lessons from tavr randomized trials and registries e murat tuzcu, md professor of medicine cleveland...

Lessons from TAVR Randomized Trials and Registries

E Murat Tuzcu, MDProfessor of Medicine

Cleveland Clinic

Financial disclosures: NonePARTNER Executive Committee member

Edwards Transcatheter Valve Evolution

UntreatedEquine Tissue

Edwards SAPIEN™ August, 2007

TreatedBovine Tissue

AndersenPig implant, May ’89

Cribier-Edwards™FIM, April 2002

Sapien XT™ January, 2010

TFX TreatedBovine /CC

UntreatedEquine Tissue

CoreValve Revalving

Generation 1Generation 125 Fr25 Fr

Generation 2Generation 221 Fr21 Fr

Generation 3Generation 318 Fr18 Fr

Dec 2006Dec 2006No Support No Support

No AnesthesiaNo Anesthesia

2005-2006 (June)2005-2006 (June)CP By-Pass + TandemHeartCP By-Pass + TandemHeart

Percutaneous SupportPercutaneous Support

2004-20052004-2005Surgical Fem-FemSurgical Fem-Fem

CP By-PassCP By-Pass

30-day Mortality 30-day Mortality

Study (%)Study (%)

REVIVE/REVIVALREVIVE/REVIVALaa

VANCOUVERVANCOUVERbb

PARTNER EUPARTNER EUcc

SOURCESOURCEdd

CANADIANCANADIANee

FRENCH RegFRENCH Regff

UK RegUK Reggg

nn

161161

114114

5959

463463

345345

9595

172172

AgeAge

83.783.7

83.983.9

82.382.3

81.781.7

8181

83.283.2

8383

Mortality (%)Mortality (%)

11.211.2

7.97.9

8.18.1

6.36.3

10.410.4

8.48.4

8.98.9

ES/STSES/STS

34.3/13.134.3/13.1

30.3/-30.3/-

25.7/11.325.7/11.3

25.7/-25.7/-

-/9.8-/9.8

25.6/15.425.6/15.4

2020

Transfemoral TAVI

a. Kodali et al TCT 2008a. Kodali et al TCT 2008b. Webb TCT 2008b. Webb TCT 2008c. Schachinger et al Euro PCR 2009c. Schachinger et al Euro PCR 2009

d. Thomas et al Euro PCR 2009d. Thomas et al Euro PCR 2009e. Rodes-Cabau et al. JACC 2010;55:In Presse. Rodes-Cabau et al. JACC 2010;55:In Pressf. Eltchaninoff H. AHA 2009f. Eltchaninoff H. AHA 2009g. LudmanEuroPCR 2010g. LudmanEuroPCR 2010

1.01.0

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

REVIVALVANCOUVER

CANADIAN UK Registry

00 22 44 66 88 1010 1212

MonthMonth

SOURCE

1.01.0

75.8%73.8%81.1%75.0%79.5%

One Year SurvivalOne Year Survival

Transfemoral TAVI

N = 699 N = 358High RiskHigh Risk InoperableInoperable

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

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 N = 179

All Cause Mortality

Numbers at RiskNumbers at Risk

TAVITAVI 179179 138138 122122 6767 2626 Standard RxStandard Rx 179179 121121 8383 4141 1212

∆ at 1 yr = 20.0%NNT = 5.0 pts

Standard Rx

TAVI

All-

caus

e m

orta

lity

(%)

Months

0

20

40

60

80

100

50.7%

30.7% HR [95% CI] =0.54 [0.38, 0.78]

P (log rank) < 0.0001

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

DeadI II III IV

Per

cent

NYHA Class Over TimeNYHA Class Over TimeAll patientsAll patients

TreatmentTreatmentVisitVisit

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

Aortic Valve Mean Gradient (Core Lab) (mmHg)

*

**

*

Douglas et al ACC 2011

Clinical Outcomes at 30 Days and 1 Year

Major VascularComplications

P<0.0001 P<0.0001

TAVI (n=179) Standard Rx (n=179)

per

cent

Major Stroke

P = 0.06 P = 0.18

Published Cost Effectiveness Estimates

Clinical Implications

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

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 AVRAVRVSVS

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 patients

2 Parallel Trials: Individually Powered

N = 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

Characteristic TAVR (N = 348) AVR (N = 351) p-value

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 0.93

NYHAII - %

III or IV - % 94.3 94.0

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

Patient Characteristics (1) Patient Characteristics (1)

Cerebrovascular disease - %

5.7 6.00.79

CharacteristicCharacteristic TAVR (N = 348)TAVR (N = 348) AVR (N = 351)AVR (N = 351) p-valuep-value

Peripheral vascular disease - % 43.0 41.6 0.76

COPD Any 43.4

Oxygen dependent 9.2 7.1 0.34

Creatinine> 2mg/dL - % 11.1 7.0 0.06

Atrial fibrillation - % 40.8 42.7 0.75

Permanent pacemaker - % 20.0 21.9 0.58

Pulmonary hypertension - % 42.4 36.4 0.15

Frailty - % 15.6 17.6 0.58

Porcelain aorta - % 0.6 1.1 0.69

Chest wall radiation - % 0.9 0.9 1.00

Liver disease - % 2.0 2.6 0.80

Patient Characteristics (2) Patient Characteristics (2)

43.0 0.94

0

0.1

0.2

0.3

0.4

0.5

0 6 12 18 24

TAVR

AVR

Months

348 298 260 147 67

351 252 236 139 65

No. at Risk

TAVR

AVR

26.8

24.2

Primary Endpoint:All-Cause Mortality at 1 Year

HR [95% CI] =0.93 [0.71, 1.22]

P (log rank) = 0.62

  30 Days 1 Year

OutcomeTAVR

(N = 348)AVR

(N = 351)p-value

TAVR(N = 348)

AVR(N = 351)

p-value

Vascular complications

All – no. (%) 59 (17.0)59 (17.0) 13 (3.8)13 (3.8) <0.01<0.01 62 (18.0)62 (18.0) 16 (4.8)16 (4.8) <0.01<0.01

Major – no. (%)Major – no. (%) 38 (11.0)38 (11.0) 11 (3.2)11 (3.2) <0.01<0.01 39 (11.3)39 (11.3) 12 (3.5)12 (3.5) <0.01<0.01

Major bleeding – no. (%)Major bleeding – no. (%) 32 (9.3)32 (9.3) 67 (19.5)67 (19.5) <0.01<0.01 49 (14.7)49 (14.7) 85 (25.7)85 (25.7) <0.01<0.01

Endocarditis – no. (%) 0 (0.0)0 (0.0) 1 (0.3)1 (0.3) 0.320.32 2 (0.6)2 (0.6) 3 (1.0)3 (1.0) 0.630.63

New AF – no. (%)New AF – no. (%) 30 (8.6)30 (8.6) 56 (16.0)56 (16.0) < 0.01< 0.01 42 (12.1)42 (12.1) 60 (17.1)60 (17.1) 0.070.07

New PM – no. (%)New PM – no. (%) 13 (3.8)13 (3.8) 12 (3.6)12 (3.6) 0.890.89 19 (5.7)19 (5.7) 16 (5.0)16 (5.0) 0.680.68

Clinical Outcomes at 30 Days and 1 Year All Patients (N=699)

  30 Days 1 Year

OutcomeTAVR

(N = 348)AVR

(N = 351)TAVR

(N = 348)AVR

(N = 351)

All Stroke or TIA – no. (%)All Stroke or TIA – no. (%) 19 (5.5)19 (5.5) 8 (2.4)8 (2.4) 0.040.04 27 (8.3)27 (8.3) 13 (4.3)13 (4.3) 0.040.04

TIA – no. (%) 3 (0.9) 1 (0.3) 0.33 7 (2.3) 4 (1.5) 0.47

All Stroke – no. (%) 16 (4.6) 8 (2.4) 0.12 20 (6.0) 10 (3.2) 0.08

Major Stroke – no. (%)Major Stroke – no. (%) 13 (3.8)13 (3.8) 7 (2.1)7 (2.1) 0.200.20 17 (5.1)17 (5.1) 8 (2.4)8 (2.4) 0.070.07

Minor Stroke – no. (%) 3 (0.9) 1 (0.3) 0.34 3 (0.9) 2 (0.7) 0.84

Death/maj stroke – no. (%)Death/maj stroke – no. (%) 24 (6.9)24 (6.9) 28 (8.2)28 (8.2) 0.520.52 92 (26.5)92 (26.5) 93 (28.0)93 (28.0) 0.680.68

Neurological Events at 30 Days and 1 Year All Patients (N=699)

p-value p-value

0 - No symptoms. 1 - No significant disability. Able to carry out all usual activities, despite

some symptoms.

2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.

3 - Moderate disability. Requires some help, but able to walk unassisted. 4 - Moderately severe disability. Unable to attend to own bodily needs

without assistance, and unable to walk unassisted. 5 - Severe disability. Requires constant nursing care and attention,

bedridden, incontinent. 6 - Dead.

The Modified Rankin Scale

Minor

Major

All-Cause Mortality at 30 DaysAll Patients

no. of patients ( %)TF Patients

no. of patients ( %)TA Patients

no. of patients ( %)

  TAVR AVR p-value TAVR AVR p-value TAVR AVR p-value

ITT 12 (3.4) 22 (6.5) 0.07 8 (3.3) 15 (6.2) 0.13 4 (3.8) 7 (7.0) 0.32

AT 18 (5.2) 25 (8.0) 0.15 9 (3.7) 18 (8.2) 0.046 9 (8.7) 7 (7.6) 0.79

Mortality and Major Stroke at 30 Days

Major Stroke at 30 DaysAll Patients

no. of patients ( %)TF Patients

no. of patients ( %)TA Patients

no. of patients ( %)

  TAVR AVR p-value TAVR AVR p-value TAVR AVR p-value

ITT 13 (3.8) 7 (2.1) 0.20 7 (2.9) 4 (1.7) 0.37 6 (5.8) 3 (3.2) 0.37

AT 13 (3.8) 7 (2.3) 0.25 6(2.5) 3 (1.4) 0.37 7 (7.0) 4 (4.4) 0.45

All-Cause Mortality at 1 YearAll Patients

no. of patients ( %)TF Patients

no. of patients ( %)TA Patients

no. of patients ( %)

  TAVR AVR p-value TAVR AVR p-value TAVR AVR p-value

ITT 84 (24.2) 89 (26.8) 0.44 54 (22.2) 62 (26.4) 0.29 30 (29.0) 27 (27.9) 0.85

AT 81 (23.7) 78 (25.2) 0.64 51 (21.3) 55 (25.2) 0.33 30 (29.1) 23 (25.3) 0.55

Major Stroke at 1 YearAll Patients

no. of patients ( %)TF Patients

no. of patients ( %)TA Patients

no. of patients ( %)

  TAVR AVR p-value TAVR AVR p-value TAVR AVR p-value

ITT 17 (5.1) 8 (2.4) 0.07 9 (3.8) 4(1.7) 0.15 8 (8.3) 4 (4.3) 0.26

AT 17 (5.2) 8 (2.7) 0.11 8 (3.5) 3(1.4) 0.15 9 (9.4) 5(5.9) 0.37

Mortality and Major Stroke at 1 year

5

4

3

9

0

2

4

6

8

10

0-5 Days 6-30 Days 31Days - 1 Year >1Year

TAVR Neuro Events in PARTNER BN

um

be

r of

Eve

nts

Nu

mb

er

of E

ven

ts

00

22

44

66

88

1010

5strokes0-3 day

8 strokes occurred when patients were in AF

Paravalvular Aortic Regurgitation

P< 0.001 P< 0.001 P< 0.001

1 Year6 Months30 Days

Pat

ient

s, %

None Trace Mild Moderate Severe

ImplicationsImplications

•TAVR is an acceptable alternative to AVR in selected high-risk operable patients.

• A multidisciplinary valve team benefits patients and recommended for all valve centers.

• Future RCT should focus on lower risk patients who are candidates for operation.