS. The Italian CoreValve Registry, EuroPCR 2010.

39. Vascular Complications
30%
25%
20%
16.9%
Percent of Patients (%)
15%
9.5%
10%
7.5%
6.5%
6.7%
3.9% 5% 0%
18 Fr S&E1* N = 125
ANZ2 N = 118
French3† N = 66
German4‡ N = 588
UK5§ N = 460
Italian6|| N = 772
Vascular complication is not defined consistently across studies.
* Defined as: Arteriovenous fistula, bowel ischemia, hematoma, pseudoaneurysm, and retroperitoneal bleed.
† Definition unknown.
‡ Defined as groin problems.
§ Defined as major vascular injury or later vascular injury requiring surgery.
|| Defined as severe bleeding/surgery of femoral access. 39

40. References
Medtronic Data on File. COR : 18 Fr Safety & Efficacy Study Re-Analysis, August 14, 2009.
Meredith IT. The Australia-New Zealand Medtronic CoreValve Registry: Outcomes in Inoperable and High Risk AS Patients. Transcatheter Cardiovascular Therapeutics 2010.
Avanzas P, Munoz-Garcia AJ, Segura J, et al. Percutaneous implantation of the CoreValve® self-expanding aortic valve prosthesis in patients with severe aortic stenosis: early experience in Spain. Rev Esp Cardiol. 2010;63:
Eltchaninoff. French Registry, TAVI Facts, Figures and National Registries. EuroPCR 2010, Paris, France.
Bosmans. Belgian Registry, TAVI Facts, Figures and National Registries. EuroPCR 2010, Paris, France.
Zahn. German Registry, TAVI Facts, Figures and National Registries. EuroPCR 2010, Paris, France.
Ludman. UK Registry, TAVI Facts, Figures and National Registries. EuroPCR 2010, Paris, France.
Petronio. Italian Registry, TAVI Facts, Figures and National Registries. EuroPCR 2010, Paris, France.
REDO study. Medtronic Data on File.
ADVANCE study. Medtronic Data on File.