1. Synergy: Short DAPT Study
Jeffrey J. Popma, MD
Professor of Medicine
Harvard Medical School
Director, Interventional Cardiology
Beth Israel Deaconess Medical Center
Boston, MA

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.
Financial Relationship
Company
Institutional Grants
Medtronic
Medical Advisory Board
Boston Scientific
Consultant
Direct Flow Medical
Abbott Vascular 2 2 2

3. PCI: It has been quite a ride . . . .
1977
POBA: Getting Artery Open
1994
BMS: Keeping Artery Open
2003
DES Decrease Restenosis
2015+
Future DES: Optimize Healing
PCI EVOLUTION
Continuous improvement in platform design and acute performance
Lower late events rates – ST, TLR
Reduced need for prolonged DAPT
Reduced risk of neoatherosclerosis

4. Freedom from stent thrombosis Long term efficacy
Now as a “recreational” interventionalist with lots of STEMI call, how do I chose what DES to use?
Deliverability
Freedom from stent thrombosis
Long term efficacy
Decisions are not always data driven but more visceral based on incomplete knowledge about the patient 4 4 4

5. DES design affects procedural success and clinical outcomes
Elements of DES Design
DES design affects procedural success and clinical outcomes
Scaffold
Delivery System
Polymer
Drug

6. Platinum Chromium (PtCr) Alloy
Platinum has over twice the density of Iron or Cobalt (improved radiopacity)
Platinum provides increased strength when alloyed with stainless steel
Specifically developed for coronary stents
Biocompatible

7. Durable Polymer Coated Distribution / thickness
Contemporary DES Platforms Strut and Coating Thickness In Perspective
Durable Polymer Coated
Bioabsorbable Polymer Coated
Xience CoCr-EES
Resolute
Biomatrix
Nobori
Ultimaster
SYNERGY
MiStent
Orsiro
Promus PtCr-EES
CoNi-ZES
316L-BES
CoCr-SES
PtCr-EES
Strut thickness
81 µm
0.0032”
89 µm
0.0035”
120 µm
0.0046”
125 µm
0.0047”
80 µm
0.0031”
74 µm
0.0029”
64 µm
0.0025”
61 µm
0.0024”
Polymer
PVDF
BioLINX
PLA
PDLLA + PCL
PLGA
PLLA
Probio*
Distribution / thickness
Conformal
7-8µm / side
6µm / side
Abluminal
10 µm
20 µm
15 µm
4 µm
5 µm / 15 µm
3.5 µm / 7.5 µm
*silicon carbide

8. PtCr Element™ Platform
Architecture
Wider peaks focus strain to
minimize recoil
Short and increased segments
per length improve conformability
and minimize gaps on a bend
Helical, two-connector design for maximum
flexibility and conformance to the vessel
Nested peaks minimize strut-to-strut contact
on bends and enhance deliverability

9. PtCr Element™ Platform Improved radial strength, flexibility, and resistance to recoil
Bench Test Data
Radial Strength
Flexibility/Conformability
Recoil
Improved radial strength
Reduced Recoil
Improved flexibility
Percent (%) Recoil
Newtons/mm
N=10
Newtons·mm
N=15
N=10
N=15
N=10
N=15
N=10
PROMUS Element™ Stent
Xience V™ Stent
PROMUS Element™ Stent
Xience V™ Stent
PROMUS Element™ Stent
Xience V™ Stent
Data on file at Boston Scientific. 2.5mm diameter stents. Bench test results may not be indicative of clinical performance.

10. (Pre-procedure minus Post-procedure)
Vessel Angulation and Straightening Change in angulation significantly lower with PROMUS Element
All Lesions
Single Stents Only
P=0.01
P=0.01
P=0.02
P=0.03
(Pre-procedure minus Post-procedure)
Change in Angulation
(50)
(50)
(50)
(50)
(48)
(41)
(48)
(41)
Xience V™ Stent
PROMUS Element™ Stent
(lesions)

11. Stent Fracture Associated with DES Restenosis
Human autopsy analysis
EES implanted in LOM, 6 months
Proximal
Distal
Foerst et al. JACC 2012;5(3):

12. DES design affects procedural success and clinical outcomes
Elements of DES Design
DES design affects procedural success and clinical outcomes
Scaffold
Delivery System
Polymer
Drug

13. How may an abluminally coated bioabsorbable polymer DES be optimal for healing?
Uncoated surface on luminal side to promote cell coverage and adhesion
Vessel Lumen
Strut
Freedom from long-term polymer exposure once coating is absorbed
Arterial Wall
Targeted drug delivery reduces risk of restenosis and inflammation

14. SYNERGY Stent Synchronous Drug Release & Polymer Absorption
Preclinical evaluation in porcine model
Everolimus Arterial Tissue Concentration
ng/mg
Everolimus Mass Remaining
PLGA Mass Remaining
Limit of Quantitation (LOQ)
Wilson, G. J., et al. Cathet. Cardiovasc. Intervent. doi: /ccd.25993

15. Time Course For Polymer Bioabsorption
Not all bioabsorbable technologies are the same
Drug Release
Bioabsorbable Polymer
References:
SYNERGY: Presented by I Meredith at TCT 2012
Abluminus: Presented by S. Dani at TCT 2012
Elixir Desyne BD and Elixir DESolve: Presented by A. Abizaid at TCT 2012
Firehawk: Presented by Bo Xu at TCT 2014
Biomatrix and Nobori: Company brochure on website
SVELTE: Presented by M Pomeranz at EuroPCR 2012
Orsiro: Presented by S Windecker at TCT 2012
BVS: Serruys et al, Lancet 2009; 373:
Reva: Presented at CRT April 2006
ART: Presented by John Ormiston at ACC 2013
MiStent: Presented by Alexandra Lansky, MD at CRT 2014
BioMime: Presented by Martin Leon, MD at TCT 2013
DREAMS: Garg et al Nat. Rev. Cardiol. 10, 248–260 (2013);
Time (Months)
Non-head to head trials not for comparative purposes. Provided for educational information only.

16. SYNERGY is associated with a high degree of intimal coverage and
Early healing assessment with OCT of SYNERGY at 3 and 6 months after implant
A-D: Different Case Examples of SYNERGY at 3 months
E-H: Different Case Examples of SYNERGY at 6 months
3 MONTH
6 MONTH
SYNERGY is associated with a high degree of intimal coverage and
apposition at 3 months post implant with additional increase at 6 months
De la Torre Hernandez, et al. Catheterization and Cardiovascular Interventions DOI /ccd.
Case study not necessarily representative of all cases. Results in other cases may vary.

17. DES design affects procedural success and clinical outcomes
Elements of DES Design
DES design affects procedural success and clinical outcomes
Scaffold
Delivery System
Polymer
Drug

18. EVOLVE Trial Design and Methods
Patients with de novo native coronary lesions
≤ 28 mm in length, RVD ≥2.25 mm ≤ 3.5, %DS>50%
(excluded LM disease, CTO, AMI or recent MI)
Randomized 1:1:1 at 29 sites (Europe, Australia, New Zealand)
PROMUS Element N=98
SYNERGY N=94
SYNERGY ½ Dose N=99
Single-blind, noninferiority design
Primary Clinical Endpoint: TLF (TV-CD, TV-MI, or TLR) at 30 days
Primary Angiographic Endpoint: In-stent late loss at 6 months
Per protocol patients were treated with clopidogrel, ticlopidine or prasugrel for at least 6 months following the index procedure
Meredith et al. J Am Coll Cardiol. 2012; 59 (15):1362

19. EVOLVE Trial Key Results
6 Months
5 Years
P=0.19
P=0.65
P=0.56
P=0.60
Patients, % mm
Late Loss
TLF ST
(Def/Prob)
PROMUS Element (n=98)
SYNERGY (n=94)
SYNERGY Half Dose (n=99)
Meredith et al. J Am Coll Cardiol. 2012; 59 (15):1362.; Presented by Meredith at EuroPCR 2016.
Intent-to-treat; P values are versus PROMUS Element (Fisher exact test)

20. Protocol-required angiogram
Late Events with Permanent vs. Bioabsorbable Polymer DES 5-year Target Lesion Failure in EVOLVE Trial
SYNERGY vs PE HR 0.77 [0.24, 2,42] P=0.65
SYNERGY ½ vs PE HR 0.74 [0.23, 2.32] P=0.60 20
Protocol-required angiogram
TLF (%)
7.2%
……………..
5.5%
5.2% 1 2 3 4 5
Years
Numbers at risk PE 98 93 92 67
SYNERGY 90 86 83 82 61
SYNERGY ½ Dose 99 88 65
Safety Population; KM Event Rate; log-rank P values. Presented by Meredith at EuroPCR 2016.

21. Protocol-required angiogram
Late Events with Permanent vs. Bioabsorbable Polymer DES 5-year TLR in EVOLVE Trial
SYNERGY vs PE HR 0.18 [0.02, 1.47] P=0.07
SYNERGY ½ vs PE HR 0.17 [0.02, 1.40] P=0.06 20
Protocol-required angiogram
TLR (%)
6.1%
1.1%
1.0% 1 2 3 4 5
Years
Numbers at risk PE 98 93 92 68
SYNERGY 90 87 84 83 61
SYNERGY ½ Dose 99 95 91 67
Safety Population; KM Event Rate; log-rank P values. Presented by Meredith at EuroPCR 2016.

22. EVOLVE II Pivotal Trial Design
Patients with ≤3 native coronary artery lesions in ≤ 2 major epicardial vessels; lesion length ≤ 34 mm,
RVD ≥2.25 mm ≤ 4.0, %DS≥50<100
(excluded LM disease, CTO, SVG, ISR or recent STEMI)
Randomized Cohort (RCT) PK
Substudy
125 global sites
PROMUS Element Plus
N=838
SYNERGY N=846
SYNERGY N=21
Diabetes Substudy
RCT Design
Multicenter noninferiority trial
Pivotal, single-blind, 1:1 randomization
Primary Endpoint: TLF (CD, TV-MI, or TLR) at 12 mo
Follow-up through 5 years
SYNERGY N=203
DAPT (ASA + clopidogrel, ticlopidine, prasugrel, ticagrelor) ≥ 6 months or longer as tolerated
Kereiakes, et al. Circ Cardiovasc Interv. 2015;8:e DOI: /CIRCINTERVENTIONS

23. EVOLVE II TLF at 2 years TLF (%) 9.4% 6.7% 8.5% 6.5% 6 12 24
PROMUS Element Plus vs SYNERGY
1 Endpoint:
12 months ITT
Pnoninferiority=0.0005 16
2 years
HR 1.10 [0.79, 1.52]
P=0.57 12
TLF (%)
9.4%
6.7%
8.5% 8 4
6.5%
No. at risk 6 12 24
PE+
838
790
772
538
SYNERGY
846
807
794
553
Months
ITT Population; Patients who did not receive a study stent were censored at 1 year; KM Event Rates; log-rank P values
Presented by Kereiakes ACC 2016

24. EVOLVE II Stent Thrombosis at 2 years
Definite/Probable : ITT Population
Acute (≤1 d)
Subacute (2-30 d)
Late (30 d – 1 y)
Very Late (1 – 2 y)
N=5
(2 Definite/3 Probable)
N=1
(Def)
0.8%
(N=6)
P=0.31
N=2
(Definite)
N=1
(Prob)
0.4% (N=3)
No definite ST in the SYNERGY arm after 24 hours
Presented by Kereiakes ACC 2016

25. ST Landmark Analysis Definite/Probable ST after 24 hours
PROMUS Element Plus vs SYNERGY
>24 h Landmark HR 0.16 [0.02, 1.37]
P=0.056 4 3
Definite/Probable ST (%) 2 1
0.8% *
0.1% 1d
6 mo
12 mo
24 mo
‡Day 715 – Definite ST: Patient was not compliant to aspirin and was not taking at P2Y12 inhibitor at time of presentation
ST occurring between 0 and 1 years have been previously reported in Kereiakes et al. Circ Cardiovasc Interv 2015
ITT; Patients who did not receive a study stent were censored at 1 year; KM Event Rate; log-rank P values
Presented by Kereiakes ACC 2016

26. SYNERGY: BSC Clinical Trials
EVOLVE
EVOLVE II RCT
EVOLVE II QCA
EVOLVE China
EVOLVE Short DAPT
First Human Use Trial. 291 patients PROMUS Element vs. SYNERGY vs. SYNERGY Half-Dose (1:1:1). Primary Endpoint: 6 month Late Loss + Composite 30 days
Global IDE Trial patients, 125 sites, 16 countries PROMUS Element Plus vs. SYNERGY (1:1) single-blind trial Primary Endpoint: 12 month TLF
Quantitative Angiography. 100 Patient Registry, 12 sites (Australia, Japan, New Zealand, Singapore).
Primary Endpoint: 9 month in-stent Late Loss
China regulatory approval trial (SFDA). 400 patients, up to 15 sites. PROMUS Element Plus vs. SYNERGY (1:1) Primary Endpoint: 9 month Late Loss
3/12 Month DAPT.
Prospective, Multi-center, Global,~1500 patients.
Primary Endpoint: Cardiac Death/ MI
Enrolling

27. EVOLVE Short DAPT Study Design Prospective, N=2000, ~100 global sites
Key Inclusion Criteria
Patients considered by the treating physician to be at high risk for bleeding
≥75 years of age and high bleeding risk
long term anticoagulation therapy
history of major bleeding
stroke, or renal insufficiency/failure
(excluded LM disease, ostial lesions, >2 lesions, CTO, SVG, ISR, NSTEMI or STEMI)
P2Y12 + ASA
ASA Only (for patients eligible for discontinuation of P2Y12) 3m
15m
Co-primary Endpoints: Death or MI, ARC def/prob ST
Secondary Endpoint: Rate of major bleeding (BARC bleeding classification 2,3,5)
Primary and secondary endpoints evaluated between 3 and 15 months
Propensity adjusted comparison to historical control patients treated with standard DAPT will be performed
Presented by Mauri at TCT 2015. 27

28. SYNERGY Clinical Trials Ongoing and Upcoming Trials
Multi-vessel Disease
SYNERGY Clinical Trials Ongoing and Upcoming Trials
Bifurcation
Lesions
SYNTAX II
BIORESORT
SWEET
IDEAL Left Main
SORT OUT VIII
MULTISTARS AMI
SCAAR
SYNERGY research program studying
>20,000 patients.
CTO
SYNTAX II
SWEET
BIORESORT
CELTIC
OCT/GSI
SCAAR
ACS
SYNTAX II
CONSISTENT
Diabetes
SENIOR
BIORESORT
SWEET
TRANSFORM OCT
SORT OUT VIII
MULTISTARS AMI
SCAAR
Long
Lesions
BIORESORT
SWEET
SCAAR
EVOLVE II
SYNTAX II
BIORESORT
SWEET
SCAAR
EVOLVE II
DAPT
Imaging /
Healing
SENIOR
EVOLVE
Short DAPT
POEM
Addressing full spectrum of cardiovascular disease complexity
BSC Core
Trials
TIMELESS
MOVES
TRANSFORM OCT
SORT OUT VIII
GREEK PLATELET
EVOLVE
EVOLVE II
EVOLVE China
EVOLVE Short DAPT
BSC Sponsored Trials
Investigator Sponsored Research

29. Summary
The SYNERGY Stent design goals are to address needs surrounding complex PCI
Best in class deliverability and acute performance
Optimal healing / rapid endothelialization
Thin struts
Abluminal coating
Low polymer load
Synchronous drug release and polymer absorption
Short-term polymer exposure
Drug present in artery while polymer degrades
May allow short DAPT without risk of ST