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

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

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  1. 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

  2. Presenter Disclosure Information for PARTNER Trial, AATS May, 2011D. 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:

  3. 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

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

  5. 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% All-cause mortality (%) 30.7% Months

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

  7. The PARTNER Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened Total = 1,057 patients Inoperable High Risk N = 358 N = 699 2 Parallel Trials: Individually Powered ASSESSMENT: Transfemoral Access ASSESSMENT: Transfemoral Access Yes No Transapical (TA) Transfemoral (TF) Yes No 1:1 Randomization 1:1 Randomization 1:1 Randomization Not In Study N = 244 N = 248 N = 104 N = 103 N = 179 N = 179 TF TAVR AVR TA TAVR AVR TF TAVR Standard Therapy VS VS VS 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 at 1 yr(Non-inferiority)

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

  9. PARTNER cohort AAll-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 24.2 0.2 0.1 0 0 6 12 18 24 No. at Risk Months TAVR AVR

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

  11. 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)

  12. Patient characteristics (AT)

  13. One year results (AT, n= 657)

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

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

  16. Risk Factors forNeurologic Events • Multiphase, multivariable non-proportional hazard analysis • Early high peaking hazard phase • Later constant hazard phase

  17. Incremental risk factors for neurologic events Early high peaking hazard phase • Atrial fibrillation not significant • in multivariable analysis R(%) = bagging reliability

  18. Early hazard of neurologic event TAVR %/mo AVR Months after Procedure

  19. TF Candidate 10699 TAVRAVR 242221 203170 179159 5451 Neurologic event- TF candidate % 7.4 TAVR 6.0 AVR 3.4 2.4 Mos

  20. TA Candidate 2627 TAVRAVR 10292 7667 6460 Neurologic event- TA candidate TAVR 12 % AVR 10 Mos

  21. Neurologic event by 1 moInfluence of smaller AVA index TAVR Candidate % TA TF AVAI (cm2/m2)

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

  23. Non-TF candidate differentiation TF stratum Female TA stratum PVD CEA CABG 0 20 40 60 80 100 %

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

  25. 10626 TAVR-TF TAVR-TA 242102 20376 17964 54 TAVR neurologic event by stratum TAVR Candidate TA % 12 TF 7.4 6.0 Mos

  26. 9927 TF TA 22192 17067 15960 51 AVR neurologic event by stratum AVR Candidate 10 % TA 3.4 TF 2.4 Mos

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

  28. 137128 TAVRAVR 344313 284239 252222 6359 Major stroke (18 TAVR, 11 AVR) 6.1 TAVR 4.8 % 4.5 2.6 AVR Mos

  29. Competing Risks ofDeath and Neurologic Events

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

  31. 11432 106 18 TAVR-TF TAVR-TAAVR-TF AVR-TA 240104 221 92 20277 170 67 17964 160 62 67 59 Neurologic event Consideringcompeting risks AVR-TA 12 % TAVR-TA 9.1 6.5 TAVR-TF 5.5 AVR-TF 2.6 2.2

  32. “Mortality Cost” of a Neurologic Event

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

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

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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. Thank You

  42. BACK-UP

  43. InferencesCan 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)

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

  45. Brain DWMRI after TAVR

  46. 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

  47. The PARTNER Trial Cohort A Death and Stroke (As Treated) n= 657 Transfemoral (TF) Substrate

  48. The PARTNER Trial Cohort A Death and Stroke (As Treated) n= 657 Transapical (TA) Substrate

  49. 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.

  50. 130125 TAVRAVR 344313 278251 243218 5858 Neurologic event 11 TAVR 8.0 % 6.7 AVR 4.5 Mos

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