1. Structural Heart Live Cases
Supported by:
Edwards Lifesciences
Medtronic inc
Bard Inc
Terumo Medical Corp

2. Disclosures
Samin K. Sharma, MD, FACC Speaker’s Bureau – Boston Scientific Corporation, Abbott Vascular Inc, ABIOMED, CSI, Trireme Inc Annapoorna S. Kini, MD, FACC Nothing to disclose George Dangas, MD, FACC Nothing to disclose regarding today’s presentation Allan Stewart, MD Nothing to disclose for today’s case

3. January 10th 2017 Structural Heart Live #15: NL, 84 yr. F
Presentation: Worsening dyspnea on exertion NYHA class III
PMH: Hypertension, Hyperlipidemia, HFpEF, Paroxysmal AF and remote DVT
Medications: ASA, Atorvastatin, Furosemide, Metoprolol
TTE (12/20/16): Severe AS; PG/MG= 68/41mmHg, Doppler valve area = 0.72 cm2, Ao peak velocity = 4.13 m/s, EF 51%
EKG (01/04/17): Sinus Rhythm with narrow QRS
Cath (12/19/16): Non-obstructive CAD with mild PAH

4. January 10th 2017 Structural Heart Live Case #15
Contd….
CT Angiography: The bilateral lower extremity peripheral arterial accesses have minimal diameters 8.1 mm
STS risk mortality: %
EuroScore II risk: %
Logistic Euroscore mortality: 10.1%
Course: Patient is determined to be intermediate risk for surgical AVR due to history of age and co-morbidities
Plan Today: Patient is planned for Sapien-3 TAVR (26 mm) via percutaneous femoral access and conscious sedation.
SLIDE TO BE EDITED BY JK

5. Transthoracic Echo
Severe valvular aortic stenosis; peak gradient = 68 mmHg, mean gradient = 41 mmHg, Doppler valve area = 0.72 sq cm, Ao peak CW velocity = 4.13 m/sec, LVEF 51%

6. CTA: Aortic Annulus Annulus Max: 25.3 mm Min: 22.2 mm Mean: 23.9 mm
Perimeter = 75.7 mm
Area = 441 mm2
Annular angle = 64°
Annulus diameter: 22.2x 25.3mm
Annulus area: 441mm2
Annulus angle: 64°°

7. CTA: SOV and STJ Sinus of Valsalva Mean Diameter = 32.7 mm
Sino-tubular junction height (above annulus)
= 21.0 mm
Ascending aorta =
32 mm
32.8mm
32.7 mm
Left Main Height
10 mm
RCA Height
14.3 mm
RCA: 14.3 mm LM: 10 mm

8. CTA: Access – 3D

9. Access: Iliac & common femoral arteries
Rt CIA: 9.2mm Lt CIA: 10.3mm
Rt CFA: 8.01mm
Lt CFA: 8.8mm

10. Valve Sizing: Sapien-3
Our Patient
441 mm2
23.9 mm

11. SAPIEN Platforms in PARTNER Trials
Device Evolution

12. Summary of Case - 84 year old female - NYHA Class III
- TTE: AS – mean gradient 41 mmHg, AVA 0.7cm2
STS mortality: 3.4%
EuroScore II mortality: 3.15%
Logistic Euroscore mortality: 10.1%
Patient is determined to be intermediate risk for surgical AVR due to age & co-morbidities.
Plan: For 26 mm Sapien-3 valve via percutaneous femoral approach under conscious sedation and pre-empt LM protection due to low LM height.

13. Issues Related To The Case
SENTINEL Trial results and update in the neuro-protection during TAVR

14. Mechanisms of Embolic Complications During and After TAVI: Acute Risk Highest, and Likely Embolic
Stortecky and Windecker, Circulation 2012; 126:2921

15. TAVI Cerebral Protection Risk and Benefit Considerations Across Surgical Risk Spectrum
Risk of cerebral embolic injury likely similar for all severe AS
Most emboli are created during crossing of the stenotic aortic valve, positioning and expanding the new valve1,2
Patients with severe AS have severely stenotic valves, by definition, regardless of surgical risk score (which has more to do with other health factors)
Risk of cerebral embolic injury ≠ surgical operative mortality risk
Benefit of cerebral protection may increase with lower-STS, younger patients
Lower surgical risk, and younger, patients likely have longer life expectancies over which to benefit from reduced neurological injury (stroke and cognitive decline)
Patients with higher cognitive function at baseline may be more likely to show decline4
Erdoes et al., EJCTS 2012;41: 778; 2. Kahlert et al., Circulation. 2012;126:1245
3. Zeinah et al., ACTA 2015; 4. Newman M et al., N Engl J Med 2001:344:395

16. What are Predictors of Stroke and Cerebral Damage in TAVI?
Logistic EuroSCORE is NOT a predictor of stroke in TAVI1
Predictors of neurological events in TAVI studies have included:
Transarterial vs Transapical access2
Post-dilatation and valve dislodgement3
Smaller indexed valve area4
Cerebrovascular disease4
Predictors of new cerebral damage (DW-MRI) in TAVI studies have included:
Age, hyperlipidemia, post-dil5
Severity of atheroma (arch and descending), catheterization time, age6
Peak transaortic gradient5
Zeinah et al., ACTA 2015;December18:1
Eggebrecht et al., Eurointervention 2012;8:129
Nombela-Franco et al., Circulation 2012;126:3041
Miller et al., J Thorac Cardiovasc Surg 2012;143:832
Samim et al., Clin Res Cardiol 2015;104:430
Fairbairn et al., Heart 2012;98:18

17. Stroke is Not Disappearing Even With Lower-Risk Patients and New Generation TAVI Valves
Second generation transcatheter aortic valves:
A. Sadra™ Lotus Medical valve, B. Portico® valve, C. Edwards SAPIEN 3 valve, D. Edwards CENTERA valve, E. JenaValve,
F. Engager™ valve, G. Symetis ACURATE™ valve, H. Direct Flow Medical® valve
Meta-analysis of ~20 non-randomized, mostly FIM, valve-company sponsored studies
2.4% major stroke at 30-days
Athappan et al., EuroIntervention 2016; 11:1034

18. 30-Day All-Stroke Rates from Recent TAVI Studies Support the Need for Embolic Protection
Extreme Risk
Extreme/High Risk
High Risk
Intermediate Risk
Meredith et al., EuroPCR 2014; Adams et al., N Engl J Med 2014;370:1790; Leon et. al., ACC 2013; Lefevre et al., J Am Coll Cardiol Intv 2016;9:68; Popma et al., J Am Coll Cardiol 2014;63:1972; Linke et. al., EuroPCR 2015; Van Mieghem et al., EuroPCR 2015; Kodali et al., ACC 2015; Holmes et al., JAMA 2015;313:1019; Meredith et al., ACC 2015; Williams et. al., ACC 2016; Thourani et al., ACC 2016

19. TVT Registry Shows No Significant Decline in Stroke Rate Over Time
Stroke after TAVR
Over 53,000 US TAVR patients
No significant decline in stroke rate over time
Self-reported rates without prospective neurologist exams pre- and post-procedure likely underestimate true rates
There is no clear volume-outcome relationship for CVA
Holmes D, et al. ACC 2016

20. Perioperative Stroke and Mortality After TAVI
Meta-Analysis of 29,043 Published Patients
With Perioperative Stroke Showing >4x Increased Risk of
30-Day Mortality
Stroke Remains a Major TAVI Complication
Overall Stroke Rate 3.07%
30-day mortality, %
Muralidharan et al., Am J Cardiol 2016;118:1031

21. New Cerebral Lesions are Found in the Vast
Majority of Patients Following TAVI
68-100% of TAVI patients affected1-11
Most patients have multiple infarcts
“Silent” infarcts associated with12-14
2-4-fold risk of future stroke
>3-fold risk of mortality
>2-fold risk of dementia
Cognitive decline
Dementia
1. Rodes-Cabau et al., JACC 2011; 57:18
2. Ghanem et al., J Am Coll Cardiol 2010; 55:1427
3. Arnold et al., J Am Coll Cardiol Intv 2010;3:1126
7. Bijuklic et al., J Am Coll Cardiol Intv 2015
8. Linke et al., TCT 2014
9. Vahanian TCT 2014
10. Lansky et al. London Valves 2015
11. Van Mieghem et al., EuroIntervention
2016;12:499
12. Sacco et al., Stroke 2013
13. Vermeer et al., Stroke 2003
14. Vermeer et al., New Engl J Med 2009
4. Kahlert et al., Circulation 2010;121:870
5. Astarci et al., EJCTS 2011; 40:475
6. Lansky et al., E Heart J 2015; May 19

22. Silent Cerebral Injury After TAVI Occurs in 77.5% of Patients
Meta-analysis of 26 prospective studies reporting DW-MRI outcomes after unprotected TAVI
Pooled analysis shows silent cerebral injury occurs in 77.5% patients
Pagnesi et al., Int J Cardiol 2016; 221; 97

23. Median lesion volume in mm3 TAVI valves used in the trial
Total Lesion Volume was Greater in Patients with Self-Expanding vs Balloon-Expandable TAVI Valves
Total DW-MRI lesion volume was greater in patients with self-expanding valves, driven by Medtronic CoreValve, vs. balloon-expandable TAVI valves (mostly Sapien 3)
Edwards Sapien 3
54%
Medtronic CoreValve
25%
Edwards Sapien XT
15%
STJ Portico 1%
Balloon dilatation 5%
Median lesion volume in mm3
TAVI valves used in the trial
MDT CoreValve
STJ Portico
EDW Sapien 3
EDW Sapien XT
van Mieghem et al., EuroIntervention 2016;12:499

24. Even Small Lesions May Increase Risk of Stroke-Related Mortality
Stroke and Death
Presence of cerebrovascular lesions smaller than 3 mm may be associated with increased risks for stroke and death
Variable
Participants (%)
Any Stroke
(n = 157 [8%])
Stroke-Related Mortality
(n = 140 [7%])
Lesion Size
HR (95% CI)
P Value
None 86
Reference
Ref
Very small
(<3 mm) only 3
3.47 (1.86 – 6.49)
<0.001
3.05 (1.04 – 8.94)
0.043
Larger (≥3 mm) only 10
1.94 (1.22 – 3.07)
0.005
1.87 (0.83 – 4.23)
0.132
Both 2
8.59 ( )
6.97 ( )
0.002
Lesions <3 mm were associated with a 3-fold increased risk for stroke and stroke related death
Lesions ≥ 3 mm were associated with 2-fold increased risk for stroke and stroke related death
Lesions of both sizes were associated with nearly 9-fold increased risk for stroke and nearly 7-fold for stroke related death
Windham et al., Ann Intern Med. 2015; 163:22

25. Most Cerebral Damage in TAVR/TAVI is Unseen
Clinically apparent
Clinical exam,
NIHSS, mRS
Subtle and often undetected
MMSE, MoCA
Neurocognitive test batteries
Clinically unrecognized
Neuroimaging
….but can have far-reaching effects

26. Embolic Protection Devices for TAVR
Claret Sentinel™
Cerebral Protection System
Edwards Embrella™
Embolic Deflector
TriGuard™ Cerebral Protection Device
Filter capture
Deflector
6F (radial)
9F (femoral)
140 micron pore size
100 micron pore size
130 x 250 micron pore size
Brachiocephalic and LCC
Aortic arch position
CE marked and commercialized
CE marked

27. Claret Medical® Sentinel® Cerebral
Protection System
Dual independent filters for embolic debris capture and removal
Right transradial 6F sheath access
Deflectable sheath facilitates cannulation of LCC
Low profile in aortic arch to minimize interaction with TAVR delivery catheter
S Kodali, TCT 2016

28. Size Matters - Claret CPS Reduces Lesion Sizes
Each 1-mm3 voxel on DW-MRI = at least 60,000 neurons and 3 million synapses1,2
An average TAVI procedure damages at least 48 million neurons and >2 billion synapses3
Using Claret filters may save >20 million neurons and 1 billion synapses3 per patient
p = .001
54% Reduction
n = 49
n = 45
Using Claret CPS in CLEAN-TAVI, significantly fewer patients have large lesions3 (>250mm3)
1. Azevedo et al., Journal of Comparative Neurology 2009;513.5:532
2. Lüders et al., Neuroreport 2002;13.17: 2371
3. Haussig et al., JAMA. 2016;316:592

29. Severe AS Undergoing TAVR: Primary Safety and Efficacy Outcomes
SENTINEL
A Prospective, Randomized Trial Evaluating Cerebral Protection in Patients with
Severe AS Undergoing TAVR:
Primary Safety and Efficacy Outcomes
Kodali S et al, TCT 2016
Kapadia S et al, JACC Dec 2016 (accepted manuscript)

30. The SENTINEL Trial
S Kodali, TCT 2016

31. SENTINEL Trial: Procedural Characteristics
SENTINEL Data
Device Arm
(n=231)
Sentinel Device Access
Radial
94.4
Brachial
5.6
Both Filters Deployed
≥ One Filter Deployed
99.6
TAVR Data
Device Arm
(n=241)
Control Arm
(n=119)
P Value1
Procedure Time2
78.0 [53.0, 110.0]
69.0 [40.0, 97.0]
0.01
Fluoroscopy Time
16.0 [11.0, 27.5]
15.0 [9.0, 20.0]
0.08
Pre-Dilatation
42.0
44.3
0.74
Post-Dilatation
10.7
13.4
0.49
S Kodali, TCT 2016

32. SENTINEL Trial: Valve Type Distribution
SAPIEN 3
(n=188)
SAPIEN XT
(n=64)
EVOLUT 3
(n=93)
CoreValve
(n=14)
S Kodali, TCT 2016

33. The SENTINEL Trial: Primary Efficacy Endpoint
New Lesion Volume in Protected Territories (mm3)
42.2% reduction
[95% CI: 3.2, 67.6]
p=0.33
Median ±95% Confidence Limit
S Kodali, TCT 2016

34. Primary Safety Endpoint
The SENTINEL Trial:
Primary Safety Endpoint
30-Day MACCE
Rate (%)
Within Sentinel Trial
Obs. Diff = -2.6%
Historical Performance
Goal 18.3%
(Pnon-inferior<0.001)
S Kodali, TCT 2016

35. 30-Day Clinical Outcomes
Control arm (n=119)
Safety + Device arm (n=121)
p=0.40
p=0.25
p=0.53
p=1.0
p=1.0 %
p=0.65
Kapadia et al., J Am Coll Cardiol 2016 Accepted Manuscript

36. Histopathology Particulate Debris Analysis%
Any debris Acute Organizing Valve Arterial Calcification Foreign Myocardium
thrombus thrombus tissue wall material
Kapadia et al., J Am Coll Cardiol 2016 Accepted Manuscript

37. The SENTINEL Trial: 30-Day Clinical
Outcomes
Device Arm,%
(n=234)
Control Arm,%
(n=111)
p Value
30-day Clinical Outcomes
Any MACCE§
7.3
9.9
0.40
Death (all-cause)
1.3
1.8
0.65
Stroke
5.6
9.1
0.25
Disabling
0.9
1.00
Non-disabling
4.8
8.2
0.22
AKI (Stage 3)
0.4
TIA
Sentinel Access Site Complications
N/A
0.53
§ MACCE defined as Death (any cause), Stroke (any), Acute Kidney Injury (Stage 3)
S Kodali, TCT 2016

38. The SENTINEL Trial: Impact of Embolic Protection on Stroke Severity
S Kodali, TCT 2016

39. The SENTINEL Trial: Impact by Valve Type Pre-Specified Analysis
S Kodali, TCT 2016

40. SENTINEL Trial: Stroke by Valve Type
Valve Usage
CoreValve 4%
EVOLUT R
26%
SAPIEN XT
18%
SAPIEN 3
52%
Valve Type
Number of Strokes
(% ratio of valve type)
Edwards SAPIEN XT
(n=64)
7.8
Edwards SAPIEN 3
(n=188)
2.7
Medtronic CoreValve
(n=14)
7.1
Medtronic EVOLUT R
(n=93)
12.9
S Kodali, TCT 2016

41. SENTINEL Trial: Conclusions
In high-risk patients undergoing TAVR, the Sentinel dual filter embolic protection device was associated with:
A favorable safety profile:
MACCE 7.3%, which was significantly below the historical goal
Low major vascular complications (0.4%)
Captured embolic debris in almost all patients (99%), consisting of diverse material
A reduction in 30-day strokes from 9.1% to 5.6%, which was not statistically significant (study was not powered for MACE)
Although there was a reduction in DW-MRI new lesion volume with embolic protection (by 42%), the primary efficacy endpoint was not met (p=0.33)
However, after adjusting for potential confounders (baseline lesion volume and valve type), there was a significant reduction in new lesion volume in protected territories (p=0.02) with embolic protection.
S Kodali, TCT 2016

43. Pre-TAVR Considerations by the Heart Valve Team
*than currently approved TAVR indications
Otto et al., J Am Coll Cardiol December 2016 Accepted Manuscript

44. Take Home Message: Sentinel trial and update in neuro-protection during TAVR/TAVI
Major and minor strokes still occurs in 3-8% of TAVR procedures and silent brain lesions are very common (>80%). Long-term effect of even silent small brain lesions may have important implications when TAVR is done in young pts
Sentinel trial using Claret cerebral-protection system (TEP) in high risk TAVR/TAVI procedure have shown device safety/success and numerically lower stroke rates & lower new brain lesions on MRI compared to no device group. Future studies need to focus the TEP device use in high risk and self expanding TAVR cases.

45. Question # 1
Following are the true statement regarding strokes after TAVR in the Sentinel trial except:
Stroke occurred in 5-9% cases
Stroke was numerically similar in the control and device gps
TIA incidence was similar in the device gp vs control gp
Disabling stroke was similar between the device vs control gp

46. Question # 2
Following are the true statement regarding silent brain infarcts post TAVR:
Incidence is <50% with TAVR
Incidence is 50-70% with TAVR
Incidence is 70-95% with TAVR
Incidence is >95% with TAVR

47. Question # 3
Clean TAVI evaluating Claret embolic protection system versus control group post TAVR used following TAVR valves:
A. CoreValve
B. Sapien-3 valve
C. Sapien XT valve
D. Lotus valve

48. Correct answer: B Question # 1
Following are the true statement regarding strokes after TAVR in the Sentinel trial except:
Stroke occurred in 5-9% cases
Stroke was numerically similar in the control vs device gp
TIA incidence was similar in the device gp vs control gp
Disabling stroke was similar between the device vs control gp
Correct answer: B

49. Correct answer: C Question # 2
Following are the true statement regarding silent brain infarcts post TAVR:
Incidence is <50% with TAVR
Incidence is 50-70% with TAVR
Incidence is 70-95% with TAVR
Incidence is >95% with TAVR
Correct answer: C

50. Correct answer: A Question # 3
Clean TAVI evaluating Claret embolic protection system versus control group post TAVR used following TAVR valve:
A. CoreValve
B. Sapien-3 valve
C. Sapien XT valve
D. Lotus valve
Correct answer: A