The Risk and Extent of Neurological Events Are Equivalent for High-Risk Patients Treated With Transcatheter or Surgical Aortic Valve Replacement Thomas G. Gleason, MD On Behalf of the CoreValve US Clinical Investigators

Under direction from Dr. Gleason, Medtronic performed all statistical analyses and assisted in the graphical display of the data. Disclosure Statement of Financial Interest Within the past 1 year, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. 2 AATS 2015 Affiliation/Financial RelationshipCompany Institutional GrantsMedtronic, Inc.

Background & Objectives Post-procedural strokes significantly affect both quality of life and survival. Rigorous neurologist-adjudicated stroke assessment has not been applied to most of the previously reported trials comparing TAVR and SAVR. Thus the extent and characteristics of stroke following AVR have not previously been well described. Neurological events from the CoreValve US Pivotal High Risk Trial and comprehensive cognitive assessments for a neurological substudy were carefully evaluated. AATS

Assessed neurological events through 2 years Assessed neurological events in detail through 1 year Patients TAVR N=391 CoreValve US Pivotal High Risk Trial SAVR N=359 TAVR N=111 SAVR N=88 Substudy Cohort N=199 Enrolled in Neurological Substudy* 4 AATS 2015 *Pivotal high-risk patients volunteered for additional testing

The CoreValve US Pivotal High Risk Trial: – Systematically collected National Institute of Health Stroke Scale (NIHSS) in all patients – Modified Rankin Scale (MRS), neurology consultation and neuroimaging triggered in any patient with neurologic abnormality and serially after any stroke Neurological substudy patients underwent comprehensive cognitive assessments by a neurologist: – Minimental State Examination – Visual fields testing – Gait & motor assessment – Writing & drawing evaluation Stroke was defined by VARC-1 criteria Stroke Assessment AATS

18F Delivery System 4 Valve Sizes (23, 26, 29, 31 mm) (18-29 mm Annular Range) Transfemoral Subclavian Direct Aortic Study Device and Access Routes AATS

Neurological Outcomes From the CoreValve Pivotal High Risk Trial AATS Days1 Year2 Years Event* TAVRSAVRPTAVRSAVRPTAVRSAVRP Stroke Major stroke Ischemic Hemorrhagic Undetermined Minor stroke TIA *Kaplan-Meier rates. 7

No. at Risk TAVR SAVR CoreValve High Risk Pivotal Trial Stroke or TIA 8 AATS 2015

CoreValve High Risk Pivotal Trial Major Stroke 9 AATS 2015 No. at Risk TAVR SAVR

Neurological Outcomes From the CoreValve Pivotal High Risk Trial By Access Route 10 AATS Days1 Year2 Years Iliofemoral Non- Iliofemoral Iliofemoral Non- Iliofemoral Iliofemoral Non- Iliofemoral Event* TAVRSAVRTAVRSAVRTAVRSAVRTAVRSAVRTAVRSAVRTAVRSAVR Any stroke or TIA Stroke Major stroke Minor stroke TIA *Kaplan-Meier rates. Yellow Text = P <0.05.

Timing of TIA, Major & Minor Strokes to 30 Days AATS Days from Implant to Event

Timing of TIA, Major & Minor Strokes to 2 Years AATS Time from Implant to Event

No. at Risk TAVR SAVR Mortality in Patients with Any Stroke Within 30 Days for TAVR & SAVR 13 AATS 2015

No. at Risk TAVR15952 SAVR11852 Mortality in Patients with Major Stroke Within 30 Days for TAVR & SAVR 14 AATS 2015

No. at Risk Major Stroke No Major Stroke Mortality in TAVR Patients with & without a Major Stroke Within 30 Days of Implant

No. at Risk Major Stroke11852 No Major Stroke Mortality in SAVR Patients with & without a Major Stroke Within 30 Days of Implant

Predictors of Early Stroke Predictors of Early (0-30 Days) Stroke Following TAVR* Kaplan Meier Rate [95% CI] no. Univariable AnalysisMultivariable HR95% CIP ValueHR95% CI P Value Peripheral vascular disease 8.3 [4.9, 13.9] , , Nocturnal bipap13.8 [5.4, 32.7] , Falls in past 6 months 9.9 [4.8, 19.6] , , AATS 2015 *There were no univariable or multivariable predictors of early stroke found for the SAVR group.

Predictors of Stroke at 1 Year Predictors of 1-Year Stroke Following TAVR* UnivariableMultivariable Kaplan Meier Rate [95% CI] no. HR95% CI P Value HR95% CI P Value Peripheral vascular disease 12.4 [8.1, 18.7] , Severe aortic calcification 17.7 [9.2, 32. 3] , , History of hypertension 7.8 [5.4, 11.1] , , Severe Charlson Comorbidity Score (≥5) 13.3 [9.3, 18.9] , , Predictors of 1-Year Stroke Following SAVR NYHA class III/IV 11.1 [7.9, 15.3] , Angina 6.0 [2.5, 13.9] , , AATS 2015

Characteristic, % or mean ± SD TAVR N=111 SAVR N=88 Age (years) 82.3 ± ± 7.3 Men STS Predicted Risk of Mortality (%) 7.0 ± ± 3.7 Logistic EuroSCORE (%) 17.2 ± ± 14.1 NYHA Class III/IV Atrial fibrillation/flutter Diabetes mellitus Prior stroke Modified Rankin 0 or Modified Rankin > NIH Stroke Scale NIH Stroke Scale Prior TIA Baseline Demographics for Patients in the Neurological Substudy 19 AATS 2015

Assessment, % or mean ± SD TAVR N=111 SAVR N=88 Home oxygen 9.1 Anemia Albumin < 3.3mg/dL Severe (≥5) Charlson comorbidity Falls in past 6 months Meter gait speed >6 seconds Katz ≥2 ADLs deficits Mini-Mental State Examination 26.7 ± ± 2.8 Non-STS Comorbidity, Frailty, Disability for the Neurological Substudy 20 AATS 2015

Neurological Assessment Changes from Baseline to Discharge in Substudy Patients 21 AATS 2015 AssessmentTAVRSAVRP Value NIH Stroke Scale – Increase by ≥ 23.5 (3/85)12.7 (8/63)0.05 Mini-Mental State Examination Decreased by > 42.5 (2/79)10.9 (6/55)0.06 New Gait Abnormality7.8 (6/77)15.5 (9/58)0.16 Weakness in Left Hand Motor Function7.2 (5/69)6.5 (3/46)>0.99 Weakness in Right Hand Motor Function7.2 (5/69)10.4 (5/48)0.74 Failed Writing Evaluation5.1 (4/79)8.5 (5/59)0.50 Failed Drawing Evaluation23.5 (12/51)25.6 (10/39)0.82

22 AATS 2015 Assessment TAVRSAVRP Value NIH Stroke Scale – Increase by ≥ 21.5 (1/65)4.9 (2/41)0.56 Mini-Mental State Examination Decreased by > 48.1 (5/62)2.5 (1/40)0.40 New Gait Abnormality6.8 (4/59)7.7 (3/39)>0.99 Weakness in Left Hand Motor Function0.0 (0/56)5.7 (2/35)0.15 Weakness in Right Hand Motor Function0.0 (0/55)5.4 (2/37)0.16 Failed Writing Evaluation1.6 (1/61)10.0 (4/40)0.08 Failed Drawing Evaluation10.9 (5/46)11.1 (3/27)>0.99 Neurological Assessment Changes from Baseline to 1 Year in Substudy Patients

This study demonstrates equivalent post-procedural, neurologist- adjudicated stroke risk and extent of neurological injury following TAVR or SAVR in a high risk population. Vascular disease, fall history, severe aortic calcification, and a severe Charlson Score appear to be predictors of stroke after TAVR. Two-year mortality rate after an early TAVR- or SAVR-associated stroke is very high. Conclusions AATS