tct 2011 | san francisco, ca | november 10, 2011 two-year outcomes of transcatheter aortic valve...

TCT 2011 | San Francisco, CA | November 10, 2011TCT 2011 | San Francisco, CA | November 10, 2011

Two-Year Outcomes of Transcatheter Aortic Two-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in “Inoperable” Valve Replacement (TAVR) in “Inoperable” Patients With Severe Aortic Stenosis: Patients With Severe Aortic Stenosis: The PARTNER TrialThe PARTNER Trial

Raj R. Makkar, MDRaj R. Makkar, MDOn behalf of The PARTNER Trial InvestigatorsOn behalf of The PARTNER Trial Investigators

DisclosuresDisclosures

Raj R. Makkar Raj R. Makkar is a principal site investigator for The is a principal site investigator for The PARTNER Trial (US) for Edwards Lifesciences and PARTNER Trial (US) for Edwards Lifesciences and is national principal investigator for the St Jude is national principal investigator for the St Jude TAVR study. He has received consulting fees, grant TAVR study. He has received consulting fees, grant support and lecture fees from Medtronic, equity from support and lecture fees from Medtronic, equity from Entourage Medical Technologies and grant support Entourage Medical Technologies and grant support from St Jude Medical.from St Jude Medical.

Background (1)Background (1)

• Transcatheter aortic valve replacement (TAVR) Transcatheter aortic valve replacement (TAVR) is the recommended treatment for is the recommended treatment for “inoperable” patients with severe aortic “inoperable” patients with severe aortic stenosis (AS), based upon 1-year results of stenosis (AS), based upon 1-year results of The PARTNER Trial which demonstrated The PARTNER Trial which demonstrated reduced mortality and improved quality of life.reduced mortality and improved quality of life.

• However, whether clinical benefit and valve However, whether clinical benefit and valve performance are sustained beyond one year is performance are sustained beyond one year is unknown and longer term outcomes will unknown and longer term outcomes will importantly alter clinical practice decisions.importantly alter clinical practice decisions.

3

Background (2)Background (2)

• Transcatheter Aortic Valve Replacement (TAVR) is the standard of care for inoperable patients with severe aortic stenosis (AS), demonstrating 1-year outcomes of the PARTNER Trial, offering reduced mortality and improved quality of life.

4

Published October 2010Published October 2010

ObjectivesObjectives

• To evaluate the clinical outcomes of To evaluate the clinical outcomes of TAVR compared to standard therapy at 2 TAVR compared to standard therapy at 2 years in “inoperable” aortic stenosis years in “inoperable” aortic stenosis patients.patients.

• To assess valve hemodynamics and To assess valve hemodynamics and durability using echocardiography.durability using echocardiography.

• To perform subgroup analyses to better To perform subgroup analyses to better define the impact of co-morbidities on define the impact of co-morbidities on outcomes.outcomes.

5

n = 358InoperableInoperable

StandardTherapyn = 179

StandardTherapyn = 179

ASSESSMENT: Transfemoral

Access


Access

TF TAVRn = 179

TF TAVRn = 179

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

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

1:1 Randomization1:1 Randomization

VS

TF TAVRTF TAVR AVRAVR

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

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

TA TAVRTA TAVR AVRAVR VS

VS

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 patients

2 Parallel Trials: Individually Powered

n = 699 High-RiskHigh-Risk


Access


Access

High-Risk TAHigh-Risk TAHigh-Risk TFHigh-Risk TF

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

6

Inclusion CriteriaInclusion Criteria

• Severe calcific aortic stenosis defined as echo Severe calcific aortic stenosis defined as echo derived valve area of < 0.8 cmderived valve area of < 0.8 cm22 (EOA index < 0.5 (EOA index < 0.5 cmcm22), and mean gradient > 40 mmHg or jet velocity ), and mean gradient > 40 mmHg or jet velocity > 4.0 m/s.> 4.0 m/s.

• NYHA functional class II or greater.NYHA functional class II or greater.

• Risk of death or serious irreversible morbidity of Risk of death or serious irreversible morbidity of AVR as assessed by cardiologist and two AVR as assessed by cardiologist and two surgeons must exceed 50%.surgeons must exceed 50%.

Surgeons must agree and attest that before Surgeons must agree and attest that before PARTNER these patients would not have received PARTNER these patients would not have received AVR treatment!AVR treatment!

7

Key End-Points for 2 Year AnalysisKey End-Points for 2 Year Analysis

• All cause mortalityAll cause mortality

• Cardiac mortalityCardiac mortality

• RehospitalizationRehospitalization

• StrokeStroke

• NYHA functional classNYHA functional class

• Days alive and out of hospitalDays alive and out of hospital

• Echo-derived valve areas, transvalvular gradients, Echo-derived valve areas, transvalvular gradients, paravalvular aortic regurgitationparavalvular aortic regurgitation

• Mortality outcomes stratified by STS scoreMortality outcomes stratified by STS score8

n = 358Randomized Inoperable

n = 358Randomized Inoperable

n = 179TAVR

n = 179TAVR

n = 179Standard therapy

n = 179Standard therapy

124/124 patients100% followed at 1 Yr




99/102 patients*97.1% followed at 2 Yr

99/102 patients*97.1% followed at 2 Yr



Study FlowStudy FlowInoperable CohortInoperable Cohort

9

• 5 withdrawals in the first year in Standard Rx arm5 withdrawals in the first year in Standard Rx arm• *3 patients followed outside of protocol window in TAVR group*3 patients followed outside of protocol window in TAVR group• No patients were lost to follow-upNo patients were lost to follow-up

Statistical MethodStatistical Method

• Primary analysis was by “intention-to-treat” (ITT).Primary analysis was by “intention-to-treat” (ITT).

• Mortality was estimated by ITT, both with and Mortality was estimated by ITT, both with and without censoring of the cross-over patientswithout censoring of the cross-over patients(n = 11 cross-over patients from 1-2 years).(n = 11 cross-over patients from 1-2 years).

• Clinical outcomes were analyzed by ITT with Clinical outcomes were analyzed by ITT with censoring of Standard Rx cross-over patients.censoring of Standard Rx cross-over patients.

• Event rates are given as Kaplan-Meier estimates.Event rates are given as Kaplan-Meier estimates.

• Core lab echo results are presented from the “as Core lab echo results are presented from the “as treated” (AT) cohort.treated” (AT) cohort.

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Patient Characteristics (1)Patient Characteristics (1)

11

CharacteristicCharacteristic TAVRTAVRn = 179n = 179

Standard RxStandard Rxn = 179n = 179

p valuep value

Age – yrAge – yr 83.1 ± 8.683.1 ± 8.6 83.2 ± 8.383.2 ± 8.3 0.950.95

Male sex (%)Male sex (%) 45.845.8 46.946.9 0.920.92

STS ScoreSTS Score 11.2 ± 5.811.2 ± 5.8 12.1 ± 6.112.1 ± 6.1 0.140.14

NYHANYHA I or II (%)I or II (%) III or IV (%)III or IV (%)

7.87.892.292.2

6.16.193.993.9

0.680.680.680.68

CAD (%)CAD (%) 67.667.6 74.374.3 0.200.20

Prior MI (%)Prior MI (%) 18.618.6 26.426.4 0.100.10

Prior CABG (%)Prior CABG (%) 37.437.4 45.645.6 0.170.17

Prior PCI (%)Prior PCI (%) 30.530.5 24.824.8 0.310.31

Prior BAV (%)Prior BAV (%) 16.216.2 24.424.4 0.090.09

CVD (%)CVD (%) 27.427.4 27.527.5 1.001.00

Patient Characteristics (2)Patient Characteristics (2)

12

CharacteristicCharacteristic TAVRTAVRn = 179n = 179

Standard RxStandard Rxn = 179n = 179

p valuep value

PVD (%)PVD (%) 30.330.3 25.125.1 0.290.29

COPDCOPD Any (%)Any (%) OO2 2 dependent (%)dependent (%)

41.341.321.221.2

52.552.525.725.7

0.040.040.380.38

Creatinine > 2 mg/dL (%)Creatinine > 2 mg/dL (%) 5.65.6 9.69.6 0.230.23

Atrial fibrillation (%)Atrial fibrillation (%) 32.932.9 48.848.8 0.040.04

Perm. pacemaker (%) Perm. pacemaker (%) 22.922.9 19.519.5 0.490.49

Pulmonary HTN (%)Pulmonary HTN (%) 42.442.4 43.843.8 0.900.90

Frailty (%)Frailty (%) 18.118.1 28.028.0 0.090.09

Porcelain aorta (%)Porcelain aorta (%) 19.019.0 11.211.2 0.050.05

Chest wall radiation (%)Chest wall radiation (%) 8.98.9 8.48.4 1.001.00

Chest wall deformity (%)Chest wall deformity (%) 8.48.4 5.05.0 0.290.29

Liver disease (%)Liver disease (%) 3.43.4 3.43.4 1.001.00

All Cause Mortality (ITT)All Cause Mortality (ITT)Crossover Patients FollowedCrossover Patients Followed

Numbers at RiskNumbers at Risk

TAVRTAVR 179179 138138 124124 110110 8383 Standard RxStandard Rx 179179 121121 8585 6767 5151

All

Cau

se M

orta

lity

(%)

Standard Rx

TAVR

∆ at 2 yr = 24.3%NNT = 4.1 pts

67.6%

43.3%

∆ at 1 yr = 20.0%NNT = 5.0 pts

50.7%

30.7%

13

Months

HR [95% CI] =0.57 [0.44, 0.75]

p (log rank) < 0.0001

All Cause Mortality (ITT)All Cause Mortality (ITT)Crossover Patients CensoredCrossover Patients Censored



All

Cau

se M

orta

lity

(%)

Standard Rx

TAVR

∆ at 2 yr = 24.7%NNT = 4.0 pts

68.0%

43.3%

∆ at 1 yr = 20.0%NNT = 5.0 pts

50.7%

30.7%

14

Months

HR [95% CI] =0.56 [0.43, 0.73]

p (log rank) < 0.0001

All Cause Mortality (ITT)All Cause Mortality (ITT)Landmark AnalysisLandmark Analysis

All

Cau

se M

orta

lity

(%)

Months

Mortality 0-1 yr Mortality 1-2yr

Standard Rx TAVR

HR [95% CI] =0.57 [0.44, 0.75]

p (log rank) < 0.0001

HR [95% CI] =0.58 [0.37, 0.92]

p (log rank) = 0.019450.7%

30.7%

35.1%

18.2%



15

Cardiovascular Mortality (ITT)Cardiovascular Mortality (ITT)Crossover Patients CensoredCrossover Patients Censored



Car

diov

ascu

lar

Mor

talit

y (%

)

Standard Rx

TAVR

∆ at 2 yr = 31.4%NNT = 3.2 pts

62.4%

31.0%

∆ at 1 yr = 24.1%NNT = 4.1 pts 44.6%

20.5%

16

Months

HR [95% CI] =0.44 [0.32, 0.60]

p (log rank) < 0.0001

Repeat Hospitalization (ITT)Repeat Hospitalization (ITT)



Rep

eat H

ospi

taliz

atio

n (%

)

Standard Rx

TAVR

∆ at 2 yr = 37.5%NNT = 2.7 pts

72.5%

35.0%

∆ at 1 yr = 26.9%NNT = 3.7 pts

53.9%

27.0%

18

Months

HR [95% CI] =0.41 [0.30, 0.58]

p (log rank) < 0.0001

Hospitalization Through 2 YearsHospitalization Through 2 Years

TAVRTAVR Standard TxStandard Tx p valuep value

Repeat Hospitalizations (No.)Repeat Hospitalizations (No.) 7878 151151 <.0001<.0001

Repeat Hospitalizations (%)Repeat Hospitalizations (%) 35.0%35.0% 72.5%72.5% <.0001<.0001

Days Alive Out of Hospital Days Alive Out of Hospital Median [IQR]Median [IQR] 699 [201-720]699 [201-720] 355 [116-712]355 [116-712] .0003.0003

19

Per

cent

Treatment VisitTreatment Visit Baseline 1 Year 2 Year

p = 0.61 p < 0.0001 p < 0.0001

92.2%

57.5%

16.9%23.7%

60.8%

93.9%

NYHA Class Over TimeNYHA Class Over TimeSurvivorsSurvivors

20

All Stroke (ITT)All Stroke (ITT)



Inci

denc

e (%

)

Months

Standard Rx

TAVR

∆ at 2 yr = 8.3%

5.5%

13.8%

∆ at 1 yr = 5.7%

5.5%

11.2%

21

HR [95% CI] =2.79 [1.25, 6.22]

p (log rank) = 0.009

All Cerebrovascular Events (%)All Cerebrovascular Events (%)

22

≤ ≤ 30 Days30 Days 31 Days – 1 Year31 Days – 1 Year 1 Year – 2 Years1 Year – 2 Years

All CVA p = 0.010 p = 0.387 p = 0.028

Ischemic Stroke p = 0.017 p = 0.155 p = 0.083

Hemorrhagic Stroke p = 0.316 p = 0.121 p = 0.415

Eve

nts

Note: Percents are of patients in the trial (n/179).

All Strokes (# pts)All Strokes (# pts)

24

≤ ≤ 30 Days30 Days 31 Days – 2 Years31 Days – 2 Years

All stroke p=0.010 p=0.319

Ischemic Stroke p = 0.017 p = 0.437

Hemorrhagic Stroke p = 0.316 p = 0.160

Eve

nts

Stroke - HemorrhagicStroke - Hemorrhagic

25

ITT armITT arm AgeAge Days post Days post randomizationrandomization DescriptionDescription TraumaTrauma MedicationMedication Procedure Procedure

related*related*Device Device related*related*

TAVR 91 9Right sided hemorrhage

NoCoumadin on

admissionYes No

TAVR 84 53Traumatic

subarachnoidFall Coumadin No No

TAVR 85 54Intraparenchy-

mal and subdural

Fall Not stated No No

TAVR 84 124 Intracranial Fall Not stated No No

TAVR 88 155Subdural

hematomaNot stated DAPT No No

Standard therapy (BAV)

91 243"Massive cerebral

hemorrhage"Not stated Not stated No n/a

*CEC adjudicated

Mortality or Stroke (ITT)Mortality or Stroke (ITT)



All

Cau

se M

orta

lity

or S

trok

e (%

)

Months

Standard Rx

TAVR

∆ at 2 yr = 21.9%NNT = 4.6 pts

68.0%

46.1%

∆ at 1 yr = 16.1%NNT = 6.2 pts 51.3%

35.2%

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HR [95% CI] =0.64 [0.49, 0.84]

p (log rank) = 0.0009

1 Year1 Yearn = 179n = 179

OutcomeOutcomeTAVRTAVR Standard Standard

RxRx P valueP value

2 Year 2 Year n = 179n = 179

TAVRTAVR Standard Standard RxRx P valueP value

Acute kidney injuryAcute kidney injury

Creatinine > 3 mg/dL, % (n)Creatinine > 3 mg/dL, % (n) 1.1 (2)1.1 (2) 2.8 (5)2.8 (5) 0.4490.449 1.1 (2)1.1 (2) 2.8 (5)2.8 (5) 0.4490.449 Renal failure (CEC), % (n)Renal failure (CEC), % (n) 2.3 (4)2.3 (4) 4.7 (7)4.7 (7) 0.2570.257 3.2 (5)3.2 (5) 7.6 (9)7.6 (9) 0.1490.149

Cardiac re-interventionCardiac re-intervention

BAV, % (n)BAV, % (n) 1.1 (2)1.1 (2) 82.3 (138)82.3 (138) <.0001<.0001 2.8 (4)2.8 (4) 85.3 (140)85.3 (140) <.0001<.0001

Re-TAVR, % (n)Re-TAVR, % (n) 1.7* (3)1.7* (3) NANA -- 1.7* (3)1.7* (3) NANA --

AVR, % (n)AVR, % (n) 0 (0)0 (0) 7.6 (10)7.6 (10) 0.0020.002 0.9 (1)0.9 (1) 8.9 (11)8.9 (11) 0.0050.005

Endocarditis, % (n)Endocarditis, % (n) 1.4 (2)1.4 (2) 0.8 (1)0.8 (1) 0.6180.618 2.3 (3)2.3 (3) 0.8 (1)0.8 (1) 0.3160.316

Bleeding – major, % (n)Bleeding – major, % (n) 24.2 (42)24.2 (42) 14.9 (21)14.9 (21) 0.0380.038 28.9 (48)28.9 (48) 20.1 (25)20.1 (25) 0.0930.093

New pacemaker, % (n)New pacemaker, % (n) 4.7 (8)4.7 (8) 8.6 (14)8.6 (14) 0.1490.149 6.4 (10)6.4 (10) 8.6 (14)8.6 (14) 0.4690.469

Myocardial infarctionMyocardial infarction

All, % (n)All, % (n) 0.8 (1)0.8 (1) 0.7 (1)0.7 (1) 0.9060.906 1.6 (2)1.6 (2) 2.5 (2)2.5 (2) 0.6940.694

Clinical OutcomesClinical Outcomes1 Year and 2 Year (ITT)1 Year and 2 Year (ITT)

27

All Cause Mortality (ITT)All Cause Mortality (ITT)Control Patients Alive on First Crossover DateControl Patients Alive on First Crossover Date


Not Crossed-OverNot Crossed-Over 3838 3232 2424 1717Crossed-OverCrossed-Over 2020 1919 1818 1717

All

Cau

se M

orta

lity

(%)

∆ at 1 yr = 11.0%

10.0%

21.0%

29

Months past first cross-over

Crossed-Over

Not Crossed-Over

Mea

n G

radi

ent (

mm

Hg)

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

EOA

Mean Gradient

N = 158

N = 162

N = 137

N = 143

N = 84

N = 89

N = 65

N = 65

N = 9

N = 9

AV

A (cm

²)Mean Gradient & Valve AreaMean Gradient & Valve Area

30


None to MildNone to Mild 147147 118118 107107 9595 7272 Moderate or SevereModerate or Severe 1717 1212 1111 1010 88

Dea

th In

cide

nce

(%)

Months

Moderate or Severe

None to Mild

41.2%

40.5%

35.3%

27.2%

Mortality Stratified by Paravalvular Leak (ITT)Mortality Stratified by Paravalvular Leak (ITT)Starting at DischargeStarting at Discharge

31

p (log rank) = 0.891

Echo Analysis PV Leak Changes Echo Analysis PV Leak Changes 30 Days Compared to 2 Years30 Days Compared to 2 Years

32

16.4% Progressed16.4% Progressed42.6% Improved42.6% Improved 41.0% Unchanged41.0% Unchanged

30 Day30 Day2 Year2 Year

NoneNone TraceTrace MildMild ModerateModerate SevereSevere

None 10 3 0 0 0

Trace 7 5 6 0 0

Mild 4 7 10 1 0

Moderate 0 4 3 0 0

Severe 0 0 1 0 0

Of the 61 patients alive with data at 2 years:

Patients With Data at Both Time Points

2828 2626 2525 2424 1616108108 8080 7676 6767 5252

4343 3232 2323 1919 1515

Dea

th In

cide

nce

(%)

Months

STS <5 STS 5-14.9

Months

STS ≥15

p value (log rank) = 0.012p value (log rank) = 0.676

1212 88 77 66 55119119 8484 5959 4242 2929

4747 2929 1919 1414 88

Mortality Stratified by STS Score (ITT)Mortality Stratified by STS Score (ITT)

TAVRTAVRStandard RxStandard Rx


33

Conclusions (1)Conclusions (1)

At 2 years, At 2 years, in patients with symptomatic severe AS in patients with symptomatic severe AS who are not suitable candidates for surgery…who are not suitable candidates for surgery…

• TAVR remained superior to standard therapy with TAVR remained superior to standard therapy with incremental benefit from 1 to 2 years, markedly incremental benefit from 1 to 2 years, markedly reducing the rates of…reducing the rates of…

All cause mortalityAll cause mortality

Cardiovascular mortalityCardiovascular mortality

Repeat hospitalizationRepeat hospitalization

• TAVR improved NYHA functional status and TAVR improved NYHA functional status and decreased Class III/IV symptoms compared to decreased Class III/IV symptoms compared to standard therapy (17% vs 64%; p < 0.001).standard therapy (17% vs 64%; p < 0.001).

34



•There were more neurologic events in TAVR patients vs There were more neurologic events in TAVR patients vs Standard Rx (16.2% vs 5.5%; p = 0.003) with 5 new Standard Rx (16.2% vs 5.5%; p = 0.003) with 5 new events (3 strokes and 2 TIAs) between 1-2 years in TAVR events (3 strokes and 2 TIAs) between 1-2 years in TAVR patients.patients.

•After 30 days, differences in stroke frequency were After 30 days, differences in stroke frequency were largely due to increased hemorrhagic strokes in TAVR largely due to increased hemorrhagic strokes in TAVR patients.patients.

•A subgroup analysis according to surgical risk score A subgroup analysis according to surgical risk score suggests that the most pronounced benefit of TAVR is suggests that the most pronounced benefit of TAVR is in patients without extreme clinical co-morbidities.in patients without extreme clinical co-morbidities.35



•TAVR hemodynamics by echo showed durable TAVR hemodynamics by echo showed durable improvements in AVA and mean gradients up to improvements in AVA and mean gradients up to 3 years after implantation.3 years after implantation.

•Moderate or severe paravalvular AR in the TAVR Moderate or severe paravalvular AR in the TAVR patients did not influence 2-year survival and there was patients did not influence 2-year survival and there was a trend towards reduced paravalvular AR between 1 and a trend towards reduced paravalvular AR between 1 and 2 years.2 years.

36

Clinical Implications Clinical Implications

• Two year data continues to support the role of TAVR Two year data continues to support the role of TAVR as the standard-of-care for symptomatic patients with as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates.aortic stenosis who are not surgical candidates.

• The ultimate value of TAVR in “inoperable” patients The ultimate value of TAVR in “inoperable” patients will depend on careful selection of patients who are will depend on careful selection of patients who are not surgical candidates, and yet do not have extreme not surgical candidates, and yet do not have extreme co-morbidities that overwhelm the benefits of TAVR co-morbidities that overwhelm the benefits of TAVR and render the intervention futile.and render the intervention futile.

37

Thank You to the Dedicated Study Thank You to the Dedicated Study Teams at All PARTNER Teams at All PARTNER Investigational SitesInvestigational Sites

tct 2011 | san francisco, ca | november 10, 2011 two-year outcomes of transcatheter aortic valve...

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