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Jeffrey J. Popma, MDDirector, Interventional Cardiology

Clinical ServicesBeth Israel Deaconess Medical Center

Associate Professor of MedicineHarvard Medical School

Boston, MA

Aortic Stenosis: Options for Treatment is Patients at High-

Risk for Conventional AVR

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Conflict of Interest StatementConflict of Interest Statement

Within the past 12 months, I have had a financial Within the past 12 months, I have had a financial interest/arrangement or affiliation with the interest/arrangement or affiliation with the organization(s) listed below.organization(s) listed below.

Physician NamePhysician Name Company/RelationshipCompany/Relationship

Jeffrey J. Popma, MD Research Grants: Cordis, Boston ScienJeffrey J. Popma, MD Research Grants: Cordis, Boston Scientific,tific,Medtronic, AbbottMedtronic, Abbott--Guidant, eV3, LabCoatGuidant, eV3, LabCoatMedical Advisory Board: Cordis, Boston Medical Advisory Board: Cordis, Boston Scientific, Abbot VascularScientific, Abbot Vascular

Disclaimer: “Caution – Percutaneous Aortic Valves are investigational devices, limited by United States to Investigation use only.”

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The Aortic Valvar Complex

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Normal Aortic Valve: Aortic View

5F Mahmood MD CT Anesthesia BIDMC

4D Echocardiography: Cubic Spline Reconstruction

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Lipid Build-Up in Non Coronary Cusp

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Calcific Degenerative Calcific Degenerative AorticAortic StenosisStenosis

DeformedEccentric

CalcifiedNodular

Rigid

• Difficult to displace• Prone to fragmentationand embolization

HOSTILEHOSTILETARGETTARGET

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3 Mensio CT Angiography 4D Reconstruction

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20%

35%

48%

1.3%

2.4%

4.0%

Age, YearsAge, Years

Prevalence of Aortic Valve Disease in the Elderly

Supino PG et al Heart Fail Clin 2006; 2: 379–93

Cardiovascular Health Study (N = 5201 patients > 65 years)

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Misconceptions About Age Prevent Appropriate Patients from AVR

• Those expecting to live for more than 5 years are likely to derive significant benefit from AVR

• For those who survive 6 months after their operation, life expectancy matches that of age-matched controls

Age

65

70

75

80

85

90

Life expectancy for US population Years

Hornick et al. Clin Geriatr Med 2006; 22: 499-513

A Healthy 90 Year Old Lives 5 More Years

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Aortic Valve Replacement in the Gold Standard For Aortic

Stenosis

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ACC-AHAIndications ForSurgicalAorticValve Replacement

Bonow Circ 2006; 114:e84-e231

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Don’t Mess With the Guidelines – or Surgeons

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Are all patients with symptomatic

aortic stenosis now being treated

with definitive surgical aortic

valve replacement?

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But 30But 30--60% of AS Patients Go Untreated60% of AS Patients Go Untreated……Severe Symptomatic Aortic StenosisPercent of Cardiology Patients Treated

Bouma B J et al. Heart 1999;82:143-148Iung B et al European Heart Journal 2003;24:1231-1243 (*includes both Aortic Stenosis and Mitral Regurgitation patients)Pellikka, Sarano et al Circulation 2005Charlson E et al. J Heart Valve Dis2006;15:312-321

No AVR

AVR

Under-treatment especially prevalent

among patients managed by Primary Care

physicians

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Re: TAVR - STS Incompletely Assesses

• Severe Pulmonary Disease• Severe Liver Disease (MELD, Childs)• RV Function and Right Heart Failure• Frailty (and Cognitive Dysfunction)• Ilio-Femoral Vascular Disease

Better accounting is needed to estimate 30-day surgical risk . . . Top five conditions

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Same age and predicted riskOne passes the “eyeball test” – one does not

Same age and predicted riskOne passes the “eyeball test” – one does not

Frailty is being studied systematically as part ofthe PARTNER U.S. IDE study

Patient A Patient Bvs.

Photos courtesy of Michael J. Mack, MDMedical City Dallas

Frailty AssessmentFrailty Assessment

Study DevicesStudy Devices

Retroflex 1EdwardsEdwards--SAPIEN THVSAPIEN THV

23mm and 26mm23mm and 26mmvalve sizesvalve sizes

22F and 24F22F and 24Fsheath sizessheath sizes

TransfemoralTransfemoral TransapicalTransapical

EDWARDS TAVREDWARDS TAVRTransfemoral and TransapicalTransfemoral and Transapical

September 22, 2010 on NEJM.orgSeptember 22, 2010 on NEJM.org

PARTNER B: All Cause PARTNER B: All Cause MortalityMortality

Numbers at RiskNumbers at RiskTAVITAVI 179179 138138 122122 6767 2626Standard RxStandard Rx 179179 121121 8383 4141 1212

∆ at 1 yr = 20.0%NNT = 5.0 pts

Standard RxTAVI

All-

caus

e m

orta

lity

(%)

Months

0

20

40

60

80

100

50.7%

30.7%

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How Much Will “Adding ‘Years

to Life’ and ‘Life to Years’ ”

Cost?

PARTNER B TAVR Admission CostsPARTNER B TAVR Admission Costs

Mean (median) LOS (days)

ICU 4.0 (2.0)Non-ICU 6.1 (5.0)

Total 10.1 (7.0)Post-Procedure 8.6 (6.0)

(N=175)

$78,540

Hospital Costs:$73,563

PARTNER B Results: Observed SurvivalPARTNER B Results: Observed Survival

TAVR

Control

Difference in In-Trial Life Expectancy= 0.49 years

Based on data available as of 28SEP2010

N = 179

N = 358InoperableInoperable

StandardTherapyStandardTherapy

ASSESSMENT: Transfemoral

Access

ASSESSMENT: Transfemoral

Access

Not In StudyNot In Study

TF TAVRTF TAVR

Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)

Co-Primary Endpoint: Composite of All-Cause Mortalityand Repeat Hospitalization (Superiority)

Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)

Co-Primary Endpoint: Composite of All-Cause Mortalityand Repeat Hospitalization (Superiority)

1:1 Randomization1:1 Randomization

VS

YesYes NoNo

N = 179

TF TAVRTF TAVR AVRAVR

Primary Endpoint: All-Cause Mortality at 1 yr(Non-inferiority)

Primary Endpoint: All-Cause Mortality at 1 yr(Non-inferiority)

TA TAVRTA TAVR AVRAVR

VSVS

N = 248 N = 104 N = 103N = 244

PARTNER Study DesignPARTNER Study Design

Symptomatic Severe Aortic StenosisSymptomatic Severe Aortic Stenosis

ASSESSMENT: High-Risk AVR Candidate3,105 Total Patients Screened

ASSESSMENT: High-Risk AVR Candidate3,105 Total Patients Screened

Total = 1,057 patients2 Parallel Trials:

Individually PoweredN = 699 High RiskHigh Risk

ASSESSMENT: Transfemoral

Access

ASSESSMENT: Transfemoral

Access

Transapical (TA)Transapical (TA)Transfemoral (TF)Transfemoral (TF)

1:1 Randomization1:1 Randomization1:1 Randomization1:1 Randomization

YesYes NoNo

CharacteristicCharacteristic TAVR (N = 348)TAVR (N = 348) AVR (N = 351)AVR (N = 351) pp--valuevalue

Age (yr) 83.6 ± 6.8 84.5 ± 6.4 0.07

Male sex - % 57.8 56.7 0.82

STS Score 11.8 ± 3.3 11.7 ± 3.5 0.61

Logistic EuroSCORE 29.3 ± 16.5 29.2 ± 15.6 0.93NYHA

II - %III or IV - % 94.3 94.0 0.79

CAD - % 74.9 76.9 0.59

Previous MI - % 26.8 30.0 0.40

Prior CV Intervention - % 72.1 71.6 0.93

Prior CABG - % 42.6 44.2 0.70

Prior PCI - % 34.0 32.5 0.68

Prior BAV - % 13.4 10.2 0.24

29.3 27.4 0.60

PARTNER A: Patient Characteristics (1) PARTNER A: Patient Characteristics (1)

Cerebrovascular disease - %

5.7 6.0

PARTNER A: AllPARTNER A: All--Cause MortalityCause MortalityTransfemoral (N=492)Transfemoral (N=492)

Months

244 215 188 119 59

248 180 168 109 56

No. at Risk

TAVR

AVR

26.4

22.2

HR [95% CI] =0.83 [0.60, 1.15]

P (log rank) = 0.25

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Options in HighOptions in High--Risk Aortic StenosisRisk Aortic Stenosis

Aortic Stenosis: The SubstrateIdentifying High-Risk PatientsSapien (PARTNER Trial)

- Inoperable Cohort B- High Risk: Cohort A

CoreValve Clinical Program- National Registries- US Pivotal Trial- SURTAVI

ComplicationsNewer TAVR Designs/Indications

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CoreValve Bioprosthesis FrameCoreValve Bioprosthesis Frame

Inflow Portion

(with skirt)

Constrained Portion

(with leaflets)

Outflow Portion

1. Intra-annular anchoring

2. Mitigates paravalvular aortic regurgitation

1. Supra-annular leaflet function

2. Designed to avoid coronaries

1. Sits in ascending aorta

2. Orientation

Photograph provided by Piazza, Serruys, and DeJaegere

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CoreValve US Trial: CoreValve US Trial: ExtremeExtreme RiskRisk

Medtronic CoreValveMedtronic CoreValveU.S. Pivotal TrialU.S. Pivotal Trial

Inclusion Criteria• Degenerative AS

- Mean gradient > 40 mmHg - Jet velocity greater than 4.0 m/s- Initial AVA ≤ 0.8 cm2

- Aortic Valve Area Index ≤ 0.5 cm2/m2

• Co-morbidities such as the probability of procedural death or serious, irreversible morbidity should equal or exceed 50% at 30 days.

“Extreme Risk”Patient Group

Iliofemoral access ?

CoreValveCoreValveObservationalObservational

Up to 100Up to 100

CoreValveCoreValveSingle ArmSingle Arm

N=487N=487

YesNo Endpoints:• Primary: All-Cause Mortality + Major

Stroke at 12 months (compared to Performance Goal)

• Secondary: MACCE, QoL• Long-Term Safety and Durability

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Medtronic CoreValveMedtronic CoreValveU.S. Pivotal TrialU.S. Pivotal Trial

CoreValve US Pivotal Trial: High RiskCoreValve US Pivotal Trial: High Risk

Inclusion Criteria• Degenerative AS

- Mean gradient > 40 mmHg - Jet velocity greater than 4.0 m/s- Initial AVA ≤ 0.8 cm2

- Aortic Valve Area Index ≤ 0.5 cm2/m2

• Estimated surgical mortality > 15% at 30 days

Endpoints:• Primary: All-Cause Mortality at 12

months (non-inferiority)• Secondary: Pre-specified

Hierarchical Testing• Long-Term Safety and Durability

Randomization 1:1

CoreValveN=395

SAVRN=395

“High Risk”Patient Group

N=790

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Unanticipated Iliac Rupture

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Piazzo N JACC: CV Intervention2008;1;310-316

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Foci of Restricted Diffusion on Postprocedural DW MRI

Example of an 82-year-old patient two days after successful TAVI

Knipp et al TCT2009

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Contemporary registries suggest that TAVI is superior to medical therapy and equivalent (or better) than sAVR in high-risk patients, but selection bias is present RCTs are needed, particularly in “intermediate-risk” patients

All cause mortality may be problematic due to co-morbidities in elderly patients cardiovascular death may be better

We need better risk scores to identify patient for TAVI

Ongoing RCTs will likely report higher complication rates (e.g.,MI, stroke) due to changing definitions and higher surveillance

Demonstration of device durability and appropriate PPM use will be essential for expanding into younger patients

Broader device availability, reducing profile, and enhancement of delivery system will allow improve patient outcomes

TAVI WorldWide: What’s Next