1. Postmarketing Report: Did We Reduce the Complication Rates in the Postmarketing Phase?
Jodi J. Akin, MS
VP Global Clinical Affairs,
Transcatheter Heart Valve Therapy
Edwards Lifesciences, LLC

2. Contemporary Post Approval Assessment Paradigms in TAVR
Outcomes and Appropriateness
Sponsor
Investigator
Societies
Government
PAS have multiple stakeholders with multiple interests and objectives.
The Primary objective of a PAS is to assess generalizable outcomes and appropriateness of therapy over time

3. Contemporary Post Approval Assessment Paradigms in TAVR
Outcomes and Appropriateness
Sponsor
Investigator
Societies
Government
-assess learning curve
-observe for safety and effectiveness signals not captured in a clinical trial
-detect opportunities for device and procedure improvements
-assess healthcare economics
-expand indications for therapy where appropriate
Speaking on behalf of the sponsor perspectives, particularly in the landscape of medical devices additional and important aims are
-assess learning curve
-observe for safety and effectiveness signals not captured in a clinical trial
-detect opportunities for device and procedure improvements
-expand indications for therapy where appropriate

4. Approval and Post Approval Surveillance SAPIEN Platforms
Edwards’ Global Post Approval Activities
‘07
‘08
‘09
‘10
‘11
‘12
‘13
‘14
CE Mark
CE Mark
Edwards SAPIEN® XT THV
Cobalt-Chromium Frame
Bovine Pericardial Tissue
Semi-closed leaflets
Reduced crimped profile
Sizes 23, 26 and 29mm
Transfemoral, transapical and transaortic
> 5000 patients in post approval surveillance
Edwards SAPIEN® THV
Stainless Steel Frame
Bovine Pericardial Tissue
23 and 26mm
Transfemoral, Transapical
I would like to take you through the First in class experience with Edwards SAPIEN platform in TAVR which began in 2007 and so now reflects more than 5 years of experience in PAS for this therapy
The CE Mark was conferred for essentially high risk and inoperable patients defined as a predecited risk of greater the 15T or Euroscore of 20
And including both transfemoral and transapical access.
A registry- know as the SOURCE Registry commenced in the first 32 consecutive commercial sites and more than 1000 patients were enrolled consecutively. This was the largest post approval study and generated tremendous interest and therefore a second cohort was added to evaluate the secnd year of experience in the same centers for learning curve and indication assessments.
The second generation platform, SAPIEN XT received CE Mark in 2010, followed by a second registry SOURCE XT. This indication included now expanded size and access options. More than 2700 patients were enrolled over a one year period.
The SOURCE Registry
The SOURCE XT Registry 4

5. Post Approval Surveillance
SOURCE
Registry
SOURCE XT
Post Approval Study
Patients
2307
2706
Enrollment
November 2007 – December 2009
July 2010 – October 2011
Centers 37 94
Countries 14 17
Access Routes
Transfemoral
Transapical
Transfemoral, Transapical,
Transaortic and Subclavian
Valve
SAPIEN
23mm, 26mm
SAPIEN XT
23mm, 26mm, 29mm
Adverse Event Adjudication
Principal Investigators
Independent Clinical Endpoint Committee, VARC Guidelines
Monitored
Min
Yes
Follow-up
30 Days,
1 Year and 2 Years
Annually to 5 Years
Here you see some information about the 2 registries side by side.
Of interest, these studies were not mandated as post approval requirements but rather for the the objectives previously stated

6. All Edwards SAPIEN® THV Studies Transfemoral (30 Day)
REVIVE
TF (n=106)
PARTNER EU*
TF (n=61)
SOURCE
Co 1 TF
(n=463)^^
Co 2 TF
(n=457)^^
Mean EuroSCORE (%)
28.9 ± 13.2
25.7 ± 11.5
25.8 ± 14.4
22.0 ± 13.7
Implant Success
88%
96.4%
95.2% NA
Freedom from Death
86.7%
91.8%
93.7%
91.2%
Freedom from Stroke
97.0%
96.7%
97.4%
Vascular Complications
(Access-Related)
15.5%**
27.9.0%
9.3% +
8.2%+
Renal Failure /Dialysis NR
1.6%
1.3%
2.4%
Freedom from Reoperation
99.0%
98.4%
99.1%
97.1%
Freedom from PPM
98.2%
93.9%
92.6%
Data Extract
Nov
Feb
Apr
The question was asked, have outcomes improved in the post approval era.
Here you can see the answer is yes when marching down the timeline from the preapproval studies REVIVE and PARTNER EU (which was the precursor to PARTNER IDE). At 30 days...
* Lefevre, T et al. One year follow-up of the multi-centre European PARTNER transcatheter heart valve study. Eur Hrt J: ;
** Pooled REVIVE/REVIVAL (TF and TA pooled)
^ Rodes-Cabau et al., Transcatheter Aortic Valve Implantation for the Treatment of Severe Symptomatic Aortic Stenosis in Patients at Very High or Prohibitive Surgical Risk: Acute and Late Outcomes of the Multicenter Canadian Experience. JACC: 2010 Mar 16; 55 (11).
^^ Wendler O. Presented at EuroPCR May Major Vascular Complications
Monitored Pooled Studies TF: PARTNER EU, REVIVAL, REVIVE, CANADA, and SOURCE

7. All Edwards SAPIEN® THV Studies Transfemoral (1 Year)
REVIVE
TF (n=106)
PARTNER EU*
TF (n=61)
SOURCE
Co 1^
TF (n=463)
Co 2^^
TF (n=457)
Freedom from Death
72.5%
78.7%
81.0%
79.2%
KM Mortality %
27.5%
21.3%
19.0%
20.8%
Freedom from Stroke
97.8%
93%
96.3%
95.6%
Freedom from PPM NR
98.2%
92.4%
91.0%
Data Extract
Nov
Feb
Apr
* Lefevre, T et al. One year follow-up of the multi-centre European PARTNER transcatheter heart valve study. Eur Hrt J: ;
** Pooled REVIVE/REVIVAL (TF and TA pooled)
^ Rodes-Cabau et al., Transcatheter Aortic Valve Implantation for the Treatment of Severe Symptomatic Aortic Stenosis in Patients at Very High or Prohibitive Surgical Risk: Acute and Late Outcomes of the Multicenter Canadian Experience. JACC: 2010 Mar 16; 55 (11).
^^ Wendler O. Presented at EuroPCR May 2011.
+ Freedom from Renal Failure
Monitored Pooled Studies TF: PARTNER EU, REVIVAL, REVIVE, CANADA,

8. Harmonization of Clinical Trial Endpoints
Standardization of ascertainment and analysis of endpoints
Reasonable comparisons of iterations
Meta analyses as guidance documents
VARC
VARC II
Data analysis point of view
Lessons learned from revascularization era MACCE
Effective comparison, but for eventuality of OPC

9. SOURCE XT Registry Rigor, Oversight, Transparency
Executive Committee
Martyn Thomas, Olaf Wendler, Alec Vahanian, Thierry Lefevre, Stephan Windecker, Helmut Baumgartner, Gerhardt Schymick, Stefan Sack, Marie Claude Morice, Philip Urban, Marc Casselman, Thomas Walther, Gerhard Wimmer-Greinecker, Axel Unbehahn
Disciplines
Societies
Regions
Clinical Event Committee
15 Members
Cardiology (7) Cardiac Surgery (4) Neurology (3)
7300 events, nearly 17% captured by CEC trigger
VARC II
7 endpoints
Death, Stroke, Vascular, Bleeding, Renal, Pacemaker, Valve performance
Monitoring
100% CEC Events
Source documents in 13 languages

10. 30-day outcomes in an international post approval clinical study with a second generation balloon expandable transcatheter heart valve using multiple access techniques Alec Vahanian, MD Hopital Bichat Paris France on behalf of the SOURCE XT Investigators

11. SOURCE XT Clinical Outcomes at 30 Days
Intensified adjudication (VARC II), decrease in major event rates
* VARC definitions /CEC Adjudicated

12. Baseline Characteristics
Results
(n = 2706)
Age (years, mean± SD)
81.3 ± 6.6
Female - % (n)
57.7 (1561)
Logistic EuroScore (mean±SD)
20.5 ± 12.6
STS Score (mean±SD)
8.5 ± 7.0
Previous Stroke / TIA - %(n)
8.4 (226) / 4.6 (123)
COPD - %(n)
20.1 (544)
Renal Insufficiency - %(n)
28.0 (758)
Peripheral Vascular Disease - %(n)
21.2 (572)
Frail Condition (mean±SD)
5.2 ± 1.4

13. Contemporary Post Approval Assessment Paradigms in TAVR
Outcomes and Appropriateness
Sponsor
Investigator
Societies
Government
There have also been investigator initiated studies

14. Pan Canadian Post Approval Study
In particular- Led by Josep Rodes and John Webb in Canada- and all canadian retrospective analysis was conducted, demonstrating similar results as previously described

15. Contemporary Post Approval Assessment Paradigms in TAVR
Outcomes and Appropriateness
Sponsor
Investigator
Societies
Government
Also in these 5 years since first commercial approvals, in an unprecedented fashion, societies teamed up with government entities to establish independent registries and we have now seen multiple European country registries presented and published

16. National TAVR Registries
The two largest series are from France and Germany, with the German Registry now being the largest in the world and inclusive not only of TAVR but all Aortic Valve interventions

17. SAPIEN TAVR Surveillance Across Types 30 Day Mortality
Edward SAPIEN (TF)
VANCOUVER (114) b
Showing results spnsor, investigator and scociety/national registries, we see fairly similar outcomes
BELGIUM (99) g
CANADIAN (168) h
FRENCH (853) i
PARTNER EU (61) c
SOURCE (920) d
FRENCH 95 ( ) e
UK (172) f
bWebb TCT 2008; cLefevre et al EurHeartJ 2011;32:148-57; dThomas et al Euro PCR 2011; eEltchaninoff Eur Heart J 2010; Sept 15, 2010 epub; fLudman EuroPCR 2010; gBelgium; hRodes-Cabau et al. JACC 2010;55:In Press; iGilard M EuroPCR 2011

18. Large Series Weighted Meta-Analysis: 16 Studies, 3519 Patients

19. Approval and Post Approval Surveillance SAPIEN Platforms
Edwards’ Global Post Approval Activities
‘07
‘08
‘09
‘10
‘11
‘12
‘13
CE Mark
FDA Approval
Edwards SAPIEN® THV
Stainless Steel Frame
Bovine Pericardial Tissue
23 and 26mm
Transfemoral, Transapical
Inoperable TF only
High Risk
Transfemoral
Transapical
Moving to the US experience, FDA approval came in late 2011 for the inoperrable patient and 2012 for the high risk for surgery population. In parallel to the approval and drawing from the global experience including VARC initiatives, national registries in Europe, remibursment objectives and sponsor commitment a new paradigm for post approval studies was introduced
STS/ACC TVT Registry
Commences
The SOURCE Registry 19

20. New outcomes registry of TAVR
STS/ACC TVT Registry
New outcomes registry of TAVR
>400 data elements
Web based data entry
Standardized data elements- VARC definitions
30 day risk adjusted clinical outcomes
Linked to CMS claims data for long term outcomes
Will be harmonized with STS database for surgical AVR
The TVT Registry is ambitious with more than 400 data elements, linkage to CMS claims data base and embedded with opportunities to address specific sponsor post approval requirements from FDA

21. Steering Committee STS Members ACC Members Registry Operations Center
Fred Edwards
Fred Grover
Michael Mack
Dave Shahian
ACC Members
Ralph Brindis
John Carroll
David Holmes
Murat Tuzcu
Registry Operations Center
NCDR
Ex Officio Members
FDA - Danica Marinac-Dabic
CMS - Jyme Schafer
NHLBI - Frank Evans
Chair TVT R&P Subcommittee - John Rumsfeld
DCRI – Eric Peterson, Matt Brennan
Data Analytics Center
DCRI
The leadership is stellar and representative of all possible stakeholders whose commitment has been exemplary. This committee meets by telecon weekly and is already making preparations for a first publication this year.
Staff
Cynthia Shewan, Hilary Kirk
Joan Michaels, Kathleen Hewitt, Barb Christensen

22. Current Status February 2013
178 enrolled sites
3,116 patient records
Nested registries for PAS II for Edwards SAPIEN Valve in progress

23. Opportunities, Challenges and Requirements of Surveillance
The Good
TAVR unprecedented in level of oversight since global commercialization
Genuine collaboration of stakeholders
Trend of improvement in outcomes through observation
The Challenge
Overlapping initiatives are expensive and burdensome
The Future
Harmonization
Technological advancements data, patient follow-up
Balancing of pre and post market evidence for rapid innovation
Economies of scale
International cooperation

24. Patient and Clinician Choices
Conclusion
Surveillance
Safety
Appropriateness
Iteration
Patient and Clinician Choices
Surveillance of TAVR is expansive
No unanticipated safety signals to date
National and International Registry Initiatives are being realized and may replace pave the way for a new paradigm in pre and post approval requirements