Martin B. Leon, MDMartin B. Leon, MDon behalf of theon behalf of the

PARTNER InvestigatorsPARTNER InvestigatorsTCT 2010; Washington, DC; September 23, 2010TCT 2010; Washington, DC; September 23, 2010

Transcatheter Aortic Valve Transcatheter Aortic Valve Implantation in Inoperable Patients Implantation in Inoperable Patients

with Severe Aortic Stenosiswith Severe Aortic Stenosis

Press ConferencePress Conference

Symptomatic Severe Aortic StenosisSymptomatic Severe Aortic Stenosis

ASSESSMENT: High Risk AVR Candidate3105 Total Patients Screened

PARTNER Study DesignPARTNER Study Design

High Risk TAHigh Risk TA

ASSESSMENT: Transfemoral

Access

TAVITAVITransTrans

femoralSurgical Surgical

AVRAVR

High Risk TFHigh Risk TF

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

TAVITAVITransTrans

femoralfemoralSurgical Surgical

AVRAVR

1:1 Randomization1:1 Randomization

VS

VS

Standard Standard TherapyTherapy

(usually BAV)(usually BAV)

ASSESSMENT: Transfemoral

Access

Not In Study

TAVITAVITransTrans

femoralfemoral

Primary Endpoint: All Cause Mortality over Primary Endpoint: All Cause Mortality over length of trial (Superiority)length of trial (Superiority)

1:1 Randomization

VS

Total = 1058 patients2 Parallel Trials:

Individually PoweredHigh RiskHigh Riskn= 700 InoperableInoperable n=358

Primary and Co-Primary EndpointsPrimary and Co-Primary Endpoints

• PRIMARY: All-cause mortality over the duration PRIMARY: All-cause mortality over the duration of the studyof the study Superiority test (two-sided), 85% power to detect a Superiority test (two-sided), 85% power to detect a

difference, difference, αα = 0.05, sample size = 350 total patients = 0.05, sample size = 350 total patients

• CO-PRIMARY: Hierarchical composite of CO-PRIMARY: Hierarchical composite of all-cause mortality and repeat hospitalizationall-cause mortality and repeat hospitalization Non-parametric method described by Finkelstein and Non-parametric method described by Finkelstein and

Schoenfeld (multiple pair-wise comparisons)Schoenfeld (multiple pair-wise comparisons) > 95% power to detect a difference, > 95% power to detect a difference, αα = 0.05 = 0.05

• Positive study if both endpoints P < 0.05, or if Positive study if both endpoints P < 0.05, or if either endpoint is < 0.025either endpoint is < 0.025

Study DevicesStudy Devices

Retroflex 1Edwards-SAPIEN THVEdwards-SAPIEN THV

23mm and 26mm23mm and 26mmvalve sizesvalve sizes

22F and 24F22F and 24Fsheath sizessheath sizes

Inclusion CriteriaInclusion Criteria

• Severe calcific aortic stenosis defined as echo derived valve area of < 0.8 cm2 (EOA index <0.5cm2), and mean gradient > 40 mmHg or jet velocity > 4.0 m/s

• NYHA functional class II or greater• Risk of death or serious irreversible Risk of death or serious irreversible

morbidity as assessed by cardiologist morbidity as assessed by cardiologist and two surgeons must exceed 50% and two surgeons must exceed 50%

All Cause All Cause MortalityMortality

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

All-

caus

e m

orta

lity

(%)

Months

HR [95% CI] =0.54 [0.38, 0.78]

P (log rank) < 0.0001

Standard Rx TAVI

All Cause All Cause MortalityMortality

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

Standard Rx TAVI

All-

caus

e m

orta

lity

(%)

Months

∆ at 1 yr = 20.0%NNT = 5.0 pts

50.7%

30.7%

• Compare, at random, every TAVI patient with every Compare, at random, every TAVI patient with every Standard Rx patient; Standard Rx patient; 179 x 179 (32,041) patient pairs, 179 x 179 (32,041) patient pairs, which did better?which did better?

• #1, compare “time to death”#1, compare “time to death” 72% chance that we know who died first72% chance that we know who died first If so, 63% chance that Standard Rx patient died first and If so, 63% chance that Standard Rx patient died first and

37% chance that TAVI patient died first37% chance that TAVI patient died first• #2, if necessary, compare “time to repeat #2, if necessary, compare “time to repeat

hospitalization” hospitalization” 17% chance that we know who had repeat hosp first17% chance that we know who had repeat hosp first If so, 75% chance that Standard Rx patient had repeat If so, 75% chance that Standard Rx patient had repeat

hosp first and 25% chance that TAVI patient had repeat hosp first and 25% chance that TAVI patient had repeat hosp first hosp first

Finklestein & Schoenfeld AnalysisFinklestein & Schoenfeld Analysis(hierarchical multiple pair-wise comparison)(hierarchical multiple pair-wise comparison)

FS MethodFS MethodProduces a Produces a

P-valueP-value< 0.0001< 0.0001

OutcomeOutcome 30 Days 30 Days n=179n=179

TAVI Standard Rx P-value

  1 Year 1 Year n=179n=179

TAVI Standard Rx P-value

Clinical Outcomes at 30 Days & 1 YearClinical Outcomes at 30 Days & 1 Year

Myocardial infarction All (%) 0 0 . 0.6 0.6 1.00 Peri-procedural (% 0 0 . 0 0 .

Stroke or TIA

All (%) 6.7 1.7 0.03 10.6 4.5 0.04 TIA (%) 0 0 . 0.6 0 1.00 Minor stroke (%) 1.7 0.6 0.62 2.2 0.6 0.37 Major stroke (%) 5.0 1.1 0.06 7.8 3.9 0.18

Death (all) or major stroke (%) 8.4 3.9 0.12 33.0 50.3 0.001

Repeat hospitalization (%) 5.6 10.1 0.17 22.3 44.1 <.0001

Death (all) or repeat hosp (%) 10.6 12.3 0.74 42.5 70.4 <.0001

Death All (%) 5.0 2.8 0.41 30.7 49.7 0.0004 Cardiovascular (%) 4.5 1.7 0.22 19.6 41.9 <.0001

OutcomeOutcome 30 Days 30 Days n=179n=179

TAVI Standard Rx P-value

  1 Year 1 Year n=179n=179

TAVI Standard Rx P-value

Clinical Outcomes at 30 Days & 1 YearClinical Outcomes at 30 Days & 1 Year

Acute kidney injury Creatinine >3 mg/dL (%) 0 1 1.00 1.1 2.8 0.45 RRT (%) 1.1 1.7 1.00 1.7 3.4 0.50

Cardiac re-intervention BAV (%) 0.6 1.1 1.0 0.6 36.9 <.0001

Re-TAVI (%) 1.7 na 1.7 na

AVR (%) 0 1.7 0.25 1.1 9.5 <.0001Endocarditis (%) 0 0 . 1.1 0.6 0.31

Vascular complications All (%) 30.7 5.0 <.0001 32.4 7.3 <.0001

Major (%) 16.2 1.1 <.0001 16.8 2.2 <.0001

Bleeding - major (%) 16.8 3.9 <.0001 22.3 11.2 0.007

Arrhythmias New atrial fibrillation (%) 0.6 1.1 1.00 0.6 1.7 0.62

New pacemaker (%) 3.4 5.0 0.60 4.5 7.8 0.27

Walking Distance

P = 0.002

Wal

king

dis

tanc

e (m

eter

s)

Baseline 30 Days

Six-Minute Walk TestsSix-Minute Walk Tests

P = 0.004

1 Year

P = 0.67

P = 0.55

NYHA Class Over TimeNYHA Class Over TimeSurvivorsSurvivors

P = 0.68 P < 0.0001 P < 0.0001 P < 0.0001

I II III IV

TAVI Standard Rx TAVI Standard Rx TAVI Standard Rx TAVI Standard Rx

Perc

ent

TreatmentTreatmentVisitVisit

Baseline 30 Day 6 Month 1 Year

BaselineN=163

30 DayN=143

6 MonthsN=100

1 YearN=89

Mea

n G

radi

ent (

mm

Hg)

50

40

30

20

60

70

10

0

Error bars = ± 1 Std DevError bars = ± 1 Std Dev

Mean Gradients Over TimeMean Gradients Over Time

P < 0.0001P < 0.0001

33.033.039.539.5

44.444.4

43.243.2 12.111.310.8

44.6

Standard Rx TAVI

Paravalvular Regurgitation: TAVIParavalvular Regurgitation: TAVI

No changes over time

None/Trace

MildModerate

Severe

30 Day 6 Month 1 Year

Conclusions - 1Conclusions - 1

In patients with severe AS and symptoms, In patients with severe AS and symptoms, who are not suitable candidates for surgery…who are not suitable candidates for surgery…

• Standard therapy (including BAV in 83.8% of pts) did not alter the dismal natural history of AS; all-cause and cardiovascular mortality at 1 year was 50.7% and 44.6% respectively

• Transfemoral balloon-expandable TAVI, despite limited operator experience and an early version of the system, was associated with acceptable 30-day survival (5% after randomization in the intention-to-treat population)

Conclusions - 2Conclusions - 2

• TAVI was superior to standard therapy, markedly reducing the rate of… all-cause mortality by 46%, P < 0.0001,

NNT = 5.0 pts cardiovascular mortality by 61%, P < 0.0001,

NNT = 4.1 pts all-cause mortality and repeat hospitalization

hierarchical (FS method), P < 0.0001 non-hierarchical (KM analysis) by 54%,

P < 0.0001, NNT = 3.4 pts

Conclusions - 3Conclusions - 3

• TAVI improved cardiac symptoms (NYHA class, P < 0.0001) and six minute walking distance (P = 0.002), after 1-year follow-up

• TAVI resulted in more frequent complications at 30 days, including… major vascular complications, 16.2% vs.

1.1%, P < 0.0001 major bleeding episodes, 16.8% vs. 3.9%,

P < 0.0001 major strokes, 5.0% vs. 1.1%, P = 0.06

Conclusions - 4Conclusions - 4

• Serial echocardiograms in TAVI patients indicated… reduced mean gradients (P < 0.0001) which

were unchanged during 1-year FU frequent paravalvular AR, which was usually

trace or mild (~90%), remained stable during 1-year FU, and rarely required further Rx.

Clinical Implications Clinical Implications

• Balloon-expandable TAVI should be the new standard of care for patients with aortic stenosis who are not suitable candidates for surgery!

• Next generation devices (e.g. SAPIEN XT) may help to reduce the frequency of procedure-related complications in the future.

• The ultimate value of TAVI will depend on careful assessment of bioprosthetic valve durability, which will mandate obligatory long-term clinical and echocardiography FU of all TAVI patients.

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