Howard C. Herrmann, MD, FACC, MSCAI - PowerPoint Presentation

1. Howard C. Herrmann, MD, FACC, MSCAIJohn Bryfogle Professor of Cardiovascular Medicine and SurgeryHealth System Director for Interventional CardiologyDirector, Cardiac Cath Labs, Hospital of the Univ of PAPerelman School of Medicine University of PennsylvaniaPhiladelphiaThe SMART Trial(SMall Annuli Randomized To evolut or sapien)

2. Disclosure Statement of Financial InterestWithin the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below:Discussion may include unapproved and off-label devices, procedures, and indicationsStock Shareholder/EquityMicrointerventional DevicesHolistick MedicalConsulting Fees/HonorariaAbbottEdwards LifesciencesMedtronicShockwaveWells FargoInstitutional Grant/Research SupportAbbott Vascular AncoraBayerBoston ScientificCardiovasc Res FoundEdwards LifesciencesHighlifeMedtronicShockwaveSt. Jude MedicalUniv. LavalW.L. GoreEditorialMass. Medical Society

3. What is Important to Young and Low Risk Patients?MortalityStrokeQuality of LifeLongevity/DurabilityHemodynamics

4. OUTLINEAdverse effects of TAVR with suboptimal hemodynamicsLessons from surgeryLessons from TAVRIncidence of small annuli in patients undergoing TAVRComparative hemodynamics of TAVR prosthesesRationale and design of the SMART trial

5. All cause mortalityCardiac mortalityLessons from surgerySevere PPM associated with almost 2-fold increase in all-cause mortality and >6-fold increase in cardiac mortality

6. Bakhtiary et al. JACC 2007Additional Lessons from SurgeryLess PPM is associated with:Better coronary flow reserveMore LV mass regressionBetter exercise toleranceImproved QOL

7. Circulation 2010;121:2123-29564 SAVR followed >6 yrsStructural valve deterioration (SVD) occurred in 7%PPM independent predictor (HR 2.29) of structural valve degeneration

8.

9. Mortality (%)Adjusted HR (95% CI)1.19 (1.09-1.31) p<0.00117.2% Severe15.8% Moderate/None62,125 commercial TAVR 2014-2017

10. HF Rehospitalization (%) US TAVR – All Cause Readmission

11. FemaleAge <75 yr (per 5 yr decrease) >75 yr (per 5 yr decrease)Non-White/HispanicValve-in-Valve ProcedureValve size <23 mmBSA (per 0.2 unit increase)Lower EF (per 5% decrease)Afib/FlutterSevere MRSevere TROdds Ratios (95% CI) for Multivariate Model Predictors of Severe PPM

12. Small Annuli Are Common: SAVR prostheses < 21 mm 1 = 22-44%Use of small TAVR prostheses in randomized trials: Higher in Southern Europe and Asia 1TAV in SAV = 70-80% 6,7Several fold higher in women who make up ~90% of small annulus population 11 Freitas-Ferraz et al, Circ 2017;139:2685 5 Mack et al, NEJM 2019;380:16952 Reardon et al, NEJM 2017;376:1321 6 Dvir et al, JAMA 2014;312:1623 Kodali et al, European Heart J 2016;37:2252 7 Webb et al, JACC 2017;69:22534 Popma et al, NEJM 2019;380:1706Area < 430 mm2(IFU 20/23 mm BE)Perimeter-derived diam < 23.4 mm(IFU 23/26 SE)Intermediate Risk Trials 2,336%22%Low Risk Trials 4,531%21%

13. Self-Expandable Valve for Aortic Stenosis in Small Aortic Annuli: The TAVI-SMALL RegistryPatients with severe AS and small annuli treated with transcatheter self-expandable valves (n = 859; Evolut R, n = 397; Evolut PRO, n = 84; ACURATE, n = 201; Portico, n = 177). 90% of Patients WomenProsthesis-Patient MismatchTranscatheter SEVs showed optimal clinical and echocardiographic results in patients with small aortic annuli. Supra-annular functioning SEVs seemed to outperform intra-annular devices.Regazzoli D et al., JACC Cardiovasc Interv. 2020;Chiarito M, presented at ESC 2020Slide courtesy R. Mehran, MD

14. The authors collected discharge and 30 day echocardiograms from the following clinical trials: Medtronic CoreValve US Pivotal trial, Medtronic CoreValve Evolut R US IDE clinical study, PARTNER 1, PARTNER 2A/2B, and PARTNER 2 S3Methods (BE):Neo LVOT measured 2 sites (outer-to-outer at bottom of stent, in-stent at annulus)PW Doppler at corresponding 2 sites (just apical to stent, within stent)Paired LV SV calculationMethods (SE):Neo LVOT at ventricular tip of prosthesisIf difficult to image, used 2D disc method (modified Simpson’s rule)PW Doppler just apical to stent frameLimitationsFlow acceleration within BE valve may overestimate gradient (outer preferred)If flow around inflow of SE valve (not apposed), then used inner-to-inner PWD JACC CV Imaging, June 2018 (E-pub)

15. A difference between direct measurement and echo-derived pressure gradients have been observed post-TAVI. Pressure recovery is a normal flow phenomenon that occurs in all patients, and is largely affected by stroke volume and size of the ascending aortaClinical practice guidelines do not recommend using the recovered pressure gradient to assess stenosis. Continuous wave Doppler remains the standard for measuring valve performance.measuring hemodynamic performancetav performance vs pressure recoveryDoppler measurement vs echo measurement1Baumgartner et al., Circulation. 1990 Oct;82(4):1467-75; 2Bach et al., J Thorac Cardiovasc Surg. 2012 Aug;144(2):453-8; 3Bahlmann et al., JACC Cardiovasc Imaging. 2010 Jun;3(6):555-62; Pibarot, presented at ACC 2020.

16. In an in vitro study, pressure recovery was shown to occur at similar magnitudes (45%) in self- and balloon-expanding valvesSelf-expanding valves had significantly lower gradients and significantly higher EOAs than balloon-expanding valves when tested in the same annular size and flow conditions.The hemodynamic advantage of self-expanding valves was most pronounced at higher flow conditions that represent stroke volumes during exercise.measuring hemodynamic performancetav performance vs pressure recoveryPibarot, presented at ACC 2020.

17. Randomized TAVR Trials (all annulus sizes at 1 year)Mean Gradient (mmHg)EOA (cm2)JACC 2015;66:791 Lancet 2019;396:669 JAMA 2018;319:27 Lancet 2019;394:1619 Circulation Oct 15, 2020

18. ‒When choosing a TAVR prosthesis, consider the hemodynamic differences on clinical outcomes, durability, and prosthesis-patient mismatch Echo core lab analysis at 30 days: Low risk trials small annulus (lowest 2 quintiles)Hahn et al, JACC CV Imaging 2019;12:25 Mack et al, NEJM 2019;38:1695 Popma et al, NEJM 2019;380:1706

19. Five-Year Follow-Up from the PARTNER 2 Aortic Valve-in-Valve Registries: Clinical Outcomes, Valve Function, and DurabilityHahn et al, TCT Connect 2020SEBEAll-cause mortalityValve-in-valve observational studies suggest differences based on size and prosthesis

20. 20APAC Proctor 8Sept2020Post AVR Gradients are accentuated with exercise (most important in younger and more active patients)Bertrand et al J Am Soc Echocardiogr 2017 30(4): 404-413.• Pibarot P et al JACC 1999;34(5):1609-1617Exercise Gradients by EOA

21. performance of 26 mm Self Expanding THV v 23 mm Balloon Expandable Valves Using Doppler and catheter gradients (IN VITRO)Stanova V et al JACC 2020; 75 (Supplement 1), epubPerformed at 37o C in vitro21Acute Valve Performance and Long-term Structural Valve Deterioration 16-Sep-2020Similar contributions of “pressure recovery” to S3 and EVCath gradients lower than Doppler and lower in low flow conditions

22. Hemodynamic measurement and outcomesDVI (Doppler Velocity Index) Challenges in measuring LVOT by echocardiography may lead to variable association between PPM and outcomes.DVI = measure of obstruction defined by the ratio of LVOT VTI to AV VTI is a better predictor of outcomes.In a pooled analysis of the CoreValve High Risk and SURTAVI clinical data, DVI ≤0.5 was associated with higher mortality at 3 years for both SAVR and TAVI patients. In small native annulus, SE valves have larger DVI than BE prosthesesRationale for DVITAVRVan Mieghem, N, et al. JACC Interv 2020;13:S48.Hahn et al, JACC CV Imaging 2019;12:25 ValveSize (lowest 2 quintiles)DVISapien 3Area < 439 mm2 0.44EvolutDiam < 23.2 mm0.61

23. Expansion of TAVR to younger and lower risk patients emphasizes the need for optimal results - both short and long-termAwareness of the risks of adverse hemodynamics (severe PPM, low DVI, high gradients) is importantThese risks include higher mortality, reduced exercise tolerance, less LV mass regression, impaired exercise tolerance, and worse durabilityThe effects of adverse hemodynamics are amplified in patients:YoungerMore activeThose with small annuli (particularly women)Utilizing the largest prosthesis based on annulus area/perimeter and manufacturer recommendations with the most optimal hemodynamics is key to best outcomes and is the rationale for the SMART TrialConclusions

24. SMART Trial design (SMall Annuli Randomized To evolut or sapien)Prospective, multi-center, international, randomized controlled, post-market study to be conducted in approximately 700 randomized subjects at 90 sites in Canada, EMEA and the United StatesSevere native aortic valve stenosis with a small annulus(< 430 mm2 by MDCT) Medtronic Evolut PRO/PRO+Edwards SAPIEN 3/SAPIEN 3 Ultra30-Day and annual 5-Year follow-ups for all patientsRandomization 1:1 Stratified by SexStudy OrganizationChair/PI: Howard C. Herrmann, MD Co-PIs: Roxana Mehran, MD and Didier Tchetche MDMajor inclusion/exclusion criteriaSmall annulus with all risk groups (low to high)An “all-comers” trial (including bicuspid valves)Patient’s anatomy must be suitable for TF TAVR treatment with both devicesExternal Support(Medtronic)Echocardiographic Core Laboratory, Clinical Events Committee (CEC), Data Safety Monitoring Board (DSMB), Subject Confirmation of Qualification/Case Planning Committee (screening phase)

25. 25SMART Trial designSMART Trial Steering Committee Kick-off | November 2020 | CONFIDENTIALCo-Primary Endpoints: - Mortality, disabling stroke, or rehospitalization (valve-related or worsening of heart failure) at 12 months (non-inferiority) - Bioprosthetic valve dysfunction (BVD) 12 months (superiority)Approximately 600 randomized subjects at90 sites in Canada, EMEA and the United StatesSevere native aortic valve stenosis with a small annulus(< 430 mm2 by MDCT) Medtronic Evolut PRO/PRO+Edwards SAPIEN 3/SAPIEN 3 Ultra30-Day and annual 5-Year follow-ups for all patientsRandomization 1:1 Stratified by Sex

26. 26Inclusion CriteriaSymptomatic subjects with predicted risk of operative mortality < 15% at 30-days per multidisciplinary local heart team assessmentSevere aortic stenosis, defined as: Aortic valve area ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), OR mean gradient ≥40 mmHg, OR maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at restAortic valve annulus area ≤ 430 mm2 based on multi-detector computed tomography (MDCT)Subject's anatomy is appropriate for both Medtronic Evolut PRO/PRO+ TAV and Edwards Sapien 3/Ultra THVSubject’s anatomy is suitable for TAVR via transfemoral vessel accessCommercial indication for transcatheter aortic valve replacement (TAVR), in conformity with both local regulations and Instructions for Use (IFU) Subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits SMART Trial Steering Committee Kick-off | November 2020 | CONFIDENTIAL

27. 27Study Endpoints (Powered)Co-Primary EndpointsPrimary Endpoint #1: mortality, disabling stroke or rehospitalization (valve-related or worsening of heart failure) at 12 months (clinical outcome)Primary Endpoint #2: bioprosthetic valve dysfunction (BVD) at 12 months (valve durability). BVD is defined as a composite of: Hemodynamic Structural Valve Dysfunction (HSVD): mean gradient >20 mmHgNon-Structural Valve Dysfunction (NSVD): severe PPM, ≥ moderate ARThrombosisEndocarditisAortic valve re-operation or re-interventionPowered Secondary Endpoints1. BVD in the female subjects at 12 months2. HSVD in all subjects at 12 months3. Hemodynamic mean gradient (continuous variable) at 12 monthsSMART Trial Steering Committee Kick-off | November 2020 | CONFIDENTIALHSVD and NVSD are based on Echo core lab data, and events thrombosis, endocarditis and aortic valve reintervention are from CEC adjudications. Bioprosthetic Valve Dysfunction Definition:HSVD: hemodynamic SVD: mean gradient ≥20mmHgNSVD: severe PPM, ≥ moderate ARThrombosis (VARC-3): clinically apparent leaflet thrombosis (leaflet thrombus formation associated with clinically relevant hemodynamic changes, symptoms, or sequela compatible with valve thrombosis or thromboembolism)Endocarditis (VARC-3): Duke endocarditis criteria or abscess/pus/vegetation confirmed at reop or autopsyAortic valve re-operation or re-interventionSevere Prosthesis-Patient Mismatch (PPM) DefinitionUsing the VARC-3 definition with obesity correctionFor subjects with BMI < 30 kg/cmSevere PPM: EOAI = ≤ 0.65 cm2/m2For subjects with BMI ≥ 30 kg/cmSevere PPM: EOAI = ≤ 0.55

28. Smart trial overviewTrial NameSMall Annuli Randomized To evolut or sapien (SMART)Study OrganizationChair/PI: Howard C. Herrmann, MD Co-PIs: Roxana Mehran, MD and Didier Tchetche MDPatientsSubjects with symptomatic heart disease due to severe native calcific aortic valve stenosis or failed surgical bioprosthetic aortic valve, and a small annulus appropriate for heart valve replacement therapyStudy DesignProspective, multi-center, international, randomized controlled, post-market study Randomization 1:1 randomization to either a Medtronic self-expandable (SE) or an Edwards balloon expandable (BE) TAV DevicesEvolut PRO and PRO+ vs. Sapien 3 and Sapien 3 UltraSample SizeApproximately 600 subjects implanted at 90 sites in Canada, and EMEA and the United StatesCo-Primary EndpointsTAV Native Cohort (n=600) Primary Endpoint #1: mortality, disabling stroke, or rehospitalization (valve-related or worsening of heart failure) at 12 months Primary Endpoint #2: bioprosthetic valve dysfunction (BVD) at 12 months. BVD is defined as a composite of: Hemodynamic Structural Valve Dysfunction (HSVD): mean gradient >20 mmHgNon-Structural Valve Dysfunction (NSVD): severe PPM, ≥ moderate PVLThrombosisEndocarditisAortic valve re-operation or re-intervention.Major inclusion/exclusion criteriaSmall annulus with all risk groups (low to high)An “all-comers” trial (including bicuspid valves)Patient’s anatomy must be suitable for TF TAVR treatment with both devicesExternal SupportEchocardiographic Core Laboratory, Clinical Events Committee (CEC), Data Safety Monitoring Board (DSMB), Subject Confirmation of Qualification/Case Planning Committee (screening phase)

29. SMART Trial design (SMall Annuli Randomized To evolut or sapien)Prospective, multi-center, international, randomized controlled, post-market study to be conducted in approximately 600 randomized subjects at90 sites in Canada, EMEA and the United StatesSevere native aortic valve stenosis with a small annulus(< 430 mm2 by MDCT) Medtronic Evolut PRO/PRO+Edwards SAPIEN 3/SAPIEN 3 Ultra30-Day and annual 5-Year follow-ups for all patientsRandomization 1:1 Stratified by SexStudy OrganizationChair/PI: Howard C. Herrmann, MD Co-PIs: Roxana Mehran, MD and Didier Tchetche MDMajor inclusion/exclusion criteriaSmall annulus with all risk groups (low to high)An “all-comers” trial (including bicuspid valves)Patient’s anatomy must be suitable for TF TAVR treatment with both devicesExternal Support(Medtronic)Echocardiographic Core Laboratory, Clinical Events Committee (CEC), Data Safety Monitoring Board (DSMB), Subject Confirmation of Qualification/Case Planning Committee (screening phase)