Transcatheter (TAVR) versus Surgical (AVR) Aortic Valve Replacement: Incidence, hazard, determinants, and consequences of neurological events in the PARTNER Trial  The PARTNER Stroke Substudy Writing Group* On behalf of The PARTNER Trial Investigators and Patients * 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 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

The PARTNER Trial Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened Total = 1,057 patients 2 Parallel Trials: Individually Powered N = 699 N = 358 High Risk Inoperable 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) 1:1 Randomization VS Yes No N = 179

All-cause mortality (%) PARTNER cohort B (inoperable) All-Cause Mortality at 1 Year HR [95% CI] = 0.54 [0.38, 0.78] P (log rank) < 0.0001 Standard Rx TAVI ∆ at 1 yr = 20.0% NNT = 5.0 pts 50.7% 30.7% All-cause mortality (%) Months Numbers at Risk TAVR 179 138 122 67 26 Standard Rx 121 83 41 12 5

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

The PARTNER Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened N = 179 N = 358 Inoperable 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) 1:1 Randomization VS Yes No Total = 1,057 patients High Risk N = 699 2 Parallel Trials: Individually Powered ASSESSMENT: Transfemoral Access Transapical (TA) Transfemoral (TF) 1:1 Randomization Yes No TF TAVR AVR Primary Endpoint: All-Cause Mortality at 1 yr (Non-inferiority) TA TAVR VS N = 248 N = 104 N = 103 N = 244

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

PARTNER cohort A All-Cause Mortality at 1 Year HR [95% CI] = 0.93 [0.71, 1.22] P (log rank) = 0.62 0.5 TAVR AVR 0.4 26.8 0.3 0.2 24.2 0.1 6 12 18 24 No. at Risk Months TAVR 348 298 260 147 67 351 252 236 139 65 AVR

All neurological events at 30 days and 1 year PARTNER Cohort A Trial (ITT) TAVR AVR P=0.04 All neuro events (%) P=0.04 Smith CR, ACC 2011, NEJM in press

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% 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% Peripheral vascular disease 62% 63% 35% COPD 64% 65% Pulmonary hypertension 42% 53% 55% 54% Atrial fibrillation 21% 32% 23% Mean aortic valve gradient (mmHg) 41 ± 13 42 ± 14 45 ± 15 43 ± 15 Aortic Valve Area Index (cm2/m2) 0.4 ± 0.1 0.3 ± 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% 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

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

Timing of neurological events AVR TAVR AVR TAVR AVR TAVR AVR TAVR AVR TAVR AVR TAVR AVR TAVR 0-2 days 3-5 days 6-10 days 11-30 days 31-364 days 1-2 years 2-3 years

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

Incremental risk factors for neurologic events Early high peaking hazard phase Risk Factor Coefficient ± SD P R (%) Early hazard phase TAVR 2.21±0.68 .001 59 Smaller AVA index in TAVR group -11.8±5.1 .02 57 Atrial fibrillation not significant in multivariable analysis R(%) = bagging reliability

Early hazard of neurologic event TAVR %/mo AVR Figure 1a Months after Procedure

Neurologic event- TF candidate % 7.4 TAVR AVR 6.0 Figure 4f 2.4 3.4 Mos 54 51 106 99 179 159 203 170 242 221 TAVR AVR

Neurologic event- TA candidate TAVR 12 % AVR Figure 4i 10 Mos 26 27 64 60 76 67 102 92 TAVR AVR

Neurologic event by 1 mo Influence of smaller AVA index TAVR Candidate % TA Figure 5c TF AVAI (cm2/m2)

Incremental risk factors for neurologic events Late constant hazard phase 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 R(%) = bagging reliability

Non-TF candidate differentiation TF stratum TA stratum Female PVD CEA Figure 9a CABG 20 40 60 80 100 %

Later hazard- assigned stratum (TAVR and AVR combined) Candidate TA Figure 2c TF Months after Procedure

TAVR neurologic event by stratum Candidate TA % 12 TF Figure 4c 7.4 6.0 Mos 54 106 26 179 64 203 76 242 102 TAVR-TF TAVR-TA

AVR neurologic event by stratum Candidate % 10 TA Figure 4d 3.4 TF 2.4 Mos 51 99 27 159 60 170 67 221 92 TF TA

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) 6.1 TAVR 4.8 % 4.5 2.6 Figure 7b AVR Mos 63 59 137 128 252 222 284 239 344 313 TAVR AVR

Competing Risks of Death and Neurologic Events

Months after Procedure Competing risks AVR Alive w/o neuro event % Death before neuro event Figure 6c Neuro event Months after Procedure

% Neurologic event Considering competing risks AVR-TA 12 TAVR-TA 9.1 6.5 5.5 TAVR-TF AVR-TF 2.2 2.6 67 59 114 32 106 18 179 64 160 62 202 77 170 240 104 221 92 TAVR-TF TAVR-TA AVR-TF AVR-TA

“Mortality Cost” of a Neurologic Event

“Mortality Cost” of neuro event AVR Hazard Ratio Observed/Expected Figure 8c Months after Neurologic Event

“Mortality Cost” of neuro event TAVR-TF Hazard Ratio Observed/Expected Figure 8f Months after Neurologic Event

“Mortality Cost” of neuro event TAVR-TA Hazard Ratio Observed/Expected Figure 8i Months after Neurologic Event

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 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 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 Conclusions 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

Limitations 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

Thank You

BACK-UP

Inferences Can TAVR stroke rate be lowered? 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)

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 91% Rodés-Cabau, Webb 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 Transfemoral (TF) Substrate 30 Days 1 Year TF AVR (n=221) TF TAVR (n=240) P value TF AVR (n=103) TF TAVR n=104 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 2 (0.8) 0.16 Major 6 (2.5) 0.37 8 (3.5) 0.15

The PARTNER Trial Cohort A Death and Stroke (As Treated) n= 657 Transapical (TA) Substrate 30 Days 1 Year TA AVR (n=92) TA TAVR (n=104) P value TA AVR (n=92) TA TAVR n=104 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 (1.0) 0.95 Major 4 (4.4) 7 (7.0) 0.45 5 (5.9) 9 (9.4)

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.

% Mos Neurologic event 11 TAVR 8.0 6.7 AVR 4.5 58 58 130 125 243 218 Figure 1d Mos 58 58 130 125 243 218 278 251 344 313 TAVR AVR

Neurological Events at 30 Days and 1 Year All Cohort A Patients N=699, ITT (not AT)   30 Days 1 Year Outcome TAVR (N = 348) AVR (N = 351) All Stroke or TIA – no. (%) 19 (5.5) 8 (2.4) 0.04 27 (8.3) 13 (4.3) TIA – no. (%) 3 (0.9) 1 (0.3) 0.33 7 (2.3) 4 (1.5) 0.47 All Stroke – no. (%) 16 (4.6) 0.12 20 (6.0) 10 (3.2) 0.08 Major Stroke – no. (%) 13 (3.8) 7 (2.1) 0.20 17 (5.1) 0.07 Minor Stroke – no. (%) 0.34 2 (0.7) 0.84 Death/maj stroke – no. (%) 24 (6.9) 28 (8.2) 0.52 92 (26.5) 93 (28.0) 0.68 p-value p-value Smith CR, ACC 2011, NEJM in press