1. Will the Future of DES be Non-Polymeric ?
CRT 2011
Washington, DC
Will the Future of DES
be Non-Polymeric ?
Alexandre Abizaid, MD, PhD, FACC
Instituto Dante Pazzanese de Cardiologia
Sao Paulo - Brazil
Columbia University
New York - USA

2. Alexandre Abizaid, MD, PhD
Consulting Fees
Abbott Laboratories
Boston Scientific Corporation
Cordis Corporation

3. Current Problems with Polymers
Shortcomings often associated with polymers during stent delivery
“Webbed” polymer surface leading to stent expansion issues”
Non uniform polymer coating
Polymer delamination
● Durable Coatings-Potential for:
- Continuing source of inflammation
- Poor healing/thrombosis risk

4. DES – Late incomplete apposition and
DES stent thrombosis
40 m
6 m
18 m
Post PCI

5. Better than any polymer is no polymer…

6. Non-Polymeric Systems:
BioFreedom (Biosensors)
Yukon (Translumina)
Pax Technology (Minvasys)
Vestasync (MIV)
Cre8 Anphilimus (CID)

7. BioMatrix Freedom Stent Micro-structured Surface
Selectively micro-structured surface holds drug in abluminal surface structures

8. BioFreedom FIM Design BioFreedom FIM 4 Months follow up
180 total patients
First Cohort
Second Cohort
4 Months follow up
75 patients
12 Months follow up
105 patients
BioFreedom
Standard dose
Low dose
TAXUS® Liberté
BioFreedom
Standard dose
Low dose
TAXUS® Liberté
This study is a prospective, single blinded, randomized study to evaluate the safety and effectiveness of Bio-FreedomTM Biolimus A9® drug-eluting coronary stent delivery system carrying a standard dose of Biolimus A9® drug, or alternately a low dose of BA9 drug compared with a TaxusTM LiberteTM control arm at two time points 4M and 1 yr. The objectives of this study are to establish the long term safety, effectiveness and performance of the Biosensors Bio-FreedomTM DES, assessed at multiple time points through assessment of clinical and/or angio/IVUS data from the primary and secondary data sets obtained from the trial. There are 75 patients in the 4M study and 105 patients in the 1 yr study. There are two dose groups in the Bio-Freedom arm at each time point: standard dose and low dose.
Enrollment Complete
Sept 2008 – Jan 2009
Enrollment Complete
Jan 2009 – Jun 2009

9. 4 Month vs 12 Month Angiographic FU In- Stent Late Lumen Loss
First Cohort
12 Month
Second Cohort
Median values

10. Non-Polymeric Systems:
BioFreedom (Biosensors)
Yukon (Translumina)
Pax Technology (Minvasys)
Vestasync (MIV)
Cre8 Anphilimus (CID)

11. Translumina Porous Surface Stent
Pure
Sirolimus
Examples of drug delivery from pure drug coated on a stent: Certain drugs can be deposited directly on the stent surface by solvent dipping or spraying methods. Here a stent with an irregular rough surface topology is employed to release sirolimus. This stent has been implanted in hundreds of patients in Europe with promising results (Kastrati,et al, Munich)

12. New-Generation Stents & Coating Device from Translumina
Yukon® CHOICE 4
Yukon® CC CoCr Stent

13. FIM-Trial: Dose-Dependent Effect of Restenosis Prevention
Angiographic (In-Segment Analysis)
TLR
P=.024
P=.006
Bare Stent
0.5 %
1.0 %
2.0 %
Hausleiter et al, Eur Heart J 2005

14. ISAR-TEST Equal Efficacy for Restenosis Prevention
Angiographic Restenosis
TLR %
all p=NS
non-polymer
Sirolimus (225)
Durable polymer Paclitaxel (225)
J Mehilli et al., Circulation 2006

15. ISAR-TEST 2: Testing Dual-Drug Sirolimus + Probucol
1007 pts with de-novo lesions randomized
Cypher
(n=333)
Dual DES
(n=335)
Endeavor
(n=339)
Polymer-free, probucol + sirolimus-eluting stent
Primary Endpoint: angiographic restenosis
Secondary Endpoint: TLR
R Byrne et al., Eur Heart J 2009

16. ISAR-TEST-2: Restenosis Analysis
Angiographic Restenosis (1ary EP)
Clinical Restenosis (TLR)
p=0.83
p=0.001
p=0.68
p=0.002 % %
The differences that we have already seen in angio restenosis, were also seen w clin restenosis
Cypher
Dual-DES
Endeavor
R Byrne et al., Eur Heart J 2009 16

17. (n=202) ISAR-TEST 3: Testing Different Sirolimus-Coating Strategies
605 pts with de-novo lesions randomized
polymer-free (n=201)
biodegradable polymer
(n=202)
durable polymer (Cypher) (n=202)
Primary Endpoint: in-stent late lumen loss
(non-inferiority trial)
Secondary Endpoint: binary restenosis rate, clinical events at 1 yr.
J Mehilli et al., Eur Heart J 2008

18. ISAR-TEST 3: Less Efficacy with Non-Polymer vs. Polymer-Based SES
Primary EP: In-Stent Late Lumen Loss at FU mm
polymer- free
biodegradable polymer
durable polymer (Cypher)
Sirolimus-eluting stents
J Mehilli et al., Eur Heart J 2008

19. ISAR-TEST 5 3002 patients with de novo lesions
Intracoronary Stenting and Angiographic Results: Test Efficacy of Rapamycis/Probucol- and Zotarolimus-Eluting STents - 5
3002 patients with de novo lesions
Probucol/Sirolimus-Eluting
Dual-DES
n=2002
Zotarolimus-Eluting
Resolute ZES
n=1000
6 to 8-month repeat angiogram
12-month clinical follow-up
Mehilli et al. TCT LBCT 2010

20. ISAR-TEST 5: Primary Endpoint Cardiac Death/TV-related MI/TLR50 % 40 30
P=0.83
RR 1.03 [ ] 20
Resolute ZES 13.1% 10
Dual-DES 13.1% 1 2 3 4 5 6 7 8 9 10 11 12
Mehilli et al. TCT LBCT 2010

21. Angiographic Restenosis
In-stent late lumen loss
In-segment binary restenosis
P=.62
P=.81 mm %
Dual-DES
ZES
Mehilli et al. TCT LBCT 2010

22. Non-Polymeric Systems:
BioFreedom (Biosensors)
Yukon (Translumina)
Pax Technology (Minvasys)
Vestasync (MIV)
Cre8 Anphilimus (CID)

23. Polymer Free Paclitaxel
Abluminal coating – 5µ thickness applied on crimped stent.
Consistent coating ensuring 98% of the drug delivered to the site.
Polymer free Paclitaxel.
2.5µg/mm² dose.
Boost-release (60% in 2 days)
Profile release established in 30 days (98% of the drug)
Back to regular Chromium Cobalt after 45 days.

24. PAX A PAX B and Bi Pax First In-Man randomized n = 30 Multicenter
(PI: A Abizaid)
AMAZONIA Pax
n = 15
Primary Endpoint: Late Loss
% obstruction
OCT tissue coverage
at 4 Months
First In-Man
randomized
n = 30
Taxus Liberte
n = 15
PAX B and Bi Pax
(PI: A Abizaid / Jean Fajadet)
AMAZONIA Pax
n = 100
Multicenter
Registry
n = 200
Primary Endpoint: Late Loss
And MACE
at 9 Months
Bi Pax
n = 100

25. PAX-A: Index Procedure
Amazonia-PAX x 24 mm A B C A B C

26. PAX A: 4-Month Follow-up

27. PAX-A Index Procedure
Taxus Liberte
3.5 x 20 mm A B A B

28. PAX A: 4-Month Follow-up
Late-acquired ISA in prox & distal edges A B B B

29. Non-Polymeric Systems:
BioFreedom (Biosensors)
Yukon (Translumina)
Pax Technology (Minvasys)
Vestasync (MIV)
Cre8 Anphilimus (CID)

30. 3D MicroPorous Nanofilm HAp

31. QCA Results Follow-up 4 months (n=15) 9 months (n=12) Variable
In-Stent
In-Lesion
MLD, mm
2.34 ± 0.33
2.05 ± 0.38
2.27 ±0.33
2.02 ± 0.29
% Diameter stenosis
13.8 ± 7.0
23.6 ± 8.8
15.9 ± 8.20
23.6 ±9.50
Late lumen loss, mm
0.29 ± 0.25
0.16 ± 0.29
0.36 ± 0.24
0.20 ± 0.31
Restenosis*, % (n)
Abizaid et al. ACC 2008.

32. IVUS Volumetric Analysis Baseline / 4 month / 9 month follow-up
IVUS variables
Baseline
N= 14 P*
4-month follow-up
9-month follow-up
Vessel Volume (mm3)
294.2 ± 117.1
286.9 ± 87.4
296.8 ± 85.6
Stent Volume (mm3)
144.5 ± 48.2
140.5 ± 36.7
143.1 ± 41.4
Lumen Volume (mm3)
144.7 ± 48.4
136.3 ± 34.2
136.8 ± 38.2
NIH Volume (mm3)
N/A
4.3 ± 3.5
6.1 ± 4.9
Mallapposition Volume (mm3)
0.34 ± 0.87
0.14 ± 0.34
0.13 ± 0.36
% Stent Obstruction
2.8 ± 2.2
3.8 ± 2.3
* 1 pt refused to undergo invasive FU at 9 months and therefore were excluded from this sub analysis.

33. PRE
POST
Lower LLL (-0.1 mm)
4 MONTH- FU
9 MONTH- FU

34. PRE
POST
FOLLOW-UP 4 MONTHS

35. VESTASYNC II Polymer-Free Sirolimus-Eluting Stent
Vestasync Eluting Stent
n = 50
First In-Man 3:1 randomized
n = 75
Primary Endpoint: Late Loss at 6 Months
Bare Metal Stent
n = 25
IVUS subanalysis: 30 pts
OCT sub-analysis : 30 pts
Endothelial function: 20 pts

36. VestaSync II trial Late Loss
P =
0.78± 0.45 mm
0.35± 0.38 mm
Vestasync
Vestacor

37. VestaSync II trial Preliminary IVUS Results
29,4± 17,9 mm3
P =
P =
15,4± 10,9 mm3

38. 9-month Major Cardiac Events Site report (no adjudication)
Vestasync
N=50
VestaCor
N=25
Death (4%)
MI (2%)
TLR (2%) (8%)
Non-TLR (2%) (4%)
MACE (4%) (12%)
No cases of stent thrombosis in either groups

39. Non-Polymeric Systems:
BioFreedom (Biosensors)
Yukon (Translumina)
Pax Technology (Minvasys)
Vestasync (MIV)
Cre8 Anphilimus (CID)

40. CID Polymer-free Abluminal Reservoir
DES Technology

41. The Bio-Inducer Surface (BIS) is made of pure carbon atoms
Bio-Inducer Surface (2° gen coating ) applied to CID bare platform (AVANTGARDE)
The Bio-Inducer Surface (BIS) is made of pure carbon atoms
Bio/haemo-compatibility % %
Graphite
Diamond
Improved Bio/Haemo-compatibility
This 2nd generation coating (≤0.3 µm) brings the cristalline structure closer to the diamond with a further improvement of its bio/haemo compatibility

42. Drug Release Polymeric Drug System CID AmphilimusTM Formulation
ACTIVE PRINCIPLE +
AMPHIPHILIC CARRIER
ACTIVE PRINCIPLE
POLYMERIC MATRIX
“Discrete” system
“Homogeneous” system 43

43. Animal data*: Complete endothelialization @ 5d
CID (Avantgarde)
Competitor BMS
Continuum endothelial layer: Clearly visible polygonal shape of the endothelial cells both original or covering stent struts.
Non-Continuum endothelial layer: Wide areas non covered with endothelium; few adherent cells are present (RBCs, leukocytes…).
* Stent implants in pig coronary arteries. University of Turin

44. The NEXT Study Clinical Angiographic/IVUS
Patients with ischemic myocardial symptoms related to de novo lesions (max 2 in 2 different vessels) in native coronary arteries
Cre8 – CID DES
(n=150 pts)
 3.0 – 3.5 mm
L – 20 – 25 mm
11 European Sites
Randomisation 1:1
100% angiographic f-up
20% IVUS f-up
PI: Prof Carrié - Fr
TAXUS LIBERTÉ
(n=150 pts)
 3.0 – 3.5 mm
L – 20 – 25 mm
Primary Endpoint:
LLL in-stent at 6 months post-procedure
Secondary Endpoints:
QCA measurements in-stent and in-segment at 6 months
IVUS measurements at 6 months (20%)
Clinical composite occurrence of death, MI, any revascularization at 1 and 6 months, and yearly up to 5 years
Thrombosis throughout the study duration, according to ARC definition
Clinical
Angiographic/IVUS
12 & 24 months
6 months
1 month
3, 4, 5 years

45. Drug fills hollow structure
Drug Filled Stent (DFS) Concept (Medtronic) Drug elution controlled by diffusion physics
Exits through holes
Drug fills hollow structure
Elution Holes
No Polymer!

46. Conclusions
First Genaration Durable Polymers with thick polymer loading are being gradually replaced to more advanced technology.
Bioabsorbable Polymers with abluminal release and reservoir technology are slowing replacing the first gen DES.
Non-Polymeric DES with surface modification will be an attractive alternative to improve safety

47. Delayed Healing - DES Severe inflammation
Lack of neointimal growth (uncovered Struts)
Persistent fibrin deposition *
Rabbit 28 days *
*Inflammation
Incomplete endothelialization
CYPHER
TAXUS
Fibrin deposition with malapposition
Severe inflammation
Porcine 28 days
Virmani et al.

48. JEMRS – Curso Revisão SBHCI – nov08
Instituto Dante Pazzanese de Cardiologia:
The Place of the First Drug Eluting Stent
14/09/2018
Dr. J>Eduardo Sousa