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

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

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

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: 3.4% EuroScore II risk: 3.15% 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

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%

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°°

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

CTA: Access – 3D

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

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

SAPIEN Platforms in PARTNER Trials Device Evolution

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.

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

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

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

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

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

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

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

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

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

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

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

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 (4.69 - 15.73) 6.97 (2.03 - 23.93) 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

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

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

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

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

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)

The SENTINEL Trial S Kodali, TCT 2016

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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