1. TAVR: State of the Field and What Does the Future Hold?
CRT 2017
TAVR: State of the Field and What Does the Future Hold?
Eberhard Grube, MD, FACC, FSCAI
University Hospital, Dept of Medicine II, Bonn, Germany
Stanford University, Palo Alto, California, USA

2. Physician Name Company/Relationship
Disclosure
Eberhard Grube, MD
Physician Name Company/Relationship
Speaker Bureau/Advisory Board: Medtronic: C, SB, AB, OF
LivaNova: C, SB, AB
Highlife: AB, SB
Boston Scientific: C, SB, AB
Equity Interest: Millipede: E, SB, C, InSeal Medical: E, AB, Valtech: E, SB,
Claret: E, AB
Shockwave: E, AB
Valve Medical: E, AB
Mitra/Trilign E, AB, 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‘

3. The State of TAVR in 2017
The tremendous momentum behind transcatheter valve therapies continued to build through the last year with many major accomplishments, including:
Regulatory approval for intermediate risk patients in Europe and the US
Initiation of multiple randomized trials for the continued expansion of TAVR indications
Regulatory approval for iterative device designs (Lotus Edge, 34 mm Evolut R)
Publication of new randomized data on cerebral embolic protection (SENTINEL)
TAVR is clearly reaching new patient populations, and as this happens, both technology and technique continue to iterate and improve.
The goal of this presentation is to provide an overview of the current state of TAVR, as well as some thoughts on where the field is headed.

4. We have successfully studied TAVR across the spectrum of risk
The State of TAVR in 2017
We have successfully studied TAVR across the spectrum of risk

5. US CoreValve Pivotal Trial
Patients at Extreme Surgical Risk
Foundational trials tested new TAVR therapy in patients without the option for a surgical aortic valve replacement
US CoreValve Pivotal Trial
PARTNER 1B
CoreValve, N=489, STS 10.3%
SAPIEN, N=179, STS 11.2%

6. Patients at Extreme Surgical Risk
3-Year Follow-Up
PARTNER showed that by 3 years, TAVR had reduced mortality by approximately 30% compared to standard medical management.
Similar survival results were achieved with CoreValve in the US Pivotal Trial
All-Cause Mortality
26.5%
31.5%
30.6%
80.9
PARTNER B All-Cause
68.0
PARTNER B Standard Rx
50.8
30% of the deaths were due to non-cardiac causes, highlighting the severe comorbidities in these patients.
Months

7. US CoreValve Pivotal Trial
Patients at High Surgical Risk
Trials randomizing high risk patients to either TAVR or SAVR soon followed
US CoreValve Pivotal Trial
PARTNER 1A
CoreValve, N=390, STS 7.3% vs.
SAVR, N=357, STS 7.5%
SAPIEN, N=348, STS 11.8% vs.
SAVR, N=351, STS 11.7%

8. PARTNER 1A 5-Year Follow-Up Presented at ACC 2015
PARTNER showed that ~35% of patients survived to 5 years, regardless of treatment
This study provided the first confirmation that TAVR is a reasonable alternative to surgery in high risk patients
1Mack, et al., presented at ACC 2015

9. CoreValve US Pivotal Trial
3-Year Follow-Up Presented at ACC 2016
The CoreValve Pivotal Trial was the first to show a survival advantage with TAVR compared to SAVR, with separation of the all-cause mortality curves maintained to 3 years
1Deeb, et al., J Am Coll Cardiol 2016 Mar 22;  doi: /j.jacc

10. Patients at Intermediate Surgical Risk
Randomized trial data comparing TAVR to SAVR in lower-risk patients recently became available
SAPIEN XT and SAPIEN 3
CoreValve

11. Intermediate Risk PARTNER 2A | SAPIEN XT
The PARTNER 2A Trial showed that TAVR with SAPIEN XT was non-inferior to surgery for the primary endpoint of all-cause mortality or disabling stroke at 2 years
1Smith, et al., presented at ACC 2016

12. Intermediate Risk PARTNER 2A | SAPIEN XT
This study also generated convincing evidence that transfemoral TAVR provides an outcome advantage to intermediate risk patients
In the as-treated population, TF TAVR significantly reduced all-cause mortality or disabling stroke vs. surgery (p = 0.04)
1Smith, et al., presented at ACC 2016

13. Intermediate Risk PARTNER 2A | SAPIEN XT
Both TAVR and SAVR significantly improved quality of life, but TAVR facilitated an earlier functional recovery as seen by the 11.4 point difference in KCCQ score at 1 month
This benefit was driven by the transfemoral approach. There was no quality of life benefit relative to SAVR for patients that had a transthoracic approach
1Cohen, et al., presented at TCT 2016

14. Intermediate Risk NOTION | The CoreValve Platform
Though the study was likely under-powered, NOTION showed all-cause mortality with TAVR with CoreValve to be non-inferior to SAVR in patients at lower surgical risk
1Sondergaard, presented at EuroPCR 2015

15. Intermediate Risk Patients
Regulatory Approvals
These data have enabled the recent approval of TAVR for patients at intermediate surgical risk in both Europe and the US
2016
SAPIEN 3
SAPIEN XT
August
Evolut R
September

16. The State of TAVR in 2017
TAVR has become the gold-standard treatment for patients with severe, symptomatic aortic stenosis at extreme surgical risk, reducing the risk of mortality by at least 30% relative to standard medical therapy.
For patients at high risk, PARTNER showed that TAVR was non-inferior to surgery, while the CoreValve US Pivotal trial showed that TAVR may provide a durable survival advantage over surgery.
Recent data from rigorous, randomized trials in intermediate risk patients have confirmed that TAVR is at least non-inferior to SAVR in terms of survival, and it facilitates a faster recovery to an improved quality of life.

17. The State of TAVR in 2017
With the outstanding clinical trial results, TAVR has been rapidly implemented across the globe

18. Treatment Trends
Current State
1Leon, presented at TVT 2016

19. (Germany not reported)
Treatment Trends
Almost half of these procedures occurred in established markets between 2013 and 2015, with over 100,000 TAVRs performed in Italy, the UK, the US, and Germany
2013 Total: 23,333
2014 Total: 34,080
2015 Total:
>> 41,000
(Germany not reported)
1Giordano, et al., J Cardiovasc Med 2016;epub; 2Moat, et al., presented at TCT 2016; 3Carroll, et al., presented at TCT 2016; 4Eggebrecht, et al., EuroIntervention 2016; 11:

20. Treatment Trends
Future TAVR Growth
1Leon, presented at TVT 2016

21. Treatment Trends United States 2012-2016
Between 2012 and 2015, the number of surgical procedures recorded in the Adult Cardiac Surgery Database remained stable at ~29,000 per year, whereas the number of TAVRs recorded in the STS/ACC TVT registry increased by 400% over the same timeframe
Data from 2016 will likely reveal that TAVR is being performed more often than SAVR
1Carroll, et al., presented at TCT 2016

22. Treatment Trends Germany 2008 - 2014
A similar trend is evident in Germany
The number of SAVRs performed between 2008 and 2014 decreased slightly by 11%, whereas the number of TAVRs increased by 2000%
1Eggebrecht, et al., EuroIntervention 2016; 11:

23. Treatment Trends
Age
As TAVR is applied to more and more patients, we see that they are usually in their 80’s, with little evidence of “age creep” into a younger population
This appears to be true across geographies
1Carroll, et al., presented at TCT 2016

24. Treatment Trends Europe 2007 - 2012
“Risk creep,” however, may be occurring.
Enrollment trends in the European registries show that TAVR has been applied to a subset patients with logistic EuroSCORE ≤20 for some time, even as early as 2007
Several of the European registries broke out their patient populations according to EuroSCORE. Enrollment windows represented on this slide are as follows:
UK: Jan 2007-Dec 2009
FRANCE 2: Jan 2010-Oct 2011
ADVANCE: March 2010-July 2011
GARY: Calendar year 2011—this is only the transvascular TAVI cohort.
Belgium: Not sure – March 2012
4292 / 8196 patients with EuroSCORE available are categorized as < 20. So, ~50%.
1 Moat, et al., J Am Coll Cardiol 2011; 58: ; 2Gilard, et al., N Engl J Med 2012; 366: ; 3Linke, et al., Eur Heart J 2014, [E-pub ahead of print], 4Mohr, et al., Eur J Cardiothorac Surg 2014, [E-pub ahead of print], 5Bosmans, et al., presented at EuroPCR 2012

25. Treatment Trends Germany 2011 - 2014
Closer examination of German data confirms an upswing in the number of lower-risk patients being treated in recent years, while fewer of the highest risk patients are undergoing the procedure
1Eggebrecht, et al., EuroIntervention 2016; 11:

26. Treatment Trends United States and UK 2012-2015
Similar trends can be seen in the US and UK, with a downshift in surgical risk scores over time
STS / ACC TVT Registry
UK TAVI Registry
1Grover, et al., J Am Coll Cardiol 2016; epub; 2Moat, et al., presented at TCT 2016

27. Treatment Trends
2015
Balloon-expandable valves are used in approximately 60% of cases globally.
Self-expanding valves are used in the remaining 40%.
1Carroll, et al., presented at TCT 2016; 2Nombela-Franco, et al., presented at TCT 2016

28. The State of TAVR in 2017
Enrollment trends show that TAVR growth is occurring rapidly worldwide, and is mainly applied to ~80 year old patients with severe aortic stenosis.
For these older patients, even those at lower surgical risk, the benefits of a minimally invasive procedure most likely outweigh the possible risks of TAVR-specific complications. This may be one reason why we are seeing a downward shift in risk scores, but no change in mean age.
We expect TAVR use to continue growing, with 4x the volume in 2025 compared to what we saw last year.
The total number of “typical” patients with severe aortic stenosis will continue to grow as Baby Boomers reach their 80s1, however we do expect TAVR to serve new patient populations as well.
1Carroll, et al., J Am Coll Cardiol 2016;68:

29. The State of TAVR in 2017
We remain cognizant that certain technical challenges need to be addressed

30. Foundational TAVR Devices
Complications
Foundational randomized trials did provoke some concern about the safety of TAVR due to the incidence of certain complications, including stroke, conduction disturbances, paravalvular leak, and vascular trauma
CoreValve
SAPIEN XT
SAPIEN

31. Weighted average (n=8,987) 4.2%
Foundational TAVR Devices
Stroke
Weighted average (n=8,987) 4.2%
1Leon, et al., N Engl J Med 2010;363: ; 2Webb, et al., J Am Coll Cardiol Intv 2015;8: ; 3Smith, et al., N Engl J Med 2011;364: ; 4Leon, et al., N Engl J Med 2016;374: ; 5Popma, et al., J Am Coll Cardiol 2014;63: ; 6Adams, et al., N Engl J Med 2014;370:1790-8;;

32. Weighted average (n=8,987) 11.3%
Foundational TAVR Devices
New Permanent Pacemaker Implantation
Weighted average (n=8,987) 11.3%
1Leon, et al., N Engl J Med 2010;363: ; 2Webb, et al., J Am Coll Cardiol Intv 2015;8: ; 3Smith, et al., N Engl J Med 2011;364: ; 4Leon, et al., N Engl J Med 2016;374: ; 5Popma, et al., J Am Coll Cardiol 2014;63: ; 6Adams, et al., N Engl J Med 2014;370:1790-8;;

33. Minimum Vessel Diameter (mm)
Foundational TAVR Devices
Vascular Complications
Weighted average (n=8987) 7.7%
*Definitions vary across studies
Minimum Vessel Diameter (mm)
8.0/7.0
7.0
6.0/6.5
6.0
1Leon, et al., N Engl J Med 2010;363: ; 2Webb, et al., J Am Coll Cardiol Intv 2015;8: ; 3Smith, et al., N Engl J Med 2011;364: ; 4Leon, et al., N Engl J Med 2016;374: ; 5Popma, et al., J Am Coll Cardiol 2014;63: ; 6Adams, et al., N Engl J Med 2014;370:1790-8;;

34. Weighted average (n=5,127) Mild 34% / Moderate-Severe 10%
Foundational TAVR Devices
Paravalvular Leak
Weighted average (n=5,127) Mild 34% / Moderate-Severe 10%
1Leon, et al., N Engl J Med 2010;363: ; 2Webb, et al., J Am Coll Cardiol Intv 2015;8: ; 3Smith, et al., N Engl J Med 2011;364: ; 4Leon, et al., N Engl J Med 2016;374: ; 5Popma, et al., J Am Coll Cardiol 2014;63: ; 6Adams, et al., N Engl J Med 2014;370:1790-8;;

35. Transfemoral TAVR Devices
Iterative Device Design
Iterative devices have been designed to mitigate complications, simplify the procedure, and improve upon current anatomic exclusions to enable the treatment of more patients
SAPIEN 3
ACURATE neo
Evolut R
Lotus
Portico
Frame
Nitinol
Cobalt Chromium
PVL Managment
Extended Skirt
Adaptive Seal
PET Fabric Skirt
Pericardial cuff
Pericardial skirt
Annular Range
18-30 mm
20-27 mm
16-28 mm
19-27 mm
21-27 mm
Positioning
Recapturable --
Caliber
14 Fr/ 16 Fr equiv.
18 Fr
14 Fr / 16 Fr
18 Fr / 19 Fr

36. SAPIEN 3 Design Features Balloon-expandable cobalt chromium frame
Bovine pericardial intra-annular valve
Outer PET fabric skirt to reduce PVL
Annular range: 16 – 28 mm
4 valve sizes: 20, 23, 26, 29 mm
Expandable 14Fr (vessels ≥ 5.5 mm) or 16Fr (vessels ≥ 6.0 mm) delivery sheaths for TF delivery
14Fr: 20, 23, 26 mm THVs
16Fr: 29 mm THV

37. Evolut R Design Features Self-expanding Nitinol frame
Porcine pericardial supra-annular valve
Optimized sealing: extended skirt and more conformable frame
Recapturable
Annular range: 18 – 30 mm
4 valve sizes: 23, 26, 29, 34 mm
14Fr –equivalent profile, vessels ≥ 5.0 mm
34 mm system: 16Fr-equivalent, vessels ≥ 5.5 mm

38. Lotus Design Features Mechanically-expanded braided Nitinol frame
Bovine pericardial valve
Adaptive seal designed to minimize PVL
Repositionable and recapturable
No rapid pacing needed to deploy
Annular range: 20 – 27 mm
3 valve sizes: 23, 25, 27 mm
18Fr sheath, vessels ≥ 6.0 mm

39. Portico Design Features Self-expanding Nitinol frame
Intra-annular bovine pericardial valve
Porcine pericardium sealing cuff
Resheathable and recapturable
Rapid pacing is not required for full deployment
Annular range: 19 – 27 mm
4 valve sizes: 23, 25, 27, 29 mm
18Fr sheath for 23 and 25 mm THVs
19Fr for 27 and 29 mm THVs

40. ACURATE Neo Design Features Self-expanding Nitinol frame
Porcine pericardial supra-annular valve
Inner and outer pericardial skirts to minimize PVL
Upper crown for supra-annular anchoring
Lower crown minimizes protrusion into the LVOT
Annular range: 21 – 27 mm
3 valve sizes: S, M, L
18Fr –sheath compatible, vessels ≥ 6.0mm

41. Real-World Evidence Base
New Transfemoral Valves
A literature search was conducted to identify studies reporting procedural and 30-day outcomes for groups of patients treated with new valves in real-world practice
The rates of paravalvular leak, new pacemaker implantation, stroke, and major vascular complications were tabulated and the weighted average was calculated for each valve type

42. Real-World Evidence Base
New Transfemoral Valves
45 unique cohorts were identified through the literature search, representing over 15,000 patients treated with new valves in real-world practice

43. Stroke Real-World Evidence
The rate of all stroke is generally less than 4% with the new valves, a reduction relative to stroke rates achieved with the foundation devices
Not Reported

44. Weighted average (n=5,547) ~3.5%
TAVR Stroke
Rates with Contemporary Devices
In contemporary practice, the overall stroke rate remains around 3.5%
Weighted average (n=5,547) ~3.5%
I added the FORWARD and US IFU data in the Medtronic section and updated the weighted average to~3%
1Manoharan, et al., J Am Coll Cardiol Intv 2015; 8: ; 2Moellman, et al., presented at PCR London Valves 2015; 3Linke, et al., presented at PCR London Valves 2015; 4Kodali, et al., Eur Heart J 2016; doi: /eurheartj/ehw112; 5Vahanian, et al., presented at EuroPCR 2015; 6Webb, et. al. J Am Coll Cardiol Intv 2015; 8: ; 7DeMarco, et al, presented at TCT 2015; 8Meredith, et al., presented at PCR London Valves 2015; 10Falk, et al., presented at EuroPCR 2016

45. New Permanent Pacemakers
Real-World Evidence
The rate of new permanent pacemaker implantation is sensitive to device type
The rates are typically around 15% with Evolut R and SAPIEN 3, and approximately 2x higher with the Lotus valve

46. Moderate / Severe Paravalvular Leak
Real-World Evidence
The Lotus valve virtually eliminates moderate or severe PVL
Other valves have brought the rates to ~5% or less

47. Major Vascular Complications
Real-World Evidence
Major vascular complications have come down under 5% across all valve types

48. Access Trends United States 2012-2016
The preferred access site has been dynamic in the US as the regulatory landscape has changed
With the introduction of Evolut R and SAPIEN 3, more than 90% of TAVRs are performed through the TF approach
FDA Approval (High Risk):
CoreValve
Sapien XT
Evolut R
SAPIEN 3
1Carroll, et al., presented at TCT 2016

49. Transfemoral Access New Valves
Multicenter cohorts of 200 patients or more show only slight differences in transfemoral accessibility according to valve type
Multicenter cohorts with >200 patients

50. Anesthesia
New Valves
Increased use of the transfemoral approach has facilitated a simpler procedure, shown by the decreased use of general anesthesia in favor of conscious sedation
Wide variation in anesthesia mode likely reflects geographical differences and individual physician preferences NR
Multicenter cohorts with >200 patients

51. 30-Day All-Cause Mortality
Anesthesia
SOURCE 3
A sub-analysis from SOURCE 3 compared outcomes between patients treated with conscious sedation and general anesthesia
Anesthesia was not randomized, so confounding factors could impact this analysis
However, it generally shows that outcomes with SAPIEN 3 are independent of anesthesia type, and that it is reasonable to leave this choice to the operator
Conscious
Sedation
General
Anesthesia
P value
30-Day All-Cause Mortality
2.1%
1.5%
0.39
30-Day Stroke
1.7%
0.6%
0.052
Post-Dilatation
7.1%
15.4%
<0.001
Moderate / Severe PVL
4.4%
2.4%
0.14
Length of Stay
8.7 ± 6.0 days
9.0 ± 6.3 days
0.13
1Neumann, et al., presented at TCT 2016

52. The State of TAVR in 2017
New devices have incorporated design improvements such as smaller delivery systems, recapturability, and sealing technologies which have effectively improved the safety profile of TAVR
Lower rates of stroke and clinically relevant PVL can be observed in real-world practice , however the overall need for permanent pacemakers remains unchanged
Improved designs have also facilitated the application of TAVR to more patients by the transfemoral approach, while simultaneously bringing down the rate of major vascular complications
Physicians now have some options to streamline their procedures, such as the implementation of conscious sedation for select patients
Can b

53. What does the future hold?
The State of TAVR in 2017
What does the future hold?

54. Low Surgical Risk Active Trials Randomizing TAVR to SAVR
Currently there is significant clinical investment in applying TAVR to younger patients at low surgical risk, both in North America and in Europe
Medtronic Low Risk1
UK TAVI3
N = ~1200
Up to 80 centers
Evolut R, all routes
Industry-sponsored
10-year follow-up
N = 1228
Up to 64 centers
SAPIEN 3, transfemoral
PARTNER 32
N = 808
All UK TAVI centers
All valves, all routes
Publically funded
5-year follow-up
NOTION-24
N = 992
All Nordic countries
All valves, transfemoral
Physician and industry-sponsored
1Popma, et al., presented at TCT 2016; 2Mack, et al., presented at TCT 2016; 3Moat, et al., presented at TCT 2016; 4Sondergaard, et al., presented at TCT 2016

55. Low Surgical Risk Trials
Overview
Medtronic Low Risk
PARTNER 3
Primary Endpoint
Death or major stroke at 2 years
Death, all stroke, or re-hospitalization (valve-related or procedure-related and including heart failure) at 1 year
Patients
Symptomatic, severe AS and a Heart Team predicted risk of 30-day mortality < 3%
Symptomatic, severe AS and Heart Team assessment of low operative risk and STS < 4%
Study Design
Multi-center, prospective, randomized
1:1 randomization to either TAVR or SAVR
Devices
Investigational TAVR Arm
Evolut R
Control Arm
Any commercially available bioprosthesis
SAPIEN 3, transfemoral only

56. Low Surgical Risk Trials
Key Exclusion Criteria
Medtronic Low Risk
PARTNER 3
Bicuspid aortic valve
Multivessel CAD
(Syntax >22, unprotected left main)
Complex CAD requiring revascularization
(Syntax >32, unprotected left main)
MI within 30 days
MI within 30 days, stroke/TIA within 90 days
Severe MR or TR amenable to surgery
Severe AR or MR
Moderate or severe mitral stenosis
LVEF <30%
Prohibitive LVOT calcification
Unsuitable iliofemoral vessels for TF
Hemodynamic or respiratory instability requiring inotropic support or mechanical ventilation within 30 days
CKD – eGFR <30 mL/min
Significant frailty (objective measurements)
Severe lung disease or home O2

57. SAPIEN 3 Ultra Delivery System
New Designs
Continued Improvements
Iterative device modifications continue to roll out
Evolut PRO
SAPIEN 3 Ultra Delivery System
Lotus Edge
On-balloon design removes valve alignment step
Pusher is eliminated, reducing steps required during deployment
Depth guard to limit implant depth
Better flexibility
First results at
CRT 2017
Pericardial tissue wrap to enhance sealing
First results at
ACC 2017

58. TAVR will be applied to asymptomatic patients with severe AS
Earlier Intervention
Active Trials
There is interest in using TAVR to intervene earlier in the AS disease process to prevent inevitable myocardial damage and functional decline
TAVR UNLOAD
TAVR will be compared to medical therapy in patients with moderate AS, symptoms of heart failure, and reduced EF
EARLY TAVR
TAVR will be applied to asymptomatic patients with severe AS

59. Coronary Artery Disease
Lifetime Management
Key Concerns
As TAVR is applied to younger patients, new strategies will be needed to manage inevitable clinical realities later in their lives
Failed TAVs
Redo TAVR or surgical revision will be required for a subset of patients
Coronary Artery Disease
Strategies to manage CAD post TAVR
will be needed
SAPIEN XT at explant (1 year)2

60. Special Anatomy Bicuspid Valve
Bicuspid aortic valves become more frequent in younger patients with severe AS
When TAVR is applied to “all-comers,” this anatomy becomes an important issue
Significantly more work needs to be done to learn optimal implant techniques and device designs for this anatomical variation
1Roberts, et al., Circulation 2005;111:920-25

61. Final Thoughts
TAVR is now proven in patients at intermediate surgical risk, which represents the culmination of many years of rigorous study.
Currently there is significant clinical investment in applying this technology to younger patients at low surgical risk.
This careful study is an absolute requirement because certain TAVR-specific complications remain a concern. However, the survival advantage and quick recovery to improved quality of life which was achieved with transfemoral TAVR in the intermediate risk trials provides a highly encouraging signal.
It is possible that TAVR will provide an alternative therapy for patients with moderate aortic stenosis and heart failure, and for asymptomatic patients with severe AS. Perhaps earlier intervention will prevent an inevitable decline in cardiac function.
Overall, the future for transcatheter valve therapy is incredibly bright, with an expected 300,000 patients served annually within the next 10 years.