Updates From NOTION The First AllComer TAVR Trial

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Updates From NOTION: The First All-Comer TAVR Trial Lars Sondergaard, MD, DMSc Professor of

Updates From NOTION: The First All-Comer TAVR Trial Lars Sondergaard, MD, DMSc Professor of Cardiology Rigshospitalet Copenhagen, Denmark

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner

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 Relationship • • Grant/Research Support Consulting Fees/Honoraria Company • • BSci, SJM, Symetis BSci, Medtronic, SJM, Symetis

Nordic Aortic Valve Intervention Trial The NOTION Trial Objective: Compare TAVR vs. SAVR in

Nordic Aortic Valve Intervention Trial The NOTION Trial Objective: Compare TAVR vs. SAVR in patients >70 years eligible for surgery (all-comers population) Composite rate of death from any cause, stroke or Primary outcome: myocardial infarction at 1 year (VARC II-defined) Secondary outcomes: Safety and efficacy (NYHA), echocardiographic outcomes (VARC II-defined) Design: Prospective, multicenter, non-blinded, randomized trial Enrollment period: December 2009 - April 2013

Enrollment Criteria Main inclusion criteria Main exclusion criteria • Severe AS • Severe CAD

Enrollment Criteria Main inclusion criteria Main exclusion criteria • Severe AS • Severe CAD • Age ≥ 70 years • Severe other valve disease • Life expectancy ≥ 1 year • Prior heart surgery • Suitable for TAVR & SAVR • Need for acute treatment • Recent stroke or MI • Severe lung disease • Severe renal failure

Device and Access Routes Self-expanding Bioprosthesis (annulus diameter 18 -29 mm ) Transfemoral 18

Device and Access Routes Self-expanding Bioprosthesis (annulus diameter 18 -29 mm ) Transfemoral 18 Fr delivery system Subclavian

Baseline Characteristics Characteristic, % or mean ± SD Age (yrs) Male STS Score <

Baseline Characteristics Characteristic, % or mean ± SD Age (yrs) Male STS Score < 4% Logistic Euro. SCORE I NYHA class III or IV TAVR n=145 SAVR n=135 pvalue 79. 2 ± 4. 9 79. 0 ± 4. 7 0. 71 53. 8 52. 6 0. 84 2. 9 ± 1. 6 3. 1 ± 1. 7 0. 30 83. 4 80. 0 0. 46 8. 4 ± 4. 0 8. 9 ± 5. 5 0. 38 48. 6 45. 5 0. 61

Trial Compliance ITT TAVR N=145 ITT SAVR N=135 Baseline 100% (145/145) 100% (135/135) 1

Trial Compliance ITT TAVR N=145 ITT SAVR N=135 Baseline 100% (145/145) 100% (135/135) 1 Month Follow-Up 96. 4% (135/140) 92. 1% (116/126) 3 Months Follow-Up 96. 4% (135/140) 93. 6% (117/125) 1 Year Follow-Up 98. 5% (134/136) 96. 0% (119/124) 2 Year Follow-Up 94. 6% (123/130) 95. 8% (113/118)

Primary Outcome* Composite rate of death from any cause, stroke or myocardial infarction 1

Primary Outcome* Composite rate of death from any cause, stroke or myocardial infarction 1 year after the procedure TAVR 13. 1% vs. SAVR 16. 3% Absolute difference -3. 2%; p=0. 43 (for superiority) *Intention-to-treat population

All-cause mortality, stroke or MI Sondergaard et al. Circ carciovasc Interv 2016

All-cause mortality, stroke or MI Sondergaard et al. Circ carciovasc Interv 2016

All-cause mortality, Stroke or MI Patients with STS <4% Sondergaard et al. Circ carciovasc

All-cause mortality, Stroke or MI Patients with STS <4% Sondergaard et al. Circ carciovasc Interv 2016

Functional Class Baseline 3 months 1 year 2 years Sondergaard et al. Circ carciovasc

Functional Class Baseline 3 months 1 year 2 years Sondergaard et al. Circ carciovasc Interv 2016

Valve Performance Δ EOA Δ Mean gradient Sondergaard et al. Circ carciovasc Interv 2016

Valve Performance Δ EOA Δ Mean gradient Sondergaard et al. Circ carciovasc Interv 2016

Aortic Valve Regurgitation 3 months 1 year 2 years Sondergaard et al. Circ carciovasc

Aortic Valve Regurgitation 3 months 1 year 2 years Sondergaard et al. Circ carciovasc Interv 2016

All-cause mortality in TAVR patients according to PVL rate Sondergaard et al. Circ carciovasc

All-cause mortality in TAVR patients according to PVL rate Sondergaard et al. Circ carciovasc Interv 2016

Conclusions (I) • The NOTION trial was the first all-comers trial to randomize lower-risk

Conclusions (I) • The NOTION trial was the first all-comers trial to randomize lower-risk patients to TAVR or SAVR • TAVR was safe and effective, and comparable to SAVR regarding the composite rate of death from any cause, stroke or myocardial infarction after 2 years

Conclusions (II) • TAVR resulted in larger EOA and lower gradients, but higher rate

Conclusions (II) • TAVR resulted in larger EOA and lower gradients, but higher rate of moderate PVL than SAVR • These two year data support the safety and effectiveness of TAVR in lower risk patients • Longer term data on durability and more randomized clinical trials in lower risk patients are necessary

All-cause mortality benefits for TAVI ALL-CAUSE MORTALITY AT 2 YEARS 4 RANDOMIZED TRIALS (N

All-cause mortality benefits for TAVI ALL-CAUSE MORTALITY AT 2 YEARS 4 RANDOMIZED TRIALS (N =3, 806) Trial TAVR SAVR HR (95% CI) PARTNER 1 A 116/348 114/351 0. 90 (0. 71 -1. 15) US Core. Valve 85/391 99/359 0. 79 (0. 61 -1. 01) NOTION 11/145 14/135 0. 72 (0. 33 -1. 59) PARTNER 2 A Overall 166/1011 170/1021 0. 92 (0. 74 -1. 13) 0. 87 (0. 76 -0. 99), P=0. 038 Siontis et al. EHJ 2016, in press

TI NO I II ON ER High TN HR 1 A ER 1 B

TI NO I II ON ER High TN HR 1 A ER 1 B Extreme PA R ER lve Va re Co TN Va lve ER STS score (%) 12 PA R re Co TN PA R RCT in TAVI Intermediate Low 10 8 6 4 2 0

TI NO I II ON ER 10 100 8 80 6 60 4 40

TI NO I II ON ER 10 100 8 80 6 60 4 40 2 20 0 0 Age (years) High TN HR 1 A ER 1 B Extreme PA R ER lve Va re Co TN Va lve ER STS score (%) 12 PA R re Co TN PA R RCT in TAVI – same age! Intermediate Low

Use of surgical bioprosthetic aortic valves Eastern Denmark 68 years 61 years De Backer

Use of surgical bioprosthetic aortic valves Eastern Denmark 68 years 61 years De Backer et al. JACC Cardiovasc Interv 2016

NOTION I – Mortality at 2 Years

NOTION I – Mortality at 2 Years

NOTION II Study design Inclusion criteria • Severe symptomatic aortic stenosis • Age ≤

NOTION II Study design Inclusion criteria • Severe symptomatic aortic stenosis • Age ≤ 75 years & STS score ≤ 4% • Anticipated usage of aortic bioprosthesis Primary end-point • Composite rate of all-cause mortality, stroke & MI at 1 year Design • RCT, 1: 1, TF TAVI vs. SAVR, superior, N=992 • Bicuspid valves & revascularization (CABG or PCI) allowed • Any aortic bioprosthesis allowed

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