Prosthesis-Patient Mismatch in High Risk Patients with Severe Aortic Stenosis in a Randomized Trial of a Self-Expanding Prosthesis George L. Zorn, III On Behalf of the CoreValve US Clinical Investigators

Under direction from Dr. Zorn, Medtronic performed all statistical analyses and assisted in the graphical display of the data. Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial RelationshipCompany 2 AATS 2015 Proctor/consultantMedtronic Proctor/consultant Edwards

Severe prosthesis-patient mismatch (PPM) after surgical aortic valve replacement (SAVR) is associated with higher mortality but the association of PPM with transcatheter aortic valve replacement (TAVR) outcomes is unclear PPM has been associated with less LV mass regression at 1 year in SAVR and TAVR patients TAVR may provide an option to reduce PPM and associated clinical events in patients undergoing aortic valve replacement Background Pibarot P, et al. J Am Coll Cardiol AATS 2015

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 4 AATS 2015

To compare the incidence of PPM between TAVR using a self-expanding prosthesis and SAVR in the CoreValve US High Risk Pivotal Trial To determine the impact of PPM after aortic valve replacement on clinical outcomes Objective 5 AATS 2015

Patients with symptomatic severe aortic stenosis at increased risk for surgery were randomized 1:1 to TAVR or SAVR in the CoreValve US High Risk Trial Postoperative PPM was defined by the effective orifice area index (EOAi) – Severe PPM was defined as EOAi ≤ 0.65 cm 2 /m 2 – Moderate PPM was 0.65 < EOAi ≤ 0.85 cm 2 /m 2 – No PPM was EOAi > 0.85 cm 2 /m 2 This subgroup analysis compares outcomes at 1 year between severe PPM and no severe PPM (EOAi > 0.65 cm 2 /m 2 ) in patients receiving TAVR or SAVR treatment Methods 6 AATS 2015

TAVRSAVR Characteristic Severe PPM (N=24) No severe PPM (N=343)P value Severe PPM (N=75) No severe PPM (N=259)P value Age81.5 (8.4)83.1 (7.0) (7.0)83.7 (6.1) Male11 (45.8)186 (54.2) (45.3)140 (54.1) BMI31.9 (7.5)27.8 (6.0) (7.9)28.0 (5.8) NYHA Class III/IV22 (91.7)292 (85.1) (89.3)223 (86.1) STS Score (Risk of Mortality, %) 7.3 (2.9)7.2 (2.9) (2.9)7.5 (3.4) Diabetes mellitus11 (45.8)121 (35.3) (57.3)111 (42.9) Coronary artery disease 17 (70.8)262 (76.4) (77.3)195 (75.3) Prior stroke 2 (8.3)43 (12.5) (13.3)39 (15.1) Prior CABG6 (25.0)105 (30.6) (34.7)76 (29.3) Prior PCI6 (25.0)118 (34.4) (42.7)97 (37.5) Home oxygen7 (29.2)40 (11.7) (12.0)28 (10.8) Clinical Demographics 7 AATS 2015

TAVRSAVR Characteristic Severe PPM (N=24) No severe PPM (N=343)P value Severe PPM (N=75) No severe PPM (N=259)P value EOAI, cm 2 /m (0.07)0.40 (0.12) )0.41 (0.12) Aortic Annulus Diameter, cm 2.07 (0.16)2.23 (0.21) (0.22)2.19 (0.21) Doppler Stroke Volume, mL69.60 (16.92)76.50 (23.93) (18.06)77.45 (20.39) LV Mass, gm (60.41) (71.69) (67.42) (63.52) LV Mass Index (gm/m 2 ) (30.64) (35.50) (33.99) (33.43) Ejection Fraction, %56.04 (12.25)58.17 (11.25) (13.04)58.30 (11.44) ≥ Moderate MR (%)5 (20.8)31 (9.2) (13.5)26 (10.4) Baseline Echocardiographic Findings 8 AATS 2015

Prosthesis-Patient Mismatch Severe PPM occurs significantly more after SAVR than TAVR 9 AATS 2015

EOA index: Change from Baseline to 1 Year 10 AATS 2015 TAVRSAVR P-value for change from baseline to 1-Year < for all

Change in Echocardiographic Findings from Baseline to 1 Year TAVRSAVR CharacteristicSevere PPM No severe PPMP valueSevere PPMNo severe PPMP value AV Peak Velocity (m/s)n=19n = 270 n = 47 n = 174 Baseline4.64 (0.63)4.38 (0.56) (0.55)4.34 (0.58) Year2.25 (0.38)2.01 (0.38) (0.60)2.22 (0.55)< Mean Gradient, mmHgn=19n = 270 n = 47 n = 174 Baseline52.63 (15.84)47.74 (13.50) (16.41)47.19 (13.69) Year11.18 (3.92)8.92 (3.41) (7.74)11.32 (6.93)< Severe PPM patients had a higher peak velocity and mean gradient than no severe PPM patients in both TAVR and SAVR groups 11 AATS 2015

LV Mass Regression % at 1 Year AATS

Moderate/Severe AR does not impact LV mass regression TAVR LV Mass Index (gm/m 2 P= P= AATS

Clinical Outcomes to 1 Year TAVRSAVROverall Characteristic Severe PPM (N=24) No severe PPM (N=343) P value Severe PPM (N=75) No severe PPM (N=259) P value Severe PPM (N=99) No severe PPM (N=602) P value All-Cause Mortality or Major Stroke 16.9%12.3% %17.6% %14.6%0.0188* All-Cause Mortality16.9%10.0% %14.5% %12.0%0.0145* Cardiovascular9.1%7.4% %9.2% %8.2% All Stroke0.0%8.3% %12.6% %10.1% Major stroke0.0%5.3% %6.1% %5.7% MI0.0%1.8% %1.6% %1.7% Reintervention0.0%1.5% % NA0.0%0.9% Life Threatening or Disabling bleeding 26.5%13.5% %38.5% %24.3% Major Vascular Complication 4.2%6.1% %1.5% %4.2% Valve Thrombosis0.0% NA0.0% NA0.0% NA Acute Kidney Injury12.5%5.5% %12.4% %8.5%0.0008* PPM was defined as severe PPM when the EOAi is ≤0.65 cm2/m2; No Severe PPM was defined as EOAi >0.65 cm2/m2. * adjusted P= for all-cause mortality or major stroke ; adjusted P= for all-cause mortality; adjusted P= for acute kidney injury AATS

All-Cause Mortality, % Months Post Procedure No. at Risk Severe PPM No severe PPM Log-rank P= Year All-Cause Mortality: SAVR AATS

All-Cause Mortality, % Months Post Procedure No. at Risk Severe PPM No severe PPM Log-rank P= Year All-Cause Mortality: TAVR 10.0 AATS

All-Cause Mortality, % Months Post Procedure No. at Risk Severe PPM No severe PPM Log-rank P= All-Cause Mortality: TAVR+SAVR 12.0 AATS

In this randomized controlled trial of TAVR vs SAVR in the treatment of aortic stenosis in a high risk population: PPM is more common with SAVR than TAVR PPM did not appear to influence LV mass regression within each treatment group but LV mass regression was notably less in the TAVR vs the SAVR group Patients with severe PPM have a higher rate of all-cause mortality and acute kidney injury than patients without severe PPM Conclusions AATS

Follow-up is only to 12 months and longer-term follow- up will provide further value There were too few patients with severe PPM in the TAVR treatment group to allow meaningful comparisons of some clinical and echo outcomes. Limitations AATS

THANK YOU to all the CoreValve Investigators!