- SYNTAX II is a single-arm international study comparing outcomes of contemporary PCI using the Synergy stent to the PCI arm of the original SYNTAX trial. - The study aims to evaluate how improvements in stent platform/design, polymer coatings, and ischemia-guided revascularization impact outcomes compared to earlier generation DES. - Preliminary data from one center shows physiological assessment with FFR/iFR may reclassify a significant portion of multivessel patients originally thought to require multi-vessel PCI based on angiography alone.

1. Javier Escaned MD PhD
Hospital Clinico San Carlos
Madrid, Spain
Syntax II: Innovación científica en
investigación biomédica con el
stent farmacoactivo Synergy.

2. PercutaneousCoronaryInterventions(PCIs)
Source: Medical Device Industry Estimates
PCI procedures in the DES era
US PCI Procedures in the DES era
DES failure
SYNTAX
DES
overuse
FREEDOM

3. Myocardial revascularization modality and extent of CAD:
2014 ESC Clinical Practice Guidelines recommendations
ESC guidelines on stable CAD / European Heart Journal (2013) 34, 2949–3003

5. How to improve the results of Syntax
• Better stratification
• Assessment of risk for both CABG and PCI
• Ischaemia driven revascularization
• Improved success rate in CTOs
• IVUS guidance
• Ancillary tools
• … and better drug eluting stents!

6. Ischemia driven TLR
RR (95%CI)
Colmenarez H, Escaned J Eurointervention 2013
Taxus (Syntax) stent versus new generation DES
Myocardial infarction
RR (95%CI)
Stent thrombosis
RR (95%CI)
Taxus as a G1 comparator
Better G2 Better TaxusBetter G2 Better Taxus
Better G2 Better Taxus

7. SYNTAX II Study: putting PCI strengths together
Ischaemia driven
revascularization
(iFR/FFR)
Higher success
rates in CTO PCI
Better risk
stratification(SYNTAX II
score)
Heart Team
discussion
New generation
DES(Synergy)
IVUS-guided DES
implantation
SYNTAX II: Clinicaltrials.gov identifier NCT02015832
Principal Investigators: J Escaned, A Banning
Chairman: PW Serruys
Deputy chairman: V Farooq

8. SYNTAX II Study: putting PCI strengths together
Ischaemia driven
revascularization
(iFR/FFR)
Higher success
rates in CTO PCI
Better risk
stratification(SYNTAX II
score)
Heart Team
discussion
New generation
DES(Synergy)
IVUS-guided DES
implantation
SYNTAX II: Clinicaltrials.gov identifier NCT02015832
Principal Investigators: J Escaned, A Banning
Chairman: PW Serruys
Deputy chairman: V Farooq

9. Restenosis in the 90´s: a time-related,
response-to-injury phenomenon
Forrester JS et al. JACC 1991;17:758-69
Platelet deposition
Thrombosis
Leukocyte recruitment
SMC proliferation

10. Stent struts
Macrophages
Lipid laden
neointima
Strut
Strut
A:OCT image obtained at Hospital Clinico San Carlos / Madrid
B and C: In-stent neotherosclerosis (B) and inflammation after DES. From Renu Virmani / TCT 2012
A B
C
Strut
Delayed healing and neoatherosclerosis
after DES: a cause of stent failure

11. Fresh thrombus with an
intense inflammatory
infiltrate of WBCs and
numerous eosinophils.
Late-acquired stent
malapposition in IVUS /
OCT
Peri-stent contrast
staining
Cook S et al. Circulation 2009; 120: 391-399
Hypersensitivity reactions and arteritis
after DES: role of polymer and drugs

12. Xience V™ Resolute
Integrity™
SYNERGY™ BVSBioMatrix
Flex™
PROMUS
Element™
Durable Polymer
Coated Stents
Bioabsorbable Polymer
Coated Stents
Bioabsorbable
scaffold
CoCr
81 µm
PtCr
81 µm
CoCr
89 µm
PtCr
74 µm
SS
120 µm
PLLA (polymer)
150 µm
Polymer and strut thickness in G2 DES
Eluting Polymer Distribution and Thickness
Conformal
8µm / side
Conformal
8µm / side
Conformal
6µm / side
Abluminal
4µm
Abluminal
10µm
Conformal
3µm / side
Polymer Load (16 mm stent)
500µg 520µg 297µg 113µg 260µg 7,404µg

13. Importance of synchronous polymer degradation
Data on file at Boston Scientific
PLGA Mass
RemainingEverolimus
%remaining
Time (days)300 60 90 120
100
80
60
40
20
0
Polymer bulk erosion Polymer surface erosion

14. Data on file at Boston Scientific
PLGA Mass
RemainingEverolimus
%remaining
Time (days)300 60 90 120
100
80
60
40
20
0
Polymer bulk erosion Polymer surface erosion
Importance of synchronous polymer degradation

15. +
+
++
+
++
+
++
+
+
+
+
From data presented by Mike Eppihimer @ EuroPCR 2013VE-cadherin used as a marker of fucntional endothelial coverage
Improved
EC function
Greater
localization of
VE-cadherin at
cell junctions
Abluminal vs conformal polymer
Improved EC barrier formation in abluminal coating
SYNERGY™PROMUS Element™

16. EVOLVE II: Stent thrombosis 12-months
Definite/Probable : ITT Population
No Definite/Probable stent thrombosis
in the SYNERGY arm after day 6
SYNERGY
PROMUS
Element Plus
Subacute (2-30 days) Late (30 days – 1 year)
0.6%
(N=5)
0.4%
(N=3)
P=0.50
Acute (≤1 day)
N=1
(Probable)
N=5
(2 Definite/3 Probable)
N=2
(Definite)

17. 0.9
4.7
1.7
0.5
4.3
2.6
0
4
8
12
Cardiac Death Target Vessel-Related
MI
Clinically-indicated
TLR
EventRate(%)
PROMUS Element Plus SYNERGY
Components of TLF
P=0.34 P=0.71 P=0.21
*Per protocol spontaneous MI is defined as rise and/or fall of cardiac biomarkers with ≥1 value >99th percentile of the URL + evidence of
myocardial ischemia. Peri-PCI MI is defined as ≥1 of the following: i) biomarker elevations within 48 hours of PCI (based on CK-MB >3X URL), ii)
new pathological Q waves, or iii) autopsy evidence of acute MI

18. Advantages of Synergy in patients with MVD
• Strut thickness
• Cell design
• Eluting polymer
• Radial strength
• Antiproliferative drug
• Navigability
• Expansion range
74 µm PtCr alloy
Open cell design
Biodegradable PLGA
Stent design + PtCr
Everolimus
Connectors + hypotube
High (max 5.7 mm)

19. SYNTAX II case presentation #2
Syntax: 43 points
Syntax II 4-year mortality: PCI 8%, CABG 18%
Male 79 y.o. Diabetes, dyslipidaemia, peripheral vascular disease, severe COPD

21. n=450
Single arm international study using SYNTAX data as
comparator
Primary endpoint:
Composite of MACCE rate at 1 year follow-up (using
SYNTAX I definitions) compared to PCI arm of the SYNTAX I
Trial
SYNTAX II: a study on the state-of-the-art PCI

22. SYNTAX II: a study on the state-of-the-art PCI
Secondary endpoints
• Rates of individual components of MACCE at 1 year
• Composite of MACCE rate and its individual
components at 2-5 years follow-up (patient reported)
• Myocardial Infarction – according to Universal MI
definition 2012 at all timepoints
• Stent Thrombosis (ARC) definitions at all timepoints
Exploratory endpoint:
• Composite of MACCE at 5 years follow-up compared to
CABG arm of the SYNTAX I Trial

23. SYNTAX II case
Syntax: 29 points
Syntax II 4-year mortality: PCI 12%, CABG 11%
Male 80 y.o. Diabetes,
dyslipidaemia,
hypertension

24. Only one stenosis (1/4) required treatment on iFR/FFR assessment
Only one stenosis required adenosine administration.
iFR 0.90
FFR 0.83
iFR 0.94
iFR 0.95
iFR 0.35
Result of physiological
stenosis assessment
SYNTAX II case

25. 74
37
16
47
10
16
0%
10%
20%
30%
40%
50%
60%
70%
80%
Anatomical Syntax I Functional Syntax I
Anatomical
SYNTAX
score
Functional
SYNTAX
score
Low Moderate High Low Moderate High
SYNTAX risk categories
(n=19)
Reclassification of multivessel disease with iFR / FFR
in multivessel disease PCI patients (SYNTAX II)
Data from Hospital Clinico San Carlos, Madrid, Spain.

26. 37% 74%
Eligible patients
For 3VD-PCI
according to
ESC guidelines (%)
Angiography
driven PCI
Ischemia-
driven PCI
Reclassification of multivessel disease with iFR / FFR
in multivessel disease PCI patients (SYNTAX II)
Data from Hospital Clinico San Carlos, Madrid, Spain.

27. SYNTAX II centres and enrolment / November 2014

28. Conclusions
• SYNTAX II will explore the benefit of contemporary state-
of-the-art PCI in MVD.
• The study will provide information on how improvements
on stent platform (thinner struts, biocompatible alloys,
open cell design) and eluting matrix (controlled
biodegradation, abluminal distribution) influence
outcomes in this complex patient subset

29. Muchas gracias por su atención