1. Transcatheter Heart Valves
SAPIEN Program Update, Next Generation Improvements, and Design Features
Martyn Thomas
VP of Medical Affairs
Transcatheter Heart Valves
Edwards Lifesciences

2. Employee and Stockholder
Disclosures
Martyn Thomas MD
Employee and Stockholder
Edwards Lifesciences

3. Outline Data from 2016 for the SAPIEN programme
Next generation device and rationale
Ongoing and planned future trials using the SAPIEN platforms

4. High Quality Sessions at EACTS In Europe…

5. First Randomized Trial in Intermediate Risk Patients: P2A and S3i Presented and published at ACC 2016 and in N Eng J Med and the Lancet
SAPIEN XT was randomized to surgery
S3i enrolled using the same exact protocol
Pre-specified S3i comparison to surgery utilizing propensity score analysis
PII A was a randomized trial of SAVR v Sapien XT in Intermediate Risk patients.
The S3 valve became available after enrollment was complete but before the 2 year Primary Endpoint of PII A (as dictated by the FDA).
PII S3i is a single arm study within P2A using the S3 valve in intermediate risk patients.
Entry criteria for patients in the randomized trial and the registry were virtually identical.
Outcomes of S3i were compared to the SAVR patients in PII A at 1 year using Propensity Scoring Methodology as agreed with the FDA

6. Even If The S3 Did Not Exist XT Would Replace SAVR In Intermediate Risk Patients If The TF Approach Is Possible
TF Sub-group was a pre-specified analysis (1484 patients)
“As Treated” (AT) is the most clinically relevant population
Early advantage is sustained to 2 year follow-up
The TF subgroup analysis of P2A was a pre-specified analysis and consisted of 1484 patients.
The “As-Treated” population consists of patients were the procedure (either TAVR or SAVR) was initiated either in the operating room or the cath lab. This is the most clinically relevant population.
TF Sapien XT had a lower incidence of All-cause Mortality or Disabling Stroke at 2 years in the AT population which was statistically significant.

7. Expected given the virtual identical entry criteria
Minimal Clinically Meaningful Differences in Baseline Characteristics Between S3i and P2A Surgery
Expected given the virtual identical entry criteria
As expected, there were little clinically meaningful differences in the raw baseline patient characteristics between the SAVR patients in PII A and the S3i patients, before propensity scoring.

8. Minimal Clinically Meaningful Differences in Baseline Characteristics Between S3i and P2A Surgery
Very similar baseline characteristics between the 2 cohorts
Not surprising since inclusion / exclusion were virtually the same
As expected, there were little clinically meaningful differences in the raw baseline patient characteristics between the SAVR patients in PII A and the S3i patients, before propensity scoring.

9. Marked Improvement in Unadjusted 30-Day and 1-Year Clinical Outcomes
Large Improvements in the most meaningful hard end-points, at all time-points
30 day and 1 year unadjusted clinical outcomes were markedly improved with S3i compared to SAVR.

10. Time-to-Event KM Curves of S3i v. P2A
Large benefit is seen early, pointing to procedural impact
Early benefit is sustained to 1 year
Parallel curves suggest populations are very similar
KM time to event curves suggest the benefit of S3i is early (probably procedural) and these benefits are maintained to 1 year.
The parallel nature of the later aspects of the KM curves suggest the populations are very similar.

11. FDA Mandated methodology. S3i-PIIA SAVR Propensity Model Variables.
Logistic regression model performed on the following variables to generate propensity score.
Performed by independent statistician. Only had Group A and Group B with no outcomes data.
NB: NOT MATCHING……………QUINTILE METHODOLOGY
Age
Sex
NYHA Class
Angina Class
BMI
Native Annular Diameter
Prior Stroke
Porcelain Aorta
COPD
Diabetes Mellitus
Renal Insufficiency
Peripheral Vascular Disease
Prior PCI
Cardiomyopathy
Carotid Disease
Coronary Artery Disease
Previous or current smoker
Hypertension
Prior Myocardial Infarction
Pacemaker
Prior Aortic Valvuloplasty
Prior CABG

12. 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

13. Mortality, Stroke or AR ≥ Moderate
Confirmed: SAPIEN 3 is Better Than Surgery for Intermediate-Risk Patients
Propensity Sore Analysis merely confirmed that the large raw differences seen in KM Curves are indeed statistically significant
Mortality, Stroke or AR ≥ Moderate
The Propensity Scoring analysis merely confirmed the differences seen in the unadjusted data and showed that the S3 patients had improved outcomes compared to surgery in the Primary Outcome of mortality, stroke or AR> Mod

14. SAPIEN 3 is Better Than Surgery for Intermediate-Risk Patients
…And also for the components of
Mortality
Stroke
AND the components of:
- Mortality
- Stroke

15. Initial and longer term recovery from Open Surgery is statistically worse than TAVR: P2A
Clinical status differences are significant at all time points
~ 70% of TAVR patients show QoL improvement already at 30 days
~ 60% of surgery patients are not better but even worse that at baseline

16. 30-Day rates of Adverse Events in Intermediate-risk Patients (AT)
30-Day outcomes
SAPIEN 3 TF
SURGERY
SAPIEN XT TF
Death
1.1%
4.0%
3.4%
Disabling Stroke
1.0%
4.4%
3.2%
Life-Threatening Bleeding
4.6%
43.4%
10.5%
Acute Kidney Injury (stage 3)
0.5%
3.3%
1.2%
Major Vascular Complications
6.1%
5.4%
8.1%

17. Product Enhancements Will Focus on Further Reducing Key Complications
Predictors Of Mortality And QOL Improvements In IR Patients
Design Contributors to
Reduced Complications
Smooth crossing – no BAV required
Less manipulation during positioning and deployment
Low profile access
Accurate positioning
Simple fast procedure with minimum contrast usage
Stroke
Acute Kidney Injury
Major Vascular Complications
Life-threatening bleeding

18. SAPIEN 3 Ultra delivery system
The Edwards SAPIEN 3 Ultra System is Designed to Further Streamline The TAVR Procedure
SAPIEN 3 valve
SAPIEN 3 Ultra delivery system
Axela sheath
On-balloon design removes the need for valve alignment
14F Axela sheath for all valve sizes with 5.5 mm vessel indication
Seamless sheath design allows for transient expansion and active contraction
SAPIEN 3 Ultra delivery system and Axela sheath are not approved for sale.

19. The Edwards SAPIEN 3 Ultra System is Designed to Further Streamline The TAVR Procedure
Edwards Commander delivery system
SAPIEN 3 Ultra system
Next-generation balloon expandable system maintains proven valve performance
On-balloon delivery system
14F compatibility for all valve sizes

20. Edwards Axela Sheath 14F expandable sheath for all valve sizes
5.5 mm minimum vessel diameter for all valve sizes
Seamless design maintains hemostasis
Transient expansion and active contraction allows for low profile entry/exit
Hydrophilic coating allows for smooth insertion into vessel
14F
14F
14F
14F
Valve Size
20 mm
23 mm
26 mm
29 mm
Sheath Size
14F
Minimum Vessel Access Diameter
5.5 mm
SAPIEN 3 Ultra delivery system and Axela sheath are not approved for sale.

21. Ongoing and future clinical studies in the SAPIEN programme

22. PARTNER III Trial design
1:1 Randomization
TAVR
(SAPIEN 3)
(n=~650)
Symptomatic low operative risk severe AS patients
Heart team agrees the patient has a risk of operative mortality < 2% (e.g., STS <4)
SAVR
(Surgical Bioprosthetic Valve)
(n= ~650)
n=1300
Follow-up: 30 day, 6 month, and annually through 10 years
CT Imaging sub-study
(n=200)
Primary Endpoint: Composite of all-cause mortality, all stroke, and re-hospitalization at 1 year post procedure (non-inferiority)

23. The previous belief of waiting to treat patients until symptoms develop based on the Braunwald curve deserves further study
Average age of subjects was 48 years
Small sample size ~64 patients2
Predates widespread use of echo
Bicuspid valves included
Rheumatic patients included
Natural course of AS assembled from clinical and post mortem studies from before 19553
Post Mortem Study 1968
Ross and Braunwald. Circulation, 1068.
Valvular Aortic Stenosis in Adults
Average Course (Post Mortem Data)
With severe symptomatic AS, survival without
intervention is 2-5 years
(1) Age at time of clinical presentation
(2) Wood, P. Aortic stenosis. Amer J Cardiol. 1:553, 1958.
(3) A few analyses after 1955 that were supported by hemodynamic information were also included

24. TAVR Rebalances the Risk/Benefit Equation
Severe Asymptomatic AS Sudden Death/Year
1% - 3%
SAVR
Peri-Operative Mortality
2% - 5%
Severe Asymptomatic AS Sudden Death/Year
1% - 3%
TAVR
Peri-Operative Mortality 1%
Watchful Waiting Warranted
EARLY TAVR Warranted!

25. Conclusions
The future of the SAPIEN family of valves and delivery systems is bright.
Ultra and Axela will further simplify the procedure and should further reduce complications that impact on 1 year mortality.
The next generation device following this is well into development but TOP SECRET!!
Current and future trials should allow TAVR to be an option for Heart Teams for all severe AS patients.