Expanding Indications for TAVR – What Should Be Next? Michael J. Reardon, M.D. Professor of Cardiothoracic Surgery Allison Family Distinguish Chair of Cardiovascular Research Houston Methodist DeBakey Heart & Vascular Center

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. Affiliation/Financial Relationship Company Consulting Fees/Honoraria MEDTRONIC

Michael J. Reardon, M.D. Serve on the executive steering committees of; Corevalve Extreme and High risk, SURTAVI, Medtronic Low Risk, Reprise III and Reprise IV National PI SURTAVI Medtronic low risk Reprise III Reprise IV

TAVR was approved in the US for patients with tri leaflet symptomatic severe aortic stenosis. Extreme and high risk are approved for Corevalve/Evolut R and Sapien. Intermediate is approved for Sapien Where do we need to go? Risk Anatomy Physiology Complications

Global TAVR Market Projection Intermediate Risk (Top 33% Surgical Risk) STS ≥ 4 High Risk (Top 10% Surgical Risk) STS ≥ 8 Extreme Risk Inoperable Cohort C Do not treat Low Risk SAVR 80% of patients in STS Database* 14% 6% Piper Jaffrey. 6-21-16. Jefferies 4-26-16. Barclays 4-27-16. UBS 3-21-16. Goldman Sachs 2-19-16. Morgan Stanley 3-7-16. Cannacord Genuity 4-26-16. JP Morgan 4-11-16. Morgan Stanley 3-7-16. Thourani, Annals of Thoracic Surgery, 2015

Asymptomatic Severe AS Multiple Potential New Indications for TAVR Could Add 100,000 more procedures by 2025 Paradigm shift in procedural risk with TAVR creates opportunities to treat a wider spectrum of patients with aortic valve disease Bicuspid Asymptomatic Severe AS Moderate AS with Heart Failure Aortic Insufficiency Planned TAV-in-TAV

Bicuspid Bicuspid aortic valves are the most common congenital valvular abnormality, occurring in 1 % - 2% of the general population with male to female ratio of 2:11 Expect to see more bicuspid patients in younger Aortic valve replacement patients2 Technical Challenges Remain for TAVR Accurate prosthetic sizing to conform to the elliptical bicuspid anatomy Sufficient sealing to achieve trace/none AR 1 Comparison of the effectiveness of TAVI in patients with STENOTIC bicuspid Versus Tricuspid valves –German TAVI registry – Bauer , Linke et al 2 Frequency by Decades of Unicuspid, Bicuspid, and Tricuspid Aortic Valves in Adults Having Isolated Aortic Valve Replacement for Aortic Stenosis, With or Without Associated Aortic Regurgitation William C. Roberts and Jong M. Ko

Asymptomatic Severe Aortic Stenosis with normal EF Risk of Sudden Cardiac Death ~1% ~3.7 fold increase in all-cause mortality (AVR vs. Medical Therapy)1 Watchful waiting for symptoms may result in irreversible ventricular damage Challenges: Patient referral and consent in absence of symptoms Guidelines are not clear Généreux et al. JACC 2016 Nishimura et al. JACC Vol. 63, No. 22, 2014 2014 AHA/ACC Valvular Heart Disease Guideline June 10, 2014:e57–185

Moderate AS with Heart Failure May prevent the development of irreversible damage to the ventricle Potential improved rate of LV regression post AVR Watchful waiting may lead unnecessary delays in treatment Challenges: No Established Criteria in Guidelines Moderate AS patients will require a valve with a large valve area to derive a clinical benefit (>1.5cm²) No clear definition on which Moderate AS Patients will benefit from AVR Dweck M. et. Al. “Markers of left ventricular decompensation in aortic stenosis.” Article in Expert Review of Cardiovascular Therapy · May 2014 Nishimura et al. JACC Vol. 63, No. 22, 2014 2014 AHA/ACC Valvular Heart Disease Guideline June 10, 2014:e57–185

Aortic Insufficiency Surgical AVR is the gold standard and reports of successful TAVR for extreme risk/inoperable patients Technical Challenges Remain for TAVR Stability even in non-calcified valve – Sufficient anchoring Accurate Prosthetic sizing and larger dimensions to conform valve size needs (in the absence of calcium) Prevent valve migration Mortality and Morbidity of Aortic Regurgitation in Clinical Practice Dujardin et al. Circulation 1999

TAV – in – TAV Life time management is key as we start to implant TAVR in younger patients – more patients expected to be a recipient of more than one TAVR in their lifetime. Technical Challenges Remain for TAVR Positional Accuracy - Implant depth No migration upon implant Good combined hemodynamics outcome Sufficient perfusion to the coronaries & allow future access to coronaries

SURTAVI Intermediate Risk Trial will be presented at ACC 2017 Low Risk

PARTNER 3 CoreValve Evolut R Low Risk, Symptomatic AS STS <4 Age >65 years RCT- TAVR vs SAVR 1,228 patients Nested Registries-3 50 Sites One year Composite Endpoint Death Stroke Rehospitalization 4D CT Imaging Substudy -400 patients CoreValve Evolut R Low Risk Symptomatic AS STS < 3 No Age Floor RCT – TAVR vs. SAVR 1,200 patients 80 sites Two Year Endpoint Death Disabling Stroke Adaptive Design 4D CT Imaging Study- 400 Patients

Anatomy Bicuspid Larger valves

For bicuspid valves the question is anatomy and will the TAVR valve work in this anatomy Risk level is not important to the anatomy

Physiology What has already been tested? Dialysis dependent renal failure Valve in Valve Severe MR and/or TR LF/LG AS

Physiology What needs to be tested? AI Asymptomatic AS Moderate AS

Necessary if we want to expand other indications Complications Necessary if we want to expand other indications PVL Pace maker Leaflet motion abnormality Durability

Conclusions –What Next? Low Risk Bicuspid valves Larger valves AI Asymptomatic AS Moderate AS

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