The TAVI Journey: Update on Evidence And Future trials

Transcription

1 The TAVI Journey: Update on Evidence And Future trials Philippe Généreux, MD Interventional Cardiologist, Hôpital du Sacré-Coeur de Montréal, Canada Director, Angiographic Core Laboratory, Cardiovascular Research Foundation, New York, NY Co-Director, Structural Heart Program, Morristown Medical Center Columbia University Medical Center, New York, NY TCT Argentina 2016 Thursday October 13 th

2 Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below Edwards LifeSciences Consultant, Speaker Fees, Proctor, Research grant Boston Scientific Research grant Abbott Vascular Consultant, Speaker Fees Cardiovascular System Inc. Consultant, Speaker Fees, Research Grant Soundbite Medical Inc. Consultant

3 Agenda The Current Evidence The Future Evidence!

4 Current Guidelines for TAVR? Class I Severe Aortic Stenosis TAVR is recommended in patients who meet an indication for AVR who have a prohibitive risk for surgical AVR and a predicted post- TAVR survival greater than 12 months Class IIA TAVR is a reasonable alternative to surgical AVR in patients who meet an indication for AVR and who have high surgical risk for surgical AVR Nishimura et al. J Am Coll Cardiol. 2014; 63(22):e57-185

5 TAVR is Available in More Than 65 Countries Around the World >250,000 total implants to date

6 Estimated Global TAVR Procedure Growth SOURCE: Credit Suisse TAVI Comment January 8, ASP assumption for 2024 and 2025 based on analyst model. Revenue split assumption in 2025 is 45% U.S., 35% EU, 10% Japan, 10% ROW In the next 10 years, TAVR growth will increase X4!

7 NO ONE Likes Surgery (of any kind)!

8 Medicare AV Cases in 2015 TAVR now accounts for 32% of all AV replacements SAVR Tissue SAVR Mech TF TAVR TA TAVR SOURCE: FY2015 MedPAR, all cases on file regardless of IPPS status

9 TAVR Underutilization is Largely Driven by Variation in Health Policy and Reimbursement 2015 Country TAVR Penetration Total TAVR Units / Millions of Inhabitants SOURCE: Eurostat, U.S. Census Bureau, Industry estimates 9

10 Procedural efficiencies are reducing TAVR costs in the US Total index hospitalization cost* (TF TAVR) $ $ $ $ $ $ PARTNER Cohort B MedPAR 2013 MedPAR 2014 MedPAR 2015 MedPAR 1 2 Length of stay (TF TAVR) Emory optimized approach 10.1 days 8.1 days 7.9 days 7.1 days 6.4 days 3.0 days *Index hospitalization cost adjusted to reflect commercial device price Reynolds et al.,cost Effectiveness of Transcatheter Aortic Valve Replacement Compared with Standard Care. Circulation. 2012;125: Babaliaros et al., Comparison of a Minimalist Approach Transfemoral TAVR with Standard Approach Transfemoral TAVR. J Am Coll Cardiol. 2014;63(12_S)

11 TAVR in 2016 for Who?

12 Who are we currently treating? The severe AS/TAVR Population Old very old Frail Lot of comorbidities Prior CABG CKD Severe COPD PVD Remission of cancer But still alive and enjoying life!

13 Futile TAVR Categories (risk is a continuum) Operable AS patients Surgery (AVR) ~65% Low Risk Not Yet ~25% Intermed Risk TAVR in 2016 equipoise TAVR or AVR Current TAVR TAVR Clinical Use ~10% High Risk OK Extr Risk* preferred Too Sick No * Extreme risk = inoperable

14 Potential TAVR Population My Favorite Drink = Double-shot Mocha Latte

15 Potential TAVR Population STS database (141,905 pts) 6.2% 13.9% High risk (STS > 8%) Intermediate risk (STS 4-8%) 79.9% Low risk (STS <4%)

16 Potential TAVR Population STS database (141,905 pts) 6.2% 13.9% High risk (STS > 8%) Intermediate risk (STS 4-8%) PARTNER 1A, 1B CoreValve Extreme/High-Risk 79.9% Low risk (STS <4%)

17 All Cause Mortality (%) All Cause Mortality (ITT) Inoperable or Extreme risk: PARTNER 1B 100% 80% Standard Rx TAVR HR [95% CI] = 0.53 [0.41, 0.68] p (log rank) < % 80.9% 26.8% 60% 50.8% 25.0% 40% 20.1% 43.0% 54.1% NNT = 3.7 pts 20% 30.7% NNT = 5.0 pts NNT = 4.0 pts 0% Months Numbers at Risk Standard Rx TAVR

18 All-Cause Mortality (ITT) All Patients High Risk: PARTNER 1A HR [95% CI] = 1.04 [0.86, 1.24] p (log rank) = % 62.4% Error Bars Represent 95% Confidence Limits No. at Risk TAVR SAVR

19 Potential TAVR Population STS database (141,905 pts) 6.2% 13.9% High risk (STS > 8%) Intermediate risk (STS 4-8%) PARTNER 2A, S3i SURTAVI, UK TAVI 79.9% Low risk (STS <4%)

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21 All-Cause Mortality or Disabling Stroke (%) Primary Endpoint (ITT) All-Cause Mortality or Disabling Stroke Surgery TAVR HR [95% CI] = 0.89 [0.73, 1.09] p (log rank) = % % 16.4% 14.5% 19.3% 0 6.1% Number at risk: Months from Procedure Surgery TAVR

22 All-Cause Mortality or Disabling Stroke (%) TF Primary Endpoint (AT) All-Cause Mortality or Disabling Stroke TF Surgery TF TAVR HR: 0.78 [95% CI: 0.61, 0.99] p (log rank) = % 20.0% % 11.7% 16.3% 0 4.5% Number at risk: Months from Procedure TF Surgery TF TAVR

23 Sapien 3 THV Intermediate Risk

24 SAPIEN Platforms in PARTNER Device Evolution SAPIEN SAPIEN XT SAPIEN 3 Valve Technology Sheath Compatibility 22-24F 16-20F 14-16F Available Valve Sizes 23 mm 26 mm 23 mm 26 mm 29 mm 20 mm 23 mm 26 mm 29 mm

25 SAPIEN 3 THV Frame design Enhanced frame geometry for low delivery profile High radial strength for circularity Low frame height Respects the cardiac anatomy Bovine pericardial tissue Scalloped leaflet shape CE ThermaFix* process is intended to minimize the risk of calcification Inner Skirt Polyethylene terephthalate (PET) Outer skirt PET outer skirt designed to reduce paravalvular leak

26 All-Cause Mortality (%) Unadjusted Time-to-Event Analysis All-Cause Mortality (AT) 40 P2A Surgery SAPIEN 3 TAVR % % 1.1% 7.4% Number at risk: P2A Surgery S3 TAVR Months from Procedure

27 Mortality and Stroke (%) PARTNER 2A/S3i Mortality and Stroke - TF (AT) Surgery (TF) SAPIEN XT TF SAPIEN 3 TF % 14.3% % Number at risk: SAPIEN 3 TF SAVR TF SAPIEN XT TF Months from Procedure

28 Other Unadjusted Clinical Outcomes At 30 Days and 1 Year (AT) Events (%) TAVR (n = 1077) 30 Days 1 Year Surgery (n = 944) TAVR (n = 1077) Surgery (n = 944) Re-hospitalization MI Major Vascular Complication AKI (Stage III) Life-Threatening/Disabling Bleeding New Atrial Fibrillation New Permanent Pacemaker Re-intervention Endocarditis

29 Paravalvular Regurgitation 3-Class Grading Scheme (VI) P < P < % Moderate 1.5% 80% Mild 39.8% 60% 40% Severe Moderate Mild None/Trace 20% 0% TAVR Surgery TAVR Surgery No. of echos 30 Days 1 Year P2A Surgery S3i TAVR

30 The PARTNER 2A and S3i Trial Clinical Implications The conclusions from the PARTNER 2A randomized trial and this propensity score analysis provide strong evidence that in intermediate-risk patients with severe aortic stenosis, SAPIEN 3 TAVR compared with surgery improves clinical outcomes and is the preferred therapy.

31 Potential TAVR Population STS database (141,905 pts) 6.2% High risk (STS > 8%) 13.9% Intermediate risk (STS 4-8%) 79.9% Low risk (STS <4%) NOTION All Comers, PARTNER 3 LR, CoreValve LR

32 All-cause Mortality MI, or Stroke (%) NOTION: Death (all-cause), Stroke or MI at 1 Year (as-treated) 20% SAVR TAVR P value (log rank) = % 15.7% 10% 11.9% 11.3% 5% 6.3% No. at risk: TAVR SAVR 0% Months Post-procedure

33 Low Risk PARTNER Trial Balloon Expandable THV

34 The PARTNER 3 Trial Study Design Symptomatic Severe Calcific Aortic Stenosis Low Risk ASSESSMENT by Heart Team (STS < 4%, TF only) TF - TAVR (SAPIEN 3) 1:1 Randomization (n=1228) Surgery (Bioprosthetic Valve) PARTNER 3 Registries Alternative Access (n=100) (TA/TAo/Subclavian) CT Imaging Sub-Study (n=200) Actigraphy/QoL Sub-Study (n=100) CT Imaging Sub-Study (n=200) Actigraphy/QoL Sub-Study (n=100) Bicuspid Valves (n=100) PRIMARY ENDPOINT: Composite of all-cause mortality, all strokes, or re-hospitalization at 1 year post-procedure ViV (AV and MV) (n=100) Follow-up: 30 days, 6 mos, 1 year and annually through 10 years

35 Potential TAVR Population After PARTNER 3 Completion You will need a 2 nd Coffee! 6.2% 13.9% High risk (STS > 8%) Intermediate risk (STS 4-8%) 79.9% Low risk (STS <4%)

36 TAVR Journey st Final Thoughts Are We There Yet? The ultimate role of TAVR is yet to be determined. But we can foresee a future time when the use of TAVR (vs. surgery) will be a risk-benefit assessment based upon clinical and anatomic factors, and not an imprecise risk stratification model!

37 TAVR New Indications?

38 New Indications for TAVR? Where SAVR already succeeded Symptomatic Severe AS for intermediate-risk Symptomatic Severe AS for low-risk Bicuspid Pure Aortic Regurgitation Concomitant AS and CAD Concomitant AS and other valvular/heart disease Where SAVR makes sense but is struggling Asymptomatic Severe AS Symptomatic Moderate AS Severe AS in shock

39 Why TAVR could go where SAVR did not? How TAVR different than SAVR? Less invasive Less peri-procedural mortality and comorbidity Better tolerability in case of instability Immediate recovery Larger effective orifice area (EOA) with TAVR vs. SAVR

40 Aortic Stenosis Spectrum: Future TAVR Indications Mild Moderate AS Moderate AS Severe AS Severe AS AS Symptoms - Symptoms + Symptoms - Symptoms + PARTNER Trials ~

41 Strategy Trials EARLY TAVR: Severe Asymptomatic AS TAVR-UNLOAD: Moderate AS with Heart Failure

42 Severe Asymptomatic Aortic Stenosis

43 Recommendations and Levels of Evidence for Diagnosis, Follow-up, and Timing of Aortic Valve Replacement in Patients With Asymptomatic Severe Aortic Stenosis ACC/AHA ESC/EACTS Indications for aortic valve replacement Left ventricular ejection fraction 50% I, B I, C Undergoing other cardiac surgery I, B I, C Symptoms on exercise test clearly related to aortic stenosis I, B I, C Decreased exercise tolerance IIa, B IIa, C Exercise fall in systolic blood pressure IIa, B IIa, C Very severe AS (PV 5.0 m/s [ACC]; >5.5m/s [ESC] and low surgical risk IIa, B IIa, C Rate of PV progression 0.3 m/s per year and low surgical risk IIb, C IIa, C 3 Class I indications 3 Class IIa indications Level of evidence B or C No Randomized trial Diagnostic Follow-up Repeatedly markedly elevated natriuretic peptide and low surgical risk - IIb, C Increase of MG with exercise by >20 mmhg and low surgical risk - IIb, C Excessive LVH in the absence of hypertension and low surgical risk - IIb, C Transthoracic echocardiography as the initial diagnostic modality I, B - Exercise testing IIa, B - Exercise echocardiography IIa, B - Echocardiography every 6-12 months 1, C - ACC = American College of Cardiology; AHA = American Heart Association; EACTS = European Association for Cardio-Thoracic Surgery; European ESC = European Society of Cardiology Nishimura et al. J Am Coll Cardiol. 2014; 63(22):e Vahanian et al. Eur Heart J. 2012; 33(19):

44 ACC/AHA and ESC/EACTS Guidelines Asymptomatic Severe AS MG 40mmhg, AVA 1.0 cm2 and EF >50% Limiting Symptoms Angina Syncope Dyspnea Exercise Testing (ACC/AHA Class IIa) Decrease exercise tolerance Abnormal SBP response (drop or <20mmhg rise) PV 5m/s (ACC/AHA) or 5.5m/s (ESC): Class IIa PV progression 0.3m/s/year: ACC/AHA IIb and ESC Class IIa Severe LVH: ESC Class IIb Repeatedly markedly elevated BNP: ESC Class IIb Exercise Imaging (ACC/AHA class IIa) Increase in MG with exercise by >20 mm Hg ACC/AHA Class I ESC Class I ACC/AHA Class IIa ESC Class IIa ESC Class IIb If Stress test and Stress Echo normal: Clinical and Echo follow-up 6-12 months ACC/AHA Class I Nishimura et al. J Am Coll Cardiol. 2014; 63(22):e Vahanian et al. Eur Heart J. 2012; 33(19):

45 In severe AS, an exercise test was performed in only 5.7% of patients with no symptoms This under-use may be explained by an insufficient implementation of the current guidelines and fear of complications or inexperience in exercise testing Lung et al. Eur Heart J 2003; 24,

46 Why Early SAVR In Asymptomatic Severe AS is Rarely Performed? Sudden Death Severe Asymptomatic AS ~1-2%/year Peri-operative Mortality SAVR ~1-5% TAVR may be a better option for Asymptomatic patients 30-day Mortality Notion Trial all-comers Core Valve TAVR SAVR 2.1% 3.7% 30-day Mortality PARTNER trial 2A Intermediate PM Sapien 3 TAVR SAVR 1.1% 4.0% Généreux et al. J Am Coll Cardiol 2016;67: ; Thourani et al. Lancet 2016; 387: ; Thyregod et al. J Am Coll Cardiol 2015;65:

47 Asymptomatic Severe AS: Rationale for Early AVR Pros Reduce irreversible myocardial damage and subsequent consequences Decreased operative risk for asymptomatic patients AS progression highly variable; potential for a very rapid deterioration Risk of late (or too late) symptoms reporting Sudden death without preceding symptoms Cons Mortality potentially low among a specific subset of low-risk and truly asymptomatic patients with normal stress test and stress echo Frequent follow-up could potentially identified patients ready for AVR in a timely fashion Inherent mortality and morbidity of AVR Long-term complication of AVR (anticoagulation, need for re-op, endocarditis, thrombosis, etc.)

48 Practical Issues with Watchful Waiting Strategy Clinicians still have a fear of stress test with Severe AS patients; low penetration and underused Stress Imaging requires expertise and specific set-up that most community hospitals don t have Sub-optimal follow-up and lost of follow-up are frequent Many sudden deaths occurred in Asx patients with no Class I indication of AVR and no preceding symptoms Wishful Thinking Strategy

49 What is the Prevalence of Asymptomatic Severe AS? ~40-50% of all Severe AS from major echo databases 1,2,3 ~10-20% are bicuspid ~20-25% have multiple valve disease, clinically significant CAD, prior AVR Isolated Asymptomatic Severe AS represents ~25-30% of all Severe AS referred to Echo lab ~500,000 patients >65 years old in US 4 1 Pellikka et al. Circulation. 2005;111: Kitai et al. Heart 2011;97:2029e Pai et al. Ann Thorac Surg 2006;82: Source U.S. Census Bureau, 2014 National Projections.

50 What is the Prognosis of Asx Severe AS Patients?

51 Généreux et al. J Am Coll Cardiol 2016;67:

52 Studies Comparing AVR vs. Observation in Asymptomatic Severe AS Patients; N=2,486 Authors AS definition N Age Female Pellikka et al.1990 Pai et al Kang et al Severe AS; Doppler PV 4m/s Severe AS AVA <0.8cm 2 Very severe AS AVA 0.75 cm 2 AND PV 4.5 m/s or a MG 50 mmhg AVR 113 Medical AVR 239 Medical 197: 102 AVR 95 Medical 72 (mean) 40 to 94 38% Follow-up (median) AVR 21 m Medical 20 m 71±15 49% 3.5 y 63±12 50% AVR 1265 d Medical 1769 d Taniguchi et al Severe AS AVA: <1cm2 MG: >40mmhg PV: >4m/s 1808: 291 AVR 1517 Medical AVR Medical % 1361 d Généreux et al. J Am Coll Cardiol 2016;67:

53 All-Cause Mortality AVR vs. Medical Therapy in Asymptomatic Severe AS; N=2,486 Unadjusted: ~3.5 fold increase in all-cause Mortality Généreux et al. J Am Coll Cardiol 2016;67:

54 Stress Test Severe Asymptomatic AS?

55 Abnormal Stress Test in Asx AS Studies Moderate-Severe AS Severe AS only % Abnormal Stress Test n N Takeda et al % % Abnormal Stress Test Amato et al % Alborino et al % Das et al % Abnormal Stress Test in Asx Severe AS: Range: 26-67% ~50% Abnormal Stress Test Das et al % Lancellotti et al % Peidro et al % Marechaux et al % Lancellotti et al % Lafitte et al % Marechaux et al % Rajani et al % % 7 18 Donal et al % Levy et al % Total % Abnormal Stress test Range: 15-66% Pooled: 36.5% Range: 28-67% Pooled: 48.8% n N Généreux et al. J Am Coll Cardiol 2016;67:

56 Abnormal stress test associated with ~6 fold increase in Cardiac Death Rafique et al. Am J Cardiol 2009;104:

57 Should and could we recommend an early intervention strategy for truly Asymptomatic Severe Aortic Stenosis patients?

58 Low hospital mortality tends to justify a policy of accepting patients for operation earlier in the natural progression of their disability, because it is recognized that there is a definite risk of rapid deterioration or sudden death in the earlier policy of deferring operation patients until their disability had become definite and progressive and until their cardiac reserve was nearly depleted. McGoon DC, Pestana C, Moffitt EA. Arch Surg.1965;Nov,91:

59 Evaluation of Transcatheter Aortic Valve Replacement Compared to SurveilLance for Patients with Severe Aortic Stenosis With or Without SYmptoms: EARLY-TAVR trial EARLY-TAVR trial Philippe Généreux, MD, Patrick T. O Gara, MD; Michael Mack, MD; Robert O. Bonow, MD; Philippe Pibarot, DVM, PhD, Linda D. Gillam, MD; Jeroen J. Bax, MD, PHD; Brian Lindman, MD; Raj Makar, MD, David J. Cohen, MD; Martin B. Leon, MD Principal Investigators: Philippe Généreux, MD, Patrick T. O Gara, MD

60 Asymptomatic Severe AS per questionnaire and 2D-TTE (PV 4m/s and AVA 1 cm 2 ) Exclusion if patients clinically symptomatic, EF<50%, concomitant surgical indications, bicuspid, or STS >10% Clinical and 2D-TTE trial eligibility Treadmill Stress Test Stress Test Normal Stress Test Abnormal CT Scan and Coronarography TF-TAVR eligibility EARLY-TAVR Randomized Trial Low risk Intermediate risk High risk Randomization1:1 Stratified by PV (<5m/s vs. >5m/s) Stratified by STS (<3 vs. >3) P3 trial TAVR as indicated TF-TAVR Medical Observation EARLY-TAVR Registry Follow-up: Clinical and 2D-TTE: 30 days, 1 year, 2 years, and yearly up to 5 years 2D-TTE before TAVR and 1 year post TAVR Primary endpoint (superiority): 2-year composite of death, all stroke, and cardiovascular repeat hospitalization

61 Moderate AS With heart Failure

62 Aortic Stenosis Spectrum: Future Indication Mild Moderate AS Moderate AS Severe AS Severe AS AS Symptoms - Symptoms + Symptoms - Symptoms + EARLY-TAVR PARTNERs Low flow Low gradient low EF no CR Low flow Low gradient Low EF with CR Low flow low gradient normal EF

63 Treatment of Low Flow AS Guidelines Recommendations Classic LF AS with CR Classic LF AS w/o CR Paradoxical LF ESC/EACTS 2012 II a, C II b, C II a, C* ACC/AHA 2014 II a, B II a, B II a, C # But what if you only have moderate AS and still have recurrent symptoms of heart failure despite the most likely cause for symptoms optimal medical therapy? * only after careful confirmation of severe AS # if clinical, hemodynamic, or anatomic data support valve obstruction as Nishimura et al. J Am Coll Cardiol. 2014; 63(22):e Vahanian et al. Eur Heart J. 2012; 33(19):

64 TAVR UNLOAD trial Concept TAVR UNLOAD Trial International Multicenter Randomized Heart Failure LVEF < 50% but >20% NYHA 2 Optimal HF therapy (OHFT) Moderate AS R TAVR + OHFT OHFT alone Follow-up: 1 month 6 months 1 & 2 years Clinical endpoints Symptoms Echo QoL PIs: Nicolas Van Mieghem, Martin B. Leon Sponsor: Edwards Lifesciences

65 Primary endpoint Hierarchical occurrence of All-cause death Disabling stroke Hospitalizations related to heart failure, aortic valve disease or non-disabling stroke Change in KCCQ *To be analyzed with the Finkelstein-Schoenfeld method, 99% Power If FS endpoint is statistically significant, proceed with MACCE endpoint, with sufficient (2-sided α = 0.05) power if 40% endpoints are reached

66 Aortic Stenosis Spectrum: Functional Classification Mild Moderate AS Moderate AS Severe AS Severe AS AS Symptoms - Symptoms + Symptoms - Symptoms + PARTNERs TAVR-UNLOAD EARLY-TAVR Low Int. High -Ext. Active Surveillance TAVR ~ P. Généreux TVT 2016

67 Conclusions: TAVR Future Indications TAVR will go where SAVR went if anatomically suitable TAVR may go where SAVR struggled, failled, or never been before! Severe Asymptomatic AS Moderate Symptomatic AS Unstable severe AS patients

68 With which TAVR devices?

69 TAVR Systems Global Inventory (#25) Sapien 3 Evolut R Symetis Direct Flow Current Lotus Leaders! Portico Engager Jena Valve Centera Venus A Valve Shanghai Valve Trinity Colibri Inovare Thubrikar Valve Medical Syntheon Future Verso Contenders? Triskele BioValve MyVal HLT NVT (Nautilus) J - Valve Xeltis Zurich TEHV

70 TAVR at TCT 2016? Tuesday, November 1 st 5 years Echo follow-up TAVR vs. SAVR Pamela S Douglas, MD Quality of Life PARTNER Trial 2A David Cohen, MD SENTINEL Trial Susheel Kodali, MD

71 Mid Term Hemodynamic Trends and Between Echo Changes in Transcatheter Aortic Valves in the PARTNER 1 Trial: Five Year Results Pamela S. Douglas, MD on behalf of The PARTNER Trial Investigators and The PARTNER Publications Office TCT Washington, DC November 1, 2016

72 Background and Aims TAVR is a safe and effective treatment for severe aortic stenosis THV long term durability, potential for deterioration, and any implications for patient outcomes, are incompletely understood The PARTNER 1 trial provides a rich, existing data resource to address the following two aims: Determine the longitudinal hemodynamic profile of THVs and factors associated with early and mid-term trends Assess the incidence and clinical correlates of large interval changes in valve parameters

73 Health Status Benefits of Transcatheter vs. Surgical Aortic Valve Replacement in Patients with Severe Aortic Stenosis at Intermediate Surgical Risk Results From The PARTNER 2 Trial David J. Cohen, MD on behalf of The PARTNER Trial Investigators and The PARTNER Publications Office TCT Washington, DC November 1, 2016

74 Study Objectives 1. To compare health-related quality of life outcomes among patients with severe AS and intermediate surgical risk treated with either TAVR or SAVR 2. To determine whether the QOL benefits of TAVR vs. SAVR vary over time 3. To examine whether the QOL benefits of TAVR vs. SAVR in the intermediate risk population differ according to access site or other patient characteristics

75 SENTINEL Study Design (TAVR RCT) US Co-PIs: Samir Kapadia Susheel Kodali German Co-PI: Axel Linke Population: Subjects with severe AS with clinical indications for TAVR with the Edwards Sapien THV/XT/S3 or Medtronic CoreValve/Evolut-R N=296 subjects randomized 1:1:1 at sites in the U.S and Germany. SAFETY ARM TAVR with Sentinel TEST ARM TAVR with Sentinel RCT CONTROL ARM TAVR only Histopathology Safety Follow-up Safety Follow-up MRI Assessments Neurological and Neurocognitive Tests Primary (superiority) Efficacy Endpoint: Reduction in median total new lesion volume assessed by 3T DW-MR by baseline subtraction (3-7 days) Primary (non-inferiority) Safety Endpoint: Occurrence of all MACCE at 30 days

76 Thanks! Low risk Intermediate risk High risk