Expanding Indications of TAVR:

Ongoing Trials and Expectations

Alan C. Yeung, MD

Li Ka Shing Professor of Medicine

Chief (Clinical), Division of Cardiovascular Medicine

Stanford University School of Medicine

Disclosure Statement of Financial Interest

• Grant/Research Support • Scientific Advisory Board • Executive Physician Council

• Edwards Lifesciences, Abbott • Medtronic, Abbott • Boston Scientific Corp

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

Estimated Global TAVR Growth

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

In the next 10 years, TAVR growth will increase X4!

TAVR Clinical Evidence

Capodanno D and Leon MB. EuroIntervention 2016;12:Y1-Y5.

19 Studies

Primary Endpoint

0 3 6 9 12

496 475 467 462 456 454 408 390 381 377

Number at risk:

TAVR Surgery

Months after Procedure

451 374

TAVR Surgery

Psuperiority= 0.001

HR [95% CI] =

0.54 [0.37, 0.79]

Death

, S

troke, or

Rehosp (

%)

Pnon-inferiority< 0.001

Upper 95% CI of

risk diff = -2.5%

8.5% 9.3%

15.1%

4.2%

0

10

20

The PARTNER 3 Trial

High

Risk

Interm

Risk

Extreme

Risk

Low

Risk

PARTNER 1B

PARTNER 1A PARTNER 2A

PARTNER 3 • RCT 1:1

• vs. Standard Rx

• N = 358 pts

• RCT 1:1

• vs. SAVR

• N = 699

pts

• RCT 1:1

• vs. SAVR

• N = 2032 pts

• RCT 1:1

• vs. Surgery

• N = 1000 pts

79.9%

13.9%

6.2%

Intermediate risk

(STS 4-8%)

Low risk

(STS <4%)

High risk

(STS > 8%)

STS database 2002-2010 (141,905 pts)

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

have been enrolled in FDA studies

(including 6 RCTs) with multiple generations of

two TAVR systems!

• Bioprosthetic aortic valve failure (Low and Inter risk)

• Bicuspid AV disease

• Moderate AS + CHF

• Severe asymptomatic AS

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

• High-risk AR

Expanding TAVR Clinical Indications A Transformative Technology

at the Crossroads?

Mortality After VIV TAVR

Dvir, et al. JAMA. 2014; 312(2):162-170

The smaller the surgical valve, the higher the mortality!

VIV TAVR case

21 mm Magna (true ID 19 mm) treated with 23 mm CoreValve Evolut

Baseline Mean gradient: 36 mmHg Aortic valve area: 0.8 cm2

After VIV TAVR Mean gradient: 26 mmHg Aortic valve area: 1.2 cm2

Bioprosthetic Valve Fracture

Final Hemodynamics

Mean gradient: 9 mmHg Aortic valve area: 1.6 cm2

Clinical Results

0

20

40

60

80

40.6 ± 16 p<0.001

8.1 ± 4.8

Baseline After VIV TAVR After BVF

19.0 ± 8.8

p<0.001

Me

an

Re

sid

ua

l G

ra

die

nt

(mm

Hg

)

0

0.5

1

1.5

2

2.5

0.8 ± 0.3

p<0.001

2.1 ± 0.8

Baseline After VIV TAVR After BVF

1.4 ± 0.8

p<0.001

Me

an

Va

lve

EO

A (

cm

2)

66 Patients undergoing VIV TAVR followed by BVF

Presented by Keith B. Allen, Western Thoracic Society Annual Meeting, 2018

The BASILICA Trial: Prospective multi-center investigation of

intentional leaflet laceration to prevent TAVR coronary obstruction

NCT03381989

Jaffar M. Khan BM BCha,b

Adam B Greenbaum MDc,d, Vasilis C Babaliaros MDc,, Toby Rogers BM BCh PhDa,b, Marvin HK Eng MDd, Gaetano Paone MDd, Bradley G Leshnower MDc, Mark Reisman MDe, Lowell Satler MDb, Ron Waksman MDb, Markus Y Chen MDa, Annette M Stine RNa, Xin Tian PhDa, Danny Dvir MDe , Robert J Lederman MDa

a: Division of Intramural Research, National Heart Lung & Blood Inst (NHLBI); b: Medstar Washington Hospital Center; c: Emory University Hospital; d: Henry Ford Hospital; e:

University of Washington jaffar.khan@n

ih.gov

CENTRAL ELIGIBILITY COMMITTEE CRITERIA FOR

CORONARY OBSTRUCTION

Criteria 1 Coronary Ostia Occlusion

• Are aortic leaflets higher than the

coronary ostia? AND

• Is the VTC <4mm?

Criteria 2 Sinus Sequestration

• Do aortic

leaflets reach

the STJ? AND

• Is there risk of sealing the

STJ (by visual assessment

with virtual valve)?

Features that mitigate risk

• Native aortic valves

• Bioprosthetic valves with internally

mounted porcine leaflets

• Functional coronary artery bypass grafts

Features that accentuate risk

• Externally mounted bioprosthetic valve leaflets

• Stentless bioprosthetic valves

• Bioprosthetic valve fracture planned

• Absent coronary filling on BAV angiography

1Ribiero et al JACC 2013

Incidence of BAV in Isolated SAVR

Roberts, WC. Circulation 2005;111:920-925

2 9

30

74

155 149

38

1 0 0 2

25

93

198

98

1 4 6 15

9 11 8 2 0

0

50

100

150

200

250

21-30 31-40 41-50 51-60 61-70 71-80 81-90 91-100

Bicuspid (49%)

Tricuspid (45%)

Others (6%)

42%

28%

Age (Year)

932 SAVR patients

BAV Classification

CTA System

27%

5%

68%

(from 14 centers in North America, Europe and Asia)

Tricommissural

3 commissures V-like orifice

“functional or acquired”

Bicommissural Raphe-type

Bicommissural Non Raphe-type

2 commissures, 1 raphe Slit-like orifice

Jilaihawi H. JACC Imaging 2016

2 commissures, no raphe Slit-like orifice

BAV - TAVI Challenges

• Valve sizing: more difficult and requires careful CTA • Valve positioning: implant depth, horizontal Ao • Increased adverse procedural events

valve embolization annulus rupture valve-in-valve conversion to SAVR new pacemakers mod-severe PVL

• Late concerns: durability (incomplete expansion) and aortopathy (untreated)

Recent Multicenter BAV - TAVI Registry

Yoon SH et al. JACC 21;2017:2579-89

TVT BICUSPID REGISTRY AT ACC 2019

TVT Registry Biscuspid vs Tricuspid propensity

matched

N=2691 each (81,822 Sapien 3)

Higher surgical conversion (0.9% vs 0.4%, p=0.03)

Higher annular rupture (0.3% vs 0%, p=0.03)

More second valve needed (0.4% vs 0.2%, p=0.16)

At 30 days, there was no difference in all-cause

mortality, life-threatening bleeding, major vascular

complications, and aortic valve reintervention

Risk of all stroke (2.4% vs 1.6%; P = 0.02) and need

for new pacemaker (9.1% vs 7.5%; P = 0.03). Little

use of CPD.

At 1-year analyses, there were no differences in

mortality, stroke mortality and stroke.

EARLY TAVR Trial Study 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 1:1 Stratified by STS (<3 vs >3)

TF- TAVR Clinical

Surveillance

Early TAVR Registry

Primary Endpoint (superiority): 2-year composite

of all-cause mortality, all strokes, and repeat

hospitalizations (CV)

• Clinical events are very frequent (61% @ 4 yrs FU) • Most events occur in the first year • In patients with events, 25% were NYHA class 1 and 42%

were NYHA class 2

Van Gils et al. JACC 2017;69:2383-92

Primary Endpoint Landmark Analysis

Impact of Moderate AS in Patients with Reduced LV Systolic Function

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 Endpoint Hierarchical 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 Trial Study Design

(600 patients, 1:1 Randomized)

AS and Atrial Fibrillation Watch-TAVR

Aortic Stenosis &

Atrial Fibrillation

TAVR + WATCHMAN

(n = 156)

TAVR +

Medical Rx

(n = 156)

1o Outcome: • Death, stroke, bleeding

@ 1 year 2o Outcome: • Components of primary • Any thromboembolism • Cardiovascular death • Re-hospitalization • QoL (KCCQ-12) • Procedural costs

National PIs: Samir Kapadia & Martin Leon Grant support: Boston Scientific

TAVR in AR Current device not optimal

Registry: 254 patients, 56% Core, 12 days in hospital and 20% pacer.

Current “Standards” for TAVR

MDT Evolut R (PRO) Edwards Sapien 3

“Next in Line” for TAVR

LOTUS (Edge) ACURATE neo PORTICO

JENA Valve CENTERA VENUS A Valve

“Rebooting” or Increasing Momentum