Martin B. Leon, MD

Columbia University Medical CenterCardiovascular Research Foundation

New York City

Sunday, October 29, 2017

12 mins

CACI in Partnership with TCT: 40 Years of Interventional Cardiology

Disclosure Statement of Financial InterestTCT 2017 Denver, CO; Oct 29 – Nov 2, 2017

Martin B. Leon, MD

Within the past 12 months, I or my spouse/partner have had a financial

interest/arrangement or affiliation with the organization(s) listed below.

• Grant / Research Support Abbott, Boston Scientific, Edwards

Lifescience, Medtronic

• Consulting Fees / Honoraria Abbott, Boston Scientific

• Shareholder / Equity Cathworks, Claret, Elixir, GDS, Medinol,

Mitralign, Valve Medical

Affiliation / Financial Relationship Company

History

TAVR in Perspective

TAVR in Perspective

History• The “proof-of-concept” first TAVI case

performed by Alain Cribier and his team in Rouen, FR deserves special attention on this 15th year anniversary!

MR

Antegrade Approach:

Guidewire Position

in LV

Valve Positioning

April 16, 2002; FIM-TAVI, Transseptal

April 16, 2002; FIM-TAVI, Transseptal

15 min Post-TAVI

April 16, 2002; FIM-TAVI, Transseptal

Current Role

TAVR in Perspective

TAVR in Perspective

Current Role

• Explosive growth in TAVR worldwide

SOURCE: Credit Suisse TAVI Comment –January 8, 2015. 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

This year > 100,000 and by 2025 almost 300,000!

Estimated Global TAVR Growth

TAVR in Perspective

Current Role

• Explosive growth in TAVR worldwide

“Drivers” of TAVR Growth

1. commitment to evidence-based medicine

2. rapid technology advancement

3. simplification of the procedure

4. striking reduction in complications

2010

2011

2012

2013

2014

2015

2016

Published

Upcoming

Low Intermediate High Extreme

NOTION

PARTNER 3

US Evolut R LR

PARTNER 2A

SURTAVI

PARTNER 1A

Corevalve US HR

PARTNER 1B

Corevalve US ER

REPRISE 3

Symptomatic AS: SAVR Risk

SALUS (stopped)

PORTICO IDE

Medtronic CoreValve/Evolut R

Edwards Sapien/Sapien XT/S3

Boston Lotus

Direct Flow Medical Direct Flow

Abbott Vascular Portico

PARTNER 2 S3i

UK TAVI

Any available TAVR system

2017

2018

2019

2017

REBOOT

CHOICE

PARTNER 2 S3

Investigational devices

SOLVE-TAV

Pipeline of TAVR Trials across the spectrum of aortic stenosis

SCOPE 1

Symetis Acurate Neo

SCOPE 2

NOTION 22020

2021

AS with no

symptoms

TAVR UNLOAD

EARLY TAVR

PARTNER 2B

24 TAVRRCTs

Capodanno D, Leon MB. EuroIntervention 2016

Since 2007, in the U.S., > 15,000 patients have been

enrolled in FDA studies (including 10 RCTs) with multiple generations

of four different TAVR systems!

TAVR Systems with CE-Approval (2007-15)

Courtesy of S. Windecker

TAVR Newcomers Global Landscape (#25)

• Sapien 3

• Evolut R

• Lotus

• Acurate

• Portico

• Direct Flow

• Engager

• Jena Valve

• Centera

• Venus A Valve

• J – Valve Ausper• VitaFlow (Microport)• Taurus One• Trinity• Colibri• Inovare• Thubrikar• Valve Medical• Triskele• BioValve (Biotronik)• MyVal (Meril Lifescience)• HLT Meridian• NVT (Nautilus)• Xeltis• Zurich TEHV

CurrentLeaders!

Future Contenders?

• Dual, independent filter (proximal and distal) cerebral embolic protection device with visible embolic debris capture and removal

• The 3rd generation CE-marked embolic protection device

• Universal size and shape

• Deflectable compound curve sheath facilitates cannulation of LCC

• Right transradial 6F sheath access using a standard 0.014” guidewire

• Filters are out of the way of TAVI delivery catheter and accessories during the TAVI procedure

Proximal Filter(Innominate Artery)

9–15 mm

Distal Filter(LCC Artery)

6.5–10 mm

TAVR Accessory DevicesCerebral Embolic Protection (CEP)

The Minimalist Strategy No general anesthesia; use “conscious sedation”

(MAC) with attendant anesthesiologist

No TEE, but available TTE support

Percutaneous TF access with percutaneous closure

Minimize IV lines, no Foley catheters, careful sedation and pain meds

No ICUs… monitor in recovery area

Rapid ambulation and early discharge plans (1-2 dys)

TAVR Perspectives

> 70% of TAVR cases worldwide aregood candidates for a “minimalist”procedural strategy!Median LOS after TAVR is 2 days atColumbia-NYP Hospital!

6.3%

5.2%

3.7%4.5%

3.5%

2.2%1.6%

1.1% 1.1%

0%

5%

10%

15%

20%

P1B (TF) P1A (All) P1A (TF) P2B (TF) P2B XT (TF) S3HR (All) S3HR (TF) S3i (All) S3i (TF)

All-Cause Mortality at 30 DaysEdwards SAPIEN Valves (As Treated)

175 344 240 271 282 583 491 1072 947

SAPIEN SXT SAPIEN 3

PARTNER 1 and 2 Trials(Overall and TF Patients)

Strokes (All) at 30 DaysEdwards SAPIEN Valves

6.7%

5.6%

4.1% 4.3%

1.5%

2.6%

0%

5%

10%

15%

20%

P1B (TF) P1A (All) P2B (TF) P2B XT (TF) S3HR (All) S3i (All)

179 344 276 284 583 1076

SAPIEN SAPIEN XT SAPIEN 3

Neurologist evaluations (pre- and post)

PARTNER 1 and 2 Trials(Overall and TF Patients)

Moderate/Severe PVL at 30 DaysEdwards SAPIEN Valves

12.0% 11.5%

16.9%

24.2%

2.9%4.2%

0%

10%

20%

30%

40%

50%

P1B (TF) P1A (Overall) P2B (TF) P2B XT (TF) S3HR (Overall) S3i (Overall)

179 344 276 284 583 1076

SAPIEN SAPIEN XT SAPIEN 3

PARTNER I and II TrialsOverall and TF Patients

TAVR in Perspective

Current Role

• Explosive growth in TAVR worldwide• Evolving recommended use guidelines

and expansion of clinical indications

TAVR GuidelinesThe “New” AHA/ACC Focused Update

Severe AS Symptomatic

Low

Surgical Risk Strata

Intermediate High Prohibitive

TAVR

IA

SAVR or TAVR

IA

SAVR or TAVR

IIa B

SAVR

IB

TAVR GuidelinesThe “New” ESC/EACTS VHD Report

Severe AS Symptomatic

Low

Surgical Risk Strata

Prohibitive

TAVR

IB

SAVR

IB

Intermediate or High

SAVR or TAVR

IB

TAVR Risk AssessmentRisk Stratification Redefined

Low Intermediate HighExtreme/

Inoperable

Traditional

Contemporary

Low Intermediate HighExtreme/inop

erableLower risk Higher risk

Courtesy of N. Piazza

• Bioprosthetic aortic valve failure

• Low-risk patients (? all-comers)

• Low-flow, low-gradient AS

• Bicuspid AV disease

• AS + concomitant disease (CAD, MR, AF)

• Severe asymptomatic AS

• Moderate AS + CHF

• High-risk AR

Expanding TAVR Clinical IndicationsA Transformative Technology

at the Crossroads?

TAVR for Bioprosthetic Valve FailureValve-in-Valve

Webb JG et al. JACC 2017;69:2253-62

• 365 high-risk patients with aortic

bioprosthesis failure treated with TAVR

• 30-day and 1-yr all-cause mortality was 2.7%

and 12.4% respectively

TAVR in Perspective

Current Role

• Explosive growth in TAVR worldwide• Evolving recommended use guidelines

and expansion of clinical indications • The Heart Team is now the central

vehicle for managing patients with complex valve disease

TAVR in Perspective

Current Role

• Explosive growth in TAVR worldwide• Evolving recommended use guidelines

and expansion of clinical indications • The Heart Team is now the central

vehicle for managing patients with complex valve disease

• Acceptance of multi-modality imaging for diagnosis, therapy guidance, and FU

TAVR Accessory DevicesNovel Imaging Systems

Multi-modality Imaging is the RULE!

Angio CTA

TTE TEE + 3D

The Future

TAVR in Perspective

TAVR in Perspective

The Future

• Improved disease awareness and access to TAVR (esp. underserved populations)

AS Based on Surgical Experience

(1) Nkomo 2006, Iivanainen 1996, Aronow 1991, Bach 2007, Freed 2010, Iung 2007, Pellikka

2005, Brown 2008, Thourani 2015,

Age

Pa

tie

nts

2015 Severe Symptomatic AS Patients in the U.S.1

Age

Pa

tie

nts

2015 Severe Symptomatic AS Patients in the U.S.1

(1) Nkomo 2006, Iivanainen 1996, Aronow 1991, Bach 2007, Freed 2010, Iung 2007, Pellikka

2005, Brown 2008, Thourani 2015,

AS Including the TAVR Experience

Age

Pa

tie

nts

2015 Severe Symptomatic AS Patients in the U.S.1

(1) Nkomo 2006, Iivanainen 1996, Aronow 1991, Bach 2007, Freed 2010, Iung 2007, Pellikka

2005, Brown 2008, Thourani 2015,

AS Patients Undiagnosed and Untreated

TAVR in Perspective

The Future

• Improved disease awareness and access to TAVR (esp. underserved populations)

• Further innovation of TAVR platforms (e.g. tissue engineered heat valves)

Zurich Tissue Engineered Heart Valve

Courtesy of Simon P. Hoerstrup, MD, PhD

A “Living” Aortic Valve

XeltisEndogenous Tissue Restoration (ETR)

• Synthetic matrix made of novel biobsorbable supramolecular polymers using electrospinning techniques

• Polymer leaflets mounted on nitinol self-expanding frame

• Regrowth of endogenous tissue coincident with bioabsorption of polymer implant

• Natural self-healing anti-inflammatory leafletsValve after

bioabsorption

XeltisEndogenous Tissue Restoration (ETR)

Animal implant

• Synthetic matrix made of novel biobsorbable supramolecular polymers using electrospinning techniques

• Polymer leaflets mounted on nitinol self-expanding frame

• Regrowth of endogenous tissue coincident with bioabsorption of polymer implant

• Natural self-healing anti-inflammatory leaflets

TAVR in Perspective

The Future

• Improved disease awareness and access to TAVR (esp. underserved populations)

• Further innovation of TAVR platforms (e.g. tissue engineered heat valves)

• Realization of ‘completely’ new clinical indications for TAVR - leveraging the advantages of less-invasive Rx

EARLY TAVR TrialStudy Flow

Stress-Test Abnormal

Treadmill Stress-Test

Asymptomatic Severe AS and 2D-TTE (PV ≥4m/s or AVA ≤1 cm2) Exclusion if patient is symptomatic, EF<50%, concomitant surgical indications, bicuspid valve, or STS >8

Stress-Test Normal

Early-TAVR Randomized Trial

CTA and Angiography

TF- TAVR eligibility

Randomization 1:1Stratified by STS (<3 vs >3)

TF- TAVRClinical

Surveillance

Early TAVR Registry

Primary Endpoint (superiority): 2-year composite

of all-cause mortality, all strokes, and repeat

hospitalizations (CV)

Heart Failure

LVEF < 50%

NYHA ≥ 2

Optimal HF

therapy

(OHFT)

Moderate AS

International

Multicenter

Randomized

TAVR

UNLOAD

Trial

R

TAVR +

OHFT

OHFT

Alone

Follow-up:

1 month

6 months

1 year

Clinical

endpoints

Symptoms

Echo

QoL

Primary EndpointHierarchical occurrence of: All-cause death Disabling stroke Hospitalizations for

HF, aortic valve disease

Change in KCCQ

Reduced AFTERLOAD

Improved LV systolic

and diastolic function

TAVR UNLOAD TrialStudy Design

(600 patients, 1:1 Randomized)

TAVR in Perspective

The Future

• Re-defining AS disease classification, pathophysiology, and “trigger points” for intervention

LMP Ventricular Load

PWA Vascular State

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

0 1 2 3 4

Mo

du

lus

(Dyn

es*

s/cm

^2)

Harmonic

Impedance spectrum

Enhanced Prediction Models• Predict who will better benefit

from TAVR• Decide when is the best timing

of intervention

Refine characterization of CV dynamics

to enable

MIT - CRF Collaboration

Redefine the Pathophysiology

TAVR in Perspective

The Future

• Re-defining AS disease classification, pathophysiology, and “trigger points” for intervention

• There are still important knowledge gaps with TAVR which must be resolved (esp. valve leaflet thickening & thrombosis, durability, and optimal adjunctive pharmacotherapy)

Valve Leaflet Abnormalities

Diastole

Systole

Makkar, et al. NEJM 2015

All TAVR systems will certainly demonstrateevidence of valve degeneration during long-term (> 5 years) assessments, especially if echo criteria

are applied in the definitions of durability!

Surgically explanted Sapien and CorveValve THVs

New EU guidance with standardized definitions and endpoints to assess bioprosthetic aortic valve deterioration and failure

Capodanno D et al. Europ Heart J 2017

TAVR Adjunct PharmacologyCustomized Patient-Based Therapy

TAVR is a breakthrough therapy

for our patients!

92 yo man withcritical AS…#1 TAVR at Columbia-NYP

• severe COPD• creat 2.8• previous CABG

(patent LIMA)• EF 30%• Class IV CHF• STS 15.5%