Le TAVI pour tout le monde?

Le TAVI pour tout le monde? Thierry Lefèvre Institut Cardiovasculaire Paris Sud, Massy

Disclosure Statement of Financial Interest I currently have, or have had over the last two years, an affiliation or financial interests or interests of any order with a company or I receive compensation or fees or research grants with a commercial company : Abbott Vascular, AstraZeneca, Boston Sci., Daiichi Sankyo, Edwards, Lily, Terumo

From compassionate cases # Patients RVAo TAVI Risk

To Surgical contraindication # Patients RVAo TAVI Risk

To Surgical contraindication # Patients RVAo TAVI Risk

To Surgical contraindication # Patients RVAo TAVI Risk

High-Risk Patients # Patients RVAo TAVI Risk

High-Risk Patients # Patients RVAo TAVI TAVI Futile Risk

Intermediate Risk and intermediate-risk patients # Patients RVAo TAVI TAVI Futile Risk

Very quick adoption Darren Mylotte

> 250 000 cases in > 65 countries!

Inoperable Evidence for TAVI

TAVI vs Conservative treatment: Inoperable patients

Inoperable High surgical Risk Evidence for TAVI Unchanged indications since 2009

TAVI vs Surgical aortic valve replacement: High-Risk patients

Mortality and None-Trace Total AR Transfemoral Patients HR [95% CI] = 0.64 [0.43, 0.95] p (log rank) = 0.03 60.9% 45.2% Error Bars Represent 95% Confidence Limits No. at Risk TAVR 70 65 55 51 43 19 SAVR 181 137 126 105 78 36 M. Mack et al. ACC 2015

Inoperable High surgical Risk Evidence for TAVI Intermediate surgical risk

TAVI vs Surgical aortic valve replacement: Intermediate-Risk and All-comers Pts

All-Cause Mortality or Disabling Stroke (%) TF Primary Endpoint (AT) All-Cause Mortality or Disabling Stroke 1 2A 50 40 TF Surgery TF TAVR HR: 0.78 [95% CI: 0.61, 0.99] p (log rank) = 0.04 30 20 15.8% 20.0% 10 7.5% 11.7% 16.3% 0 4.5% Number at risk: 0 3 6 9 12 15 18 21 24 Months from Procedure TF Surgery 722 636 624 600 591 573 565 555 537 TF TAVR 762 717 708 685 663 652 644 634 612

Other Clinical Endpoints (ITT) At 30 Days and 2 Years 2A Events (%) TAVR (n = 1011) 30 Days 2 Years Surgery (n = 1021) p-value* TAVR (n = 1011) Surgery (n = 1021) p-value* Rehospitalization 6.5 6.5 0.99 19.6 17.3 0.22 MI 1.2 1.9 0.22 3.6 4.1 0.56 Major Vascular Complications Life-Threatening / Disabling Bleeding 7.9 5.0 0.008 8.6 5.5 0.006 10.4 43.4 <0.001 17.3 47.0 <0.001 AKI (Stage III) 1.3 3.1 0.006 3.8 6.2 0.02 New Atrial Fibrillation 9.1 26.4 <0.001 11.3 27.3 <0.001 New Permanent Pacemaker 8.5 6.9 0.17 11.8 10.3 0.29 Re-intervention 0.4 0.0 0.05 1.4 0.6 0.09 Endocarditis 0.0 0.0 NA 1.2 0.7 0.22 *Event rates are KM estimates, p-values are point in time

TAVI in intermediate risk Pts August 1, 2016 - Medtronic Evolute R August 19 2016 Edwards Sapien XT and Sapien 3 August 18 2016 Edwards Sapien XT and Sapien 3

Inoperable High surgical Risk Evidence for TAVI Low surgical risk Intermediate surgical risk

TAVI in Low-risk Pts: Ongoing Trials

Safety Rationale for TAVI in Low-risk Pts

TAVI vs Surgical aortic valve replacement: Meta-analysis of randomised trials Siontis et al. Eur heart j 2016; 37: 3503-12

All-Cause Mortality at 30 Days Edwards SAPIEN Valves PARTNER 1 and 2 20% 15% Inoperable High risk Combined inoperable and high risk Intermediate risk 10% 5% 6,3% 5,2% 3,7% 4,5% 3,5% 2,2% 1,6% 1,1% 1,1% 0% P1B (TF) P1A (All) P1A (TF) P2B (TF) P2B XT (TF) S3HR (All) S3HR (TF) S3i (All) S3i (TF) 175 344 240 271 282 583 491 1072 947 SAPIEN SXT SAPIEN 3

Strokes (All) at 30 Days Edwards SAPIEN Valves PARTNER 1 and 2 20% 15% Inoperable High risk Combined inoperable and high risk Intermediate risk 10% 5% 6,7% 5,6% Neurologist evaluations (pre- and post) 4,1% 4,3% 1,5% 2,6% 0% P1B (TF) P1A (All) P2B (TF) P2B XT (TF) S3HR (All) S3i (All) 179 344 276 284 583 1076 SAPIEN SAPIEN XT SAPIEN 3

Sub-Group Analysis for 3-Year Mortality ACC 2016

Notion Trial STS < 4% Sondergaard et al. TCT 2015

Safety Rationale for TAVI in Low-risk Pts Mismatch

Patient-Prosthesis Mismatch

Patient-Prosthesis Mismatch

Safety Mismatch Rationale for TAVI in Low-risk Pts Hospital stay PVL Recovery

PVL with New generation PHV 100% 80% 60% 40% 20% 2.5 2.7 33.2 29.1 64.3 68.1 Severe Moderate Mild None / Trace 0% 30 Days 1 Year N= 364 N=364 PARTNER 2 S3 Trial

Paravalvular Leak at 30 Days PVL with New generation PHV 20% 15% 13,0% 11,4% 10% 9,0% 5% 5,4% 3,4% 0% CoreValve ADVANCE (N=697) CoreValve Extreme Risk (N=418) CoreValve High Risk (N=356) Evolut R US Study (N=227) Evolut R CE Study (N=58) 1 Linke, et al., Eur Heart J 2014; 35: 2672-84; 2 Popma, et al., J Am Coll Cardiol 2014; 63: 1972-81; 3 Adams, et al., N Engl J Med 2014; 370: 1790-8; 4 Williams, et al., presented at ACC 2016; 5 Manoharan, et al., J Am Coll Cardiol Intv 2015; 8: 1359-67

Safety Mismatch Rationale for TAVI in Low-risk Pts Hospital stay Need for PPM PVL Recovery

Permanent Pacemaker implantation

Safety Mismatch Cost Lower Rationale for TAVI in Low-risk Pts Hospital stay Need for PPM PVL Recovery

Cost comparable to or lower than surgery Screening simplified and short Procedure simplification Short hospital stay Low complication rate Quick recovery Valve price decreasing

Valve Quality, Durability Cost Lower Safety Rationale for TAVI in Low-risk Pts Mismatch Hospital stay Need for PPM PVL Recovery

Valve in Valve International Registry

Legacy trials, 5-year follow-up REVIVE II, TRAVERCE, PARTNER EU 410 Pts, age 82.3±5.6 years, Log. EuroSCORE 28.4±13.3 % 114 patients survived Mean gradient 11.7±5.4 mmhg (+ 2.2±5.7 mmhg, p=0.0900) Aortic valve area 1.6±0.6 cm² (+ 0.1±0.7 cm², p=0.3956). 2 cases of valve thrombosis (first year of follow-up) No severe aortic regurgitation, no degeneration Lefèvre et al. ESC 2015

Aortic Valve Area p < 0.0001 Error Bars = ± 1 Std Dev TAVR 304 211 151 106 79 53 SAVR 294 154 121 84 60 46 M. Mack et al. ACC 2015

Valve Hemodynamics (P<0.001)

Notion Trial Baseline 3 mo 1 year 2 years Lars Sondergaard, TVT 2016

Rouen Experience 239 pts from 2002-2011 234 FU > 5 years (98%) Freedom from reintervention, mean gradient > 40 mmhg or severe AR Only one patient with severe AR had reintervention (VIV) Eltchaninoff TVT 2016

Valve Quality, Durability Cost Lower Safety Rationale Bicuspid Valves for TAVI in Low-risk Pts Mismatch Hospital stay Need for PPM PVL Recovery

Epidemiology of Pts undergoing savr Roberts et al. Am J Cardiol 2012; 109:1632-6

Multicenter experience Mylotte, Lefèvre et al. JACC 2014; 64:2330-9

New-generation TAVI device Yoon et al. JACC 2016; 68:1185-205

TAVI for lower-risk Pts? Screening is now simple and very well defined The procedure is well standardised and simplified Femoral approach is the default approach when feasible The outcome is predictable The risk of stroke is low 30-day mortality is always < to STS or Euroscore Valve performance is excellent and mismatch very low Durability in younger patients will be carefully assessed through ongoing randomized studies

Merci pour votre attention!

Back up Slides

What conditions should be fulfilled in order to extend TAVI to all patients? Safety at least similar to surgery Patient-prosthesis mismatch at least similar Hospital stay and recovery shorter Risk of PVL acceptable Need for PPM acceptable Cost lower Valve performance and durability at least similar

Medtronic TAVR in low-risk patients

All-Cause Mortality or Disabling Stroke (%) Primary Endpoint (ITT) All-Cause Mortality or Disabling Stroke 1 50 40 Surgery TAVR HR [95% CI] = 0.89 [0.73, 1.09] p (log rank) = 0.253 30 21.1% 20 10 8.0% 16.4% 14.5% 19.3% 0 6.1% Number at risk: 0 3 6 9 12 15 18 21 24 Months from Procedure Surgery 1021 838 812 783 770 747 735 717 695 TAVR 1011 918 901 870 842 825 811 801 774

All-Cause Mortality or Disabling Stroke (%) TF Primary Endpoint (AT) All-Cause Mortality or Disabling Stroke 1 50 40 TF Surgery TF TAVR HR: 0.78 [95% CI: 0.61, 0.99] p (log rank) = 0.04 30 20 15.8% 20.0% 10 7.5% 11.7% 16.3% 0 4.5% Number at risk: TF Surgery TF TAVR 0 3 6 9 12 15 18 21 24 Months from Procedure 722 636 624 600 591 573 565 555 537 762 717 708 685 663 652 644 634 612

Other Clinical Endpoints (ITT) At 30 Days and 2 Years Events (%) TAVR (n = 1011) 30 Days 2 Years Surgery (n = 1021) p-value* TAVR (n = 1011) Surgery (n = 1021) p-value* Rehospitalization 6.5 6.5 0.99 19.6 17.3 0.22 MI 1.2 1.9 0.22 3.6 4.1 0.56 Major Vascular Complications Life-Threatening / Disabling Bleeding 7.9 5.0 0.008 8.6 5.5 0.006 10.4 43.4 <0.001 17.3 47.0 <0.001 AKI (Stage III) 1.3 3.1 0.006 3.8 6.2 0.02 New Atrial Fibrillation 9.1 26.4 <0.001 11.3 27.3 <0.001 New Permanent Pacemaker 8.5 6.9 0.17 11.8 10.3 0.29 Re-intervention 0.4 0.0 0.05 1.4 0.6 0.09 Endocarditis 0.0 0.0 NA 1.2 0.7 0.22 *Event rates are KM estimates, p-values are point in time

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

Notion Trial Log. Euroscore: 8.4+4.0% Log. Euroscore: 8.9+5.5% Thyregod et al. JACC Interv 2015;65:2184-94

Notion Trial Thyregod et al. JACC Interv 2015;65:2184-94

Notion Trial Outcomes, % TAVR n=142 SAVR n=134 p-value Death, any cause 2.1 3.7 0.43 Bleeding, life-threatening+major 11.3 20.9 0.03 Cardiogenic shock 4.2 10.4 0.05 Vascular lesion, major 5.6 1.5 0.10 Acute kidney injury (stage II+III) 0.7 6.7 0.01 Stroke 1.4 3.0 0.37 TIA 1.4 0 0.17 Myocardial infarction 2.8 6.0 0.20 Atrial fibrillation 16.9 57.8 <0.001 Pacemaker 34.1 1.6 <0.001 Thyregod et al. JACC Interv 2015;65:2184-94

The PARTNER II S3 Trial Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT by Heart Valve Team n = 1076 Patients Intermediate Risk Operable (PII S3i) SAPIEN 3 2 Single Arm Non-Randomized Historical-Controlled Studies High Risk Operable / Inoperable (PII S3HR) n = 583 Patients ASSESSMENT: Optimal Valve Delivery Access PII A SAVR PI A SAPIEN ASSESSMENT: Optimal Valve Delivery Access Transfemoral (TF) Transapical / Transaortic (TA/TAo) Transfemoral (TF) Transapical / Transaortic (TA/TAo) TF TAVR SAPIEN 3 TAA TAVR SAPIEN 3 TF TAVR SAPIEN 3 TAA TAVR SAPIEN 3