1. Durable-Polymer DES 5-Year Outcomes XIENCE/PROMUS and PROMUS Element Update
Gregg W. Stone, MD
Columbia University Medical Center
NewYork-Presbyterian Hospital
Cardiovascular Research Foundation

2. Disclosures
Gregg W. Stone
None

3. XIENCE V / PROMUS Fluoropolymer-based everolimus-eluting stent
Durable Fluorinated Copolymer
Everolimus
ML VISION
Stent Delivery System
ML VISION Stent Platform

4. XIENCE: Fluoropolymer Coating Design and Mechanical Properties
81 mm
Primer
Matrix
PBMA primer:  The full name for the polymer is poly(n-butyl methacrylate).  We call it a primer as we coat it first on the CoCr surface to enhance the adhesion of the PVDF-HFP to the stent.  I have found that physicians don’t always know what “primer layer” means.  So sometimes I call it an “adhesion layer.”  The PBMA sticks well to metal and when the PVDF-HFP is coated on top of the PBMA, it is partially miscible with the PBMA, so the two layers are bonded together.
PVDF-HFP:  The full name for this polymer is poly(vinylidene fluoride-co-hexafluoropropylene).  It is a fluorinated polymer.  You could technically call it a fluorinated copolymer as it is made from two monomers.  The everolimus and PVDF-HFP are dissolved together in solvents and sprayed onto the stent.  The drug is largely dissolved in the PVDF-HFP.  There may be a small amount of phase separated drug in the PVDF-HFP layer but we are confident that the high majority of the drug is dissolved in the PVDF-HFP.  When the stent is exposed to bodily fluids, such as blood, the drug starts to diffuse out of the coating.  The release mechanism of the everolimus out of the PVDF-HFP is primarily diffusion.
This is why we choose fluorinated co poymer for our surface and the great outcomes from our clinical data continues to support that.
Next step is to transfer and ideal polymer structure into a functional and manufacturable coating
REPEAT:
I want to repeat that the XV FLUORINATED COPOLYMER is an ideal and optimized DES coating with respect to Drug release, mechanical integrity, and
PBMA
PVDF-HFP
Fluorinated copolymer
poly(n-butyl methacrylate)
enhances adhesion of the PVDF-HFP to the stent
poly(vinylidene fluoride-co-hexafluoropropylene)
Everolimus and PVDF-HFP are dissolved together and sprayed onto the stent. Everolimus is released into tissue primarily by diffusion.

5. Fluoropolymer: Less Adherence of Thrombus
Study Details:
Dacron vascular graft compared to a fluoropolymer coated Dacron vascular graft
Each graft implanted in an ex-vivo shunt primate model
Results show a markedly visible reduction in the thrombus layer on the fluoropolymer coated graft vs. untreated graft
Garfinkle AM et al. Trans Am Soc Artif Organs 1984;30:432-9

6. Stent Thrombosis is Affected by Stent Design, Deployment and Polymer
Impact of strut thickness and Xience V polymer coating
In vitro pulsatile Chandler loop model with porcine blood 2
49%; P<0.001
1.8
1.6
1.4
LDH Adsorbance for Stent formulation /
LDH Adsorbance for ML VISION (81 µm)
1.2
Relative platelet cell adhesion
1.0
24%; P=0.002
0.8
0.6
0.4
0.2
0.0
ML VISION (81 µm)
TS VISION (162 µm)
XIENCE V (96.6 µm)
Kolandaivelu K et al. Circulation 2011;123:

7. DES Strut and Polymer Thickness Data on file at Abbott Vascular
3.0 mm diameter stents, 500x magnification
CYPHER
TAXUS
ENDEAVOR
XIENCE V
Strut Thickness:
140 mm
Polymer Thickness:
12.6 mm
Total:
165.2 um
Strut Thickness:
132 mm
Polymer Thickness:
16 mm
Total:
164 um
Strut Thickness:
91 mm
Polymer Thickness:
5.3 mm
Total:
101.6 um
Strut Thickness:
81 mm
Polymer Thickness:
7.8 mm
Total:
96.6 um
Data on file at Abbott Vascular

8. 14 Day Endothelialization: Rabbit Iliac Model
XIENCE V
CYPHER
TAXUS
ENDEAVOR
Joner M et al. JACC 2008;52:333-42

9. Kereiakes DJ et al. EuroIntervention 2011:7:74-83
SPIRIT/COMPARE Pooled Patient Level Analysis SPIRIT II, SPIRIT III, SPIRIT IV, COMPARE (N=6,789)
HR[95%CI] =
0.56 [0.41,0.77]
P=0.0003
HR[95%CI] =
0.56 [0.39,0.79]
P=0.0009
HR[95%CI] =
0.30 [0.16,0.55]
P<0.0001
HR[95%CI] =
0.60 [0.21,1.71]
P=0.33
Kereiakes DJ et al. EuroIntervention 2011:7:74-83

10. Network Meta-analysis: Long-term Definite ST
77 RCTs, 57,138 pts, 117,762 pt-yrs of FU
OR [95% CrI]
0.10 OR
(95% Crl)
1.00
10.00
Favors
Control
Treatment
BMS (Ref)
Sirolimus
Paclitaxel
Zotarolimus-E
Zotarolimus-R
Everolimus
0.88 (0.62, 1.26)
1.12 (0.77, 1.64)
1.28 (0.59, 2.50)
58.04 (0.92, )
0.32 (0.19, 0.58)
Sirolimus (Ref)
1.28 (0.90, 1.83)
1.45 (0.71, 2.64)
65.21 (1.16, )
0.37 (0.20, 0.66)
Paclitaxel (Ref)
1.16 (0.53, 2.14)
52.75 (0.91, )
0.30 (0.15, 0.50)
Everolimus (Ref)
3.79 (1.60, 10.02)
(2.95, )
47.84 (0.91, )
Zotarolimus-E (Ref)
100.00
Bangalore S et al. Circulation 2012;125:

11. Valgimigli M et al. BMJ 2014;349:g6427
Meta-analysis of EES vs. BMS 5 RCTs, 4,896 pts: Baseline Features
Patient Characteristics
PRODIGY
N=1,003
EXAMINATION
N=1,498
BASKET PROVE
N=1,539
SPIRIT
First
N=56
XIMA
N=800
Overall
N=4,896
Age
69±11
61±12
64±11
63±9
83±3
67±13
Female (%) 25 17 24 27 40
Diabetes (%) 22 15 11 19
Prior MI (%) 26 5 12
Target population
All comers
STEMI
Low risk
Octogenarians –
STEMI (%) 34
100 7* 44
NSTEACS (%) 20 80
68*
Stent control arm
BMS mix
Vision
DAPT duration
- EES
6 or 24 mos
12 months
≥ 3 months
- BMS
≤6 or 24 mos
3 months
Follow-up (years) 2 1
1-5
Valgimigli M et al. BMJ 2014;349:g6427

12. Meta-analysis of EES vs. BMS 5 RCTs, 4,896 pts: Cardiac Death
12/774
28/751
14/501
13/399
0/27
2.7%
BASKET PROVE
EXAMINATION
PRODIGY
XIMA
SPIRIT I
Total
BMS
better
Co-Cr
EES better
21/765
28/747
31/502
19/401
0/29
4.1%
EES HR
(95% CI)
0.56 (0.28 , 1.14)
0.99 (0.59 , 1.68)
0.45 (0.24, 0.84)
0.69 ( ) -
0.67 (0.49, 0.91)
0.25
0.5 1 2
Trial 5
BMS
Co-Cr EES 4 3 2
Adj HR (95%CI) =
0.67 ( )
P=0.01 1
200
400
600
800
Days
Valgimigli M et al. BMJ 2014;349:g6427

13. Valgimigli M et al. BMJ 2014;349:g6427
Meta-analysis of EES vs. BMS 5 RCTs, 4,896 pts: MI
MI (%)
BMS
Co-Cr EES
Adjusted HR (95%CI) =
0.71 ( )
P=0.01
Days 2 3 4 5 1
200
400
600
800 6 HR
(95% CI) HR
(95% CI)
Trial
BASKET PROVE
EXAMINATION
PRODIGY
SPIRIT I
XIMA
Total
0.67 (0.33, 1.35) 0.83 (0.36, 1.91)
0.78 (0.53, 1.13)
5.7e+15 (0.00, ?)
0.48 (0.27, 0.86)
0.71 (0.55, 0.92)
4.0% vs. 5.6%
0.25
0.5 1 2
Co-Cr
EES better
BMS
better
Valgimigli M et al. BMJ 2014;349:g6427

14. Valgimigli M et al. BMJ 2014;349:g6427
Meta-analysis of EES vs. BMS 5 RCTs, 4,896 pts: Def/prob stent thrombosis
Stent thrombosis (%)
BMS
Co-Cr EES
HR (95%CI) =
0.42 ( )
P=0.006
0.6
0.9
1.2
1.5
Days
0.3
200
400
600
800 HR
(95% CI) HR
(95% CI)
Trial
BASKET PROVE
EXAMINATION
PRODIGY
XIMA
SPIRIT I
Total
0.33 (0.07, 1.61) 0.37 (0.14, 0.95)
0.39 (0.12, 1.25)
2.02 (0.18, 22.31) -
0.42 (0.22, 0.78)
0.6% vs. 1.4%
0.25
0.5 1 2
Co-Cr
EES better
BMS
better
Valgimigli M et al. BMJ 2014;349:g6427

15. Valgimigli M et al. BMJ 2014;349:g6427
Meta-analysis of EES vs. BMS 5 RCTs, 4,896 pts: TVR
TVR (%)
BMS
Co-Cr EES
Days
200
400
600
800
HR (95%CI) =
0.29 ( )
P<0.001 5 10 15
BASKET PROVE
EXAMINATION
PRODIGY
SPIRIT I
XIMA
Total
BMS
better
Co-Cr
EES better HR
(95% CI)
0.40 (0.25, 0.64) 0.59 (0.39, 0.90)
0.31 (0.21, 0.46)
0.36 (0.10, 1.36)
0.28 (0.13, 0.62)
0.29 (0.20, 0.42)
0.25
0.5 1 2
4.3% vs. 10.2%
Trial
Valgimigli M et al. BMJ 2014;349:g6427

16. Xience DAPT Discontinuation Study
2-year patient flow and stent thrombosis
SPIRIT II, III, IV, SPIRIT V, Women, V USA, V India
13,259 total pts
2,040 pts (15.4%) without complete DAPT data (11 ST events, 0.54%)
Analysis population
11,219 pts (84.6%) with complete DAPT data through 2 years (2-year complete follow-up rate 94.3%)
One patient did not have loading dose, and had ST on day 0 and therefore was off DAPT at ST. The patient started DAPT on day 1 and did not interrupt from day
Interruption is defined as not on DAPT for any 1 day between 1 and 730 days. On/off DAPT is only for the day of ST.
There were 18 total events off DAPT. 17 were in the interruption group, 1 is in the no interruption group. Patients on loading dose with ST on day 0 were considered on DAPT at time of ST.
85 events in 83 pts (0.74%) through 2 years
45 ST events occurred in 44 pts with no DAPT interruption from day 1 through 2 yrs
40 ST events occurred in 39 pts with some DAPT interruption from day 1 though 2 yrs
45 events occurred “On” DAPT*
23 events occurred “On” DAPT
►68/85 ST events (80.0%) occurred “On” DAPT
17 events occurred “Off” DAPT
*One pt did not receive LD and was off DAPT at ST event (day 0) but started day 1 and never interrupted through 730 days.
Genereux P et al. Circ CV Interv. 2015:on-line

17. Genereux P et al. Circ CV Interv. 2015:on-line
Stent Thrombosis According to the Timing of Permanent DAPT Interruption (or until ST)
Stent thrombosis
through the entire year follow-up period:
ST, %
No DAPT interruption except possibly after ST
Permanent DAPT discontinuation in this interval* HR
[95% CI] P
Value
Between 0 and 1 mos
0.83% (58)
(N at risk = 7,152)
4.95% (11)
(N at risk = 229)
6.13
[3.22, 11.68]
<0.0001
Between 1 and 3 mos
2.78% (2)
(N at risk = 76)
3.38
[0.82, 13.82]
0.07
Between 3 and 6 mos
0.78% (1)
(N at risk = 146)
0.85
[0.12, 6.13]
0.87
Between 6 and 12 mos
0.45% (4)
(N at risk = 934)
0.52
[0.19, 1.43]
0.20
Between 12 and 24 mos
0.16% (3)
(N at risk = 1,925)
0.19
[0.06, 0.60]
0.002
Between 0 and 24 mos
0.64% (21)
(N at risk = 3,310)
0.77
[0.47, 1.27]
0.30
Rates are KM estimates
Genereux P et al. Circ CV Interv. 2015:on-line

18. SPIRIT III: 5-Year Target Lesion Failure
TAXUS Express (n=332)
XIENCE V (n=669)
30%
5-year HR
0.64 [0.46, 0.89]
25%
p=0.008
1-year HR
20%
19.0%
0.56 [0.34, 0.90]
p=0.01
TLF (%)
Δ6.3%
15%
9.2%
12.7%
10%
Δ3.8% 5%
5.4% 0% 6 12 18 24 30 36 42 48 54 60
Months
Number at risk
XIENCE V
669
646
616
601
582
571
565
548
537
529
521
TAXUS
332
310
288
274
269
262
255
248
243
231
223
TLF = cardiac death, target vessel MI, or ischemic-driven TLR
Gada H et al. JACC CV Interv. 2013;6:1263-6

19. XIENCE V / PROMUS stents
XIENCE Prime and Expedition
PROMUS Element and Premier
Same fluoropolymer, same drug,
same release kinetics

20. Everolimus-Eluting Stents
Everolimus concentration: 100 ug/cm2
Polymer: PBMA & PVDF‑HFP (7m thickness)
10% Nickel
XIENCE V / PROMUS (CoCr-EES)
3% Iron
15% Tungsten
52% Cobalt
20% Chromium
1.5% Manganese
2.6% Molybdenum
PROMUS Element (PtCr-EES)
18% Chromium
9% Nickel
0.05% Manganese
33% Platinum
37% Iron
PBMA=poly (n‑butyl methacrylate) (primer layer);
PVDF-HFP=poly (vinylidene fluoride‑co‑hexafluoropropylene) (drug matrix layer)
Stone GW et al. JACC 2011;57:1700–8

21. Months Since Index Procedure Stone GW et al. JACC 2015;65/10S(Suppl A)
Target Lesion Failure
5-Year Follow-up
CoCr-EES (N=749)
Target Lesion Failure =
cardiac death or TV-MI or ID-TLR
PtCr-EES (N=758)
HR [95% CI] =
0.97 [0.69, 1.37]
P = 0.87
9.3%
TLF (%)
9.1%
749
721
683
658
633
445
758
736
702
690
662
458
Months Since Index Procedure
No. at risk
CoCr-EES
PtCr-EES
Stone GW et al. JACC 2015;65/10S(Suppl A)

22. Safety Measures at 5 Years
CoCr (N=749)
PtCr (N=758)
Event Rate (%)
P=0.60
P=0.32
P=0.94
P=0.35
P=0.79
Cardiac Death
All Death
ARC ST (Def/Prob) MI
Q-wave MI
n=1
n=3
n=2
PtCr- EES
CoCr- EES
ARC ST by Time Period
0-30d
1-5y
31-364d
Stone GW et al. JACC 2015;65/10S(Suppl A)
Time to event rates 22

23. Months Since Index Procedure Stone GW et al. JACC 2015;65/10S(Suppl A)
ID-TLR at 5 Years
CoCr-EES (N=749)
PtCr-EES (N=758)
HR [95% CI] =
0.84 [0.54, 1.29]
P = 0.43
ID-TLR (%)
6.2%
5.3%
Months Since Index Procedure
749
724
687
663
639
447
758
739
710
696
669
464
No. at risk
CoCr-EES
PtCr-EES
Stone GW et al. JACC 2015;65/10S(Suppl A)

24. Longitudinal Stent Deformation Stent designs
Ormiston JA et al. J Am Coll Cardiol Intv 2011;4:1310-7

25. Axial compression vs. force (3.0 mm stents)
Cypher
ML 8/
Xience Prime
Integrity
Force (N)
Distance (mm)
Ormiston JA et al. J Am Coll Cardiol Intv 2011;4:1310-7

26. Promus PREMIER Everolimus-Eluting Stent (and REBEL BMS)
Customized platinum chromium (PtCr) stent architecture
4 connectors on prox end (for 3 mm stent)
More robust to provide increased longitudinal strength
2 connectors throughout body
Maintain flexibility, conformability, and fracture resistance
Enhanced Stent Delivery System
Shorter tip to improve flexibility
PTFE coating on hypotube to
reduce friction

27. Point Force Applied (N)
Stent Longitudinal Strength Assessed Using Point Compression: Updated Test
Proximal deformation after application of 0.5 N force to a point on the proximal hoop
Integrity
Multi-Link 8
Promus Premier
Vision
Omega/Element
Biomatrix Flex
1.0
0.8
Biomatrix vs. Integrity
P=0.003
Premier vs. Element
P=0.006
P=NS
0.6
Point Force Applied (N)
0.4
0.2
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Compression (mm)
Ormiston JA et al. Circ Cardiovasc Interv. 2014;7:62-9

28. Conclusions: Fluoropolymer-coated everolimus-eluting stents at 5 years
The results with fluoropolymer-coated EES at 5 years demonstrating enhanced safety and efficacy compared to BMS and first generation DES have established a new benchmark for event-free survival after DES
The simultaneous reduction of TLR and stent thrombosis with fluoropolymer-coated EES demonstrates that “low late loss” may be achieved with DES without sacrificing safety
The 2 commercially available fluoropolymer-coated EES have evolved with different platform metals and architecture, resulting in subtle differences in visibility, flexibility, deliverability, mechanical strength and recoil, although to date no meaningful differences in clinical outcomes have been demonstrated