Comment éviter la thrombose de stent tardive · No difference in all-MI Spaulding C., Daemen J, Boersma E, ... N Engl J Med 2007 epub February 13. MACE rates individual data (pooled

Comment Comment ééviter la thrombose de viter la thrombose de stent tardivestent tardive

Christian Spaulding

Service de cardiologie

Hôpital Cochin

Université Paris Descartes

Paris

Sus aux idSus aux idéées rees reççues !!!!!ues !!!!!

• On tue les patients avec les stents actifs!

• La thrombose de stent nue n’existe pas!!!

• Il ne faut pas poser de stents actifs en phase aigu e d’infarctus du myocarde !!!

• Les stents de nouvelle génération font moins de thrombose aigues que les premières générations!!

• En dehors du clopidogrel, point de salut!

• Alors que faire pour diminuer la thrombose de stent (en dehors du traitement antiaggrégant plaquettaire )?

ESC 2006, Camenzind E. et al.

0 360 720 1080 1440

80%

85%

90%

95%

100%

Total population

N=1748

94.6%

93.3%

Logrank P-value: 0.27

14831624167217151748

Patients at risk

14831624167217151748

Patients at risk

Sirolimus eluting stent group

Bare metal stent group

ALL CAUSE DEATH

No significant difference between groupsDiverging curvesNo difference in all-MI

Spaulding C., Daemen J, Boersma E, Cutlip D and Serruys PN Engl J Med 2007 epub February 13

MACE rates individual data (pooled data HCRI & Cardialysis) vs. Camenzind

RAVEL, SIRIUS,

E-SIRIUS, C-SIRIUS

N = 1748

Camenzind Real data to 1440 days

Cypher Control P-value Cypher Control P-value

Death total 4.7% 3.3% 0.18 6.5% 5.1% 0.22

Q-MI 1.6% 0.6% 0.06 2.1% 1.3% 0.26

Non-Q-MI - - - 4.3% 4.9% 0.57

Death total and Q-MI 6.3% 3.9% 0.03 8.0% 6.1% 0.13

Death total and all MI - - - 11.4% 10.1% 0.40

Independent physician-directed meta-analysis

versus

Independent physician-assessed patient level meta-analysis

Cum

ulat

ive

prob

abili

ty o

f ste

nt th

rom

bosi

s (%

)

Days after stent implantation0 200 400 600 800 1000 1200

0

1

2

3

N=8,146 PatientsBetween 30 days to 3 years:

Slope = 0.6% / year

Early and Late Coronary Stent Thrombosis of Drug-Eluting Stents in Routine Clinical Practice

Daemen J, Wenaweser P et al, Lancet 2007 369: 667–78

Days after PCI

10

8

6

4

2

00 30 60 120 600

N

Early1.2%

(N=71)

Late0.4%

(N=24)

Late Stent Thrombosis and Bare Metal StentsWenaweser P et al. Eur Heart J 2005;26:1180-7

Study population 1995-2002

-6058 patients undergoing PCI

with bare metal stents

Thrombose de stent: ExpThrombose de stent: Expéérience Mayo rience Mayo ClinicClinic

• 4053 patients suivis après implantation de BMS

• 0.5% à 30 jours, 0.8% à un an et 2% à 10 ans avec 17 cas après 5 ans

• Facteurs prédictifs: SCA, greffon saphène, lésion ulcerée

• Resténose sur 10 ans: 18,1% avec IDM dans 2,1%

Doyle B et al, Circulation. 2007;116:2391-2398







TYPHOONLower TVF Risk vs BMS

25

20

10

5

0

Pat

ient

s (%

)

15

0

60 120 180 240 300 360Time (days)

3.14.2

7.3

2.8

6.2

14.3

49%p=0.0036*

CYPHER® BMS

1º Endpoint: TVF at 1 year*

* Defined as ischaemia driven TVR, recurrent MI, or target vessel-related cardiac death

Spaulding C, et al. N Engl J Med. 2006;355:1093-104.

Intention-to-Treat Analysis at 1 year

CYPHER® Stent vs BMS: No difference in Stent ThrombosisSummary of CYPHER ® Stent vs BMS Trials

Pat

ient

s (%

)

10

6

4

2

MULTISTRATEGY

2.7

8-month

Diaz

3.4

1.8

MISSION

1.32.0

TYPHOON

3.4 3.6

SESAMI

4.7

6.0

STRATEGY

1.2

4.6

8

0

1-year 1-year 1-year 2-year 2-year

4.0

Definitions of ST vary by trial: ARC Def/Probable used when possible

Dual APTRecommendation

n=745

3 months

n=120

9 months

n=308

12 months

n=712

6 months

n=320

12 months

n=175

6 months

p=NS for all trialsCYPHER® BMS

Patient compliance and AMIPatient compliance and AMI

Jackevicius CA et al, N Engl J Med 2008 359:1802-10

BARE METAL STENTS !!!! S


• La thrombose de stent actif tue !!!






Time after Initial Procedure (days)Time after Initial Procedure (days)

Cum

ulat

ive

Inci

denc

e of

C

umul

ativ

e In

cide

nce

of

Def

/Pro

b S

T (

AR

C)

Def

/Pro

b S

T (

AR

C)

360360 450450 540540 630630 7207200.0%0.0%

0.5%0.5%

1.0%1.0%

1.5%1.5%

2.0%2.0%

2.5%2.5%

0.9%0.9%

0.1%0.1%

EndeavorTaxus

1-2year HR0.17 [0.20, 1.39]

P=0.059P=0.059

Endeavor 726 726 Endeavor 726 726 709 705 709 705 699699Taxus 725 725 Taxus 725 725 706 703 706 703 699 699

ENDEAVOR IV ENDEAVOR IV –– 2yr FU2yr FUARC Def/Prob ST 12ARC Def/Prob ST 12 --24 mos (VLST) 24 mos (VLST)

SORT-OUT III: A Prospective Randomized Comparison of Zotarolimus-Eluting and Sirolimus-Eluting Stents in Patients with

Coronary Artery Disease

Jens Flensted Lassen, Klaus Rasmussen, Anders Galløe,

Per Thayssen, Henning Kelbæk, Jan Ravkilde, Ulrik Abildgaard,Lisette Okkels Jensen, Evald Høj Christiansen, Knud Nørregaard Hansen,

Hans Henrik Tilsted, Peter Riis Hansen, Lars Romer Krusell,Thomas Engstrøm, Jens Aarøe, Jan Skov Jensen, Hans Erik Bøtker,

Steen Dalby Kristensen, Steen Z Abildstrøm, Anne Kaltoft, Michael Maeng, Morten Madsen, Søren Paaske Johnsen

& Leif Thuesen

Target Lesion Revascularization

Hazard Ratio (95% CI) 4.19 (2.10 – 8.35)

p< 0.0001

Definite Stent Thrombosis

Hazard Ratio (95% CI) 4.62 (1.33 – 16.1)

p=0.02

Target Lesion Revascularization (lesion)

Adjusted RR (95% CI) = 2.39 (1.82 – 3.13)

P<0.0001

Cypher (n) 5095 4320 3347 2081 751 143Endeavor (n) 3090 2338 1339 637 122 0

TLR

(%

)

EndeavorCypher

Western Denmark Registry, TCT 08

Definite Stent Thrombosis (lesion)Adjusted RR (95% CI) = 1.78 (1.06 – 3.00)

P<0.05

Cypher (n) 5095 4320 3347 2081 751 143Endeavor (n) 3090 2338 1339 637 122 0

Def

inite

ste

nt th

rom

bosi

s (%

)

EndeavorCypher







TRial to Assess Improvement in Therapeutic Outcomes by Optimizing

Platelet Inhibitio N with Prasugrel

TRITONTRITON--TIMI 38TIMI 38AHA 2007AHA 2007

Orlando, FloridaOrlando, Florida

Disclosure StatementDisclosure Statement : : The TRITONThe TRITON--TIMI 38 trial was supported by a research grant TIMI 38 trial was supported by a research grant support from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.support from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.

Active Metabolite Active Metabolite FormationFormation

PrasugrelPrasugrel

Niitsu et al Semin Thromb Hemost 31: 184, 2005

Pro-drugPro-drug

Oxidation(Cytochrome P450)


Hydrolysis(Esterases )

Hydrolysis(Esterases )

ClopidogrelClopidogrel

85% Inactive Metabolites

Esterases

85% Inactive Metabolites

Esterases Intermediary Intermediary MetaboliteMetabolite

Intermediary Intermediary MetaboliteMetabolite

Active MetaboliteActive Metabolite

Active Active MetaboliteMetabolite



Redundancy in CYP P450 Redundancy in CYP P450

pathways used for metabolismpathways used for metabolism

STUDY DESIGN

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch

CV death, MI, UTVRStent Thrombosis

Key Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

Enrollment CriteriaEnrollment Criteria

•Inclusion CriteriaPlanned PCI for :

High Risk UA/NSTEMI (TIMI Risk Score > 3)STEMI: < 14 days (ischemia or Rx strategy)STEMI: Primary PCI

•Major Exclusion Criteria :– Severe comorbidity– Increased bleeding risk– Prior hemorrhagic stroke or any stroke < 3 mos– Any thienopyridine within 5 days– No exclusion for advanced age or renal function

KnownAnatomy

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

HR 0.80P=0.0003

HR 0.77P=0.0001

Days

Prim

ary

End

poin

t (%

) 12.1(781)

9.9 (643)

138 events

Primary EndpointPrimary EndpointCV Death,MI,StrokeCV Death,MI,Stroke

NNT= 46

ITT= 13,608ITT= 13,608 LTFU = 14 (0.1%)LTFU = 14 (0.1%)

0

2

4

6

8

0 1 2 3

1

0

3060 90 180 270 360 450

HR 0.82(0.71-0.96)

P=0.01

HR 0.80(0.70-0.93)

P=0.003

5.6

4.7

6.9

5.6

Days

Prim

ary

End

poin

t (%

)

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel

Loading Dose Maintenance Dose

Timing of BenefitTiming of Benefit(Landmark Analysis)(Landmark Analysis)

Stent ThrombosisStent Thrombosis(ARC Definite + Probable)(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48(0.36-0.64)P <0.0001

Prasugrel

Clopidogrel2.4

(142)

74 events

NNT= 77

1.1 (68)

Days

End

poin

t (%

)

Any Stent at Index PCIAny Stent at Index PCIN= 12,844N= 12,844

TRITON TIMI-38 STEMI cohort

Montalescot et al. ESC 2008

Stent thrombosisARC Definite/probable

HR=0.58 (0.36–0.93) NNT=83

p=0.02RRR=42%

0 100 200 300 4000

1

2

3

Pro

port

ion

of p

atie

nts

(%)

Time (Days)

2.4

1.2

2.8

1.6p=0.008RRR=51%

ClopidogrelPrasugrel

Age-adjusted HR=0.59 (0.37-0.96)


• La thrombose de stent actif tue !!!




• En dehors du clopidogrel point de salut!!


CYPHER® Stent vs BMS: No difference in Stent ThrombosisSummary of CYPHER ® Stent vs BMS Trials

Pat

ient

s (%

)

10

6

4

2

MULTISTRATEGY

2.7

8-month

Diaz

3.4

1.8

MISSION

1.32.0

TYPHOON

3.4 3.6

SESAMI

4.7

6.0

STRATEGY

1.2

4.6

8

0

1-year 1-year 1-year 2-year 2-year

4.0

Definitions of ST vary by trial: ARC Def/Probable used when possible

Dual APTRecommendation

n=745

3 months

n=120

9 months

n=308

12 months

n=712

6 months

n=320

12 months

n=175

6 months

p=NS for all trialsCYPHER® BMS

Predictors of Stent Thrombosis at 1 YearPredictors of Stent Thrombosis at 1 YearUrban P et al. Urban P et al. CirculationCirculation 2006;113:14342006;113:1434--4141

• Post-procedure TIMI flow < 3 4.4 (1.8 – 9.3) p=0.0003

• Insulin-dependent diabetes 2.8 (1.7 – 4.3) p<0.0001

• Calcifications (heavy/moderate) 1.9 (1.3 – 2.9) p=0.0012

• Total occlusion of target lesion 1.9 (1.1 - 3.1) p=0.0107

• ACS at presentation 1.8 (1.1 – 2.7) p=0.0105

• Multivessel disease 1.6 (1.1 – 2.6) p=0.0383

• Number of treated lesions 1.3 (1.0 – 1.7) p=0.0317

• Age (10 year increment) 1.3 (1.1 – 1.5) p=0.01

Multivariate analysis, odds ratio (95% CI)

Logistic fixed model - Predictors chosen by stepwise procedure using an entry criterion of 0.20 with a stay criterion of 0.10

Note: no systematic information on compliance with antiplatelet medication was collected

13437 patients

Comment Comment ééviter la thrombose de stent?viter la thrombose de stent?

• Sélectionner les lésions et les patients, et reflec hir – Diabétiques– Lésions de bifurcation– Lésions longues– Lésions calcifiées– Stents multiples

• Optimiser la technique d’angioplastie– Rotablator– Hautes pressions, IVUS

ROTAXUS: Study DesignROTAXUS: Study Design

Elective PCI, native coronaries, moderate/severe calcif ication+ long (>15mm) and/or ostial and/or bifurcational le sion

Rotablation plus TAXUS StentRotablation plus TAXUS StentPTCA plus TAXUS StentPTCA plus TAXUS Stent

Primary endpoint: In-stent late lumen loss at 9 monthsPrimary endpoint: In-stent late lumen loss at 9 months

Secondary endpoints:MACE at 9 months, In-segment late loss, Binary Rest enosis,

Primary angiographic success, Procedural duration, Contrast amount

Secondary endpoints:MACE at 9 months, In-segment late loss, Binary Rest enosis,

Primary angiographic success, Procedural duration, Contrast amount

Randomization 1:1Randomization 1:1

Comment Comment ééviter la thrombose de stent?viter la thrombose de stent?

• Sélectionner les patients et éviter d’en faire trop ….– Lésions longues– Calcifications– Bifurcations– Stents mutliples

• Optimiser la technique– Préparer l’artère: rotablator (?)– Poser de façon opitmale le stent: hautes

pressions, échographie endocoronaire (?)

• Avenir: optimiser le traitement pharmacologique (prasugrel)

https://decidemedical.com/https://decidemedical.com/

Documents

Comment éviter la thrombose de stent tardive · No difference in all-MI Spaulding C., Daemen J, Boersma E, ... N Engl J Med 2007 epub February 13. MACE rates individual data (pooled