Drug Eluting Stents Using Bioresorbable Polymers are
the Best Clinical Choice
Juan F. Granada, MD Executive Director and Chief Scientific Officer
Skirball Research Center
Cardiovascular Research Foundation
Columbia University Medical Center, New York
TCT at SOLACI-CACI 2014,Thursday April 24rd
Disclosure Statement of Financial Interest
• Grant/Research Support: Abbott Vascular, Alumend, Amaranth
Medical, Bioventrix Inc., Boston Scientific, Caliber Therapeutics Inc.,
Cardia Inc., Cardiosystems Inc., Cardiosolutions Inc., Circulite Inc.,
Corindus Vascular Robotics, Direct Flow Medical, Intact Vascular,
Juventas, Lutonix, Meril Life Sciences, Mitralign, Orbus Neich
Medical Inc., Stentys S.A., Surmodics, Thoratec, Tubrikar, Valve
Medical, Volcano, WL Gore
Within the past 12 months, I or my spouse/partner have had a financial
interest/arrangement or affiliation with the organization(s) listed below:
The Technological Evolution of PCI “A Band Aid Developmental Approach”
Acute dissections, abrupt vessel
closure & chronic negative
remodeling
Neointimal proliferation
Delayed healing & stent thrombosis
PTCA
BMS
DES
SPIRIT II, III, IV and COMPARE trials
Pooled Database Analysis (n=6,789)
Kereiakes DJ et al. EuroIntervention 2011:7:74-83
Target-Lesion Revasc
@ 4 Years
Favors BP DES Favors SES
Biodegradable Polymer DES
Versus Durable Polymer SES
Definite ST
@ 4 Years
N = 4,062 – IPD Pooled Analysis of LEADERS, ISAR-TEST 3 and 4
Favors BP DES Favors SES
Stefanini G et al. Eur Heart J 2012; 33, 1214–1222
0 to 1 year:
HR 0.80
(95% CI 0.47-1.38)
p=0.43
1 to 4 years:
HR 0.22
(95%CI 0.08 – 0.61)
p=0.004
1 to 4 years:
HR 0.73
(95% CI 0.53 – 1.00)
p=0.05
0 to 1 year:
HR 1.02
(95% CI 0.78-1.31)
p=0.91
Definite ST Cardiac Death or MI
Biodegradable Polymer DES versus Durable Polymer SES Through 4 Years
% %
A Pooled Analysis of ISAR-TEST 3, ISAR-TEST 4, and LEADERS trial
Stefanini G et al. Eur Heart J 2012; 33:1214-22
PROMUS Element™ Plus
Drug: Everolimus
Platform: Platinum-Chromium
Polymer: PVDF
Xience Prime™
Drug: Everolimus
Platform: Cobalt-Chromium
Polymer: PVDF
Non-Absorbable Polymers in 3rd Generation DES: Is There Room to
Improve Clinical Outcomes? Resolute Integrity™
Drug: Zotarolimus
Platform: Cobalt-Chromium
Polymer: Biolinx
• We currently have DES platforms delivering drugs from non-absorbable
polymers showing excellent restenosis rates and clinical outcomes
• Still, in high risk patients and complex lesions: – Acute device performance can be challenging
– Prolonged DATP therapy needs to be maintained
– Stent thrombosis rates are still high (compared to low risk cases)
Technology Drug Drug
Dose
Absorption
Time
Polymer Polymer
Thickness
Absorption
Time
Stent
Material
Stent
Thickness
SYNERGY1 Everolimus 38 - 179 µg 3 m PLGA 3-4 µm 4 m PtCr 74 µm
Abluminus2 Sirolimus 6 m PLA N/A 6-8 m CoCr 73 µm
Desyne BD3 Novolimus 85 µg 3 m PLA <3 µm 6-9 m CoCr 81 µm
Biomatrix4,5 Biolimus A9 15.6 µg/mm 9 m PLA 10 µm 6-9 m SS 112 µm
Nobori6,7 Biolimus A9 15.6 µg/mm 9-12 m PLA 20 μm 9-12 m SS 120 µm
SVELTE8 Sirolimus 220 μg/cm2 2 m AA 6 µm 12 m CoCr 81 µm
Orsiro9,10 Sirolimus 1.4 μg/mm2 3 m PLLA Abl: 7.5 µm
Lum: 3.5 µm
15 m CoCr 60 µm
FIREHAWK11 Sirolimus 3 µg/mm 3 m PLA 8 µm 9 m CoCr 86 µm
MiStent12 Sirolimus 3 µg/mm 6 m PLLA Abl: 10-15 µm
Lum: 3-5 µm
3 m CoCr 64 µm
BioMime13 Sirolimus 1.25
μg/mm2
30 d PLGA +
PLLA
2 µm N/A CoCr 65 µm
Remedee
Combo14,15
Sirolimus &
CD34 ABD
5 µg/mm N/A N/A 3-5 µm N/A SS 100 µm
Inspiron16 Sirolimus 56 μg N/A PLA +
PLGA
5 µm N/A CoCr 75 µm
Ultimaster17 Sirolimus 3.9 µg/mm N/A PDLLA+
PCL
N/A 3-4 m CoCr 80 µm
1. Meredith IT, J Am Coll Cardiol. 2012;59:1362-1370, 2. Dani S. TCT2012, 3. Abizaid AA. TCT2011, 4. Windecker S. TCT2007, 5. Windecker S. TCT2008,
6. Ostojic M. EuroIntervention. 2008;3:574-579, 7. Smits PC. The Lancet. 2013, 8. Pomeranz M. EuroPCR. 2012, 9. Windecker S. TCT2012, 10. Hamon M.
EuroIntervention. 2013;8:1006-1011, 11. Gao R-L. EuroIntervention. 2013;9:75-83, 12. Ormiston J, JACC Cardiovasc Interv. 2013, 13. Seth A. TCT2012, 14.
Haude M. TCT2012, 15. Haude M. JACC Cardiovasc Interv. 2013;6:334-343, 16. Lemos P. TCT2012, 17. Stefanini GG,Heart. 2013
Polymer Type, Distribution and
Loading in Different DES Designs
Commercially Available DES Systems Strut and Coating Thickness In Perspective
Xience CoCr-
EES
Promus PtCr-
EES
Biomatrix
316L-BES Nobori
316L-BES BVS
PLLA-EES SYNERGY PtCr-EES
Resolute
CoNi-ZES
Durable
Polymer Coated Stents
Bioabsorbable
Polymer Coated Stents
Bioabsorbable
Stent
Strut Thickness
81µm 89µm 120µm 125µm 74µm 150µm
Polymer Coating Conformable
7-8µm / side
Conformable
6µm / side
Abluminal
11µm
Abluminal
20µm
Abluminal
4µm
Conformable
3µm / side
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 Absorption Time: 3-4 mo
% R
eco
very
Time (months)
Drug Release-Polymer Absorption Profiles
SYNERGY
Everolimus
PLGA
Nobori and Biomatrix Flex
% R
eco
very
Polymer: PLA Absorption Time: >9 mo
BA9
PLA
Orsiro
% R
eco
very
Time (months)
Polymer: PLLA Absorption Time: >12 mo
Time (months)
Sirolimus
PLLA
(molecular
weight
change)
% R
eco
very
Time (months)
Absorb BVS
Scaffold: PLLA Polymer: PDLLA
Absorption Time: >2 yrs
Everolimus
PLLA
DES Using Bioresorbable Polymers
0,7
0,28
0,6
0,15
1,3
0,3
0,62
0,31
1,4
0,7
1,24
0,53
2,14
0,54
1,1
0,3
0
0,5
1
1,5
2
2,5
Stent Thrombosis: Latest Generation DES 1 vs. 3 Year Thrombotic Events
PLATINUM Presented by Ian Meredith AM, MBBS, PhD at ACC 2013; SPIRIT III presented by Gregg Stone at TCT 2001; SPIRIT IV
presented by Gregg Stone, MD at TCT 2011; COMPARE Presented by Peter Smits, MD at TCT 2011; Resolute All-Comers presented by
Stephan Windecker at PCR 2012; Resolute International presented by F-J. Neumann at TCT2012; LEADERS Presented by Patrick Serruys,
MD at TCT 2010
PROMUS Element
Xience V
Resolute
A A B C D E E F
ARC ST (Def/Prob)
3-Year Cumulative
VLST (Def/Prob)
From 1 to 3 Years
A A B C D E E F
A: PLATINUM Trial
B: SPIRIT III Trial
C: SPIRIT IV Trial
D: COMPARE Trial
E: RESOLUTE All-Comers Trial
F: RESOLUTE International
<1-YEAR STENT THROMBOSIS
• Non-device related variables
• Patient, lesion and technique
• Device thrombogenicity
• Polymer-drug
• Stent design
>1-YEAR STENT THROMBOSIS
• Vascular response to implant
• Acquired malapposition
• Neoatherosclerosis
• Delayed strut healing
• DATP compliance
Early Stent Thrombogenicity Non-Absorbable vs. Absorbable Polymer
Conformal distribution of non-
absorbable polymer and drug
Luminal Side Luminal Side
Abluminal distribution of
absorbable polymer and drug
“+” denotes biological activity of drug eluting polymer
*Technology dependent
+ + +
+
+
+
+ + +
+
+ +
+ + +
+
+
Abluminal Side Abluminal Side
4 to 12 month polymer
absorption time*
According to the polymer-drug absorption time*, the net effect
on healing may be comparable between bioresorbable and
durable polymers within the first 6 to 9 months
Early Stent Thrombogenicity of EES Durable PVDF Polymer + Drug vs. CoCr Control
Kolandaivelu K, Circulation 2011, 123:1400-1409
Comparable degree of
thrombogenicity of PVDF-coated
EES vs. CoCr metal only controls
Late Stent Thrombogenicity Non-Absorbable vs. Absorbable Polymer
Conformal distribution
of non-absorbable
polymer ONLY
Metallic surface
ONLY
Healing and thrombogenicity differences?
NO DRUG PRESENT
Platelet Adhesion and Activation PVDF Durable Polymer vs. Metallic Surfaces
% S
urf
ac
e A
rea
(+
) P
-Se
lec
tin
%
Su
rfa
ce
Are
a (
+)
CD
41
NS p < 0.05
compared to
PVDF
P= NS
p < 0.05
compared to
PVDF
Eppihimer M, Granada JF, TCT2012
Platelet Accumulation on Stent Surface PVDF Durable Polymer vs. Metallic Surfaces
*
*
*
Eppihimer M, Granada JF, TCT2012
Metallic
Surface
Cell
Migration
(mm)
Cell
Morphology
Cell
Size
Cell
Confluence
Cell
Concentration
Surface 1 1.99 ± 0.25 ++ Normal ++ ++
Surface 2 1.62 ± 0.37 ++ Normal ++ ++
Surface 3 1.57 ± 0.33 ++ Normal ++ ++
Surface 4 1.3 ± 0.4 + Elongated - +
Surface 5 1.18 ± 0.43 - Elongated - +
Surface 6 1.08 ± 0.29 + Elongated - -
Endothelial Cell Migration Correlates with Surface Coverage and Morphology
Left figure (modified) courtesy of A. Tellez, SCCR
0
0,5
1
1,5
2
2,5
Surface 6 Surface 5 Surface 4 Surface 3 Surface 2 Surface 1
<1.4 mm >1.4 mm
Cell M
igra
tio
n (
mm
)
Chen CS, Science 1997
Induced cell spreading
stimulates growth and
decreases apoptotic
rate in vitro
Impact of Stent Surface on EC Coverage PVDF Durable Polymer vs. Metallic Surfaces
Eppihimer M, Circ Cardiovasc Interv. 2013;6:370-377
Cadherin Expression on Stent
Surface at 90 Days
Coronary FH Swine Model
Skirball Research Center
Figure Courtesy of M. Eppihimer
Sprague E, Circ Cardiovasc Intervent, 2012;5:499
Biological Effect of Micro-Grooved Stent
Surfaces on EC Migration and Function Smooth
Grooved
3-Day Stent EC Coverage
GS= 81.3% vs. NGS= 67.5%, P<0.05
DES Surface Type and Long
Term Para-Strut Inflammation
Hypersensitivity Reactions (180 Days) • Familial hypercholesterolemic swine model
• Coronary DES Implantation (3 arteries)
• Inflammation at 30 Days:
• DES<<<BMS (Drug Effect)
• Inflammation at 90 Days:
• DES>>>BMS (Polymer Effect)
• Inflammation at 180 Days:
• DES with BRP<<<DES with DP (Residual
Surface Effect)
Eppihimer M, Granada JF 2014
Vascular Response to Polymeric Carriers PVDF (PROMUS) CONFORMAL DURABLE POLYMER ONLY COATED STENTS
PLGA (SYNERGY) ABLUMINAL BIOABSORBABLE POLYMER ONLY COATED STENTS
Eppihimer M, Circ Cardiov Int. 2013 Aug;6(4):370-7
DAPT Agent 1 Month
Cost ($)
12 Month
Cost ($)
3 Month
Cost ($)
Cost
Savings ($)
(per patient)
Share of
Market
(%)
Weighted
Average
Plavix® 277 3324 831 2493 3.7 92.24
Effient® 299 3588 897 2691 5.3 142.62
Brilinta® 340 4080 1020 3060 .8 24.48
Mean Drug Cost Savings per Patient $300
Cost of DATP: Type and Duration
(3 versus 12 Months)
• High end considers Effient®, Plavix®, and Brilinta® in model
• Low end assumes all DAPT is Clopidogrel at $5 per month cost
• In the high end scenario, model utilized 30 day AWP Prices and IMS share of market data for:
– Plavix (clopidogrel bisulfate), Effient (prasugrel), Brilinta (tricagretor)
• Assumed additional incidence of major bleeding of 1.3% between 3 and 12 month DAPT*
• Assumed Effient and Brilinta have similar incidence of major bleed as Clopidogrel /Plavix
• Assumed 3 and 12 month DAPT patients are compliant and adherent
Hypothetical Group of 1,000 PCI patients • Major Bleeds
-1.3% higher incidence with 12 month DAPT (13 patients)
- $8,000 cost per major bleeding event $104,000 additional costs
- Overall cohort consists of 1,000 patients $104 per patient
• Additional Major Bleeds (post secondary surgery)
- 25% will have second surgery 250 patients
- 25% taking DAPT during 2nd surgery 62.5 patients
- 3.3% higher incidence with 12 month DAPT 2.1 patients
- $10,000 cost/major bleeding event $21,000 additional costs
- Overall cohort consists of 1,000 patients $21 per patient
Duration of DATP and Cost of
Treating Bleeding Complications
Duration of DATP + Reduction of
Stent Thrombosis???
Absorbable vs. Non-Absorbable DES
Polymers on Metallic Stent Platforms
• In the initial healing phase (9 to 12 months) and due to the
comparable nature of the biological process induced by the
presence of polymer and drug, minimal differences in device
thrombogenicity may be seen
• In vivo human data suggests that at the end of this phase,
stent surface exposure caused by delayed healing occurs in
a small proportion of the patients
• In these cases, the exposure of a metallic stent surface (over
a durable polymer) may offer biological advantages in
healing and thrombogenicity
• However, due to the very low incidence of this biological
event, large RCT may be required to prove this hypothesis
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