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.