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

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10

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20

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1991

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% S

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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

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ent

Cu

mu

lati

ve p

rob

abiit

y o

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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

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of

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tele

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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

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of

Pla

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reg

atio

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Inh

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of

Pla

tele

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gg

reg

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%)

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