SOLACI – CACI 2014
The Evolution of PCI - Stents: From Bare Metal to DES, BVS & PLLA
George D. Dangas, MD, FACC, FSCAI, FESC
Mount Sinai Medical Center
New York, NY
SOLACI – CACI 2014
Sirolimus-eluting stent: 7 year F/U
Pre Post 1 Year
2 Years 4 Years 7 Years
SOLACI – CACI 2014
Drug-eluting Stents: 1st Generation TA
XU
S
Polyolefin derivative Paclitaxel
Drug Polymer Stent
Cyphe
r
PEVA + PBMA blend Sirolimus BX Velocity
Liberté
SOLACI – CACI 2014
1st Gen Drug-Eluting Stents
The good, the bad, and the ugly!
7 years
40 mos
BMS DES
Incomplete
apposition
Late stent
thrombosis -20
-15
-10
-5
0
5
10
15
20
25
Prox. Ref. Prox. Stent Distal Distal Ref.
Abn Vasomotion
*P<0.001 vs. control
Sirolimus
Control
* *
Delayed Healing!
Angioscopy
BMS
DES Late loss = 0
Eos
Giant cells
IVUS
Inflammation
SOLACI – CACI 2014
All-Cause Mortality: All SES/PES RCTs
I-V Overall (I-squared = 0.0%, p = 0.918)
BASKET (SES only)
TAXUS II
HAAMU-STENT
Seville
Ortolani et al
TAXUS IV
E-SIRIUS
Study ID
DIABETES
PRISON II
STRATEGY
RAVEL
SES-SMART
TAXUS V
Typhoon
MISSION!
SCORPIUS
SESAMI
D+L Overall
Passion
C-SIRIUS
Pache et al
SIRIUS
0.97 (0.81, 1.15)
0.82 (0.37, 1.84)
1.61 (0.57, 4.53)
2.00 (0.63, 6.38)
1.35 (0.23, 7.78)
2.00 (0.19, 21.38)
0.89 (0.63, 1.25)
1.08 (0.25, 2.24)
ES (95% CI)
1.44 (0.48, 4.33)
0.50 (0.09, 2.67)
0.84 (0.36, 1.96)
1.75 (0.73, 4.16)
0.21 (0.02, 1.71)
0.97 (0.57, 1.65)
1.01 (0.38, 2.65)
0.48 (0.09, 2.59)
1.28 (0.35, 4.61)
0.43 (0.11, 1.63)
0.97 (0.81, 1.15)
0.70 (0.36, 1.36)
0.68 (0.11, 4.04)
1.40 (0.45, 4.35)
1.02 (0.67, 1.54)
100.00
4.80
2.87
2.30
1.00
0.55
26.29
2.57
(I-V)
2.55
1.07
4.30
4.08
0.62
10.92
3.27
1.09
Weight
1.86
1.70
6.99
0.95
2.40
17.82
%
0.97 (0.81, 1.15)
0.82 (0.37, 1.84)
1.61 (0.57, 4.53)
2.00 (0.63, 6.38)
1.35 (0.23, 7.78)
2.00 (0.19, 21.38)
0.89 (0.63, 1.25)
1.08 (0.25, 2.24)
ES (95% CI)
1.44 (0.48, 4.33)
0.50 (0.09, 2.67)
0.84 (0.36, 1.96)
1.75 (0.73, 4.16)
0.21 (0.02, 1.71)
0.97 (0.57, 1.65)
1.01 (0.38, 2.65)
0.48 (0.09, 2.59)
1.28 (0.35, 4.61)
0.43 (0.11, 1.63)
0.97 (0.81, 1.15)
0.70 (0.36, 1.36)
0.68 (0.11, 4.04)
1.40 (0.45, 4.35)
1.02 (0.67, 1.54)
100.00
4.80
2.87
2.30
1.00
0.55
26.29
2.57
(I-V)
2.55
1.07
4.30
4.08
0.62
10.92
3.27
1.09
Weight
1.86
1.70
6.99
0.95
2.40
17.82
%
1.1 1 10
8,867 pts, 21 trials, mean F/U 2.9 years
Favors BMS
Estimate (95% CI) Weight (%)
0.97 (0.81,1.15)
0.97 (0.81,1.15), p=0.72
Random Effects
*Fixed Effects (I2=0.0%)
Favors DES
Kirtane A et al. Circulation. 2009;119:3198-3206
SOLACI – CACI 2014
MI: All SES/PES RCTs 8,850 patients, 20 trials , mean F/U 2.9 years
D+L Overall (I-squared = 3.0%, p = 0.420)
I-V Overall
SCORPIUS
TAXUS II
PRISON II
TAXUS V
Passion
STRATEGY
MISSION!
Typhoon
SIRIUS
TAXUS IV
BASKET (All)
RAVEL
Ortolani et al
DIABETES
HAAMU-STENT
Study ID
E-SIRIUS
SES-SMART
SCANDSTENT
SESAMI
C-SIRIUS
1.1 1 10
I-V Overall (I-squared = 3.0%, p = 0.420)
SESAMI
Passion
C-SIRIUS
RAVEL
TAXUS IV
TAXUS V
SCORPIUS
SIRIUS
DIABETES
MISSION!
E-SIRIUS
SCANDSTENT
Study ID
Ortolani et al
SES-SMART
STRATEGY
HAAMU-STENT
BASKET (All)
Typhoon
TAXUS II
PRISON II
D+L Overall
0.94 (0.79, 1.13)
1.00 (0.20, 4.88)
0.83 (0.26, 2.69)
0.59 (0.14, 2.47)
1.24 (0.49, 3.14)
0.99 (0.66, 1.48)
1.27 (0.79, 2.04)
0.82 (0.23, 2.95)
0.96 (0.59, 1.55)
0.60 (0.20, 1.50)
0.62 (0.28, 1.39)
1.94 (0.93, 4.02)
0.33 (0.09, 1.18)
ES (95% CI)
1.50 (0.26, 8.61)
0.16 (0.04, 0.67)
0.82 (0.31, 2.40)
0.25 (0.03, 2.19)
1.15 (0.64, 2.08)
0.80 (0.22, 2.97)
0.63 (0.23, 1.72)
0.83 (0.26, 2.64)
0.94 (0.78, 1.13)
100.00
1.29
2.40
1.59
3.80
20.13
Weight
14.59
2.02
14.07
3.23
5.11
6.13
%
1.98
(I-V)
1.07
1.65
3.13
0.71
9.45
1.94
3.24
2.44
1.1 1 10
Estimate (95% CI) Weight (%)
0.94 (0.78,1.13)
0.95 (0.79,1.13), p=0.54
Favors DES Favors BMS
Random Effects
*Fixed Effects (I2=3.0%)
Kirtane A et al. Circulation. 2009;119:3198-3206
SOLACI – CACI 2014
TVR: All SES/PES RCTs
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 53.2%, p = 0.006)
Pache et al
Study ID
HAAMU-STENT
C-SIRIUS
Typhoon
STRATEGY
SIRIUS
SCANDSTENT
TAXUS II
PRISON II
TAXUS IV
E-SIRIUS
MISSION!
Ortolani et al
SESAMI
I-V Overall
TAXUS V
RAVEL
0.45 (0.37, 0.54)
0.38 (0.23, 0.64)
ES (95% CI)
0.33 (0.09, 1.19)
0.30 (0.10, 0.93)
0.42 (0.25, 0.69)
0.34 (0.16, 0.77)
0.48 (0.37, 0.62)
0.17 (0.09, 0.33)
0.61 (0.35, 1.08)
0.37 (0.19, 0.69)
0.57 (0.45, 0.72)
0.35 (0.21, 0.56)
0.38 (0.17, 0.85)
0.58 (0.25, 1.36)
0.36 (0.17, 0.79)
0.51 (0.45, 0.57)
0.77 (0.60, 0.98)
0.51 (0.25, 1.04)
100.00
7.14
(D+L)
1.91
2.45
7.20
4.22
11.51
5.44
%
6.44
5.49
11.94
Weight
7.45
4.08
3.78
4.36
11.75
4.83
1.1 1 10
7,291 patients, 16 trials , mean F/U 3.2 years
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
0.45 (0.37,0.54), p<0.001
0.51 (0.45,0.57)
*Random Effects (I2=53.2%)
Fixed Effects
SOLACI – CACI 2014
Target Lesion Revascularization at 5 Years TAXUS I, II-SR, IV & V
12.3% (n=162)
21.0% (n=284)
5-Year HR [95% CI]:
0.53 [0.44, 0.65]
P<0.001
0%
0 1 2 3 4 5
30%
20%
10%
TLR (
%)
BMS (n=1397)
TAXUS (n=1400)
Years
Event Rate ± 1.5 SE Stone GW et al. JACC CV Int 2011;4:530–42
SOLACI – CACI 2014
Myocardial Infarction: Landmark Analysis TAXUS I, II-SR, IV & V (n=2,797)
0%
5%
10%
0 1 2 3 4 5
4.0%
4.5%
2.3%
3.8%
Years
Event Rate ± 1.5 SE
1-5 Year HR [95% CI]:
1.67 [1.06, 2.65]
P=0.03 0-1 Year HR [95% CI]:
0.89 [0.62, 1.27]
P=0.52
Myo
ca
rdia
l in
farc
tio
n (
%)
BMS (n=1397)
TAXUS (n=1400)
Stone GW et al. JACC CV Int 2011;4:530–42
Mohr FW et al. Lancet 2013
5-year GO and ST in SYNTAX • P.W. Serruys TCT • Miami, FL • 22 October 2012 • Slide 11 SOLACI – CACI 2014
SYNTAX: Definite/Probable ARC Stent Thrombosis to 5 Years (Per Patient)
0
6
12
(3/896) (23/893) (15/874) (11/850) (12/830)
Days Post-procedure
Acute ≤1d
Subacute 2-30d
Late 31-365d
Very Late
(10/803) (7/768)
366- 730d
731- 1095d
1096- 1460d
1461- 1825d
0
6
12
10.4
(76/730)
Total 5 year
0.3
2.6
1.7 1.3 1.4 1.2
0.9
Rate was ~ same in the LM and 3VD cohorts, and roughly independent of Syntax Score
Farooq V et al. JACC 2013:62:2360–9
~4.5% ST
in year 1
~1.2% ST/yr
in years 2-4
5-year GO and ST in SYNTAX • P.W. Serruys TCT • Miami, FL • 22 October 2012 • Slide 12 SOLACI – CACI 2014
MACCE following Stent Thrombosis (Per Protocol Defn, Per Patient [n=47 STs])
Cardiac Death 30% (n=14)
Nonfatal MI 36% (n=17)
Revascularization only 34% (n=16)
47/903 MACCE (5.2%) attributed to stent thrombosis
~1/3 of pts with ST died
~2/3 of pts with ST had death or MI
100% of pts with ST had MACCE
Farooq V et al.
JACC 2013:62:2360–9
SOLACI – CACI 2014
Drug-eluting Stents: 2nd Generation
Drug Polymer
Xie
nce V
VDF + HFP copolymer Everolimus Vision
O
O
O O HO
O
O
O O H O
O O
N O
H O
Stent
Pro
mu
s
Ele
men
t
VDF + HFP copolymer Everolimus Element (Ion)
O
O
O O HO
O
O
O O H O
O O
N O
H O
SOLACI – CACI 2014
Stent Thrombosis is Affected by Stent
Design, Deployment and Polymer
Kolandaivelu K et al. Circulation 2011;123:1400-09
Impact of Xience / Promus polymer coating
In vitro pulsatile Chandler loop model with porcine blood
LD
H A
dso
rban
ce
Rela
tiv
e p
late
let
ad
hesio
n
24%
P=0.002
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
ML VISION (81 µm) XIENCE V (96.6 µm)
SOLACI – CACI 2014
SPIRIT II, III, IV and COMPARE trials
Pooled database analysis (n=6,789)
Stent thrombosis (ARC def/prob) at 2 years
Planer D et al. JACC Cardiovasc Interv. 2011;4:1104-15
1,8
2,9
0,7 0,7
0
1
2
3
4
Stable angina ACS
2-y
r S
ten
t th
rom
bo
sis
(%
)
Taxus (PES) Xience V (EES)
0.25 (0.12–0.52)
P=0.0002 0.34 (0.19–0.62)
P=0.0002
SOLACI – CACI 2014
Stent Thrombosis
Baber U, …, Dangas G JACC 2011
SOLACI – CACI 2014
Target Vessel Revascularization
Baber U, …, Dangas G JACC 2011
SOLACI – CACI 2014
Myocardial Infarction
Baber U, …, Dangas G JACC 2011
SOLACI – CACI 2014
Statistical Model
Random (13)
Fixed (13)
Clopidogrel Duration
6 months (5)
12 months (7)
Follow-up
≤ 1 year (12)
> 1 year (7)
DES
PES (5)
ZES (1)
SES (7)
Stent Thrombosis TVR MI
0,1 1 10 0,4 4 0,4 4
Favors EES Favors non-EES Favors EES Favors non-EES Favors EES Favors non-EES
SOLACI – CACI 2014
ST Regression Analysis
-3,5
-2,5
-1,5
-0,5
0,5
0 1 2 3 4
Non everolimus-eluting drug eluting stent ST rate, %
Ris
k D
iffe
ren
ce,
%
R2=0.89, p<0.001 Sirolimus eluting stent
Zotarolimus eluting stent
Paclitaxel eluting stent
Baber U, …, Dangas G JACC 2011
SOLACI – CACI 2014
EXAMINATION Trial
0 1 2 3
Xience V
Vision
Acute Subacute Late
p = 0.01
1504 pts with STEMI undergoing PCI within 48 (85% primary PCI
within 12) were randomized to Xience V EES vs. Vision BMS
Stent thrombosis (Def/prob) within 1 year
2.6%
0.9%
Definite ST was reduced with Xience V from 1.9% to 0.5%, p=0.01
Sabate M et al. Lancet 2012
SOLACI – CACI 2014
Stent Thrombosis Network Meta-analysis Primary EP: ARC Definite ST (FU through 2 years)
49 RCTs, 50,844 pts
Evidence
network
Palmerini T et al. Lancet 2012:On-line
9 studies PES BMS
SES End-ZES
Res-ZES Pt-Cr-EES
CoCr-EES
6 studies
SOLACI – CACI 2014
Stent Thrombosis Network Meta-analysis ARC Definite ST at 1 year
49 RCTs, 50,844 pts
Odds Ratio
[95%] 1-year definite stent thrombosis*
CoCr-EES vs BMS
CoCr-EES vs PES
CoCr-EES vs SES
CoCr-EES vs Res-ZES
CoCr-EES vs End-ZES
SES vs BMS
End-ZES vs SES
0.23 (0.13-0.41)
0.28 (0.16-0.48)
0.41 (0.24-0.70)
0.14 (0.03-0.47)
0.21 (0.10-0.44)
0.57 (0.36-0.88)
1.92 (1.07-3.90)
Favors Stent 1 Favors Stent 2
10 1 0.1 0.01
*Only statistically significant
results are shown Palmerini T et al. Lancet 2012:On-line
SOLACI – CACI 2014
0
1
2
3
4
5
6
0 3 6 9 12 15 18 21 24 27 30 33 36
PLATINUM: Target Lesion Failure
Months Since Index Procedure
CoCr-EES
PtCr-EES
No. at risk
4-Year Follow-up (Primary Endpoint at 1 Year)
749 738 735 715 701 683 656 473
758 747 745 727 715 702 687 480
CoCr-EES (N=749)
PtCr-EES (N=758)
0
3
6
9
12
15
0 6 12 18 24 30 36 42 48
TL
F (
%) 8.5%
7.4%
Treatment Group PROMUS Element 0-4YPROMUS 0-4Y
Primary Endpoint
HR [95% CI] =
0.86 [0.60, 1.24]
P = 0.43
Kereiakes DJ et al. JACC 2014;63 (12):2905-4 (SuppA)
SOLACI – CACI 2014
Reso
lute
BioLinx Zotarolimus Driver
Drug Polymer Stent
Zotarolimus-eluting DES: 2nd Generation
Hydrophilic
Hydrophobic
En
deavo
r
Phosphorylcholine Zotarolimus Driver
SOLACI – CACI 2014
Days after Initial Procedure
Cu
mu
lati
ve In
cid
en
ce o
f E
ven
ts
11.2% 10.7%
0%
0 180 360 540 720
20%
5%
15%
10%
EES (n=1,152)
R-ZES (n=1,140)
95% CI = 0.6% [-2.0%, 3.2%]
P = 0.73
RESOLUTE All-Comers: TLF (Cardiac Death, TV-MI or clinically-driven TLR)
Silber S et al. Lancet. 2011;377:1241-7
SOLACI – CACI 2014
TWENTE (n=1,387)
Target Vessel Failure at 2-Year Follow-up
Tandjung K et al. J Am Coll Cardiol 2013;61:2406–16
0 60 120 180 240 300 360 420 480 540 600 660 720
TV
F (
%)
Follow-up (days)
0
5
10
15
20
25
30
Xience V (n=692)
Resolute (n=695)
P = 0.67
11.6%
10.9%
SOLACI – CACI 2014
Endeavor ZES
PROTECT Study Design
Largest RCT and first powered for ST
Cypher SES
6mo 4yr 3yr 30mo 18mo 24mo 12mo Clinical endpoints
5yr 30d
Real-world patients – N=8709 Single and multiple coronary artery lesions No limitations on number of lesions/vessels
1:1 Randomization
196 sites world wide in 5 continents
3-12 months of aspirin and clopidogrel
Primary endpoint: ARC definite or probable ST at 3 years
Powered for a 40% reduction with ZES
Camenzind E et al. Lancet 2012
SOLACI – CACI 2014
Definite or probable stent thrombosis to 3 years
Patients at Risk
E-ZES 4357 4347 4222 4119
C-SES 4352 4344 4211 4100
PROTECT Primary Endpoint
Time After Initial Procedure (Years)
AR
C D
efi
nit
e / P
rob
ab
le S
T
0%
0 1 3
5%
2%
2
1%
Endeavor ZES (N = 4357)
Cypher SES (N = 4352)
1.42%
1.79%
3%
4%
Camenzind E et al. Lancet 2012
HR [95%CI =
0.81 [0.58-1.14]
P=0.22
SOLACI – CACI 2014
Definite or probable stent thrombosis to 3 years
PROTECT Primary Endpoint
Camenzind E et al. Lancet 2012
0,7
0,4 0,3
0,6
0,1
1,1
0
0,3
0,6
0,9
1,2
1,5
Ste
nt
thro
mb
osis
(%
)
Cypher SES (n = 4159) Endeavor ZES (n = 4181)
Late
(1 -12 months)
Early
(0-30 days)
Very late
(1-3 years)
P = 0.60
P = 0.02
P<0.001
SOLACI – CACI 2014
Sarno G et al. EHJ 2012;33:606–13
Relative Distribution of Stent Types
BMS vs 1st Gen DES vs. 2nd Gen DES SCAAR: 94,384 consecutive pts in Sweden 2006-2010
(BMS 64,631; 1st gen DES 19,202; 2nd gen DES 10,551 1st gen = Cypher, Taxus , Endeavor. 2nd gen = Resolute, Xience, Promus Element
2006-1
1
20%
Year and month
2007-0
1
40%
0%
60%
80%
100%
2007-0
3
2007-0
5
2007-0
7
2007-0
9
2007-1
1
2008-0
1
2008-0
3
2008-0
5
2008-0
7
2008-0
9
2008-1
1
2009-0
1
2009-0
3
2009-0
5
2009-0
7
2009-0
9
2009-1
1
2010-0
1
2010-0
3
2010-0
5
2010-0
7
2010-0
9
1st gen DES 2nd gen DES
BMS
SOLACI – CACI 2014
BMS vs 1st Gen DES vs. 2nd Gen DES SCAAR: 94,384 consecutive pts in Sweden 2006-2010
(BMS 64,631; 1st gen DES 19,202; 2nd gen DES 10,551 1st gen = Cypher, Taxus , Endeavor. 2nd gen = Resolute, Xience, Promus Element
Sarno G et al. EHJ 2012;33:606–13
Adjusted Event Rates: Death
Months
Adj HR of 2nd gen DES
vs. 1st gen DES: 0.77 [0.63–0.95]
vs. BMS: 0.55 [0.46–0.67]
BMS
1st gen DES
2nd gen DES
6%
0
5%
4%
3%
2%
1%
0%
3 6 9 12 15 18 21 24
De
ath
(%
)
SOLACI – CACI 2014
Number at risk
XIENCE V 2458 2390 2364 2323 2281 2238 2212 2187 2162 2132 2116 2095 2074
TAXUS 1229 1166 1138 1119 1095 1069 1060 1049 1029 1019 1008 994 979
Targ
et
lesio
n f
ailu
re (
%)
Months
XIENCE V (n=2,458)
TAXUS Express (n=1,229)
p=0.02
HR [95%CI] =
0.78 [0.63, 0.97]
6.7%
4.0%
p=0.001
HR [95%CI] =
0.61 [0.46, 0.81]
Δ 2.7%
0
5
10
15
20
25
0 3 6 9 12 15 18 21 24 27 30 33 36
11.7%
9.2%
Δ 2.5%
p=0.004
HR [95%CI] =
0.71 [0.56, 0.90]
SPIRIT IV: Target Lesion Failure @3 years
TLF = cardiac death, target vessel MI, or ischemic-driven TLR
Stone GW et al. JACC 2011 (abstract)
~2.6%/yr event rate after year 1
SOLACI – CACI 2014
15-year Follow-up After BMS (1990-1993)
N=405
Yamaji K et al. Circ CV Int 2010
Sudden
death
Cardiac
death
All-cause
death
All-cause
death /MI/
revasc
All-cause
death/MI
83.8%
Years after Stent Implantation
51.6%
45.4%
20.6%
7.1%
100
80
60
40
20
0
0 5 4 10 15 20
Cardiac
death/
TV-MI
Cardiac
death/
TV-MI/
TLR
Years after Stent Implantation
50.6%
25.5%
100
80
60
40
20
0
0 5 4 10 15 20
~2.1%/yr event
rate after year 1
SOLACI – CACI 2014
Very Late Adverse Events After BMS
Yamaji K et al. Circ CV Int 2010
Pre Post 5 years 15 years
Pre Post 2 years 17 years
Pre Post 5 years 13 years
In-stent restenosis at 15 years
Stent thrombosis at 17 years
Aneurysm formation at 13 years
SOLACI – CACI 2014
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
SOLACI – CACI 2014
6-mo Taxus
%NC 8%
%DC 2%
9-mo Taxus
%NC 28%
%DC 8%
22-mo Taxus
%NC 39%
%DC 20%
48-mo BMS
%NC 40%
%DC 25%
57-mo BMS
%NC 57%
%DC 15%
Neoatherosclerosis: Transformation of Neointimal
Hyperplasia to Necrotic Core in BMS and DES
Kang SJ et al. AJC 2010;106:1561-1565
SOLACI – CACI 2014
Three Approaches to Improve Late
DES Outcomes
1. Metallic DES with bioabsorbable polymers
2. Metallic DES, polymer-free
3. BioResorbable vascular scaffolds (BVS)
SOLACI – CACI 2014
Stefanini GG et al. EHJ 2012;33:1214–22
Ste
nt
thro
mb
os
is (
%)
2
0
0
3
4
5
HR (95% CI) DP BP
ISAR-TEST 3 1/202 2/202
ISAR-TEST 4 9/1299 10/652
LEADERS 20/857 32/850
Overall 30/2358
0.47 (0.04, 5.04)
0.45 (0.18, 1.12)
0.62 (0.35, 1.08)
44/1704 0.56 (0.35, 0.90)
0.1
Favors BP HR
10
Favors DP
0.22 [0.08, 0.61]
P=0.004
0.02 [0.47, 1.38]
P=0.43
1 2 3 4
1
Ste
nt
thro
mb
os
is (
%)
Years
2
0
0
3
4
5
HR [95%CI] = 0.56 [0.35, 0.90]
P=0.015
1 2 3 4
1
Biodegradable polymer Durable polymer
Years
Test for heterogeneity P=0.84
Test for inconsistency 12=0%
Test for overall effect z2=2.43 (P=0.015)
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)
Definite Stent Thrombosis
1.3%
2.8%
SOLACI – CACI 2014
Abluminal Bioabsorbable Polymer
SYNERGY Stent (BSC)
Abluminal bioabsorbable
polymer (PLGA)
3-4 um thick
Thin PtCr stent
(74 – 81 um)
PLGA bioabsorbable
polymer + everolimus on
abluminal side of stent
Coating weight on 16 mm
stent ~200 µg (vs ~685 µg
for Xience / Promus)
Everolimus elutes over
~3 months (similar to
Xience / Promus)
PLG undetectable by
~4 months, leaving
behind a BMS
SOLACI – CACI 2014
291 Pts Randomized to
Promus Element vs. Synergy vs Synergy ½ dose Primary Endpoints
Meredith I et al. JACC 2012;59:1362–70
P=0.19
Late Loss at 6 Months TLF at 30 Days
La
te lo
ss, m
m
0.0
0.5
0.6
PROMUS
Element
SYNERGY SYNERGY
½ Dose
P=0.56
0.4
0.3
0.2
0.1
0.15 0.10 0.13
P=0.49
Targ
et
lesio
n f
ail
ure
, %
0.0
8.0
10.0
PROMUS
Element
SYNERGY
P=0.25
6.0
4.0
2.0
0
1.1
3.1
SYNERGY
½ Dose
SOLACI – CACI 2014
EVOLVE II Study Design SYNERGY Stent Pivotal Trial
Randomized cohort (RCT)
SYNERGY
N=842
PROMUS Element
N=842
RCT Design
Multicenter noninferiority trial
Single-blind, 1:1 randomization
Primary Endpoint: TLF (CD, TV-MI, or TLR) at 12 mo
Follow-up: 30d, 6m, 12m, 18m and annual 2-5 yrs
1,954-2,006 pts with native coronary lesions ≤34 mm in length, RVD ≥2.25 mm - ≤4.0, %DS ≥50%
Up to 3 lesions in 2 vessels
(excludes LM disease, CTO, ISR, STEMI)
SYNERGY
N=250-292
SYNERGY
N=20-30
Diabetes
Substudy
PK
Substudy
Up to 160 global sites
Enrollment Complete
SOLACI – CACI 2014
Selectively micro-structured surface holds
drug in abluminal surface structures
BioFreedom Stent (Biosensors) Hypothesis: Polymer-free drug
release via porous-eluting
stents may reduce late events
caused by polymer stent
coatings.
Potential advantages
• Avoid long term late adverse
effects that might be attributable to
the polymer
• Improved surface integrity since
there is no polymer to be sheared
or pealed away from the stent
struts
• Possible shorter need of dual
antiplatelet therapy
Biolimus A9 - lipophilic
SOLACI – CACI 2014
DFS: Drug Filled Stent (Medtronic)
Drug elution controlled by diffusion physics
Elution Holes
SOLACI – CACI 2014
Bioresorbable Vascular Scaffolds (BRS)
Igaki-Tamai PLLA
Magnesium
(eluting sirolimus) Biotronik Dreams
PLLA
(eluting everolimus) Abbott Absorb
Reva ReSolve Iodinated tyrosine-
derivative
(eluting sirolimus)
Elixir DESolve PLLA
(eluting novolimus)
SOLACI – CACI 2014
Igaki-Tamai Stent (2000)
Hideo Tamai, MD Died 14 Feb, 2009
SOLACI – CACI 2014
A
B
C
C
B
A
D
D
E
E
I-T stent
@10
Years!
Onuma Y et al. EuroInt 2009
SOLACI – CACI 2014
SOLACI – CACI 2014
Mass L
os
s (
%)
BVS Resorption: Molecular Weight and Mass Loss
Resorption by 36 Months in Porcine Coronary Model
Images and data on file with Abbott Vascular
1 month 12 months 18 months 24 months 30 months 36 months 42 months
Mo
lecu
lar
Weig
ht
(%)
Months
100
80
60
40
20
0 0 6 12 18 24 30 36 42
Limit of measurement
Months
100
80
60
40
20
0 0 6 12 18 24 30 36 42 48
SOLACI – CACI 2014
BVS: Restoration of Pulsatility in the Porcine
Coronary Model
Data on file, Abbott Vascular
Δ D
iasto
le-S
ys
tole
Lu
me
n A
rea
Months
BVS
EES
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
1 3 6 12 18 24 30 36 42
SOLACI – CACI 2014
ABSORB: Vasomotion Restoration Restoring Natural Vessel Function
1,2Serruys PW. ACC 2011; 3Serruys PW et al. Lancet 2009;373:897-910
in
Vessel
Dia
mete
r (m
m)
-1.0
-0.5
0.0
0.5
1.0
(N = 15)
6 Months1
(N = 6) (N = 19)
12 Months2
(N = 13) (N = 9)
24 Months3
(N = 7)
Vaso
dilati
on
V
aso
co
nstr
icti
on
Cohort B1 Cohort B2 Cohort A
(pre
-dru
g infu
sio
n t
o p
ost-
dru
g infu
sio
n)
Methergine
Acetylcholine
SOLACI – CACI 2014
Cu
mu
lati
ve f
req
ue
nc
y d
istr
ibu
tio
n (
mm
)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
-0,75 -0,5 -0,25 0 0,25 0,5 0,75 1 1,25 1,5 1,75 2
Late loss (mm)
6 month (SPIRIT II): 0.17 ± 0.32 mm (N=97)
24 month (SPIRIT II): 0.33 ± 0.37 mm (N=97)
Claessen BE et al. Circ CV Int. 2009;2:339-47
Late Loss with Absorb Cohort B vs. Xience V
SOLACI – CACI 2014
Cu
mu
lati
ve f
req
ue
nc
y d
istr
ibu
tio
n (
mm
)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
-0,75 -0,5 -0,25 0 0,25 0,5 0,75 1 1,25 1,5 1,75 2
Late loss (mm)
Late Loss with Absorb Cohort B vs. Xience V
6 month (SPIRIT II): 0.17 ± 0.32 mm (N=97)
24 month (SPIRIT II): 0.33 ± 0.37 mm (N=97)
6 month (Cohort B): 0.19 ± 0.18 mm (N=42)
24 month (Cohort B): 0.27 ± 0.20 mm (N=38)
Claessen BE et al. Circ CV Int. 2009;2:339-47
Serruys PW. ESC 2012
SOLACI – CACI 2014
BL 1Y
3Y
5Y
• At baseline, the scaffold shields the vessel wall from wall stress (Lancet 2009)
• During the first year, thick struts generating low shear stress serve as a template for neointimal formation
• At 3 years, neointimal growth has been fully compensated by the outward shift of malleable remnants of the scaffold, so that the lumen late loss remains unchanged.
100
40
70
80
90
60
50
0.6 1.2 1.8 2.4
30
20
10
0
0 -0.6
1Y cohort B
• At 4 and 5 years, vessel wall thinning ( ± plaque-media reduction) will result in progressive late lumen enlargement
3Y cohort B
2 Year 3 Year 4 Year
c/o Serruys PW
SOLACI – CACI 2014
Months
mm2
6
6,5
7
7,5
8
8,5
9
0 6 12 18 24 30 36
B2
Δ- 0.31mm2
P=0.004
Δ+0.73 mm2
P<0.0001
Δ+0.46mm2
P=0.0006
Δ+0.58mm2
P=0.0002
Cohort B2: Serial Quantitative IVUS (n=45)
Mean Scaffold Area Mean Lumen Area Total Plaque Area
Serruys PW et al.
EuroInt 2014
SOLACI – CACI 2014
%
mm2
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25
Plaque
Mean Vessel area at 18 months Mean Vessel area at 60 months
Mean Plaque area at 18 months Mean Plaque area at 60 months
Mean Lumen area at 18 months Mean Lumen area at 60 months
Lumen = Vessel
Cohort A: CFD Curves of Vessel Area, Plaque Area
and Lumen Area on MSCT at 18 and 60 Months
Onuma Y et al. JACC CV Int 2013;6:999–1009
SOLACI – CACI 2014
Vessel area (mm2) 15.72 15.34 14.09 13.76
Mean lumen area (mm2) 6.95 6.17 6.56 8.09
Plaque area (mm2) 8.78 9.17 7.54 7.07
Interventional Plaque Regression by BVS:
Substantial lumen enlargement due to plaque
regression with adaptive remodeling (cohort A pt)
Pre-PCI Post-PCI 6 months 2 years 5 years
c/o Patrick Serruys
SOLACI – CACI 2014
ABSORB III + IV
A clinical program consisting of
2 integrated randomized trials designed to:
1) Achieve approval of ABSORB in the US
and
2) Demonstrate superiority of ABSORB
compared to best in class DES
ABSORB III: 2,000 randomized pts (enrolled)
ABSORB IV: 3,000 randomized pts (to begin soon)
SOLACI – CACI 2014
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
• If clinical trials prove that BRS reduce very late events
from 1-5 years and/or stabilize or regress plaque, the
4th revolution in IC will have arrived!
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