Biodegradable vs. Durable
Polymer DES Outcomes
Ajay J. Kirtane, MD, SM
Center for Interventional Vascular Therapy
Columbia University Medical Center /
New York Presbyterian Hospital
Financial Conflict of Interest Disclosure
• Ajay J. Kirtane

Research Grants (to Columbia University):
from Medtronic, Boston Scientific, Abbott
Vascular, St. Jude Medical, Abiomed, Eli
Lilly, Vascular Dynamics
Rationale for Stents
Which Problems Did We Want to Solve With Stents?
• Mechanically scaffold
the artery
• (Re)create a larger
circular lumen
• Prevent abrupt
vessel closure
• Prevent late restenosis
c/o Helmut Schühlen
S Goldberg, TCT 2004
Restenosis – Causes & Solution
Causes
Recoil & Negative Remodeling (70%)
Neointimal Hyperplasia (30%)
Solution
1. A stent to block recoil and remodeling
2. A therapeutic agent to prevent neointimal hyperplasia
Drug-Eluting Stents
The Concept
Stent design and delivery system
Pharmacologic
agent
DrugEluting
Stent
Drug carrier
vehicle
Drug-Eluting Stents….
the good, the bad, and the ugly!
Late loss = 0
BMS
DES
Giant cells
DES
Angioscopy
BMS
48 months
Eos
Inflammation
Delayed Healing!
Incomplete
apposition
25
20
Abn Vasomotion
15
Sirolimus
Control
10
5
0
Late stent
thrombosis
-5
-10
-15
40 mos
IVUS
-20
*P<0.001 *vs. control
Prox. Ref.
Prox.
Stent
*
Distal
Distal Ref.
Definite/Probable ARC Stent Thrombosis to
5 Years (Per Patient)
12
12
10.4%
6
~4.6% in year 1
~1.2%/year after year 1
6
2.6
1.7
1.3
1.4
1.2
0.9
(10/803)
(7/768)
0.3
0
(3/896)
(23/893)
(15/874)
Acute
Subacute
Late
≤1d
2-30d
31-365d
(11/850)
(12/830)
366730d
7311095d
Days Postprocedure
Serruys PW et al. TCT2012
SYNTAX 4-year Outcomes •
EACTS 2011 • Serruys • October 2011 • Slide 8
(76/730)
Total
Very Late
10961460d
0
14611825d
5 year
Timing and Mechanism of DES Thrombosis
Early (<30d)
Late (1-12 Mo)
Very late (>12 Mo)
Procedural
Delayed healing
Abnormal vascular response
Underexpansion
Uncovered struts
Hypersensitivity
Edge dissection
Fibrin deposition
Extensive fibrin deposition
Residual plaque
Late malapposition?
Neoatherosclerosis
Nakazawa et al. J Cardiol 2011;58:84-91
Stent Thrombosis is Affected by Stent
Design, Deployment and Polymer
Impact of Xience / Promus polymer coating
In vitro pulsatile Chandler loop model with porcine blood
1.4
24%
P=0.002
LDH Adsorbance
Relative platelet
adhesion
1.2
1.0
0.8
0.6
0.4
0.2
0.0
ML VISION (81 µm)
XIENCE V (96.6 µm)
Kolandaivelu K et al. Circulation 2011;123:1400-09
SPIRIT II, III, IV and COMPARE trials
Pooled database analysis (n=6,789)
Ischemic TLR
EES (n=4,247)
PES (n=2,542)
Ischemic TLR (%)
10
HR: 0.60 [0.48, 0.75]
P<0.001
6.6%
∆=2.5%
4.7%
5
4.1%
∆=2.4%
2.3%
0
0
3
6
9
12
15
18
21
24
Time in Months
Number at risk
XIENCE
TAXUS
4247
2542
4143
2416
4004
2328
3891
2260
Kereiakes DJ et al. EuroIntervention 2011:7:74-83
3363
2018
SPIRIT II, III, IV and COMPARE trials
Pooled database analysis (n=6,789)
Stent thrombosis (ARC definite/probable)
Stent thrombosis
ARC def or prob (%)
HR: 0.30 [0.19, 0.47]
p<0.001
EES (n=4,247)
PES (n=2,542)
3
2.3%
2
1
0.7%
0
0
3
6
9
12
15
18
21
24
Time in Months
Number at risk
XIENCE
TAXUS
4247
2542
4177
2463
4082
2408
3998
2350
Kereiakes DJ et al. EuroIntervention 2011:7:74-83
3479
2110
RESOLUTE All-Comers (n=2,292)
Target Lesion Failure to 5 Years
40
Resolute ZES (N=1140)
Xience V EES (N=1152)
Log rank P=0.65
TLF (%)
30
Primary endpoint
Pnon-inferiority <0.001
20
17.1%
16.3%
8.3%
8.2%
10
2.0% per year
0
No. at risk:
Resolute
Xience V
0
1
1140
1152
1110
1122
2
3
Time after Procedure (years)
1035
1031
992
995
Windecker S. TCT 2014
4
5
960
959
920
926
Etiology of metallic stent events beyond 1 yr
Very late thrombosis and restenosis
Possible causes
1. Uncovered stent struts (thrombosis)
2. Persistent stimulation of SMCs, from adherent fibrin
and/or loss of normal vessel curvature
3. Abnormal shear stress from protruding struts and/or
loss of cyclic strain relief (compliance mismatch)
4. Chronic inflammation due to late foreign body
reactions and polymer hypersensitivity
5. Positive remodeling with strut malapposition
6. Strut fracture
7. Neoatherosclerosis
Three Approaches to Improve Late
DES Outcomes
1. Metallic DES, polymer-free
2. Bioresorbable scaffolds (BRS)
3. Metallic DES with bioabsorbable polymers
Bioabsorbable Polymers as Drug Carriers
BioMatrix™ Stent Platform
Biodegradable Drug/Carrier:
BioFlex™ II
•
•
•
•
•
•
Biolimus A9® / Poly Lactic Acid 50:50
15.6 g/mm drug = 250 g /16mm
500 mcg drug+polymer
Abluminal surface only
10 microns coating thickness
Degrades in 9 months
BioFlex I
Meta-analysis of Bioresorbable Polymer DES:
ISAR-TEST 3, ISAR-TEST 4, and LEADERS at 4 yrs
4,062 randomized pts assigned to bioresorbable polymer
eluting sirolimus or biolimus A (2,388) or Cypher (1,704)
Stent thrombosis (%)
Definite Stent Thrombosis
Durable polymer
5
4
Biodegradable polymer
HR [95%CI] = 0.56 [0.35, 0.90]
P=0.015
3
DP
HR (95% CI)
1/202
2/202
0.47 (0.04, 5.04)
ISAR-TEST 4 9/1299
10/652
0.45 (0.18, 1.12)
LEADERS
20/857
32/850
0.62 (0.35, 1.08)
Overall
30/2358 44/1704
0.56 (0.35, 0.90)
ISAR-TEST 3
2
1
1.3%
0
0
1
2
3
4
Years
Stent thrombosis (%)
BP
2.8%
5
4
3
2
0.02 [0.47, 1.38]
P=0.43
Test for heterogeneity P=0.84
Test for inconsistency 12=0%
Test for overall effect z2=2.43 (P=0.015)
0.22 [0.08, 0.61]
P=0.004
1
0.1
0
0
1
2
3
4
Favors BP
Years
Stefanini GG et al. EHJ 2012;33:1214–22
10
HR
Favors DP
COMFORTABLE-AMI
1161 pts with STEMI at 11 sites randomized 1:1 to the BioMatrix
bioabsorbable polymer (PLLA) coated biolimus-eluting stent vs BMS
MACE*: 1 EP
1-year events
10
BMS
Biomatrix
8.7%
8
6
Death
4.3%
HR (95%CI) =
0.49 (0.30-0.80)
P=0.004
2
0
0
60
120
180
240
300
365
Days
P
3.2%
4.1%
0.46
- Cardiac
2.9%
3.5%
0.53
Reinfarction
2.0%
3.7%
0.08
0.5%
2.7%
0.01
Stroke
1.1%
0.7%
0.51
TLR, ischemic
1.6%
5.7%
<0.001
TVR, ischemic
2.0%
6.2%
<0.001
- Definite
0.9%
2.1%
0.10
- Def/prob
2.5%
3.7%
0.25
- TV related
4
BioMatrix
BMS
(n=575) (n=582)
Stent thrombosis
*cardiac death, RV-MI or ischemic TLR
Raber L et al. JAMA. 2012;308:777-787
Bioflow II: TLF at 24 Months
SYNERGY Stent
Everolimus Drug
PLGA Polymer
Platform
Platinum chromium
• 74 μm (0.0029in)
Drug & Polymer Coating
Abluminal (4μm)
SEM of coating (x5000)
Luminal
Polymer Coating
PLGA
• Abluminal
• 4 µm thick
• 85:15 ratio
Drug
Everolimus
• 100 μg/cm2
SYNERGY Stent
Synchronous Drug Release & Polymer Absorption
Preclinical evaluation in porcine model
ng/mg
Everolimus Arterial Tissue Concentration
Everolimus Mass Remaining
PLGA Mass Remaining
Limit of Quantitation (LOQ)
EVOLVE II TLF at 1 and 2 years
PROMUS Element Plus vs SYNERGY
Primary Endpoint:
12 month 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
Timing of SYNERGY ARC def ST
% of Patients
5
Acute def ST (≤1 day)
Late def ST (30 days – 1 year)
Subacute def ST (2–30 days)
Very Late ST (1–2 years)
2.5
0.1
0.1
1.5
0
N:
0.2
0.1
0.3
0.3
0.2
0.1
0
0
0
0
SCAAR
Registry
SYNERGY
EVOLVE II
SYNERGY
SWEET
Registry*
Fribourg
Exp.
Belfast
Exp.
EVOLVE
FHU
SYNERGY
EVOLVE II
QCA
SYNERGY
EVOLVE
China
SYNERGY
7880
846
820
671
100
94
100
205
*Cumulative adjusted ST
SWEET Registry: Cook TCT 2015., SCAAR Registry: James TCT 2015., EVOLVE II: Kereiakes, et al. Circ Cardiovasc Interv. 2015; Fribourg Experience: Arroyo CRT 2016.; Belfast
Experience: Noad TCT 2015., EVOLVE FHU: Meredith et al. J Am Coll Cardiol. 2012; 59 (15):1362., EVOLVE II QCA: Meredith ACC 2015.; EVOLVE China: Han CIT 2016.
SYNERGY Clinical Trials
Ongoing and Upcoming Trials
Bifurcation
Lesions
Multi-vessel
Disease


CTO
SYNERGY research program studying
>20,000 patients.

ACS


Long
Lesions
DAPT
BSC Core
Trials




Imaging /
Healing



EVOLVE

EVOLVE II 
EVOLVE China
EVOLVE DAPT


SENIOR
EVOLVE
DAPT





Diabetes
SYNTAX II
BIORESORT
SWEET
SCAAR
EVOLVE II







BIORESORT
SWEET
SCAAR
EVOLVE II





SYNTAX II
CONSISTENT
SENIOR
BIORESORT
SWEET
TRANSFORM OCT
SORT OUT VIII
MULTISTARS AMI
SCAAR





SYNTAX II

SWEET

BIORESORT

CELTIC

OCT/GSI
SCAAR
SYNTAX II
BIORESORT
SWEET
IDEAL Left Main
SORT OUT VIII
MULTISTARS AMI
SCAAR
TIMELESS
TRANSFORM OCT
SORT OUT VIII
MOVES
GREEK PLATELET


BSC Sponsored Trials
Investigator Sponsored Research
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
i) ≥75 years of age and high bleeding risk iii) history of major bleeding
ii) long term anticoagulation therapy
iv) stroke, or renal insufficiency/failure
(excluded LM disease, ostial lesions, >2 lesions, CTO, SVG, ISR, NSTEMI or STEMI)
Actively
Enrolling!
P2Y12 + ASA
0
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 (GUSTO severe/life-threatening + moderate)
Primary and secondary endpoints evaluated between 3 and 15 months
Propensity adjusted comparison to historical control patients treated with standard DAPT will be performed
PANDA III: Definite/Probable Stent
Thrombosis at One Year (n=2,350)
PTE
One-Year Event Rate (%)
Acute ST (0-1 day) n=3
Subacute ST (2-30 days) n=0
Late ST (31-365 days) n=3
2.0
Acute ST (0-1 day) n=4
Subacute ST (2-30 days) n=5
Late ST (31-365 days) n=6
P = 0.047
1.5
1.29%
(n=15)
1.0
0.52
0.51%
(n=6)
0.5
0.43
0.26
0.26
0.34
0.0
BuMA
N=1169
Excel
N=1164
Acute ST (0-1 day) n=2
Subacute ST (2-30 days) n=0
Late ST (31-365 days) n=2
One-Year Event Rate (%)
ITT
2.0
P = 0.01
1.34%
(n=15)
1.5
0.54
1.0
0.5
0.0
Acute ST (0-1 day) n=4
Subacute ST (2-30 days) n=5
Late ST (31-365 days) n=6
0.35%
(n=4)
0.45
0.18
0.18
0.36
BuMA
N=1130
Excel
N=1118
Time Course For Polymer Bioabsorption
1
BioMime (PLLA+PLGA)
SYNERGY (PLGA)
≤2
3
MiStent (PLGA)
≤4
3
6-8
6-8
ABLUMINUS (PLA)
ELIXIR DESyne BD (PLA)
3
FIREHAWK (PLA)
3
6-9
9
BIOMATRIX (PLA)
6
NOBORI (PLA)
6
9
9
2
SVELTE (Amino Acid)
12
3
ORSIRO (PLLA)
DREAMS 2 (Mg w/PLA coat)
Drug Release
Bioabsorbable Polymer
Fully Resorbable Stent (FRS)
9
15
Drug release, polymer coating degradation time?
9
ART (PDLLA)
(no drug)
ELIXIR DESolve (PLLA)
3
BVS (PLLA)
3
REVA ReZolve (Polycarb)
3
0
Slide c/o Boston Scientific
12-18
24
36
42
5
10
15
20
25
30
Time (Months)
35
40
45
Evolution of DES Technology – Strut Thickness in Perspective
First Gen
Resolute
Integrity
Second Gen
Resolute
Xience
Onyx
Xpedition
Promus
PREMIER
Permanent
Polymer Stents
Cypher
Strut Thickness
140 µm
132 µm
96 µm
89 µm
81 µm
81 µm
81 µm
Coat Thickness
7 µm / side
16 µm / side
14 µm / side
6 µm / side
6 µm / side
8 µm / side
8 µm / side
Bioabsorbable
Polymer Stents
Biomatrix
TAXUS Express
TAXUS Liberte
Ultimaster
Nobori
Orsiro
ABLUMINAL SIDE
MiStent
BioMime
SYNERGY
ABLUMINAL SIDE
Strut Thickness
120 µm
125 µm
80 µm
61 µm
64 µm
65 µm
74 µm
Coat Thickness
10 µm
20 µm
15 µm
3.5 / 7.5 µm
5 / 15 µm
2 µm
4 µm
Fully Bioresorbable
Scaffold
BVS
ELIXIR DESolve
DREAMS II
Polymer Free
Stents
BIOFREEDOM
Drug Eluting Stent
Strut Thickness
150 µm
150 µm
150 µm
112 µm
86 µm
Coat Thickness
3 µm / side
< 3 µm / side
< 8 µm / side
NA
NA
Slide c/o Boston Scientific Corporation
Bioabsorbable Polymer-based vs. Durable
Polymer-based DES and BMS
Evidence network: 89 RCTs, 85,490 pts
BMS
PtCr-EES
PES
CoCr-EES
SES
BP-BES
Re-ZES
Palmerini T et al. JACC 2013: on line
PC-ZES
Exchangeability: 2014 FIFA World Cup
Group D Round Robin Play
0:1???
Loss
Italy
Win (2:1)
Should we therefore infer
that Italy will beat Uruguay
and Costa Rica and
advance?
0:1???
Loss
Uruguay
England
Draw (0:0)
Win (1:3)
Costa Rica
Or is it more likely /
intuitive that these
games are not entirely
exchangeable
(especially playing in
South America)?
Adapted from D. Cohen
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
• Bioabsorbable polymer DES may offer advantages
over durable polymer DES, but are NOT a
homogenous class of devices
• Appropriately sized, randomized clinical trials are
needed (and ongoing) to determine whether any/all of
these devices improve long-term outcomes compared
to best in class durable polymer metallic DES