The PARTNER Stroke Substudy Writing Group* On behalf of The PARTNER Trial Investigators and Patients...

The PARTNER Stroke Substudy Writing Group*

On behalf of The PARTNER Trial Investigators and Patients

Transcatheter (TAVR) versus Surgical (AVR) Aortic Valve Replacement: Incidence, hazard,

determinants, and consequences of neurological events in the PARTNER Trial

* Miller DC, Mack MJ, Svensson LG, Kodali SK, Kapadia S, Anderson WN, Rajeswaran J, Blackstone EH

Presenter Disclosure Information

for PARTNER Trial, AATS May, 2011

D. Craig Miller , M.D.

Affiliation/Financial Relationship Company

Grant/ Research Support: NHLBI research grant RO1 HL67025

Consulting Fees/Honoraria:•The PARTNER U.S. Pivotal Trial Executive Committee, Edwards Lifesciences (uncompensated)•Stanford PI – The PARTNER Trial, Edwards Lifesciences (uncompensated)•Consultant, Abbott Vascular (MitraClip)•Consultant, Medtronic CardioVascular Division•Consultant, St. Jude Medical

Major Stock Shareholder/Equity Interest:Royalty Income:Ownership/Founder:Salary:Intellectual Property Rights:Other Financial Benefit:

Background Surgical AVR is the standard of care for

symptomatic aortic stenosis

Survival after TAVR is superior compared to medical therapy in inoperable patients, and is non-inferior to that after AVR in high-risk operative candidates, but neurological complications occur more frequently after TAVR

No randomized trial comparing TAVR and AVR focusing on neurological events has been performed

N = 699 N = 358

High RiskHigh Risk

InoperableInoperable

The PARTNER TrialThe PARTNER TrialStudy DesignStudy Design

Symptomatic Severe Aortic StenosisSymptomatic Severe Aortic Stenosis

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


Total = 1,057 patients

2 Parallel Trials: Individually Powered

StandardTherapyStandardTherapy

ASSESSMENT: Transfemoral

Access


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)



1:1 Randomization1:1 Randomization

VS

YesYes NoNo

N = 179 N = 179

Numbers at RiskNumbers at Risk

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

Standard Rx

TAVI

All

-cau

se m

ort

alit

y (%

)

Months

∆ at 1 yr = 20.0%NNT = 5.0 pts

50.7%

30.7%

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

P (log rank) < 0.0001

PARTNER cohort B (inoperable)All-Cause Mortality at 1 Year

Neuro events at 30 days and 1 year- Inoperable cohort B

Major Stroke

P = 0.06P = 0.18

All Stroke or TIA

P = 0.03P = 0.04

TAVR (n=179) Standard Rx (n=179)

per

cen

t

N = 179

N = 358InoperableInoperable

StandardTherapyStandardTherapy


Access


Access

Not In StudyNot In Study

TF TAVRTF TAVR





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 VS

VS

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

The PARTNER Study DesignThe PARTNER Study Design

Symptomatic Severe Aortic StenosisSymptomatic Severe Aortic Stenosis



Total = 1,057 patients

2 Parallel Trials: Individually Powered

N = 699 High RiskHigh Risk


Access


Access

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

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

YesYes NoNo

TransfemoralTransfemoral TransapicalTransapical

TAVRTransfemoral (TF) and Transapical (TA)

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

PARTNER cohort AAll-Cause Mortality at 1 Year

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

P (log rank) = 0.62

All neurological eventsat 30 days and 1 yearPARTNER Cohort A Trial (ITT)

5.5

8.3

2.44.3

0

10

20

30 Days 1 Year

All

neur

o ev

ents

(%

) TAVR AVR

Smith CR, ACC 2011, NEJM in press

P=0.04P=0.04P=0.04P=0.04

Purpose• Analyze stroke and TIA after TAVR and surgical AVR in high-risk (≈15%, floor= STS 8-9%), operable patients with symptomatic, severe aortic stenosis in the PARTNER Trial

• “As Treated” (AT) patients n= 657 (vs. ITT)

• Captured all neurological events at all times

• Prospective, independent, blinded adjudication of adverse neurological events by CEC, supplemented by CEC retrospective assessment of stroke severity

• Unblinded re-review of all CEC summaries and source documents by 2 investigators (DCM, MJM)

Patient characteristics (AT)Transapical Stratum Transfemoral Stratum

Variable

AVR(n = 92)

TA-TAVR(n = 104)

AVR(n = 221)

TF-TAVR(n = 240)

Age (years) (± 1 SD) 83 ± 6 83 ± 7 85 ± 7 84 ± 7

STS risk Score (± 1 SD) 12.1 ± 3.5 11.7 ± 3.6 11.5 ± 3.3 11.9 ± 3.2

Logistic EuroSCORE (± 1 SD) 30 ± 15 30 ± 16 29 ± 15 29 ± 17

NYHA class III-IV 96% 92% 95% 95%

Carotid endarterectomy / stent 17% 24% 6% 10%

Stroke or TIA within last 6-12 mo 7% 1% 1% 4%

Previous CABG 56% 50% 40% 40%

Coronary artery disease 84% 75% 75% 75%

Previous MI 38% 28% 26% 27%

Cerebrovascular disease 31% 43% 26% 24%

Peripheral vascular disease 62% 63% 35% 35%

COPD 64% 64% 65% 63%

Pulmonary hypertension 42% 53% 55% 54%

Atrial fibrillation 21% 32% 26% 23%

Mean aortic valve gradient (mmHg)

41 ± 13 42 ± 14 45 ± 15 43 ± 15

Aortic Valve Area Index (cm2/m2) 0.4 ± 0.1 0.4 ± 0.1 0.3 ± 0.1 0.4 ± 0.1

LV ejection fraction (%) 54 ± 11 54 ± 12 54 ± 13 52 ± 14

One year results (AT, n= 657)

Transapical Stratum

Transfemoral Stratum

Outcome at 1 year

AVR(n = 92)

TA-TAVR(n = 104)

AVR(n = 221)

TF-TAVR(n = 240) P-value

All-cause mortality 25% 29% 25% 21% .33

All neurological events

9.7% 14.1% 1.9% 6.1% 0.03

Major stroke 5.9% 9.4% 1.4% 3.5% .15Minor stroke 1.1% 1.0% 0% 0.8% .16TIA 3.9% 3.7% 0.6% 1.8% .25

47 patients, 49 neuro eventsIschemic- 72%, hemorrhagic- 0%,

ischemic evolving to hemorrhagic- 4%, unknown- 24%

Distribution of types of neurological events

0

2

4

6

8

10

12

14

TIA

Minor Stroke

Major Stroke

Timing of neurological eventsAVR

AV

AV

RRT

AV

TA

VRR

AV

AV

RRT

AV

TA

VRR

AV

AV

RRT

AV

TA

VRR

AV

AV

RRT

AV

TA

VRR

AV

AV

RRT

AV

TA

VRR

AV

AV

RRT

AV

TA

VRR

AV

AV

RRT

AV

TA

VRR

0-20-2daysdays

3-53-5daysdays

31-36431-364daysdays

11-3011-30daysdays

6-106-10daysdays

2-32-3yearsyears

1-21-2yearsyears

Risk Factors forNeurologic Events

Multiphase, multivariable non-proportional hazard analysis

Early high peaking hazard phase Later constant hazard phase

Risk FactorCoefficient ±

SD PR

(%)

Early hazard phase

TAVR 2.21±0.68 .001 59

Smaller AVA index in TAVR group

-11.8±5.1 .02 57

Incremental risk factors for neurologic events

R(%) = bagging reliability

Early high peaking hazard phase

Atrial fibrillation not significant in multivariable analysis

Early hazard of neurologic event

%/mo

0

20

40

60

80

.25 .50 .75 1.0

TAVR

AVR

Months after Procedure

Neurologic event- TF candidate

%%

0

5

10

15

20

25

30

6 12 18 24

AVR TAVR

MosMos5451

10699

179159

203170

242221

TAVRAVR

3.4

6.0

2.4

7.4

TF Candidate

Neurologic event- TA candidate

%%

0

5

10

15

20

25

30

6 12 18 24

TAVR

AVR

MosMos2627

6460

7667

10292

TAVRAVR

12

10

TA Candidate

Neurologic event by 1 moInfluence of smaller AVA index

%%

AVAI (cmAVAI (cm22/m/m22))

TF

TA

CandidateCandidate

TAVR

5

10

15

20

0.2 0.3 0.4 0.5 0.6

Risk Factor Coefficient ± SD P R (%)

Constant hazard phase

TAVR 0.40±0.43 0.4 22

(Higher) NYHA 0.95±0.40 .02 75

Stroke or TIA within 6-12 mo 1.93±0.64 .002 60

Non-TF TAVR candidate 2.3±0.45 <.0001 96

History of PCI (less risk) -1.60±0.63 .01 77

COPD (less risk) -1.06±0.47 .03 79

Incremental risk factors for neurologic events

R(%) = bagging reliability

Late constant hazard phase

Non-TF candidate differentiation

Female

PVD

CEA

CABG

100200 40 8060

%

TF stratumTA stratum

Later hazard- assigned stratum(TAVR and AVR combined)

%/m%/m

0

1

2

3

4

6 12 18 24

TF

TA

Candidate

Months after ProcedureMonths after Procedure

TAVR neurologic event by stratum

%%

TAVR

TF

TA

MosMos

Candidate

7.4

12

6.0

5410626

17964

20376

242102

TAVR-TFTAVR-TA

0

5

10

15

20

25

30

6 12 18 24

%%

0

5

10

15

20

25

30

6 12 18 24MosMos

AVR

TF

TA

3.4

10

2.4

519927

15960

17067

22192

TFTA

Candidate

AVR neurologic event by stratum

Major Stroke

Small number of events n= 29Conservative definition (modified Rankin score ≥2)

If stroke severity unclear, categorized as major

Major stroke (18 TAVR, 11 AVR)

%%

0

2

4

6

8

10

6 12 18 24

TAVR

AVR

MosMos6359

137128

252222

284239

344313

TAVRAVR

4.5

4.8

2.6

6.1

Competing Risks ofDeath and Neurologic Events

Competing risks

%%

0

20

40

60

80

100

6 12 18 24

Neuro event

Alive w/o neuro event

Months after ProcedureMonths after Procedure

Death before neuro event

AVR

Neurologic event

0

5

10

15

20

25

6 12 18 24

%%

AVR-TA

Consideringcompeting risks

TAVR-TA

67

59

11432

10618

17964

16062

20277

17067

240104221 92

TAVR-TFTAVR-TAAVR-TFAVR-TA

AVR-TF

12

5.59.1

2.2 2.6

6.5TAVR-TF

“Mortality Cost” of a Neurologic Event

“Mortality Cost” of neuro event

0

2

4

6

8

3 6 9 12

Observed/Expected

AVR

HazardRatio

Months after Neurologic EventMonths after Neurologic Event

0

2

4

6

8

3 6 9 12

Observed/Expected

HazardRatio


TAVR-TF


0

2

4

6

8

3 6 9 12

Observed/Expected

HazardRatio


TAVR-TA


• Prospective, independently adjudicated 30 day neurological event rates (stroke and TIA) were low

AVR= 2.6% TAVR= 5.6% p= .05

TF- AVR= 1.4% TAVR= 4.6% p= .04

Conclusions

• Remarkably low 30 day mortality rates in these elderly, very high-risk AS patients in both arms of study

AVR= 8% (O:E= 0.68) TAVR= 5.2% (O:E= 0.42) p= .15

TF- AVR= 8.2% TAVR= 3.7% p= 0.05

• Major stroke rates at 30 days were even lower

AVR= 2.3% TAVR= 3.8% p= .25

TF- AVR= 1.4% TAVR= 2.5% p= .37

Incremental risk factors for neurological events

• Early peaking high hazard phase:TAVRSmaller AVA index (TAVR group only)

• Later constant hazard phase:

Generalized heavy arteriosclerotic burden (“non-TF TAVR candidate”)

Stroke/TIA within 6-12 monthsHigher NYHA class

Conclusions

• Higher observed incidence of neurological events in the “non-TF candidate” stratum reflected the patient substrate, and was not related to the TA-TAVR or AVR procedures per se

Conclusions

• Taking competing hazard of death into consideration, the likelihood of a neurologic event was lowest in AVR patients and highest in TA-TAVR group

• A neurologic event raised the risk of mortality

• In AVR group: High peak, quickly returning to baseline hazard

• In TAVR groups: After initial peak, risk remained elevated throughout the 24 months of follow-up, particularly in TA stratum

Conclusions

• These results can only be interpreted within the constraints of the PARTNER Trial protocol:

• Carefully controlled patient selection

• Regimented training and proctoring

• Critical case monitoring and review

• Dedicated multi-disciplinary “Heart Valve Team” in these 26 centers

• “TF first” protocol philosophy and TAVR sheath sizes available

• Learning curve, first generation TAVR device

• Not adequately powered for TF vs. TA comparison

Limitations

Thank You

BACK-UP

EARLY HIGH HAZARD PHASE

• Peri-procedural anticoagulation management• Clopidogrel load, + dual antiplatelet Rx• Warfarin or dabigatran Rx• No protamine reversal (TF)• Bridge AF patients with heparin

• Cerebral embolic prevention devices

• Newer low profile THV deployment systems

• Carotid compression during BAV, THV deployment

LATE CONSTANT HAZARD PHASE

• More rigorous patient selection (TA)

InferencesCan TAVR stroke rate be lowered?

Brain DWMRI after TAVR

J Am Coll Cardiol 2010;55:1427–32

Brain DWMRI after TAVR

Valve New MRI lesions

Stroke

Ghanem CoreValve 73% 10%

Knipp SAPIEN 58% 4%

Kahlert Both 84% 0%

Astarci Both 91% 0%

Rodés-Cabau, Webb

SAPIEN 68% 3.3%

Embrella® Embolic Deflector

Initial Vancouver experience in 4 patients, 3 with TAVI and 1 with BAV

Effectiveness?

Safety?

Nietlispach et al., J Am Coll Cardiol Intv 2010;3:1133– 8

The PARTNER Trial Cohort A Death and Stroke (As Treated) n= 657

30 Days 1 Year

TF AVR

(n=221)TF TAVR (n=240) P value

TF AVR (n=103)

TF TAVR n=104

P value

Death 18 (8.2) 9 (3.7) 0.05 55 (25.2) 51 (21.3) 0.33

Stroke or TIA

All 3 (1.4) 11 (4.6) 0.04 4 (1.9) 14 (6.1) 0.03 TIA 0 (0.0) 3 (1.3) 0.08 1 (0.6) 4 (1.8) 0.25

Stroke Minor 0 (0.0) 2 (0.8) 0.16 0 (0.0) 2 (0.8) 0.16 Major 3 (1.4) 6 (2.5) 0.37 3 (1.4) 8 (3.5) 0.15

Transfemoral (TF) Substrate

The PARTNER Trial Cohort A Death and Stroke (As Treated) n= 657

30 Days 1 Year

TA AVR (n=92)

TA TAVR (n=104) P value

TA AVR (n=92)

TA TAVR n=104 P value

Death 7 (7.6) 9 (8.7) 0.79 23 (25.3) 30 (29.1) 0.55

Stroke or TIA

All 5 (5.5) 8 (7.9) 0.50 8 (9.7) 13 (14.1) 0.37

TIA 1 (1.1) 0 (0.0) 0.31 3 (3.9) 3 (3.7) 0.97

Stroke

Minor 1 (1.1) 1 (1.0) 0.95 1 (1.1) 1 (1.0) 0.95

Major 4 (4.4) 7 (7.0) 0.45 5 (5.9) 9 (9.4) 0.37

Transapical (TA) Substrate

Stroke Definition- The Modified Stroke Definition- The Modified Rankin ScaleRankin Scale

Minor• 0- No Symptoms• 1- No significant disability. Able to carry out all

usual activities, despite some symptomsMajor

• 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.

Neurologic event

%%

0

5

10

15

6 12 18 24

TAVR

AVR

MosMos5858

130125

243218

278251

344313

TAVRAVR

11

6.78.0

4.5

30 Days 1 Year

OutcomeOutcome TAVRTAVR(N = 348)(N = 348)

AVRAVR(N = 351)(N = 351)

TAVRTAVR(N = 348)(N = 348)

AVRAVR(N = 351)(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 Cohort A PatientsN=699, ITT (not AT)

p-valuep-value p-valuep-value

Smith CR, ACC 2011, NEJM in press

The PARTNER Stroke Substudy Writing Group* On behalf of The PARTNER Trial Investigators and Patients...

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