Reduction in Stent Reduction in Stent Thrombosis – better Thrombosis – better tablets or better tablets or better stents? stents? Dr James Cotton MD FRCP Dr James Cotton MD FRCP Heart and Lung Centre Wolverhampton
Jan 16, 2016
Reduction in Stent Thrombosis Reduction in Stent Thrombosis – better tablets or better – better tablets or better
stents?stents?
Dr James Cotton MD FRCPDr James Cotton MD FRCPHeart and Lung Centre
Wolverhampton
MY CONFLICTS OF INTEREST ARE
• Speaker Fees/Honoraria/Travel Support– Lilly/Daiichi Sankyo– Schering-Plough– The Medicines Company– Medtronic
• Research Support– J&J Cordis
24
7.66
1.4 0.5 1.5 0.9 1.6 1 0.4 0.30
5
10
15
20
25
Serr
uys
1991
Rou
bin
1992
Scha
tz 1
991
Col
ombo
199
5Le
on M
B 19
98M
ouss
a 19
99C
utlip
200
1W
enaw
eser
200
5M
oren
o 20
06K
hedi
201
0St
one
2010
% S
ten
t T
hro
mb
osi
s
ASA and Oral Anticoag
ASA and Ticlopidine
ASA and Clopidogrel
New Generation DES
PrasugrelTicagrelor
Risk of Definite Stent Risk of Definite Stent ThrombosisThrombosis
Stable
Angina
UA/
NSTEMISTEMI
Bare Metal Bare Metal StentsStents
0-0.5% 1.4-1.6% 2.9%
Drug Drug Eluting Eluting StentsStents
0.3-0.4% 1.2-1.9% 3.1%
Cook, Windecker Circulation 2009
Angiographic DES Stent ThrombosisAngiographic DES Stent ThrombosisBern - Rotterdam Cohort StudyBern - Rotterdam Cohort Study
33
22
11
00
Days after stent implantation Days after stent implantation
Cu
mu
lati
ve p
rob
abiit
y o
f st
ent
Cu
mu
lati
ve p
rob
abiit
y o
f st
ent
th
rom
bo
sis
(%)
thro
mb
osi
s (%
)
Wenaweser et al. ESC, Barcelona Sept 2006
N = 8,146 Patients (SES=3875;PES=4271) N = 8,146 Patients (SES=3875;PES=4271)
Incidence = 1.3/100 pts year
Cumulative Incidence 1.1% 1.2% 1.7% 2.3% 2.9%
2.9 %2.9 %
N = 152 Patients N = 152 Patients
00 200200 400400 600600 800800 10001000 12001200
Early91 pts(60%)
Late61 pts(40%)
Between 30 days to 3 years
Between 30 days to 3 years
Slope = 0.6% / year
Slope = 0.6% / year
Better Drugs?
Discontinuation of thienopyridine therapy:Milan-Siegburg Cohort Study
Airoldi F et al Circulation 2007 116:745-54
Stent Thrombosis and 2C19 Stent Thrombosis and 2C19 polymorphismspolymorphisms
Mega J et al JAMA 2010, 304(16) 1829-40
-20.0-20.0
0.00.0
20.020.0
40.040.0
60.060.0
80.080.0
100.0100.0
Inh
ibit
ion
of
Pla
tele
t A
gg
reg
atio
n (
%)
Inh
ibit
ion
of
Pla
tele
t A
gg
reg
atio
n (
%)
Response to Response to prasugrelprasugrel
Response to Response to clopidogrelclopidogrel
clopidogrel responder
clopidogrel non-responder
*Responder = 25% IPA at 4 and 24 h
Clopidogrel (300 mg) vs. prasugrel (60 mg)Clopidogrel (300 mg) vs. prasugrel (60 mg)Phase I – healthy subjectsPhase I – healthy subjects
Brandt JT et al. Am Heart J 2007;153:66.e9-e16
Inh
ibit
ion
of
Pla
tele
t A
gg
reg
atio
n (
%)
Inh
ibit
ion
of
Pla
tele
t A
gg
reg
atio
n (
%)
Response to Response to prasugrelprasugrel
Response to Response to clopidogrelclopidogrel
0.00.0
20.020.0
40.040.0
60.060.0
80.080.0
100.0100.0
clopidogrel responder
clopidogrel non-responder
Clopidogrel (300 mg) vs. prasugrel (60 mg)Clopidogrel (300 mg) vs. prasugrel (60 mg)Phase I – healthy subjectsPhase I – healthy subjects
*Responder = 25% IPA at 4 and 24 h
-20.0-20.0
Brandt JT et al. Am Heart J 2007;153:66.e9-e16
TRITON-TIMI 38: Stent thrombosis ratesTRITON-TIMI 38: Stent thrombosis ratesat end of studyat end of study
All Stents Bare-metal Stents
0
1
2
3
4
Ste
nt
Th
rom
bo
sis*
(%
)
Drug-eluting Stents
2.35 2.312.41
N=6,422N=6,422 n=2,878n=2,878 n=3,224n=3,224
1.130.84
1.27
N=6,422N=6,422 n=2,865n=2,865 n=3,237n=3,237
clopidogrelprasugrel
52% RRR(1.2% ARR)
64% RRR(1.5% ARR)
48% RRR(1.1% ARR)P=0.0009P=0.0009P<0.0001P<0.0001P<0.0001P<0.0001
*Stent thrombosis defined as Academic Research Consortium definite plus probable
ARC = Academic Research ConsortiumARR = Absolute Risk ReductionHR = Hazard Ratio NNT = Number Needed to TreatPCI = Percutaneous Coronary InterventionRRR = Relative Risk Reduction Wiviott SD et al. Lancet 2008;371:1353-1363
P=NS
Life Threatening
P=NSP=0.002
IntracranialFatal Nonfatal
P=0.01
(n=6,716)
(n=6,741)
En
d P
oin
t (%
)
Subsets of Life Threatening Bleeds
n=85
n=56
0.9%
1.4%
n=5
0.1% n=21
0.4%
n=51
0.9% n=64
1.1%
n=17 n=19
0.3% 0.3%
both + aspirinboth + aspirin
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
TRITON-TIMI 38: Life Threatening BleedsTRITON-TIMI 38: Life Threatening Bleedsat 15 months (All ACS)at 15 months (All ACS)
NS = Not Significant
Will duration of DAPT be key?
• DAPT - 2014
• REAL –LATE - 2011
• OPTIDUAL - 2013
Better Stents?
New stent New stent technologiestechnologies
Comparative Endothelial Cell CoverageComparative Endothelial Cell CoverageRabbit Denudation Model (14 Days) Rabbit Denudation Model (14 Days)
EC
Str
ut
Covera
ge (
%)
(14
Days)
EC
Str
ut
Covera
ge (
%)
(14
Days)
p=0.05 Express p=0.05 Express vs.vs. Liberte Libertep=0.001 Express p=0.001 Express vs. Element Element
ExpressExpress LibertéLiberté ElementElement
Ste
nt S
trut T
hickn
ess (µ
m)
Ste
nt S
trut T
hickn
ess (µ
m)
Soucy. EuroPCR 2010Soucy. EuroPCR 2010
SPIRIT IVSPIRIT IV
The Abluminal Biodegradable Polymer DES
PLA biodegradation and BA9™ elution
Abluminal biodegradable coating absorbed after 6-9 months*
19* In vivo testing in porcine model demonstrates abluminal coating is absorbed after 6 to 9 months - Data on file at Biosensors Intl
Leaders Trial - Stent thrombosis
Other Bioabsorbable polymer studies
• COSTAR – II
• ISAR-TEST 3
• ISAR TEST 4
• NOBORI CORE
• NOBORI-I
• RESELUTION
No reduction ST for DES BPVs DES PP
Salinas P Abs AHA 2010 6032
Genous- E-healing Registryn=4939
Acute Thrombosis
0.2%
Subacute thrombosis
0.7%
Late Thrombosis 0.2%
Silber S et al, Euro intervention In Press
Evolutions of Nevo Stent
• RES – 1 ( no coating)• 200 patients NO ST
• ? Heparin coating may improve haemocompatability
Combo Bio-engineered Sirolimus Eluting Stent
Granada, et al. CIRC Cardiovasc Interv, June 2010; 3
The Lancet The Lancet Vol 373 March 14 2009Vol 373 March 14 2009
Absorb: histology and OCTAbsorb: histology and OCT
Further studies?Further studies?
• Clinical trial aiming to demonstrate a reduction in ST from 0.4 to 0.2%
• 80% power
• 284,000 subjects!
? Training
THANKYOUTHANKYOU
ARC Definitions of STARC Definitions of ST
• Definite Stent Thrombosis– Angiographic or pathological conformation of partial or total
thrombotic occlusion within the peri-stent region AND at least one of:
– Acute ischaemic symptoms– Ischaemic ECG changes– Elevated biomarkers
• Probable Stent Thrombosis– Any unexplained death within 30 days of stent implantation– Any MI related to ischemia in the territory of the implanted stent
without angiographic conformation of ST
• Possible Stent Thrombosis– Any unexplained death beyond 30 days