Bioresorbable Stents: Innovation or
Bust?
Rajiv Jauhar, MD FACC, FSCAI
Chief of Cardiology
Director of Cardiac Cath Labs
Northshore University Hospital
San Diego July, 2016
Conflict of Interest Disclosure

Rajiv Jauhar, MD
Speakers Bureau: AbioMed
 Advisory Board: Medinol, CeloNova


Off-label use will be discussed
Elements of DES Design – DES Design Affects
Procedural Success and Clinical Outcomes
Metal Alloy
Stent Delivery System
Stent Architecture
Polymer Carrier
Problems Related to Durable Polymers
Non-uniform
distribution
Detachment
Delamination
• Durable polymers:
– Continuous source of inflamation
– Delayed endothelialization
– Higher risk for thrombosis
1st-Generation DES was not Ideal for Healing
• Thick struts





• Thick, durable coating (~15 µm)
• High drug dose
Uncovered struts
Hypersensitivity
Malapposition
Late stent thrombosis
Neoatherosclerosis
• High polymer load
Th
Uncovered struts
Virmani, CRT 2014
Th
Hypersensitivity
reaction
Th
Malapposition from
excessive fibrin
deposition
Th
Neoatherosclerosis
CoCr EES 24-month
CoCr EES 36-month
Prevalence of Neoatherosclerosis (%)
Neoatherosclerosis Remains a Concern
for 1st and Current Generation
DURABLE Polymer DES
SES
40
PES
CoCr-EES
P=0.19
P=0.91
35
30
25
20
15
10
5
0
Prevalence of
neoatherosclerosis
1st Gen Drug-Eluting Stents
The good, the bad, and the ugly!
Late loss = 0
DES
BMS
Giant cells
DES
Angioscopy
BMS
7 years
Delayed Healing!
Incomplete
apposition
Late stent
thrombosis
40 mos
Eos
Inflammation
IVUS
25
20
15
10
5
0
-5
-10
-15
-20
Abn Vasomotion
*
Prox. Ref.
Prox.
*
Stent
Distal
Sirolimus
Control
*P<0.001 vs. control
Distal Ref.
Target Lesion Revascularization
at 5 Years TAXUS I, II-SR, IV & V
30%
TAXUS (n=1400)
BMS (n=1397)
5-Year HR [95% CI]:
0.53 [0.44, 0.65]
P<0.001
21.0%
(n=284)
TLR (%)
20%
10%
12.3%
(n=162)
0%
0
Event Rate ± 1.5 SE
1
2
Years
3
Stone GW et al. JACC CV Int 2011;4:530–42
4
5
Myocardial Infarction: Landmark
Analysis TAXUS I, II-SR, IV & V (n=2,797)
Myocardial infarction (%)
10%
TAXUS (n=1400)
BMS (n=1397)
1-5 Year HR [95% CI]:
1.67 [1.06, 2.65]
P=0.03
3.8%
4.5%
5%
0-1 Year HR [95% CI]:
0.89 [0.62, 1.27]
P=0.52
4.0%
2.3%
0%
0
1
2
3
Years
Event Rate ± 1.5 SE
Stone GW et al. JACC CV Int 2011;4:530–42
4
5
Event Rates Persist Beyond 1 Year with
Current DURABLE Polymer DES
Resolute All Comers 5-year TLF
TLF (target Lesion Failure) is defined as cardiac death, TVMI, of clinically driven TLR.
Presented by Stephan Windecker, MD PCR 2014.
Next Phase for the Future of PCI:
Optimal Healing
1977
PCI
EVOLUTION
Continuous
improvement
in platform
design and
acute
performance
1986
2003
2015+
• POBA: Getting Artery Open
• BMS: Keeping Artery Open
• DES Decrease Restenosis
• Future DES: Optimize Healing
• Lower late events rates – ST, TLR
• Reduced need for prolonged DAPT
• Reduced risk of neoatherosclerosis
What is Optimal Healing Post-implant?
Uniform
Strut Coverage
Mature
Neointimal Layer
CONTINUOUS,
FUNCTIONAL Endothelial Layer
{
Endothelial Cells
Neointimal Layer
Strut
Strut
Strut
Role of Endothelial Cell:
• Communicate
• Stabilize
• Prevent further neointimal formation
• Provide a barrier for thrombosis
Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation
2007;115:2435– 41. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol
2006;48:193–202. Joner et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol. 2008 Jul 29;52(5):333-42.
Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an
observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006;48:2584 –91. Rodriguez AE, Mieres J, Fernandez-Pereira C, Vigo CF,
Rodriguez-Alemparte M, Berrocal D, Grinfeld L, Palacios I. Coronary stent thrombosis in the current drug-eluting stent era: insights from the ERACI III trial. J
Am Coll Cardiol 2006;47:205–7. Tsimikas S. Drug-eluting stents and late adverse clinical outcomes lessons learned, lessons awaited. J Am Coll Cardiol
2006;47:2112–5
SYNTAX: Definite/Probable ARC Stent
Thrombosis to 5 Years (Per Patient)
12
12
10.4
~4.5% ST
in year 1
~1.2% ST/yr
in years 2-4
6
6
2.6
1.7
0.3
0
(3/896)
(23/893)
Acute Subacute
≤1d
2-30d
(15/874)
Late
31-365d
1.3
(11/850)
366730d
1.4
(12/830)
1.2
(10/803)
Very Late
7311095d
10961460d
0.9
(7/768)
14611825d
0
(76/730)
Total
5 year
Days Post-procedure
Rate was ~ same in the LM and 3VD cohorts, and roughly independent of Syntax Score
Farooq V et al. JACC 2013:62:2360–9
Etiology of metallic stent events beyond 1 yr:
Very late thrombosis and restenosis
•
Uncovered stent struts (thrombosis)
•
Persistent stimulation of SMCs, from adherent fibrin and/or loss of
normal vessel curvature
•
Abnormal shear stress from protruding struts and/or loss of cyclic
strain relief (compliance mismatch)
•
Chronic inflammation due to late foreign body reactions and
polymer hypersensitivity
•
Positive remodeling with strut malapposition
•
Strut fracture
•
Neoatherosclerosis
Three Approaches to Improve
Late DES Outcomes
1. Metallic DES with bioabsorbable polymers
2. Metallic DES, polymer-free
3. Bioresorbable scaffolds (BRS)
Do we really want change?
Abluminal Bioabsorbable Polymer
SYNERGY Stent (BSC)
Everolimus Drug
PLGA Polymer
Drug & Polymer Coating
Abluminal (4μm)
SEM of coating (x5000)
Luminal
Platform
Polymer Coating
Drug
Platinum chromium
• 74 μg (0.0029in)
PLGA
• Abluminal
• 4 µm thick
• Undetectable in 4 mo
Everolimus
• 100 μg/cm2
• Elutes in 3 months
EVOLVE II Clinical Trial
12 Month Primary Noninferiority Endpoint of Target
Lesion Failure
Incidence Rate (%)
15.0
Pnoninf =0.0003
10.0
P=0.99
P=0.71
6.5 6.7
P=0.21
P=0.34
Components of TLF
4.7 4.3
5.0
1.7
2.6
0.9 0.5
0.0
TLF
Target Vessel
MI
PROMUS Element Plus Stent
System
TLR
Cardiac Death
SYNERGY Stent System
The SYNERGY stent is an investigational device and not for sale in the US. CE Mark Approved 2012.
Presented
by Dean
Kereiakes
Information for the SYNERGY Stent is for use in countries
with applicable
product
registrations at AHA 2014
EVOLVE II TLF at 2 years
PROMUS Element Plus vs SYNERGY
1 Endpoint:
12 months ITT
Pnoninferiority=0.0005
TLF (%)
16
12
8
6.7%
4
6.5%
2 years
HR 1.10 [0.79, 1.52]
P=0.57
9.4%
8.5%
0
No. at risk
PE+
SYNERGY
0
6
12
24 Months
838
790
772
538
846
807
794
553
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
EVOLVE II Stent Thrombosis at 2 years
Definite/Probable : ITT Population
Acute (≤1 d)
Subacute (2-30 d)
PROMUS
Element Plus
Late (30 d – 1 y)
N=5
N=1
(2 Definite/3 Probable)
(Def)
Very Late (1 – 2 y)
0.8%
(N=6)
P=0.31
SYNERGY
N=2
N=1
(Definite)
(Prob)
0.4%
(N=3)
No definite ST in the SYNERGY arm after 24 hours
Presented by Kereiakes ACC 2016
DFS: Drug Filled Stent (Medtronic)
Drug elution controlled by diffusion physics
Elution Holes
From TAXUS to XIENCE to ABSORB
30%
Absorb BVS (theoretical)
XIENCE V (n=669)
TAXUS Express (n=332)
TLF (%)
25%
SPIRIT III
19.0%
20%
15%
9.2%
10%
12.7%
5%
7.2%
5.4%
5.3%
0%
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
Spirit III: Gada H et al. J Am Coll Cardiol Intv 2013;6:1263–6
Absorb BVS
Everolimus/PDLLA (1:1) matrix
coating
• 7 µm
• Conformal coating
• Controlled drug release similar
to Xience CoCr-EES
PLLA Backbone
• Semi-crystalline
Fully
Bioresorbable
• Circumferential sinusoidal
rings connected by linear links
• Strut thickness 150 µm
• Platinum markers in each end
ring
Potential Benefits of Bioresorbable Scaffolds over
Standard DES
Absence of Permanent Rigid Metallic Cage
 Restoration of vasomotion
 Late luminal enlargement
 Preservation of targets for CABG
 Appeal to physician/patient
 Freedom from long-term polymer
exposure
Is there evidence these “potentials” will
improve patient outcomes?
Metallic DES vs. Absorb BVS
Representative Human images at 5 Years
Metallic DES1
1Atherosclerosis
2
Absorb-Treated Artery2
2014;237:23e29
Images courtesy of S Windecker, ABSORB Cohort B 5 Yrs
!
OCT Imaging
ABSORB BVS
6 months
12 months
18 months
24 months
XIENCE V
Representative photomicrographs of porcine coronary arteries (Movat’s Pentachrome, 2X magnification)
Representative optical coherence tomography images of porcine coronary arteries
30 months
36 months
6 Months1
Cohort B1
(N=15)
12 Months2
24 Months3
Cohort B2
(N=6)
(N=19)
(N=13)
Cohort A
(N=9)
(N=7)
0.5
Vasodilation
1
0
-0.5
Acetylcholine
-1
1. Adapted from Serruys, PW. ACC 2011
2. Adapted from Serruys, PW. ACC 2011
3. Adapted from Serruys, PW, et al. Lancet 2009; 373: 897-910.
Methergine
Vasoconstriction
 in Vessel Diameter (mm)
(pre-drug infusion to post-drug infusion)
ABSORBTM Vasomotor Function
Testing
Lifecycle of a Bioresorbable Scaffold
- Drug elution to reduce risk of restenosis
- Mechanical support to maintain patency
REVASCULARIZATION
Scaffold Mass
Scaffold Support
Drug Elution
0
3
6
Months
Forrester, et al. J Am Coll Cardiol. 1991:758-69. Oberhauser, et al. EuroInterv. 2009: F15-22.
Lifecycle of a Bioresorbable Scaffold
- Drug elution complete
- Mechanical support to maintain
patency
RESTORATION
Scaffold Mass
Scaffold Support
Drug Elution
0
3
6
Months
Forrester, et al. J Am Coll Cardiol. 1991:758-69. Oberhauser, et al. EuroInterv. 2009: F15-22.
Lifecycle of a Bioresorbable Scaffold
- Polymer exposure complete
- Scaffold support no longer required
- Natural vasomotion and positive
remodeling enabled
RESORPTION
Scaffold Mass
Scaffold Support
Drug Elution
0
3
6
Months
Forrester, et al. J Am Coll Cardiol. 1991:758-69. Oberhauser, et al. EuroInterv. 2009: F15-22.
?
Issues of Concern with
First Generation BRS
• Implant procedure
- Profile, deliverability, visibility, overlap, retention
- Technique more critical than w/metallic DES
- Accurate sizing essential; ? need for imaging
- Greater recoil?
• Greater peri-procedural MI?
• Greater stent thrombosis?
Acute Success
Absorb
(N=1322)
(L=1385)
Xience
(N=686)
(L=713)
p-value
Device Success
94.3%
99.3%
<0.0001
Procedural Success
94.6%
96.2%
0.12
• Device Success (lesion basis)


Successful delivery and deployment of study scaffold/stent at intended target lesion
Successful withdrawal of delivery system and final in-scaffold/stent DS <30% (QCA)
• Procedure Success (patient basis)



Successful delivery and deployment of at least one study scaffold/stent at intended
target lesion
Successful withdrawal of delivery system and final in-scaffold/stent DS <30% (QCA)
No in-hospital (maximum 7 days) TLF
TLF (%)
Target Lesion Failure
100%
20%
80%
15%
60%
10%
40%
5%
20%
0%
Absorb BVS (n=1322)
Xience CoCr-EES (n=686)
Diff [95% CI] =
1.7% [-0.5% to 3.9%]
Psuperiority=0.16
7.7%
6.0%
0
1
2
3
4
5
6
7
8
9 10 11 12 13
0%
0
No. at Risk:
Absorb
1322
Xience
686
1
2
3
4
5
6
7
8
9
10
11
12
13
Months Post Index Procedure
1254
661
1230
651
1218
643
1196
634
1-Year TLF Components
10
1-Year TLF (%)
8
Absorb (N=1322)
Xience (N=686)
P=0.16
7.8
P=0.18
6.1
6.0
6
4.6
P=0.50
4
3.0
2.5
P=0.29
2
0.6
0.1
0
TLF
Cardiac death
TV-MI
ID-TLR
Device Thrombosis to 1 Year
Absorb
(N=1322)
Xience
(N=686)
p-value
1.54%
0.74%
0.13
- Early (0 to 30 days)
1.06%
0.73%
0.46
- Late (> 30 to 1 year)
0.46%
0.00%
0.10
- Definite* (1 year)
1.38%
0.74%
0.21
- Probable (1 year )
0.15%
0.00%
0.55
Device Thrombosis (def*/prob)
*One “definite ST” in the Absorb arm by ITT
was in a pt that was treated with Xience
Technology is beautiful!!!!
?
Perspectives on Fully Bioresorbable Stents (BRS)
BRS have promise, but first gen technologies must be
improved if BRS are to become a workhorse solution
for real world patients
• Reduced absorption times
• Thinner struts
• Improved acute performance
• DAPT
Advantage or even comparability to current DES must
be demonstrated in robust clinical trials
Potential Benefits
Current BRS
Limitations / Potential Risks
Conclusions: Current and future directions in stenting
• Current DES have appreciably improved safety and
efficacy profiles in ACS and stable CAD compared to
first generation devices
• By utilizing small amounts of a bioabsorbable polymer,
polymer-free systems, or fully bioresorbable scaffolds,
future generation DES will likely further reduce stent
thrombosis and improve late outcomes
• Clinical trials are ongoing to determine whether
bioresorbable scaffolds improve long-term outcomes
compared to metallic DES
The Essence of our Being
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