Comment éviter la thrombose de stent tardive. Christian Spaulding Service de cardiologie Hôpital Cochin Université Paris Descartes Paris

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1 Comment éviter la thrombose de stent tardive Christian Spaulding Service de cardiologie Hôpital Cochin Université Paris Descartes Paris

2 Sus aux idées reçues!!!!! 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)?

3 ESC 2006, Camenzind E. et al.

4 ALL CAUSE DEATH Total population N= % 94.6% 95% 90% 85% 93.3% Logrank P-value: % Patients at risk 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 Sirolimus eluting stent group Bare metal stent group

5 MACE rates individual data (pooled data HCRI & Cardialysis) vs. Camenzind RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS Camenzind Real data to 1440 days N = 1748 Cypher Control P-value Cypher Control P-value Death total 4.7% 3.3% % 5.1% 0.22 Q-MI 1.6% 0.6% % 1.3% 0.26 Non-Q-MI % 4.9% 0.57 Death total and Q-MI 6.3% 3.9% % 6.1% 0.13 Death total and all MI % 10.1% 0.40 Independent physician-directed meta-analysis versus Independent physician-assessed patient level meta-analysis

6 Early and Late Coronary Stent Thrombosis of Drug- Eluting Stents in Routine Clinical Practice Cumulative probability of stent thrombosis (%) Between 30 days to 3 years: Slope = 0.6% / year N=8,146 Patients Daemen J, Wenaweser P et al, Lancet : Days after stent implantation

7 Late Stent Thrombosis and Bare Metal Stents Wenaweser P et al. Eur Heart J 2005;26: Early 1.2% (N=71) Late 0.4% (N=24) N 6 4 Study population patients undergoing PCI with bare metal stents Days after PCI

8 Thrombose de stent: Expérience Mayo 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:

9 Sus aux idées reçues!!!!! 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)?

10 TYPHOON Lower TVF Risk vs BMS Intention-to-Treat Analysis at 1 year 25 CYPHER BMS 20 Patients (%) º Endpoint: TVF at 1 year* % p=0.0036* Time (days) * Defined as ischaemia driven TVR, recurrent MI, or target vessel-related cardiac death Spaulding C, et al. N Engl J Med. 2006;355:

11 CYPHER Stent vs BMS: No difference in Stent Thrombosis Summary of CYPHER Stent vs BMS Trials CYPHER BMS p=ns for all trials 10 8-month 1-year 1-year 1-year 2-year 2-year 8 Patients (%) Dual APT Recommendation MULTI STRATEGY n=745 3 months Diaz n=120 9 months MISSION n= months TYPHOON n=712 6 months SESAMI n= months STRATEGY n=175 6 months Definitions of ST vary by trial: ARC Def/Probable used when possible

12 Patient compliance and AMI BARE METAL STENTS!!!! S Jackevicius CA et al, N Engl J Med :

13 Sus aux idées reçues!!!!! 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)?

14 ENDEAVOR IV 2yr FU ARC Def/Prob ST mos (VLST) Cumulative Incidence of Def/Prob ST (ARC) 2.5% 2.0% 1.5% 1.0% 0.5% 0.0% Endeavor Taxus 1-2year HR 0.17 [0.20, 1.39] P= Time after Initial Procedure (days) Endeavor Taxus % 0.1%

15 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

16 Target Lesion Revascularization Hazard Ratio (95% CI) 4.19 ( ) p<

17 Definite Stent Thrombosis Hazard Ratio (95% CI) 4.62 ( ) p=0.02

18 Target Lesion Revascularization (lesion) Western Denmark Registry, TCT 08 Adjusted RR (95% CI) = 2.39 ( ) P< TLR (%) Endeavor Cypher Cypher (n) Endeavor (n)

19 Definite Stent Thrombosis (lesion) Adjusted RR (95% CI) = 1.78 ( ) Definite stent thrombosis (%) P<0.05 Endeavor Cypher Cypher (n) Endeavor (n)

20 Sus aux idées reçues!!!!! 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)?

21 TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel TRITON-TIMI TIMI 38 AHA 2007 Orlando, Florida Disclosure Statement: The TRITON-TIMI TIMI 38 trial was supported by a research grant support from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.

22 Clopidogrel Pro-drug Active Metabolite Formation Prasugrel 85% Inactive Metabolites Esterases Hydrolysis (Esterases) Intermediary Metabolite Intermediary Metabolite Active Metabolite Oxidation (Cytochrome P450) Oxidation (Cytochrome P450) Active Metabolite Redundancy in CYP P450 pathways used for metabolism Niitsu et al Semin Thromb Hemost 31: 184, 2005

23 STUDY DESIGN ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N= 13,600 Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1 o endpoint: CV death, MI, Stroke 2 o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis Key Substudies: Pharmacokinetic, Genomic

24 Enrollment Criteria Inclusion Criteria Planned PCI for : Known Anatomy 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

25 Primary Endpoint CV Death,MI,Stroke 15 Primary Endpoint (%) 10 5 HR 0.77 P= HR 0.80 P= Clopidogrel 138 events Prasugrel 12.1 (781) 9.9 (643) HR 0.81 ( ) P= NNT= 46 0 ITT= 13,608 LTFU = 14 (0.1%) Days

26 Timing of Benefit (Landmark Analysis) 8 Primary Endpoint (%) Clopidogrel Prasugrel HR 0.82 ( ) P= Clopidogrel Prasugrel HR 0.80 ( ) P= Loading Dose Days Maintenance Dose

27 Stent Thrombosis (ARC Definite + Probable) 3 Any Stent at Index PCI N= 12,844 Clopidogrel 2.4 (142) Endpoint (%) events Prasugrel HR 0.48 ( ) P < NNT= Days 1.1 (68)

28 TRITON TIMI-38 STEMI cohort Stent thrombosis ARC Definite/probable Proportion of patients (%) p=0.008 RRR=51% HR=0.58 ( ) NNT=83 Age-adjusted HR=0.59 ( ) Time (Days) Clopidogrel Prasugrel p=0.02 RRR=42% Montalescot et al. ESC 2008

29 Sus aux idées reçues!!!!! 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)?

30 CYPHER Predictors Stent vs BMS: of Stent No difference Thrombosis in Stent Thrombosis at 1 Year Summary Urban of P et CYPHER al. Circulation 2006;113: Stent vs BMS 41 Trials Multivariate analysis, odds ratio (95% CI) 10 CYPHER 8-month BMS p=ns for all trials Post-procedure TIMI flow < ( ) p= year 1-year 1-year 2-year 2-year Insulin-dependent diabetes 2.8 ( ) p< Calcifications (heavy/moderate) 1.9 ( ) p= Patients (%) Total 6 occlusion of target lesion 1.9 ( ) p= ACS at presentation 1.8 ( ) p= Multivessel disease 1.6 ( ) p= Number of treated lesions 1.3 ( ) p= MULTI Diaz MISSION TYPHOON SESAMI STRATEGY Age (10 year increment) 1.3 ( ) p=0.01 STRATEGY n=745 n=120 n=308 n=712 n=320 n=175 Dual APT Recommendation Note: no systematic 3 months information 9 months on compliance 12 months 6 months 12 months 6 months patients with antiplatelet medication was collected Logistic fixed model - Predictors chosen by stepwise procedure using an entry criterion of 0.20 with a stay criterion of 0.10 Definitions of ST vary by trial: ARC Def/Probable used when possible

31 Comment éviter 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

32 ROTAXUS: Study Design Elective PCI, native coronaries, moderate/severe calcification + long (>15mm) and/or ostial and/or bifurcational lesion Randomization 1:1 PTCA plus TAXUS Stent Rotablation plus TAXUS Stent Primary endpoint: In-stent late lumen loss at 9 months Secondary endpoints: MACE at at 9 months, In-segment late loss, Binary Restenosis, Primary angiographic success, Procedural duration, Contrast amount

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34 Comment éviter 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)

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