A Thoughtful Synthesis of the TAVR Landscape: What s New, What s Needed and is There a Best-in-Class?

Transcription

1 TVT Chicago Thursday 16th of June 2016 Session 1: TAVR 2016 Highlights and Controversies A Thoughtful Synthesis of the TAVR Landscape: What s New, What s Needed and is There a Best-in-Class? Ian T. Meredith AM MBBS, PhD, FRACP, FCSANZ, FACC, FSCAI, FAPSIC MonashHeart, Monash Medical Centre & Monash University Melbourne, Australia

2 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 Consulting Fees/Honoraria Company Boston Scientific, Medtronic

3 TAVR in 2016 Remarkable flow of sophisticated and impactful studies (RCTs) Invaluable insights from large national registries and systematic reviews Continued improvement in safety & efficacy metrics Emerging evidence of superiority over savr in intermediate risk Parallel improvements in savr outcomes Rich pipeline of iterative and innovative new technologies Adjunctive devices to mitigate risk, include stroke, vascular and BAV risk More technically advanced CT and Echo based imaging algorithms, More mature and complete end to end patient management plans All supporting rapid and wide adoption and the relentless march toward every low risk patient Except for the cautionary notes on leaflet thickening, asymptomatic dysfunction and potential long term integrity

4 TAVR in 2016 and beyond Low risk severe and symptomatic patients As distinct from young patients Asymptomatic and severe AS patient Low flow but severe AS Bicuspid aortic valve disease Pure Aortic Regurgatation Routine use in failed savr

5 30-Day All-Cause Mortality TAVR All-Cause Mortality at 30 Days Minimal correlation between baseline risk and mortality 15% 10% 8.4 5% % SAPIEN P 1B N=179 CoreValve US Extreme Risk N=489 SAPIEN XT P 2B N=284 SAPIEN P 2B N=276 SAPIEN P 1A N=348 CoreValve US High Risk N=390 Lotus Nordic Registry N=154 SAPIEN XT P 2A N=1,011 CoreValve NOTION N=142 Extreme High Intermediate Low 1 Leon, et al., N Engl J Med 2010;363: ; 2 Popma, et al., J Am Coll Cardiol 2014;63: ; 3 Webb, et al., J Am Coll Cardiol Intv 2015;8: ; 4 Smith, et al., N Engl J Med 2011;364: ; 5 Adams, et al., N Engl J Med 2014;370:1790-8; 6 Leon, et al., N Engl J Med 2016;374: ; 7 Thyregod, et al., J Am Coll Cardiol 2015;65: De Backer, et al. Int. Jour. of Card. 219 (2016)

6 2-Year All-Cause Mortality TAVR All-Cause Mortality at 2 years Baseline risk appears to correlate mortality for TAVI at 2yr 50% % % 20% % 8.0 0% SAPIEN P 1B N=179 CoreValve US Extreme Risk N=489 SAPIEN XT P 2B N=284 SAPIEN P 2B N=276 SAPIEN P 1A N=348 CoreValve US High Risk N=390 SAPIEN XT P 2A N=1,011 CoreValve NOTION N=142 Extreme High Intermediate Low 1 Leon, et al., N Engl J Med 2010;363: ; 2 Popma, et al., J Am Coll Cardiol 2014;63: ; 3 Webb, et al., J Am Coll Cardiol Intv 2015;8: ; 4 Smith, et al., N Engl J Med 2011;364: ; 5 Adams, et al., N Engl J Med 2014;370:1790-8; 6 Leon, et al., N Engl J Med 2016;374: ; 7 Thyregod, et al., J Am Coll Cardiol 2015;65:

7 All-Cause Mortality or Disabling Stroke (%) PARTNER II A Primary Endpoint (ITT) All-Cause Mortality or Disabling Stroke Surgery TAVR HR [95% CI] = 0.89 [0.73, 1.09] p (log rank) = % % 16.4% 14.5% 19.3% 0 6.1% Number at risk: Months from Procedure Surgery TAVR

8 All-Cause Mortality or Disabling Stroke (%) PARTNER II A TF Primary Endpoint (ITT) All-Cause Mortality or Disabling Stroke TF Surgery TF TAVR HR: 0.79 [95% CI: 0.62, 1.00] p (log rank) = % 20.4% % 12.3% 16.8% 0 4.9% Number at risk: Months from Procedure TF Surgery TF TAVR

9 P2A Surgery vs S3 TAVR Unadjusted Time-to-Event Analysis All-Cause Mortality and All Stroke (AT) All-Cause Mortality / Stroke Rate (%) 40 P2A Surgery SAPIEN 3 TAVR % % 10.8% 3.7% 0 Number at risk: P2A Surgery S3 TAVR Months from Procedure

10 Remaining Challenges with TAVR Aortic Valve Accurate primary positioning Ability to reposition / retrieve / replace Consistency of valve hemodynamics /EOA / flow and shear forces if frame distorted or mal-positioned Long term durability Paravalvular aortic regurgitation Cardiac Annular Rupture Ventricular perforation / tamponade Need for permanent pacemaker Vascular Stroke Access issues / Vascular complications / Bleeding General Learning curve / ease of use Device preparation

11 What s Needed Wish List Low profile, flexible, intuitive and easily navigated delivery system Get the valve in the right place every time Repositionable, retrievable and replaceable Valve largest EOA, excellent hemodynamics, least frame distortion No (or trivial) paravalvular leak Long term valve leaflet durability Minimal risk of the need for a new Pacemaker Absolute minimum risk of major complications Stroke, TAV in TAV, Embolization, Coronary ostial obstruction, Vascular complications and bleeding

12 Rapid Iteration and Innovation in Supporting TAVR Technologies Vascular Access Custom designed introducer sheaths Access site specific introducer sheaths Improved large artery closure devices Support Wires Custom designed pre-curved, re-curvable and LV safe and device specific Aortic Valvuloplasty Balloons Stable, rupture resistant, multiple sizes, noncompliant Device Delivery and Release Handles Ergonomic, intuitive, uncomplicated and fail safe Lotus Edge, Acurate Neo, Evolut R, Direct Flow DirecTrack, Jena Next Gen Embolic protection Devices

13 Current and Future TAVR Landscape CoreValve Sapien XT Direct Flow Lotus Portico Symetis Sapien 3 Centera Evolut R Valve Med Frame Material Nitinol Cobalt chromium Polyester fabric Braided Nitinol Nitinol Nitinol Cobalt chromium Nitinol Nitinol Nitinol Tissue Porcine pericardial inner skirt Bovine Pericardial inner skirt Bovine Pericardial Bovine Pericardial with PET outer skirt Bovine Pericardial inner skirt Porcine Pericardial inner and outer skirt Bovine Pericardial Polyester outer skirt Bovine Pericardial inner skirt Porcine pericardial inner skirt (outer skirt in development) Bovine Leaflet Valve Design Supraannular Intraannular Intraannular Intraannular Intraannular Intraannular Intraannular Intraannular Supraannular Intraannular Vascular Access ID: 18Fr OD: 21.7Fr ID: 18-22Fr OD: 21-30Fr (16Fr esheath) ID: 18FR OD: 21.7FR ID:? OD: 21.7Fr ID: 18Fr OD: 21.7Fr ID: 18Fr OD: 21.7mm ID: 14FR esheath OD: 26FR * ID: 14FR esheath OD: 22FR * ID: 18Fr OD: 18Fr (14Fr Inline Sheath) ID: 12FR OD: 14FR Other AOA ThermaFix Anti-Ca++ Recapture Recapture Linx Recapture None Therma- Fix Future GLX Therma- Fix Future GLX Recapture AOA Recapture Modular approach

14 Current and Future TAVR Landscape Self-expanding Manual & mechanically - expanded Balloon-expanded Biovalve, Venus, J-Valve, Allegra, Vitaflow, Trinity and many others not shown

15 What s Needed?

16 What s Needed Wish List Low profile, flexible, intuitive and easily navigated delivery system Get the valve in the right place every time Repositionable, retrievable and replaceable Valve largest EOA, excellent hemodynamics least frame distortion No (or trivial) paravalvular leak Longterm valve leaflet durability Minimal risk of the need for a new Pacemaker Absolute minimum risk of major complications Stroke, TAV in TAV, Embolization, Coronary ostial obstruction, Vascular complications and bleeding

17 30-Day Permanent Pacemaker Permanent Pacemaker Within 30 days - First Generation TAVI 30% 20% % % Extreme Risk P 1B N=179 Extreme Risk P 2B N=276 High Risk P 1A N=348 Extreme Risk P 2B N=284 Intermediate Risk P 2A N=1,011 Extreme Risk US Pivotal N=489 High Risk US Pivotal N=390 SAPIEN SAPIEN XT CoreValve 1 Leon, et al., N Engl J Med 2010;363: ; 2 Webb, et al., J Am Coll Cardiol Intv 2015;8: ; 3 Smith, et al., N Engl J Med 2011;364: ; 4 Leon, et al., N Engl J Med 2016;374: ; 5 Popma, et al., J Am Coll Cardiol 2014;63: ; 6 Adams, et al., N Engl J Med 2014;370:1790-8;;

18 30-Day Permanent Pacemaker Permanent Pacemaker at 30 days with Current Generation TAVI 30% % 10% % CE Study N=60 US Study N=241 SAVI Registry N=1,000 CE Study N=220 P2 S3 IR N=1,078 P2 S3 HR/ER N=583 S3 CE IR N=101 S3 CE N=150 DISCOVER Registry N=375 DISCOVER N=100 REPRISE II N=250 RESPOND N=1,014 Evolut R ACURATE Neo Portico SAPIEN 3 Direct Flow Lotus 1 Manoharan, et al., J Am Coll Cardiol Intv 2015; 8: ; 2 Williams, et al., presented at ACC 2016; 3 Moellman, et al., presented at EuroPCR 2016; 4 Linke, et al., presented at PCR London Valves 2015; 5 Kodali, et al., Eur Heart J 2016; doi: /eurheartj/ehw112; 6 Vahanian, et al., presented at EuroPCR 2015; 7 Webb, et. al. J Am Coll Cardiol Intv 2015; 8: ; 8 DeMarco, et al, presented at TCT 2015; 9 Lefevre, et al., J Am Coll Cardiol Intv 2016; 9: 68-75; 10 Meredith, et al., presented at PCR London Valves 2015; 11 Falk, et al., presented at EuroPCR 2016

19 What s Needed - Pacemaker Increase length of stay Increase total procedural costs Increased risk of procedural complications Probably don t adversely influence long term survival May potentially impact on rate of SUD May impact LV and RV function or recovery

20 Lotus TAVR in RP II/ IIExt Predictors of New PPM Insertion Baseline RBBB (OR 12.79, , p<0.001) LVOT area overstretch > 10% (OR 3.42, , p<0.001) 1 st degree AV block (OR 2.49, , p=0.02) LVOT total calcium (OR 1.80, , p=0.04) Reprise II / II Extension 2 valve sizes 23 mm and 27 mm 1 Dumonteil, et al., presented at ACC 2015

21 LOTUS Implant Depth and New PPM rate Monash Lotus Study, Zaman et al., JACC Intervention submitted Variable Univariate Multivariate Pre-existing RBBB Depth of Implantation >5mm HR (95% CI) P-value HR (95% CI) P- value 3.6 ( ) ( ) ( ) ( ) Nordic Lotus Study, De Backer et al., Int J Cardiol 2016;219: N=246 N=237

22 Average depth below Basal Plane (mm) Monash Lotus TAVR Study Average Depth and New PPM Implants Basal Plane 7 new PPM when Lotus above 4 mm 3 had No RBBB PPM 3 1 o AVB 1 LBBB New PPM 21 new PPM implanted when Lotus inflow deployed below 4 mm -12 Total 125 patients, 12 with pre-existing pacemakers excluded. Total of 28 new PPM, Actual PPM rate 28 / 113 =24.7% 1 Sarah Zaman JACC Int submitted for publication, adapted from McCormick et al., EuroPCR 2016

23 Av Depth below Annulus (mm) % new PPM Higher Lotus implants may reduce new PPM Implantation Average Depth of Implantation Before & After Modified Technique New PPM Implantation Rate Before & After Modified Technique Chart Title Chart Title p < 0.05 p < ± % ± 1.4 8% 8.3 Before After Before After Liam McCormick et al., Monash Lotus Program presented at EuroPCR 2016

24 Depth Guard Limiting LVOT interaction and depth with LOTUS Edge Al Current Lotus Valve Optimizing Valve Deployment: LOTUS Edge with Depth Guard Controls implantation depth reducing LVOT interaction Virtually no ventricular foreshortening once valve is anchored Standardizes implantation technique Virtually zero foreshortening at end of deployment Under development, not available for sale

25 Evolut R FDA Cohort New PPM Analysis Evolut R US FDA Cohort Evolut R CE Study 1 3 N=60 Evolut R US Study 4 N=91 *Enrollment ongoing at the time of this analysis. 151 patients, 22 pre-existing PPM, 129 patients at risk and 20 who received a pacemaker 1 Manoharan G, et al. JACC Intv 2015; 8: Meredith IT, et al. EuroPCR May, Paris 3 Manoharan G, et al. TCT Oct, San Francisco. 4 Williams M, et al. ACC 2016, 02 April, Chicago. 26

26 Total (Aortic Root & LVOT) Calcification (mm 3 ) Evolut R FDA Cohort Total Calcium (Aortic Root and LVOT ) & New PPM Total (Aortic Root & LVOT) Calcification (mm 3 ) No difference in the total volume or distribution of calcium between patients with or without a new pacemaker New PPI N=20 No PPI N=109 0 PPI at Baseline N=22 Error bars = standard deviations RCC=right coronary cusp

27 Annular Sizing Ratio (%) Evolut R New PPM Insertion and % Annular oversizing 40.0 The need for a new PPI was marginally lower using a sizing threshold of 20% (13.9% vs 17.6%, p = 0.51, for 20% sizing vs. < 20%) Meredith et al EuroPCR 2016 Patients with a new PPI within 30 days Patients in order of annular sizing ratio 28

28 Evolut R US FDA Cohort Average Depth of Implant New PPM Insertion Distance from Annular Plane (mm) Recommended implant depth of 3-5 mm below the annular plane = annular plane All patients with depth data Patients with a new PPI within 30 days

29 Evolut R US FDA Cohort Determinants of new PPM Implantation UNIVARIABLES MULTIVARIABLES Variable Hazard Ratio [95% CI] P Value Hazard Ratio [95% CI] P Value Average implant depth (>5 mm) 4.67 [1.77, 12.31] [2.4, 19.6] Presence of RBBB 3.42 [1.36, 8.57] [2.3, 15.9] mm valve 0.56 [0.21, 1.55] Oversizing > 20% 1.34 [0.56, 3.22] Overall root calcification (>480 mm 3 ) 1.33 [0.51, 3.50] Overall LVOT calcification (>4 mm 3 ) 1.97 [0.73, 5.34] Overall total calcification (>510 mm 3 ) 1.03 [0.40, 2.66] CI = confidence interval; RBBB = right bundle branch block. 30

30 Evolut R US FDA Cohort Determinants of new PPM Implantation Excluding RBBB UNIVARIABLES MULTIVARIABLES Variable Hazard Ratio [95% CI] P Value Hazard Ratio [95% CI] P Value Average implant depth (>5 mm) 9.98 [2.18, 45.59] [2.5,149.9] Oversizing > 20% 1.59 [0.54, 4.74] Overall LVOT calcification (>4 mm 3 ) 1.59 [0.51, 5.02] Overall root calcification (>480 mm 3 ) 0.64 [0.20, 2.01] Overall total calcification (>510 mm 3 ) 0.61 [0.19, 1.93] mm valve 0.30 [0.07, 1.36] CI = confidence interval; RBBB = right bundle branch block. 31

31 EnVeo R Delivery Catheter System Control During Deployment, Ability to Recapture and Reposition Capsule Flare Nitinol Reinforced Capsule Flare Enable uniform and controlled valve expansion and self-centering Low Delivery Profile 14Fr-equivalent Vessel Access 5.0 mm 1:1 Response Direct correlation between movement of the deployment knob and movement of the capsule *Up to ~ 80% deployment. Medtronic Data on File.

32 What s Needed - Pacemaker Uniformly and consistently express the rate of new PPM implants as a % of patients potentially at risk not as % of all patients in the TAVR cohort Develop better models to understand the inter-relationship between annular and LVOT oversizing and depth of implantation on the need for PPM Analyze the potential predictors of new PPM in both the presence and absence of powerful determinants of need for a new PPM (such as RBBB) as they my mask important TAVR and device specific determinants Develop and implement more sophisticated, ambulatory monitoring to offset pragmatic early PPM implantation

33 What s Needed Wish List Low profile, flexible, intuitive and easily navigated delivery system Get the valve in the right place every time Repositionable, retrievable and replaceable Valve largest EOA, excellent hemodynamics least frame distortion No (or trivial) paravalvular leak Longterm valve leaflet durability Minimal risk of the need for a new Pacemaker Absolute minimum risk of major complications Stroke, TAV in TAV, Embolization, Coronary ostial obstruction, Vascular complications and bleeding

34 % Patients with Mod/Severe PVL 1-Month Moderate/Severe PVL TAVI Clinical Trials Month Mod/Severe PVL CoreValve ADVANCE 1 CoreValve High Risk 2 Evolut R 3 Portico SAPIEN 3 SAPIEN 3 CE Study 4 EU 5 PARTNER II S Direct Flow DISCOVER LOTUS REPRISE II & EXT LOTUS RESPOND* 9 N=696 N=356 N=58 N=75 N=113 N=1504 N=81 N=177 N=996 *7d/Discharge; 30d angiography not mandated per protocol; Results from different studies are not directly comparable. Information provided for educational purpose only. 1 Linke A, Eur Heart J 2014; 35: Adams D, N Engl J Med 2014; 370: Meredith I, TCT Manoharan G, TCT Webb J, JACC 2014;64: Kodali S, ACC Lefevre T, JACC:CI 2016;9: Meredith I, London Valves Falk V, PCR2016. CAUTION: Lotus is an investigational device and restricted under federal law to investigational use only. Not available for sale.

35 % Patients with Mod/Severe PVL 12-Month Moderate/Severe PVL TAVI Clinical Trials Month Mod/Severe PVL SAPIEN XT PARTNER II 1 SAPIEN PARTNER II 1 Portico CE Study 2 SAPIEN PARTNER B 3 CoreValve ADVANCE 4 SAPIEN PARTNER A 5 CoreValve High Risk 6 CoreValve Ext Risk DirectFlow DISCOVER 8 LOTUS REPRISE II/II EXT 9 STS Score: N: Results. from different studies are not directly comparable. Information provided for educational purpose only. 1 Leon M, ACC Manoharan G, TCT Leon M, NEJM Linke A, Eur Heart J Smith CR, NEJM Adams D, N Engl J Med Popma J, JACC Lefevre T, JACC:CI Meredith I, PCR LV CAUTION: Lotus is an investigational device and restricted under federal law to investigational use only. Not available for sale.

36 Discharge or 30-Day Paravalvular Leak PVL at 30d for Current Generation TAVI 100% 80% 60% 3.4 Weighted average for Mild PVL = 30% (n=3914) Weighted average for Moderate/Severe PVL = 3% (n=3914) Mild PVL Mod/Severe PVL 40% 20% 0% 63.8 CE Study N= US Study N= SAVI Registry N=240 CE Study N= P2 S3 N=1, CE IR Extension N=87 CE Study N= DISCOVER Registry N=247 DISCOVER N=81 REPRISE II N= RESPOND N=929 Evolut R ACURATE Neo Portico SAPIEN 3 Direct Flow Lotus 1 Manoharan, et al., J Am Coll Cardiol Intv 2015; 8: ; 2 Williams, et al., presented at ACC 2016; 3 Moellman, et al., presented at PCR London Valves 2015; 4 Linke, et al., presented at PCR London Valves 2015; 5 Kodali, et al., Eur Heart J 2016; doi: /eurheartj/ehw112; 6 Vahanian, et al., presented at EuroPCR 2015; 7 Webb, et. al. J Am Coll Cardiol Intv 2015; 8: ; 8 DeMarco, et al, presented at TCT 2015; 9 Lefevre, et al., J Am Coll Cardiol Intv 2016; 9: 68-75; 10 Meredith, et al., presented at PCR London Valves 2015; 11 Falk, et al., presented at EuroPCR 2016

37 What s Needed - PVL We know that it matters Surgeons don t leave it Improvement in PVL is multifactorial Better imaging, routine use of CT, better technique, more valve sizes Greater understanding of the 3D nature of the Aorto-ventricular interface and the volume and distribution on calcium Ability to reposition some prosthesis However seals, cuff and skirts work the best

38 Medtronic Evolut PRO Innovating to Improve PVL Performance Medtronic TAVR 2.0 Clinical Study Indication ER / HR Patients Clinical Design Study Start/ Duration Single-arm, N=60 30-day Endpoint NOW ENROLLING 6-8 months Pericardial Tissue Wrap to Continue to Improve PVL Performance

39 30-Day All Stroke Stroke at 30 days for Current Generation TAVI 10% 8% Weighted average = 2.7% (n=5261) INA IINA N 6% 5.5 4% 2% % 0.0 CE Study N=60 SAVI Registry N=1,000 CE Study N=220 P2 S3 IR N=1,078 P2 S3 HR/ER N=583 S3 CE IR N=101 S3 CE N=150 DISCOVER N=100 REPRISE II N=250 RESPOND N=1,014 Evolut R ACURATE Neo Portico SAPIEN 3 Direct Flow Lotus 1 Manoharan, et al., J Am Coll Cardiol Intv 2015; 8: ; 2 Moellman, et al., presented at PCR London Valves 2015; 3 Linke, et al., presented at PCR London Valves 2015; 4 Kodali, et al., Eur Heart J 2016; doi: /eurheartj/ehw112; 5 Vahanian, et al., presented at EuroPCR 2015; 6 Webb, et. al. J Am Coll Cardiol Intv 2015; 8: ; 7 DeMarco, et al, presented at TCT 2015; 8 Lefevre, et al., J Am Coll Cardiol Intv 2016; 9: 68-75; 9 Meredith, et al., presented at PCR London Valves 2015; 10 Falk, et al., presented at EuroPCR 2016

40 30-Day Major Vascular Complications* Vascular Complications* for Current Generation TAVI at 30d 20% Universal Sheath Dimensions Max ED mm Max ID mm 15% 10% 5% % CE Study N=60 Minimum Vessel Diameter (mm) US Study N=241 SAVI Registry N=1,000 CE Study N=220 P2 S3 IR N=1,078 P2 S3 HR/ER N=583 S3 CE IR N=101 S3 CE N=150 DISCOVER Registry N=375 DISCOVER N=100 REPRISE II N= / Evolut R ACURATE Portico SAPIEN 3 Direct Flow Lotus Neo RESPOND N=1,014 *Definitions vary across studies 1 Manoharan, et al., J Am Coll Cardiol Intv 2015; 8: ; 2 Williams, et al., presented at ACC 2016; 3 Moellman, et al., presented at EuroPCR 2016; 4 Linke, et al., presented at PCR London Valves 2015; 5 Kodali, et al., Eur Heart J 2016; doi: /eurheartj/ehw112; 6 Vahanian, et al., presented at EuroPCR 2015; 7 Webb, et. al. J Am Coll Cardiol Intv 2015; 8: ; 8 DeMarco, et al, presented at TCT 2015; 9 Lefevre, et al., J Am Coll Cardiol Intv 2016; 9: 68-75; 10 Meredith, et al., presented at PCR London Valves 2015; 11 Falk, et al., presented at EuroPCR 2016

41 TAVR in 2016 Is there a Best in Class Scoring 1-5 for the top five Programs Weight, volume impact on the field of their clinical trial program? Speed and number of iterations? Overall safety bench marks? Mortality and Stroke? Paravalvular leak? Repositionability? Consistent Acess to Coronaries? EOA and mean gradients? TAVR in Failed savr? TAVR in Bicuspid Valves? Vascular access options and ease? Ease of use?

42 Final Word It should be all about patient are not the device nor the technology - We are the patient s advocate All current and emerging TAVR have good results - horses for courses More design options and choices should expand the spectrum of therapeutic opportunities an drive innovation The real question how do we provide this therapy to all deserving patients We need to identify potential predictors of late valve failure