Comment
Comment é é viter la thrombose de viter la thrombose de stent tardive
stent tardive
Christian Spaulding Service de cardiologie
Hôpital Cochin
Université Paris Descartes
Paris
Sus aux id
Sus aux id é é es re es re ç ç ues !!!!! 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 aigue 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
1483 1624
1672 1715
1748
Patients at risk
1483 1624
1672 1715
1748
Patients at risk
Sirolimus eluting stent group Bare metal stent group
ALL CAUSE DEATH
No significant difference between groups
Diverging curves
No difference in all-MI
Spaulding C., Daemen J, Boersma E, Cutlip D and Serruys P
N 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
Cumulative probability of stent thrombosis (%)
Days after stent implantation
0 200 400 600 800 1000 1200
0 1 2 3
N=8,146 Patients Between 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
0 0 30 60 120 600
N
Early 1.2%
(N=71)
Late 0.4%
(N=24)
Late Stent Thrombosis and Bare Metal Stents
Wenaweser 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: Exp
Thrombose de stent: Exp é é rience Mayo rience Mayo Clinic
Clinic
• 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
Sus aux id
Sus aux id é é es re es re ç ç ues !!!!! ues !!!!!
• La thrombose de stent nue n’existe pas!!!
• Il ne faut pas poser de stents actifs en phase aigue 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)?
TYPHOON
Lower TVF Risk vs BMS
25
20
10
5
0
Patients (%)
15
0
60 120 180 240 300 360
Time (days)
3.1
4.2
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 Thrombosis
Summary of CYPHER
®Stent vs BMS Trials
Patients (%)
10
6
4
2
MULTI STRATEGY
2.7
8-month
Diaz
3.4 1.8
MISSION
1.3 2.0
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 APT
Recommendation
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 trials
CYPHER® BMS
Patient compliance and AMI Patient compliance and AMI
Jackevicius CA et al, N Engl J Med 2008 359:1802-10 BARE METAL STENTS !!!! S
Sus aux id
Sus aux id é é es re es re ç ç ues !!!!! ues !!!!!
• La thrombose de stent actif tue !!!
• La thrombose de stent nue n’existe pas!!!
• Il ne faut pas poser de stents actifs en phase aigue 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)?
Time after Initial Procedure (days) Time after Initial Procedure (days) Cumulative Incidence of Cumulative Incidence of Def/Prob ST (ARC)Def/Prob ST (ARC)
360360 450450 540540 630630 720720
0.0%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%
Endeavor Taxus
1-2year HR 0.17 [0.20, 1.39]
P=0.059 P=0.059
Endeavor 726 726
Endeavor 726 726 709 705 709 705 699699 Taxus 725 725
Taxus 725 725 706 703 706 703 699 699
ENDEAVOR IV
ENDEAVOR IV – – 2yr FU 2yr FU ARC Def/Prob ST 12
ARC 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 751 143
Endeavor (n) 3090 2338 1339 637 122 0
TLR (%)
Endeavor Cypher
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 751 143
Endeavor (n) 3090 2338 1339 637 122 0
Definite stent thrombosis (%)
Endeavor Cypher
Sus aux id
Sus aux id é é es re es re ç ç ues !!!!! ues !!!!!
• La thrombose de stent nue n’existe pas!!!
• Il ne faut pas poser de stents actifs en phase aigue 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)?
TRial to Assess Improvement in
Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel
TRITON
TRITON - - TIMI 38 TIMI 38 AHA 2007
AHA 2007
Orlando, Florida Orlando, Florida
Disclosure Statement Disclosure Statement: :
The TRITON
The 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
Formation Formation
Prasugrel Prasugrel
Niitsu et al Semin Thromb Hemost 31: 184, 2005
Pro-drug Pro-drug
Oxidation
(Cytochrome P450)
Oxidation
(Cytochrome P450)
Hydrolysis
(Esterases)
Hydrolysis
(Esterases)
Clopidogrel Clopidogrel
85% Inactive Metabolites
Esterases
85% Inactive Metabolites
Esterases Intermediary Intermediary
Metabolite Metabolite
Intermediary Intermediary
Metabolite Metabolite
Active Metabolite Active Metabolite
Active Active Metabolite Metabolite
Oxidation
(Cytochrome P450)
Oxidation
(Cytochrome P450)
Redundancy in CYP P450 Redundancy in CYP P450 pathways used for metabolism pathways used for metabolism
STUDY DESIGN
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI ASA
PRASUGREL
60 mg LD/ 10 mg MD CLOPIDOGREL
300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, Stroke
2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR
Stent Thrombosis
Key Substudies: Pharmacokinetic, Genomic
Median duration of therapy - 12 months
N= 13,600
Enrollment Criteria Enrollment Criteria
•Inclusion Criteria Planned 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
Known Anatomy
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 0.80 P=0.0003 HR 0.77
P=0.0001
Days
Primary Endpoint (%)
12.1 (781)
9.9 (643)
138 events
Primary Endpoint Primary Endpoint CV Death,MI,Stroke CV Death,MI,Stroke
NNT= 46
ITT= 13,608
ITT= 13,608 LTFU = 14 (0.1%)LTFU = 14 (0.1%)
0 2 4 6 8
0 1 2 3
1
0 30 60 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
Primary Endpoint (%)
Prasugrel Clopidogrel
Prasugrel Clopidogrel
Loading Dose Maintenance Dose
Timing of Benefit
Timing of Benefit
(Landmark Analysis)
(Landmark Analysis)
Stent Thrombosis Stent 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 Clopidogrel
2.4 (142)
74 events
NNT= 77 1.1 (68)
Days
Endpoint (%)
Any Stent at Index PCI Any Stent at Index PCI
N= 12,844 N= 12,844
TRITON TIMI-38 STEMI cohort
Montalescot et al. ESC 2008
Stent thrombosis
ARC Definite/probable
HR=0.58 (0.36–0.93) NNT=83
p=0.02 RRR=42%
0 100 200 300 400
0 1 2 3
Proportion of patients (%)
Time (Days) 2.4
1.2
2.8
p=0.008 1.6 RRR=51%
Clopidogrel Prasugrel
Age-adjusted HR=0.59 (0.37-0.96)
Sus aux id
Sus aux id é é es re es re ç ç ues !!!!! ues !!!!!
• La thrombose de stent actif tue !!!
• La thrombose de stent nue n’existe pas!!!
• Il ne faut pas poser de stents actifs en phase aigue 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)?
CYPHER® Stent vs BMS: No difference in Stent Thrombosis
Summary of CYPHER
®Stent vs BMS Trials
Patients (%)
10
6
4
2
MULTI STRATEGY
2.7
8-month
Diaz
3.4 1.8
MISSION
1.3 2.0
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 APT
Recommendation
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 trials
CYPHER® BMS
Predictors of Stent Thrombosis at 1 Year Predictors of Stent Thrombosis at 1 Year
Urban P et al.
Urban P et al. CirculationCirculation 2006;113:14342006;113:1434-41-41
• 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 é é viter la thrombose de stent? viter la thrombose de stent?
• Sélectionner les lésions et les patients, et reflechir – Diabétiques
– Lésions de bifurcation – Lésions longues
– Lésions calcifiées – Stents multiples
• Optimiser la technique d’angioplastie – Rotablator
– Hautes pressions, IVUS
ROTAXUS: Study Design ROTAXUS: Study Design
Elective PCI, native coronaries, moderate/severe calcification + long (>15mm) and/or ostial and/or bifurcational lesion
Rotablation plus TAXUS Stent Rotablation plus TAXUS Stent PTCA plus TAXUS Stent
PTCA plus TAXUS Stent
Primary endpoint: In-stent late lumen loss at 9 months
Primary endpoint: In-stent late lumen loss at 9 months
Secondary endpoints:
MACE at 9 months, In-segment late loss, Binary Restenosis, Primary angiographic success, Procedural duration, Contrast amount
Secondary endpoints:
MACE at 9 months, In-segment late loss, Binary Restenosis, Primary angiographic success, Procedural duration, Contrast amount
Randomization 1:1 Randomization 1:1
Comment
Comment é é viter 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)
