THE RELENTLESS DRIVE TOLOW RISK: OBSTACLESAND OPPORTUNITIES

Michael J. Reardon, M.D.

Professor of Cardiothoracic Surgery

Allison Family Distinguish Chair of Cardiovascular

Research

Houston Methodist DeBakey Heart & Vascular Center

COI

Steering committeesCoreValveEvolut RSurTAVI

Reprise IIISalus

National Surgical PISurTAVI

Reprise IIIEvolut R low risk trial

EXTREMERISK

DONE

DONE

HIGH RISK

DONE

DONE

HIGH RISK CLINICALOUTCOMES

Events TAVR SAVRP

Value

Life threateningor disablingbleeding

19.1 41.3 <0.001

Acute kidney injury 6.2 15.1 <0.001

Atrial fibrillation 19.8 36.3 <0.001

Reintervention 2.5 0.4 0.020

Major vascular complications 7.1 2.0 0.001

Pacemaker implant 28.0 14.5 <0.001

Aortic valve hospitalization 27.6 21.9 0.087

Endocarditis 0.9 1.7 0.346

6

Subgroup

All-cause Deathat 3 YearsKM

RatesHazard Ratios

(95%CI)

Interaction PValue

TAVR SAVRAge 0.35

>85 38.8 41.9 0.89 (0.63, 1.24)≤85 27.5 36.8 0.70 (0.49, 1.00)

Gender 0.65Male 34.8 40.7 0.84 (0.60, 1.16)Female 30.7 37.1 0.75 (0.52, 1.08)

BMI 0.82≤30 35.4 41.3 0.80 (0.60, 1.06)>30 26.5 34.2 0.75 (0.46, 1.23)

LVEF 0.24≤60 35.7 38.7 0.89 (0.66, 1.21)>60 28.3 38.8 0.65 (0.43, 1.00)

Diabetes 0.70No 34.7 43.0 0.74 (0.55, 1.01)Yes 29.6 34.5 0.82 (0.55, 1.25)

1.00 2.000.500.250 125

ACC2016 7

Subgroup

All-cause Deathat 3 YearsKM

RatesHazard Ratios

(95%CI)

InteractionP

ValueTAVR SAVR

Prior CABG 0.90No 34.8 42.2 0.78 (0.59, 1.04)Yes 28.3 32.5 0.81 (0.50, 1.32)

PVD 0.56No 34.4 38.6 0.84 (0.61, 1.16)Yes 30.0 38.8 0.73 (0.49, 1.07)

Hypertension

0.46

No 50.4 59.8 0.56 (0.21, 1.44)Yes 32.1 38.2 0.80 (0.62, 1.03)

STSScore 0.14≤7% 27.1 38.5 0.66 (0.46, 0.95)>7% 39.3 39.8 0.95 (0.68, 1.32)

1.00 2.000.500.250 125

ACC2016 8

0

0.001

0.002

0.003

0.004

0.005

0.006

0.007

0 30 60 90 120 150 180 210 240 270 300 330 360

Est

imat

ed

Haza

rdR

ate

Days Post Procedure

HRPivotal TAVR

HRPivotal SAVR

Perip ocedural ElevatedHazard

Constant Hazard

Delayed Recovery

TAVR vs. AVR must showequivalent or better

mortalityhemodynamics

morbidityquality of life

durabilitypatient acceptance

PVL/ Pace

maker

?

What do randomized trial tellus?

TAVR is the treatment ofchoice in anatomically TAVR

suitable high-risk patients

How About Lower Risk Data?

Evolution in Patient Selection inU.S. TAVR Clinical Trials

11 2% 11 0%11.8%

0%

2%

4%

6%

8%

10%

12%

14%

PARTNERBTAVR

PARTNERIIB

SAPIEN

PARTNERIIB

SAPIEN XT

CoreValveER

Iliofemoral

CoreValveER

ContinuedAccess

TVTRegistry

SAPIENTF

PARTNERATAVR

PARTNERTF

ContinuedAccess

CoreValveHR

TVTRegistry

SAPIENTF

STS

Score

Inoperable (extreme risk) High-Risk

Partner IIA

SurTAVI

SurTAVI data will bepresented in 2017

TAVR vs. AVR must showequivalent or better

mortalityhemodynamics

morbidityquality of life

durabilitypatient acceptance

PVL/ Pace

maker

?

Intermediate risk

Low Risk Randomized Trials

UK “ALL-COMERS”TRIAL

Severe symptomatic aortic stenosis

Age ≥80 years (ie all comers in this age group)

Or Age ≥70 years + >/= 1 co-morbid state

Both AVR and TAVI deemed to be acceptable

options (Eligibility determined by the MDT)

Randomised to TAVI or surgical AVR (1:1)

– with any CE marked device

N = 808 patients

Primary end point - All-cause mortality at one year

6.2%

13.9%

79.9%

FDAApproved

FDA Approved

Trials

PVL?

CURRENTHMH VALVES

Nitinol wire frame,bovine tissue

valve; outer PUskirt; mechanical

expansion andlocking

Evolut RSelf-expanding,Nitinol frame, 3

sizes, Recapture,Reposition andRedeployment

balloon exp(4 sizes),

cobalt frame;bovine tissuevalve; outerskirt; precisepositioning

CURRENTHMH VALVES

Polyester fabric cuff withtwo inflatable rings;positioning wires for

placement; bovine tissuevalve

Portico:Nitinol frame, Bovine

and Porcinepericardial valve.

Reposition, redeployand recapture

Open cell and intraannular

68.8%79.5%

72.4%

28.6%15.4%

24.1%

2.6% 5.1% 3.4%100%

TF TAA Overall

None/Trace Mild Moderate Severe

SAPIEN 3 TAVR (CE Study)

Femoral TA All

0.1%

S3PVL at 30

days (n

=1500)

Moderate/severe PVL at 30days is 3.4%

Evolut 2.0

REPRISEII TRIAL

Direct Flow TAVR (DISCOVERY)

24.2

16.9

14.2

11.49.0

4.0 3.41.4 0.6

0

5

10

15

20

25

30

%Pat

ients

wit

hM

od/S

eve

rePV

L

SAPIENXT

PARTNER

II, Inop1

SAPIENPARTNERII Inop1

CoreValveADVANCE2

CoreValveExtreme

Risk3

CoreValve HighRisk4

Portico

CEStudy5

SAPIEN36

DirectFlow

DISCOVER7

LOTUSREPRISE

II &EXT8

N=236 N=225 N=639 N=412 N=356 N=75 N=116 N=74 N=1771Leon M, ACC2013, 2LinkeA, PCR2014. 3PopmaJ, JACC2014; 63(19): 1972-81, 4AdamsD, N Engl JMed 2014; 370: 1790-98. 5Manoharan, et al. TCT2014. 6Webb J, EuroPCR2014. 7Schofer, JACC2013. 8Ian Meredith, London Valves2014. Resultsfrom different studiesnot directlycomparable. Informationprovided for educational purposeonly

1 Month Moderate & Severe PVLTAVI Clinical Trials

29.2

20.9

119.4

6.8 6.14.3

00

5

10

15

20

25

30

3512-mo Mod/ Severe PVLrate

Adverse Clinical OutcomesTAVI Clinical Trials

PARTNERII SAPIEN

XT5

PARTNERII SAPIEN5

PARTNERB

SAPIEN6

CoreValve

ADVANCE1

PARTNERA SAPIEN7

CoreValveHigh Risk3

CoreValveExt Risk4

LOTUSREPRISE

II2

N: 284 276 179 996 348 390 489 120

%o

fPat

ients

1LinkeA, PCR2014., 2Ian Meredith, TCT2014 3AdamsD, N En179gl JMed 2014, 4PopmaJ, JACC2014, 5Leon M, ACC2013., 6Leon, NEJM 2010., 7Smith, NEJM2011.Resultsfrom different studiesnot directly comparable. Information provided for educational purpose only

PREDICTIONS FOR2020

PVL will be largely solvedand similar to SAVR with

engineering designimprovements

78.176.06

78.71 80.07 80.53

77.4

63.89

68.44

74.4976.32

40

50

60

70

80

90

Baseline Discharge 30 days 6 months 12 mo

TAVR

SAVR P=0.023

P=0.19

Volu

me

(mL)

0

20

40

60

80

100

P=0.1288

Seve

rePPM

(%)

TAVR SAVR TAVR SAVR TAVR SAVR

baseline Discharge 12 mo

None Mild Moderate Severe

Prosthesis-Patient Mismatch

• Severe PPM occurssignificantly more afterSAVR than TAVR

Zorn AATS2015

PREDICTIONS FOR2020

SAVR hurts the heart for atleast 6 months and this isunlikely to change by 2020

Durability

DVIR DATA

PREDICTIONS FOR2020

We will not get an answer ondurability until intermediate andlow risk trials reach 10 years

PREDICTIONS FOR2020

SAVR is a mature techniquewhile

TAVR is young and likely tounder go substantial

improvements

Technical disasters have alreadydecreased and will decrease

0

0.001

0.002

0.003

0.004

0.005

0.006

0.007

0 30 60 90 120 150 180 210 240 270 300 330 360

Est

imat

ed

Haza

rdR

ate

Days Post Procedure

HRPivotal TAVR

HRPivotal SAVR

Pe procedural ElevatedHazard

Constant Hazard

DelayedRecovery

PREDICTIONS FOR2020

SAVR is technique drivenTAVR is technology driven

TAVR will enjoy a wideradoption than SAVR

PREDICTIONS FOR2020

We used to ask “Which casesare bad for SAVR” and do

TAVR

We will ask “Which cases arebad for TAVR” and consider

SAVR

PREDICTIONS FOR2020

Surg

icalR

isk

Low Risk Intermediate Risk High Risk Extreme Risk

Both dividing linesmoving to the leftbut how far?Durablity

PREDICTIONS FOR2020

Surg

icalR

isk

Low Risk Intermediate Risk High Risk Extreme Risk

Both dividing linesmoving to the leftbut how far?

If proven durablity found

All risk categories will be TAVR candidates

Thank You

0.0

10.0

20.0

30.0

40.0

50.0

60.0

Baseline Discharge 1 Month 1 Year 2 Years 3 Years

TAVR SAVR

AV

Mean

Gra

die

nt,

mm

Hg

In 18 TAVR(9.5%) and 17 SAVR(12.6%) with a >50%increase in AV mean gradient:

72*Site-reported

Structural Hemodynamic Deterioration*ACC2016

6.2%

13.9%

79.9%

FDAApproved

FDA Approved

Trials