Over-‐expan*on and Op*mal Healing in LM-‐PCI: Background and
update of the IDEAL-‐LM Trial
Robert-‐Jan van Geuns, MD, PhD Keith Oldroyd, MD, PhD.
Requirements of LM stents Special subset of procedures: § Large diameter: Large over-expansion capabilities § Ostial stenting: High Radial strength* § And/or Bifurcation treatment (63% of LM in Syntax) > 1 stent with overlap or 2 stent bifurcation (39% in
Syntax LM) treatment: thin struts for better coverage
§ Older patients/non-surgical patients: (Syntax PCI Registry vs Randomized patients: 71.2 vs 65.2) Higher bleeding risk, preference for less DAPT
*The coronary ostia are particularly prone to stent recoil due to the fibroelastic properties of the aortic wall and the increased frequency of calcification. Topol EJ, Ellis SG, Fishman J, Leimgruber P, Myler RK, Stertzer SH, O’Neill WW, Douglas JS, Roubin GS, King SB, 3rd. Multicenter study of percutaneous transluminal angioplasty for right coronary artery ostial stenosis. J Am Coll Cardiol. 1987;9:1214-8
Larger Diameter
CCI 2013: James Shand, Simon Walsh
5.0 3.6 4.4 5.6 6.2 6.7 7.1
Distal LM CSA
Circle of 4.0 =12.6 mm2
Circle of 5.0 =19.6 mm2
IVUS LM in male pts (Rotterdam)
§ IVUS data on 865 LAD->LM pullbacks, male patients
§ ‘non-diseased’ LM (i.e. minimal plaque burden, <50% of LM circumference with intimal thickening) in only 17.6% of pts (N=152)
§ Average vessel diameter, vessel area
§ Correlation with body surface area (BSA)
IVUS LM vessel diameter (VD)
§ Average VD: 5.60 mm Mean VD: 5.47 mm
§ Only in 13% <5 mm
RelaGon with BSA
• No clear correlaGon of VD or VA with BSA
y = 5,095x + 15,117 R² = 0,03485
10
15
20
25
30
35
40
45
1,50 1,70 1,90 2,10 2,30 2,50 2,70
y = 0,605x + 4,3401 R² = 0,03571
4
4,5
5
5,5
6
6,5
7
7,5
8
1,50 1,70 1,90 2,10 2,30 2,50 2,70
Large diameter: No all stents are the same
*SYNERGY Stent, Promus PREMIER Stent, Xience Xpedition Stent and Resolute Integrity Stent DFU.
Xience Xpedition™
Stent System
Promus PREMIER™ Stent System
(mm) 3.00 3.50 3.75 4.00 2.75 2.50 2.25 4.25 4.75 5.00 5.25 4.50 3.25 5.50 5.75
Labeled Nominal: Labeled Post-Dil Limit:
2.25
2.50 to 2.75
3.00 to 3.50
4.00
2.25 to 2.50
3.50 to 4.00
2.75 to 3.25
Resolute Integrity™ Stent System
2.25 to 2.75
3.00 to 4.00
SYNERGY Stent System
2.25 to 2.75
3.00 to 3.50
4.00
Labeled Post-Dilatation Limits*
Overexpanition has limitations, especially when sizing to the distal main branch of a bifurcation. Potential resulting in serious malapposition
Bench testig FKBD and POT in LM § Different sizes of Balloons for FKBD § Different pressures for POT and FKBD § Recoil and radial strenght for PlatinumChromium Stent of
4.0 mm, target to reach 6 mm Second Post-Dilation
PostDilation Method
Group Number
Sample Size
Post-Deployment
Catheter Size (mm) Pressure
(atm)
POT-SC/LP 1 3 Maverick XL 6.0 x15 6
POT-SC/SP 2 10 Maverick XL 6.0 x15 14
POT-NC/HP 3 3 NC Emerge 6.0 x15 24
FKBD-US/SP 4 3 Apex 4.0x15 + 3.5x15 12
FKBD-OS/LP 5 3 Apex 5.0x15 + 4.0x15 4
FKBD-OS/SP 6 3 Apex 5.0x15 + 4.0x15 12 1 Finet G. Gilard M. Perrenot B. Rioufol G. Motreff P. Gavit L. Prost R. Fractal geometry of coronary bifurcations : a quantitative coronary angiography and intravascular ultrasound analysis. EuroIntervention 2008; 3: 490-98
Methods
Max SD
Min SD Max Inner SD Min Inner SD EI:
SD: Stent Diameter
Malapposition Area (MA/mm2) = Tube ID Area– Stent OD Area
Stents deployed in an aqueous bath at standard temperature of 37 +/- 1 degree Celsius
Stent expansion and malpposition were evaluated by implanting the stents in silicon tube phantom models of 6 mm
Precalibrated Measurement Scope
Stent and Tube Dimensions
Ellipticity Index (EI)
Malapposition
FKBD in large vessels: Results
0 2 4 6 8
FKBD-US
FKBD-LP
FKBD-RPB
Outer Diameter
0 1 2
FKBD-US
FKBD-LP
FKBD-RPB
Ellipticity
0 10 20 30
Area
3.5 + 4.0 4.0 + 5.0
3.5 + 4.0 4.0 + 5.0
4 at
ms
12 a
tms
12 a
tms
FKBD in large vessels: Results
0 2 4 6 8
FKBD-US
FKBD-LP
FKBD-RPB
Outer Diameter
0 10 20 30
Area
§ Size § Adequate size necessary
§ Pressure § High pressure indicated
§ Serious ellipticity 4 at
ms
12 a
tms
3.5 + 4.0 4.0 + 5.0
Optimalization of the POT § Semi- Compliant vs Non-compliant
balloons? § Pressure
o 6 vs 14 or 24 atm.
Stent/Balloon Size
Pressure Stent/Balloon Dimensions
(mm) (atm) Synergy IITM
4.0mm Nominal 11.0 OD 4.24 RBP 16.0 OD 4.48
NC Quantum ApexTM 5.0mm
Nominal 12.0 4.95 RBP 18.0 5.15
ApexTM 5.0mm
Low 4.0 4.79 Nominal 6.0 4.99 RBP 12.0 5.30
Maverick 6.0mm
Nominal 6.0 6.00 RBP 14.0 6.46
Emerge NC
6.0mm Nominal 6.0 6.09 RBP 14.0 6.28
Optimalization of the POT
0
2
4
6
8
POT-LP POT-RPB POT-NC
Outer Diameter
0 0,5
1 1,5
POT-LP POT-RPB POT-NC
Ellipticity
0 10 20 30 40
Area
6 atm 14 atm
Maverick 6 mm balloon
6 at
m
12 a
tms
24 a
tms
Emerge NC 6 mm
24 atm
4.0 to 5.75 Synergy
Requirements of LM stents
LM stents Synergy
Large Diameter Labeled expansion till 5.75mm. Data till 6.0 mm
Ostial stenting 0.27 N/mm
Frequent overlapping stents
Strut thickness 74-81 µm, Biodegradable coating
Frequent 2 stent bif approach
Strut thickness 74-81 µm Biodegradable coating
Elderly Population Abluminal coating only Biodegradable coating
0.18 0.17
0.27 0.3
0.2
0.1
0.0 SYNERGY
Stents Xience
Xpedition™ Stent
Resolute Integrity™
Stent
0.13
BioMatrix Flex™ Stent
Radial Strength of current DES
Summary
§ LM PCI requires optimized stent design § 6.22 mm = 30.3 mm2 is possible with Synergy
§ Undersized FKBD: § Serious Ellipticity + Serious malapposition
§ Adequate sized FKBD § Serious Ellipticity + Minimal malapposition if adequate
pressures are used
§ POT § Does not follow normal compliance chart. § At High pressures: full apposition
IDEAL-Left Main: Improved Drug Eluting stent for ALl
comers Left Main Sponsor : Glasgow Jubilee National Hospital Principal Investigators: Professor Keith Oldroyd, MD(Hons)
Professor Robert-Jan van Geuns, MD, PhD Paul Barragan Principle Investigator France
Maciej Lesiak Principle Investigator Poland
Robert Byrne Principle Investigator, Germany
Evgeny Merkulov Principle Investigator, Russia
Evelyn Regar OCT substudy
Objective
This study will investigate the short term angiographic and long term clinical outcome of after implantation of an improved drug eluting coronary artery stent (Everolimus-eluting Platinum Chromium Stent with Abluminal Bioabsorbable Polymer) with shorter post interventional dual antiplatelet therapy (DAPT) in comparison to a conventional drug eluting stent with a permanent Polymer followed by 12 months DAPT for treatment of unprotected left main coronary artery disease
Study design:
A multicenter, prospective, randomized study (Synergy vs Xience) with a clinical follow-up of 5 years
Subjects with an indication for coronary artery revascularisation by ESC guidelines and accepted for PCI of the left main coronary artery will be included in the study
Study population:
The primary endpoint
The primary endpoint is MACCE, including death from any cause, MI, stroke, or ischemia-driven target vessel revascularization (TVR) at 2 years after the procedure. (Non-inferiorty)(N=818)
Primary invasive endpoint
Superiority Healing Score by OCT at 3 months follow-up (N=100)
First patient in 31 Dec 2014:
SYNERGY Stent Case Study Complete Strut Coverage at 2 Months (OCT Assessment)
Case study not necessarily representaGve of all cases. Results in other cases may vary.
TIMELESS
TRANSFORM OCT
Enrolling
Enrolling
Healing/Endothelial Coverage at 3m
Single arm registry 50 paIents
Endothelial coverage at 3m and neo-‐atherosclerosis at 18m compared to RI. 90
paIents.
The IDEAL LM Study (Improved drug eluting stent for percutaneous coronary intervention of the left main artery in a real world all-comers population)
Co-‐Principal invesIgators: Prof. Keith Oldroyd -‐ Golden Jubilee Hospital Glasgow Prof. Robert-‐Jan van Geuns – Erasmus MC RoXerdam
Primary Outcome: MACE defined as death from any cause or MI or ischemia-‐driven target vessel revascularizaIon (TVR) at 2 years a\er the procedure. Secondary outcome: strut coverage on OCT at 3/12 (n=100)
818 paIents Randomized 1:1 SYNERGY plus 4/12 DAPT vs Xience plus 12/12 DAPT ESC guideline indicaIons for PCI of the le\ main coronary artery
IDEAL LM n = 818 pts
Enrollment & Follow-‐Up 2 Y
12.2014 02.2016 02.2018
Current enrollment
§ Sept 2015: 17 of 24 sites open: 167 patients.
Thank You
Vascular healing post PCI
§ Strut coverage
§ Resolultion of malapposition
§ Minimalized intimahyperplasia
§ Bioabsorbable polymer (PLGA)
§ Everolimus applied only to the abluminal surface (rollcoat)
§ Thin strut plaGnum chromium stent
Stent Strut Cross SecGon AnimaGon
74μm
SYNERGY Stent
The SYNERGY™ stent is an invesGgaGonal device and not for sale in the US. CE Mark Approved 2012.
Arterial Wall
Strut coverage 1. Strut thickness
2. Coating
3. Embedded/Appposed/non-Malapposed
77 88
94,8
0
20
40
60
80
100
Express Liberté Element
BMS Strut Coverage at 14 days in Rabbit
132 μm 97 μm 81 μm
P=0.05 P=0.001
Soucy N, Feygin J et al, EuroInterven6on. 2010 Nov;6(5):630-‐7
%
Finn A, Joner M et al, CirculaIon 2007;115:2435-‐41
Express Liberté Element
Microscopy
Uncovered struts predicIve of late stent thrombosis
1. Turbulent flow and thrombogeneity Strut positioning relative to the vessel wall modulates thrombogenicity
Kolandaivelu et al. Circulation 2011; 5;123(13):1400-9.
Thin Strut (81µm)
Apposed
Severely Malapposed
Thin Strut (162µm)
Lessons from Computational Modeling
CE
NTE
RLI
NE
DIS
PLA
CE
ME
NT
Presented by Yen Lane Chen, PhD at EuroPCR 2012; World J Cardiol 2011 March 26; 3(3): 84-‐92; Garg, S, J Am Coll Cardiol. 2010;56(10s1):S43-‐S78. doi:10.1016. Presented by Stephen Windecker, MD, TCT2012.
Polymer: PLGA AbsorpIon Time: 3-‐4 mo
% Recovery
Time (months)
2. Difference in bioresorbable coa*ng Drug Release and Polymer AbsorpIon Profiles
SYNERGY
Everolimus
PLGA
Nobori and Biomatrix Flex
% Recovery
Polymer: PLA AbsorpIon Time: >9 mo
BA9
PLA
Orsiro
% Recovery
Time (months)
Polymer: PLLA AbsorpIon Time: >12 mo
Time (months)
Sirolimus
PLLA (molecular weight change)
% Recovery
Time (months)
Absorb BVS
Scaffold: PLLA Polymer: PDLLA
AbsorpIon Time: >2 yrs
Everolimus
PLLA
3. Apposition related to coverage
Vascular healing
§ Strut coverage
§ Resolultion of malapposition
§ Minimalized intimahyperplasia
Vascular reaction to acute malapposition, categorized according to morphological pattern at follow-up: Homogeneous (A), layered (B), crenellated (C), bridged (D), partially bridged (E), or bare (F).
Gutiérrez-Chico J et al. Circ Cardiovasc Interv 2012;5:20-29
Resolution of malapposition
Minimize Neointimahyperplassia Thin struts reduces restenosis
1ISAR STEREO II JACC Vol. 41, No. 8, 2003 April 16, 2003:1283-8. 2ISAR STEREO I Circulation June 12, 2001
Thin Multi-link™
Thick
6 month binary restenosis
ISAR STEREO1
Thin, Binary Restenosis (6 months), 15%
Thick, Binary Restenosis (6 months), 26%
Thick
6 month binary restenosis
Thin Multi-link™
ISAR STEREO2
Thin, Binary Restenosis (6 months), 18%
Thick, Binary Restenosis (6 months), 31%
§ Bioabsorbable polymer (PLGA)
§ Everolimus applied only to the abluminal surface (rollcoat)
§ Thin strut plaGnum chromium stent
Stent Strut Cross SecGon AnimaGon
74μm
SYNERGY Stent
The SYNERGY™ stent is an invesGgaGonal device and not for sale in the US. CE Mark Approved 2012.
Arterial Wall
IC-29614-AE Jan 2014 Page 37
SYNERGY: BSC Clinical Trials First Human Use Trial. 291 paGents.
PROMUS Element vs. SYNERGY vs. SYNERGY Half-‐Dose (1:1:1). Primary Endpoint: 6 month Late Loss + Composite Safety @ 30 days
Quan*ta*ve Angiography. 100 PaGent Registry, 10-‐15 sites (Australia, Japan, New Zealand, Singapore). Primary Endpoint: 9 month in-‐stent Late Loss
China regulatory approval trial (SFDA). 400 paGents, up to 15 sites. PROMUS Element Plus vs. SYNERGY (1:1) Primary Endpoint: 9 month Late Loss
3/12 Month DAPT. ProspecGve, MulG-‐center, Global,4000 paGents.
Primary Endpoint: Cardiac Death/ MI
Global IDE Trial. 1684 paGents, 150 sites, 19 countries . PROMUS Element Plus vs. SYNERGY (1:1) single-‐blind trial.
Primary Endpoint: 12 month TLF
EVOLVE
EVOLVE II
EVOLVE II QCA
EVOLVE China
EVOLVE DAPT
HORIZONS II RCT Synergy in AMI.
8000 paGents with STEMI, Primary Endpoint: 1 year TLF
HORIZONS II is a partnership between Boston ScienGfic, the Cardiovascular Research FoundaGon and medicines companies The SYNERGY™ stent is an invesGgaGonal device and not for sale in the US. CE Mark Approved 2012.
0,15 0,10 0,13
0,0
0,1
0,2
0,3
0,4
0,5
0,6
6,1
0
5,5
0
5,2
0 0
2
4
6
8
10
Presented by Ian Meredith AM, MBBS PhD, at EuroPCR 2013. Meredith et al. J Am Coll Cardiol. 2012; 59 (15):1362 Intent-‐to-‐treat; P values are versus PROMUS Element (Fisher exact test)
PaIe
nts, %
ST (Def/Prob)
P=0.85
2 Years
mm
P=0.19
6 Months
Late Loss TLF
P=0.56 P=0.81
PROMUS Element (n=98) SYNERGY (n=94) SYNERGY Half Dose (n=99)
EVOLVE Trial Key Results
IC-29614-AE Jan 2014 Page 39
Mul6-‐vessel Disease
Bifurca6on Lesions
Diabetes Long Lesions
DAPT
CTO
Imaging / Healing
ACS
Ø EVOLVE
Ø EVOLVE II
Ø EVOLVE II QCA
Ø CONSISTENT
Ø BIORESORT
Ø SYNTAX II
Ø SENIOR
Ø SYNTAX II
Ø BIORESORT
SYNERGY Clinical Program Ongoing and Upcoming Trials
Ø BIORESORT
Ø HORIZONS II Ø EVOLVE DAPT Ø TIMELESS
Ø TRANSFORM OCT
BSC Core Trials
Ø EVOLVE China Ø EVOLVE DAPT Ø HORIZONS II
Ø EVOLVE II
Ø InvesIgator Sponsored Research Ø BSC Sponsored Trials
Ø HORIZONS II
Ø SENIOR Ø BIORESORT Ø TRANSFORM OCT Ø EVOLVE II
Ø SYNTAX II Ø BIORESORT
Ø SYNTAX II
$50M investment in SYNERGY research program studying >20,000 paIents.
Ø LEFT MAIN
Ø SORT OUT VIII
Ø SORT OUT VIII
Ø SORT OUT VIII
Boston ScienIfic is not responsible for the collecIon, analysis or reporIng of the invesIgator-‐sponsored research output which is the sole responsibility of the invesIgators. Boston ScienIfic’s involvement in invesIgator-‐sponsored research is limited to providing financial support for research that advances medical and scienIfic knowledge about our products. HORIZONS II is a partnership between Boston ScienIfic, the Cardiovascular Research FoundaIon and medicines companies. Safety and performance of the SYNERGY Coronary Stent System has not been established for use in paIents with STEMI, chronic total occlusion, bifurcaIon and mulI-‐vessel disease stenIng. The SYNERGY Stent System is indicated for improving coronary luminal diameter in paIents with symptomaIc ischemic heart disease due to discrete de novo naIve coronary artery lesions. The SYNERGY™ stent is an invesIgaIonal device and not for sale in the US. CE Mark Approved 2012.
SYNERGY: BSC Clinical Trials First Human Use Trial. 291 paGents.
PROMUS Element vs. SYNERGY vs. SYNERGY Half-‐Dose (1:1:1). Primary Endpoint: 6 month Late Loss + Composite Safety @ 30 days
Quan*ta*ve Angiography. 100 PaGent Registry, 10-‐15 sites (Australia, Japan, New Zealand, Singapore). Primary Endpoint: 9 month in-‐stent Late Loss
China regulatory approval trial (SFDA). 400 paGents, up to 15 sites. PROMUS Element Plus vs. SYNERGY (1:1) Primary Endpoint: 9 month Late Loss
3/12 Month DAPT. ProspecGve, MulG-‐center, Global,4000 paGents.
Primary Endpoint: Cardiac Death/ MI
Global IDE Trial. 1684 paGents, 150 sites, 19 countries . PROMUS Element Plus vs. SYNERGY (1:1) single-‐blind trial.
Primary Endpoint: 12 month TLF
EVOLVE
EVOLVE II
EVOLVE II QCA
EVOLVE China
EVOLVE DAPT
HORIZONS II RCT Synergy in AMI.
8000 paGents with STEMI, Primary Endpoint: 1 year TLF
HORIZONS II is a partnership between Boston ScienGfic, the Cardiovascular Research FoundaGon and medicines companies The SYNERGY™ stent is an invesGgaGonal device and not for sale in the US. CE Mark Approved 2012.