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 Risk Inoperable The PARTNER Trial Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened Total = 1,057 patients 2 Parallel Trials: Individually Powered Standard Therapy Standard Therapy ASSESSMENT: Transfemoral Access Not In Study TF TAVR Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) 1:1 Randomization VS Yes No N = 179

Numbers at Risk Numbers at Risk TAVR TAVR Standard Rx Standard Rx Standard Rx TAVI All-cause mortality (%) 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) < PARTNER cohort B (inoperable) All-Cause Mortality at 1 Year

Neuro events at 30 days and 1 year- Inoperable cohort B Major Stroke P = 0.06 P = 0.18 All Stroke or TIA P = 0.03 P = 0.04 TAVR (n=179) Standard Rx (n=179) per cent

N = 179 N = 358 Inoperable Standard Therapy Standard Therapy ASSESSMENT: Transfemoral Access Not In Study TF TAVR Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) Co-Primary Endpoint: Composite of All-Cause Mortality and Repeat Hospitalization (Superiority) 1:1 Randomization VS Yes No N = 179 TF TAVR AVR Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) TA TAVR AVR VS N = 248N = 104N = 103N = 244 The PARTNER Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened Total = 1,057 patients 2 Parallel Trials: Individually Powered N = 699 High Risk ASSESSMENT: Transfemoral Access Transapical (TA) Transfemoral (TF) 1:1 Randomization Yes No

Transfemoral Transapical TAVR Transfemoral (TF) and Transapical (TA)

TAVR AVR Months No. at Risk TAVR AVR PARTNER cohort A All-Cause Mortality at 1 Year HR [95% CI] = 0.93 [0.71, 1.22] P (log rank) = 0.62

All neurological events at 30 days and 1 year PARTNER Cohort A Trial ( ITT ) All neuro events (%) TAVR AVR Smith CR, ACC 2011, NEJM in press P=0.04 P=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 StratumTransfemoral Stratum Variable AVR (n = 92) TA-TAVR (n = 104) AVR (n = 221) TF-TAVR (n = 240) Age (years) (± 1 SD) 83 ± 683 ± 785 ± 784 ± 7 STS risk Score (± 1 SD) 12.1 ± ± ± ± 3.2 Logistic EuroSCORE (± 1 SD) 30 ± 1530 ± 1629 ± 1529 ± 17 NYHA class III-IV 96%92%95% Carotid endarterectomy / stent 17%24%6%10% Stroke or TIA within last 6-12 mo 7%1% 4% Previous CABG 56%50%40% Coronary artery disease 84%75% Previous MI 38%28%26%27% Cerebrovascular disease 31%43%26%24% Peripheral vascular disease 62%63%35% COPD 64% 65%63% Pulmonary hypertension 42%53%55%54% Atrial fibrillation 21%32%26%23% Mean aortic valve gradient (mmHg) 41 ± 1342 ± 1445 ± 1543 ± 15 Aortic Valve Area Index (cm 2 /m 2 ) 0.4 ± ± ± 0.1 LV ejection fraction (%) 54 ± 1154 ± 1254 ± 1352 ± 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%.15 Minor stroke 1.1%1.0%0%0.8%.16 TIA 3.9%3.7%0.6% 1.8%.25

47 patients, 49 neuro events Ischemic- 72%, hemorrhagic- 0%, ischemic evolving to hemorrhagic- 4%, unknown- 24% Distribution of types of neurological events

Timing of neurological events AVR AVR TAVR AVR TAVR AVR TAVR AVR TAVR AVR TAVR AVR TAVR AVR TAVR 0-2days3-5days31-364days11-30days6-10days2-3years1-2years

Risk Factors for Neurologic Events Multiphase, multivariable non-proportional hazard analysis  Early high peaking hazard phase  Later constant hazard phase

Risk Factor Coefficient ± SD P R (%) Early hazard phase TAVR 2.21± Smaller AVA index in TAVR group -11.8± 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 TAVR AVR Months after Procedure

Neurologic event- TF candidate % AVR TAVR Mos TAVR AVR TFCandidate

Neurologic event- TA candidate % TAVR AVR Mos TAVR AVR TACandidate

Neurologic event by 1 mo Influence of smaller AVA index % AVAI (cm 2 /m 2 ) TF TA Candidate TAVR

Risk Factor Coefficient ± SD P R (%) Constant hazard phase TAVR0.40± (Higher) NYHA 0.95± Stroke or TIA within 6-12 mo 1.93± Non-TF TAVR candidate 2.3±0.45< History of PCI (less risk) -1.60± COPD (less risk) -1.06± Incremental risk factors for neurologic events R(%) = bagging reliability Late constant hazard phase

Non-TF candidate differentiation Female PVD CEA CABG % TF stratum TA stratum

Later hazard- assigned stratum (TAVR and AVR combined) %/m TF TA Candidate Months after Procedure

TAVR neurologic event by stratum % TAVR TF TA Mos Candidate TAVR-TF TAVR-TA

% Mos AVR TF TA TF TA Candidate AVR neurologic event by stratum

Major Stroke Small number of events n= 29 Conservative definition (modified Rankin score ≥2) If stroke severity unclear, categorized as major

Major stroke (18 TAVR, 11 AVR) % TAVR AVR Mos TAVR AVR

Competing Risks of Death and Neurologic Events

Competing risks % Neuro event Alive w/o neuro event Months after Procedure Death before neuro event AVR

Neurologic event % AVR-TA Considering competing risks TAVR-TA TAVR-TF TAVR-TA AVR-TF AVR-TA AVR-TF TAVR-TF

“Mortality Cost” of a Neurologic Event

“Mortality Cost” of neuro event Observed/Expected AVR Hazard Ratio Months after Neurologic Event

Observed/Expected Hazard Ratio Months after Neurologic Event TAVR-TF “Mortality Cost” of neuro event

Observed/Expected Hazard Ratio Months after Neurologic Event TAVR-TA “Mortality Cost” of neuro event

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: TAVR Smaller AVA index (TAVR group only) Later constant hazard phase: Generalized heavy arteriosclerotic burden (“non-TF TAVR candidate”) Stroke/TIA within 6-12 months Higher 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) Inferences Can TAVR stroke rate be lowered?

Brain DWMRI after TAVR J Am Coll Cardiol 2010;55:1427–32

Brain DWMRI after TAVR ValveNew MRI lesions Stroke GhanemCoreValve73%10% KnippSAPIEN58%4% KahlertBoth84%0% AstarciBoth91%0% Rodés-Cabau, Webb SAPIEN68%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= Days1 Year TF AVR (n=221) TF TAVR (n=240)P value TF AVR (n=103) TF TAVR n=104 P value Death18 (8.2)9 (3.7) (25.2)51 (21.3)0.33 Stroke or TIA All3 (1.4)11 (4.6)0.044 (1.9)14 (6.1)0.03 TIA0 (0.0)3 (1.3)0.081 (0.6)4 (1.8)0.25 Stroke Minor0 (0.0)2 (0.8)0.160 (0.0)2 (0.8)0.16 Major3 (1.4)6 (2.5)0.373 (1.4)8 (3.5)0.15 Transfemoral (TF) Substrate

The PARTNER Trial Cohort A Death and Stroke (As Treated) n= Days1 Year TA AVR (n=92) TA TAVR (n=104)P value TA AVR (n=92) TA TAVR n=104P value Death7 (7.6)9 (8.7) (25.3)30 (29.1)0.55 Stroke or TIA All5 (5.5)8 (7.9)0.508 (9.7)13 (14.1)0.37 TIA1 (1.1)0 (0.0)0.313 (3.9)3 (3.7)0.97 Stroke Minor 1 (1.1) 1 (1.0) (1.1)1 (1.0)0.95 Major 4 (4.4) 7 (7.0) (5.9)9 (9.4)0.37 Transapical (TA) Substrate

Stroke Definition- The Modified Rankin Scale Minor 0- No Symptoms 1- No significant disability. Able to carry out all usual activities, despite some symptoms Major 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 % TAVR AVR Mos TAVR AVR

30 Days 1 YearOutcome TAVR (N = 348) AVR (N = 351) TAVR (N = 348) AVR (N = 351) All Stroke or TIA – no. (%) 19 (5.5) 8 (2.4) (8.3) 13 (4.3) 0.04 TIA – no. (%)3 (0.9)1 (0.3)0.337 (2.3)4 (1.5)0.47 All Stroke – no. (%)16 (4.6)8 (2.4) (6.0)10 (3.2)0.08 Major Stroke – no. (%) 13 (3.8) 7 (2.1) (5.1) 8 (2.4) 0.07 Minor Stroke – no. (%)3 (0.9)1 (0.3)0.343 (0.9)2 (0.7)0.84 Death/maj stroke – no. (%) 24 (6.9) 28 (8.2) (26.5) 93 (28.0) 0.68 Neurological Events at 30 Days and 1 Year All Cohort A Patients N=699, ITT (not AT) p-value p-value Smith CR, ACC 2011, NEJM in press