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Diabetes and antiplatelet therapy  Dr Johanne SILVAIN Pr Jean-Philippe COLLET Pr Gilles MONTALESCOT GH Pitié-Salpêtrière Institut de Cardiologie  - INSERM 937  Pharmacogénétique - INSERM 621 Diabétique et anti-agrégant plaquettaire
[object Object],[object Object],En prévention primaire ?  En prévention secondaire ?  Aspirine  Clopidogrel (PLAVIX ou générique) Inhibiteur de la GpIIbIIIa (abciximab …) Cilostazol  Prasugrel  (EFIENT)  Ticagrelor  (en attente d’AMM)
Le diabetique est-il si différent qu’il mérite  un traitement antithrombotique spécial?
Etat prothrombotique Altération coagulation : ↑  fibrinogene ↑ vWF ↑  Thrombine ↑  FVII et VIII ↓ AT-III Baisse fibrinolyse ↑  PAI-1 ↓ t-PA DYSFONCTION   ENDOTHELIALE ↑  molécules d’adhesion (VCAM) ↑  Stress Oxydatif Altération vasodilatation Altération génération endothelium
« Thrombopathie du diabétique » Altération homéostasie Ca et Mg++ Augmentation métabolisme Acide Arachidonique Augmentation synthèse TXA2 Diminution production prostacycline Diminution production NO Diminution production antioxydant ,[object Object],[object Object],[object Object],[object Object],Fonction plaquettaire ↑   Adhésion ↑  Agrégation ↑  Activation Up-regulation du récepteur plaquettaire P2Y12  = Cible majeures des antiagrégants
PREVENTION PRIMAIRE Aspirine  ?
Anti-Thrombotic Trialist Lancet 2009 Métaanalyse étude randomisées n=95 000  IDM  RRR -23% * DC+ IDM  RRR -18% * DC+ IDM + Stroke  RRR -12% *  BHS (88), PHS(88), TPT(98)  HOT(98), PPP(01), WHS(05)
De Berardis BMJ 2009 Métaanalyse étude randomisées  chez le DT2 n=10 117  RRR 10% p=NS RRR 10% p=NS RRR 23% p=NS RRR 10% p=NS RRR 3% p=NS RRR 20% p=NS
Bénéfice de l’ASA en prévention IR ? De Berardis BMJ 2009 IDM  = RRR de 14% p=NS  +++ pour les hommes = RRR d’IDM de  43% **  AVC   = RRR de 17% p=NS  pour les femmes RRR de 25% p=NS  Mortalité CV  = RRR de  6 % p=NS Mortalité  = RRR de  7 % p=NS RRR de  10% *
Le diabetique répond il différemment à l’aspirine  ?
Stable CAD outpatients (n=120) successive doses / randomized / double blinded AS pirin-Induced  P latelet  E ffe CT  (ASPECT) Influence du Diabète sur la réponse  à l’Aspirine Gurbel PA. Diabetes. 2007 Dec;56(12):3014-9.  + de résistant à l’aspirine     Augmenter les doses d’aspirine  chez le diabétique
Aspirine faible dose et diabète 50 40 30 20 10 0.0 Residual aggregation ≥20% with 0.5mh/mL AA Incidence of HPR  (%) H2 P =0.002 H24 100 mg H24 75mg Drouet el  al. ESC 2008  Passer à 2 prises par jour chez le diabétique/IMC>30
Diabète type 1 ou 2 âge> 40 ans Aspirine 100mg Placebo Omega-3 Placebo Omega-3 Placebo Critères primaires: = événements cardiovasculaires (IDM, AVC) Aspirine (100mg) en prévention IR ASCEND n=10 000 En cours  ACCEPT -D n=5 170  ASA + Simvastatine vs.  Placebo  DT2 asymptomatique Dose suffisante ?  2 prises par jour ?
PREVENTION SECONDAIRE
SCA +/-  angioplastie
[object Object],n=19 185 Lancet 1996  Bénéfice du  Clopidogrel  > ASA  dans l’athérothrombose (IDM / AVC / AOMI symptomatique) 36 mois  8.7% †  RRR  (p=0.043) 14.9% †  RRR  (p=0.045) CURE  CLARITY  COMMIT Bénéfice de la bithérapie  Clopidogrel + ASA  > ASA  dans le SCAST-  traité par ATL ou non  n=12 562 NEJM  2001  20% †  RRR  (p<0.001) 31% †  RRR  (p=0.002) n=12 562 NEJM  2005  n=45 885 Lancet  2005 Bénéfice de la bithérapie  Clopidogrel + ASA  > ASA  dans le SCAST+ thrombolysé traité par ATL ou non  20% †  RRR  (p=0.026) 46% †  RRR  (p=0.008) Bénéfice du  Clopidogrel + ASA  > ASA  dans le SCAST+  9% †  RRR  (p=0.002) CHARISMA n=15 603 NEJM  2006  Bénéfice du  Clopidogrel + ASA  > ASA  en prévention primo-secondaire  7% RRR  (p=0.2) 12% †  RRR  (p=0.046)
Diabetics in CAPRIE Relative risk reductions for different endpoints – 50% 0% 50% Aspirin better Clopidogrel better Vasc. death, MI, stroke, hosp: ischemia, bleeding Hosp: ischemia, bleeding Stroke MI Vascular death Death D. Bhatt, ACC 2000
GP IIb/IIIa – dans le SCAST- Roffi M et al. Circulation. 2001;104:2767-2771 30-Day Mortality In non-diabetics: 3.0 vs 3.0%, p=0.99 In diabetics with PCI: 4.0 vs 1.2%, p=0.002 Metaanalysis 2163 687 362 1677 412 1157 6458 PURSUIT PRISM PRISM-PLUS GUSTO IV PARAGON A PARAGON B Pooled 6.1% 4.2% 6.7% 7.8% 6.2% 4.8% 6.2% 5.1% 1.8% 3.6% 5.0% 4.6% 4.9% 4.6% P =.33 P =.07 P =.17 P =.022 P =.51 P =.93 P =.007 Trial N Odds Ratio & 95% Cl Placebo IIb/IIIa Breslow-Day:  P =.50 IIb/IIIa Better Placebo Better OR=0.74 0 0.5 1 1.5 2
GP IIb/IIIa – dans le SCAST+  Montalescot et al. N Engl J Med 2002 Death, re-MI, revascularization at 30 days ADMIRAL  Trial
Primary Composite EP @ 12m p=0.91 Presented at AHA Scientific Sessions 2004 Bénéfice des GpIIbIIIa dans l’ATL élective ? % Insulin-dependent Diabetes Subgroup Primary Composite Endpoint at 12 months p=0.66 Benefit of abciximab in elective PCI with 600mg LD clopidogrel ?  n=701 ISAR-SWEET Trial
PREVENTION PRIMO- SECONDAIRE
CAPRIE: Bénéfice amplifié chez les diabétiques  1. Bhatt DL et al.  Am J Cardiol  2002; 90: 625  628.  *MI, stroke, vascular death or rehospitalization for ischemic events/bleeding † Number of events prevented per 1000 patients per year compared with ASA ASA Clopidogrel 12.7% 17.7% 21.5% 11.8% 15.6% 17.7% 0 5 10 15 20 25 Patients without diabetes (n=15,233) Patients with diabetes (n=3866) Patients treated  with insulin (n=1134) Event rate*/year (%) 9 † 21 † 38 † p=0.096 p=0.042 p=0.106
Patients avec de Multiple Facteurs de Risques Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268. ,[object Object],ABI= Ankle Brachial Index Minor risk factors SBP   150 mm Hg (despite therapy) Primary hypercholesterolemia Currently smoking (>15 cigarettes per day) Male aged   65 years or female aged   70 years Major risk factors Type 1 or 2 diabetes (treated with medications) Diabetic nephropathy  ABI <0.9 Asymptomatic carotid stenosis   70% Presence of at least one carotid plaque
CHARISMA * All patients received ASA 75-162 mg/day Bhatt DL.  Presented at ACC 2006. Placebo + ASA* 5.5% Multiple Risk Factor  (N=3,284) Clopidogrel + ASA* 6.6% RRR: -20% [95% CI: -58.8%, 9.3%] p=0.20 Primary outcome event rate (%) 0 2 4 6 8 10 Months since randomization 0 6 12 18 24 30 IDM , AVC ou AOMI symptomatique  (N=12,153) Clopidogrel + ASA* 6.9% Placebo + ASA* 7.9% RRR: 12.5% [95% CI: 0.2%, 23.2%] p=0.046 Primary outcome event rate (%) 0 2 4 6 8 10 Months since randomization 0 6 12 18 24 30
Patients diabétiques n=2009 Topol et al . Am J Cardiol 2009;103:1359 –1363) Effet délétère de la bithérapie (ASA+Clopidogrel) chez les diabétiques atteint de néphropathie (Albuminurie )
Le problème de la réponse au clopidogrel
p=0.04 Influence du Diabète sur la réponse au clopidogrel  Angiolillo DJ et al.  Diabetes 2005; 54:2430-5   DM No-DM Acute phase of treatment Long-term phase of treatment 24 hrs post 300 mg LD Angiolillo DJ et al.  J Am Coll Cardiol 2006; 48: 298-304 78% 14% 8% Non responders (Platelet inhibition   10%)  Low  responders (Platelet inhibition 10-29%)  Responders (Platelet inhibition >30%)  56% 6% 38% 0 20 40 60 80 Platelet aggregation (%) p=0.002 p<0.0001 ADP 20  M ADP 6  M DM No-DM DM No-DM
Marqueurs de mauvaise réponse au clopidogrel  #1 Génétique x3  #2 Diabète x2 Hochholzer et al.  J Am Coll Cardiol 2010 Phase aigue (600mg LD)  n=760
CYP 2C19 Chromosome 10 Cytogenetic band :  10q23.33 Position :  chr10:96,512,453-96,602,661
Est-ce que l’hyperéactivité plaquettaire et la résistance aux antiagrégants  ont un impact clinique ?
Platelet reactivity after ACS  Predicts 5-Year Outcomes Trip MD, et al. N Engl J Med. 1990;322:1549-1554. Avant les stents  Platelet Aggregability Status 0 10 20 30 40 50 Death  Cardiac Events 10.3 6.4 14.9 24.1 46.2 34.6 Patients (%) Negative (n=94) Intermediate (n=29) Positive (n=26)
Platelet response after PCI (DES)  Predicts 6-Months Outcomes P  < 0.001 P  < 0.001 P  < 0.001 Antoniucci D et al.  JACC 2008. Depuis les stents  Double résistance ASA +Plavix ? Thrombose de stent x 3.18  (1.14 to 8.83, p = 0.027)  Mortalité CV x 2.94 (1.16 to 7.41, p = 0.022)
Solutions pour diminuer la non réponse ?
OPTIMUS-1 n = 20 n = 20 p <0.0001  Late ADP Induced  (20 µmol/L) Platelet Aggregation Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716.  75 mg 150 mg 150 mg 75 mg Augmentation des doses de  Clopidogrel
Clopidogrel: Double vs. Standard Dose Primary Outcome and Components Standard Double  HR 95% CI P CV Death/MI/Stroke Overall (2N=25,087) 4.4 4.2 0.95 0.84-1.07 0.370 MI Overall (2N=25,087) 2.2 1.9 0.86 0.73-1.03 0.097 CV Death Overall (2N=25,087) 2.2 2.1 0.96 0.81-1.14 0.628 Stroke Overall (2N=25,087) 0.5 0.5 0.99 0.70-1.39 0.950 Bleedings TIMI Major 1 0.95 1.04 1.09 0.85-1.40 0.50 CURRENT Major 2 2.0 2.5 1.25 1.05-1.47 0.01 CURRENT Severe 3 1.5 1.9 1.23 1.02-1.49 0.03 Fatal 0.11 0.13 1.15 0.56-2.35 0.71 ICH 0.05  0.03 0.67 0.19-2.37  0.53 RBC transfusion  ≥   2U 1.76 2.21 1.26 1.06-1.51 0.01
0.50 1.50 Overall NSTEMI/UA  STEMI Male Female  Age <= 65 yrs Age > 65 yrs Non-Diabetic Prev Diabetic No Inhosp GPIIb/IIIa GPIIb in hosp No Prot Pump Inhib Prot Pump Inhib Non-smoker Current Smoker ASA Low ASA High 17232 10886 6346 13009 4223 10975 6257 13400 3831 12288 4936 7675 5557 10845 6380 8620 8612 4.5 4.2 5.0 4.1 5.8 3.0 7.1 4.2 5.6 3.9 6.0 3.8 5.7 4.9 3.8 4.2 4.8 3.9 3.6 4.2 3.6 4.6 2.7 6.0 3.6 4.9 3.5 4.7 3.2 4.2 4.6 2.6 4.3 3.5 0.805 0.419 0.702 0.836 0.465 0.408 0.045 0.024 0.50 1.50 3.7 3.6 4.0 3.5 4.6 2.9 5.2 3.6 4.1 3.1 5.2 3.1 4.8 3.9 3.4 3.6 3.8 3.0 3.1 2.8 3.0 3.0 2.2 4.4 2.8 3.6 2.5 4.1 2.3 3.3 3.5 2.1 3.2 2.7 0.248 0.148 0.418 0.567 0.894 0.613 0.050 0.191 CV Death, MI or Stroke MI or Stent Thrombosis Clopidogrel: Double vs Standard Dose PCI Cohort Subgroups Std % Double % Std % Double % Intxn P Intxn P Double Dose Better Double Dose Better Std Dose Better Std  Dose Better 2N
Le cilostazol ? (Inhibiteur des PDE3)
Withdrawal due  to side effects N=4 (migraine, GI symptoms, tachycardia)  Withdrawal due  to side effects N=1 (GI symptoms) OPTIMUS-2 Cilostazol N=13 Placebo  N=12 20 patients Randomized N=25 Crossover Placebo  N=9 Cilostazol N=11 Side effects  not  leading to withdrawal of study medication: cilostazol (N=3) and placebo (N=1) T2DM patients with coronary disease on :  aspirin (81 mg) + clopidogrel (75 mg) Angiolillo, et al. Eur Heart J. 2008 Sep;29(18):2202-11.  CILOSTAZOL  PLACEBO  p=0.0002 Primary Endpoint % P2Y12 reactivity Index (VASP)  20 40 60 0 100 80
Les nouveaux antiagrégants ? (inhibiteur du P2Y12)
Biotransformation and mode of action  P2Y12 Inhibitors
90 80 70 60 50 40 30 20 10 0 300mg 100 600mg 900mg 90mg 10mg 60mg Clopidogrel  Ticagrelor  Prasugrel  TRITON  CURRENT  CURE  180mg PLATO  Meilleur inhibition plaquettaire ALBION  Platelet Aggregation at 4 hours ISAR-CHOICE  –  Von Beckerhat et al .Circulation 2005  ALBION  –  Montalescot et al.  JACC 2007 RELOAD  –  Collet et al. Circulation 2008 DIPSERSE 2  –  Storey et al. JACC 2007 PRINCIPLE TIMI-44  –  Wiviot et al. Circulation 2007
0 30 60 90 180 270 360 450 days 5 10 15 Endpoint (%) 0 9.8 11.7 Ticagrelor 90mg x2 HR 0.84 (0.77–0.92) p=0.0003* TRITON and PLATO Primary endpoint  = CV Death / MI / Stroke 12-15 months  Meilleur Inhibition =  Meilleur efficacité n= 13,608 n= 18,624 12.1 9.9 Prasugrel 10mg Clopidogrel 75mg HR 0.81 (0.73-0.90) p=0.0004*
p=0.03* p=0.025* K-M estimated rate 6 5 4 3 2 1 0 2.8 2.2 Safety  = TIMI Major Non-CABG Bleeds 1.8 2.4 p=0.001* 2.7 3.7 450 days 360 days 360 days +27% +25% +22% Meilleur Inhibition =  Plus de saignements  Ticagrelor Clopidogrel 75 Prasugrel TRITON PLATO CURE
Diabetics in TRITON (n=3 146) 0 2 4 6 8 10 12 14 16 18 0 30 60 90 180 270 360 450 HR 0.70 P<0.001  Days Endpoint (%) CV Death / MI / Stroke TIMI Major  NonCABG Bleeds NNT = 21 N=3146 17.0 % 12.2 %  Prasugrel  Clopidogrel Prasugrel   Clopidogrel 2.6 2.5 TRITON – Circulation 2008 Bleedings  Ischemia (death/MI/stroke)
Efficacité  des nouvelles approches pour améliorer le pronostic du SCA du diabétique  TRITON-TIMI 38 17.0 12.2 0.70 (0.58 – 0.85)* PLATO 16.2 14.1 0.88 (0.76 – 1.03) CURRENT OASIS 7 5.6 4.9 0.87 (0.66 – 1.15) (PCI Cohort) Ferreiro JL, Angiolillo DJ.  Circulation.  2010.  In press. Study % of Events Hazard Ratio (95% confidence interval) Standard  New Drug/Approach New Drug/Approach Better Standard Clopidogrel Better 0 0.5 1 1.5 Prasugrel  Ticagrelor  Clopidogrel X2
Adapter le traitement selon la réponse ?
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],ARCTIC  (n=2500) A ssessment with a double  R andomization of 1) a monitoring-adjusted antiplatelet treatment  vs.  a  C ommon antiplatelet  T reatment for DES implantation, and 2)  I nterruption  vs.  C ontinuation of double antiplatelet therapy, one year after stenting Coord Center:  ACTION Study PI:  Gilles Montalescot & JP Collet ,[object Object],[object Object],[object Object],Randomization before DES implantation  ,[object Object],[object Object],[object Object]
CONCLUSION
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],En prévention primaire  Ce que nous savons
En prévention Secondaire  ,[object Object],[object Object],[object Object],[object Object],[object Object],Ce que nous savons
En prévention Secondaire  ,[object Object],[object Object],[object Object],Ce que nous ignorons
Dr Johanne SILVAIN Pr Jean-Philippe COLLET Pr Gilles MONTALESCOT GH Pitié-Salpêtrière Institut de Cardiologie  - INSERM 937  Pharmacogénétique - INSERM 621 Merci

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Johanne silvain

  • 1. Diabetes and antiplatelet therapy Dr Johanne SILVAIN Pr Jean-Philippe COLLET Pr Gilles MONTALESCOT GH Pitié-Salpêtrière Institut de Cardiologie - INSERM 937 Pharmacogénétique - INSERM 621 Diabétique et anti-agrégant plaquettaire
  • 2.
  • 3. Le diabetique est-il si différent qu’il mérite un traitement antithrombotique spécial?
  • 4. Etat prothrombotique Altération coagulation : ↑ fibrinogene ↑ vWF ↑ Thrombine ↑ FVII et VIII ↓ AT-III Baisse fibrinolyse ↑ PAI-1 ↓ t-PA DYSFONCTION ENDOTHELIALE ↑ molécules d’adhesion (VCAM) ↑ Stress Oxydatif Altération vasodilatation Altération génération endothelium
  • 5.
  • 7. Anti-Thrombotic Trialist Lancet 2009 Métaanalyse étude randomisées n=95 000 IDM RRR -23% * DC+ IDM RRR -18% * DC+ IDM + Stroke RRR -12% * BHS (88), PHS(88), TPT(98) HOT(98), PPP(01), WHS(05)
  • 8. De Berardis BMJ 2009 Métaanalyse étude randomisées chez le DT2 n=10 117 RRR 10% p=NS RRR 10% p=NS RRR 23% p=NS RRR 10% p=NS RRR 3% p=NS RRR 20% p=NS
  • 9. Bénéfice de l’ASA en prévention IR ? De Berardis BMJ 2009 IDM = RRR de 14% p=NS +++ pour les hommes = RRR d’IDM de 43% ** AVC = RRR de 17% p=NS pour les femmes RRR de 25% p=NS Mortalité CV = RRR de 6 % p=NS Mortalité = RRR de 7 % p=NS RRR de 10% *
  • 10. Le diabetique répond il différemment à l’aspirine ?
  • 11. Stable CAD outpatients (n=120) successive doses / randomized / double blinded AS pirin-Induced P latelet E ffe CT (ASPECT) Influence du Diabète sur la réponse à l’Aspirine Gurbel PA. Diabetes. 2007 Dec;56(12):3014-9. + de résistant à l’aspirine  Augmenter les doses d’aspirine chez le diabétique
  • 12. Aspirine faible dose et diabète 50 40 30 20 10 0.0 Residual aggregation ≥20% with 0.5mh/mL AA Incidence of HPR (%) H2 P =0.002 H24 100 mg H24 75mg Drouet el al. ESC 2008  Passer à 2 prises par jour chez le diabétique/IMC>30
  • 13. Diabète type 1 ou 2 âge> 40 ans Aspirine 100mg Placebo Omega-3 Placebo Omega-3 Placebo Critères primaires: = événements cardiovasculaires (IDM, AVC) Aspirine (100mg) en prévention IR ASCEND n=10 000 En cours ACCEPT -D n=5 170 ASA + Simvastatine vs. Placebo DT2 asymptomatique Dose suffisante ? 2 prises par jour ?
  • 15. SCA +/- angioplastie
  • 16.
  • 17. Diabetics in CAPRIE Relative risk reductions for different endpoints – 50% 0% 50% Aspirin better Clopidogrel better Vasc. death, MI, stroke, hosp: ischemia, bleeding Hosp: ischemia, bleeding Stroke MI Vascular death Death D. Bhatt, ACC 2000
  • 18. GP IIb/IIIa – dans le SCAST- Roffi M et al. Circulation. 2001;104:2767-2771 30-Day Mortality In non-diabetics: 3.0 vs 3.0%, p=0.99 In diabetics with PCI: 4.0 vs 1.2%, p=0.002 Metaanalysis 2163 687 362 1677 412 1157 6458 PURSUIT PRISM PRISM-PLUS GUSTO IV PARAGON A PARAGON B Pooled 6.1% 4.2% 6.7% 7.8% 6.2% 4.8% 6.2% 5.1% 1.8% 3.6% 5.0% 4.6% 4.9% 4.6% P =.33 P =.07 P =.17 P =.022 P =.51 P =.93 P =.007 Trial N Odds Ratio & 95% Cl Placebo IIb/IIIa Breslow-Day: P =.50 IIb/IIIa Better Placebo Better OR=0.74 0 0.5 1 1.5 2
  • 19. GP IIb/IIIa – dans le SCAST+ Montalescot et al. N Engl J Med 2002 Death, re-MI, revascularization at 30 days ADMIRAL Trial
  • 20. Primary Composite EP @ 12m p=0.91 Presented at AHA Scientific Sessions 2004 Bénéfice des GpIIbIIIa dans l’ATL élective ? % Insulin-dependent Diabetes Subgroup Primary Composite Endpoint at 12 months p=0.66 Benefit of abciximab in elective PCI with 600mg LD clopidogrel ? n=701 ISAR-SWEET Trial
  • 22. CAPRIE: Bénéfice amplifié chez les diabétiques 1. Bhatt DL et al. Am J Cardiol 2002; 90: 625  628. *MI, stroke, vascular death or rehospitalization for ischemic events/bleeding † Number of events prevented per 1000 patients per year compared with ASA ASA Clopidogrel 12.7% 17.7% 21.5% 11.8% 15.6% 17.7% 0 5 10 15 20 25 Patients without diabetes (n=15,233) Patients with diabetes (n=3866) Patients treated with insulin (n=1134) Event rate*/year (%) 9 † 21 † 38 † p=0.096 p=0.042 p=0.106
  • 23.
  • 24. CHARISMA * All patients received ASA 75-162 mg/day Bhatt DL. Presented at ACC 2006. Placebo + ASA* 5.5% Multiple Risk Factor (N=3,284) Clopidogrel + ASA* 6.6% RRR: -20% [95% CI: -58.8%, 9.3%] p=0.20 Primary outcome event rate (%) 0 2 4 6 8 10 Months since randomization 0 6 12 18 24 30 IDM , AVC ou AOMI symptomatique (N=12,153) Clopidogrel + ASA* 6.9% Placebo + ASA* 7.9% RRR: 12.5% [95% CI: 0.2%, 23.2%] p=0.046 Primary outcome event rate (%) 0 2 4 6 8 10 Months since randomization 0 6 12 18 24 30
  • 25. Patients diabétiques n=2009 Topol et al . Am J Cardiol 2009;103:1359 –1363) Effet délétère de la bithérapie (ASA+Clopidogrel) chez les diabétiques atteint de néphropathie (Albuminurie )
  • 26. Le problème de la réponse au clopidogrel
  • 27. p=0.04 Influence du Diabète sur la réponse au clopidogrel Angiolillo DJ et al. Diabetes 2005; 54:2430-5 DM No-DM Acute phase of treatment Long-term phase of treatment 24 hrs post 300 mg LD Angiolillo DJ et al. J Am Coll Cardiol 2006; 48: 298-304 78% 14% 8% Non responders (Platelet inhibition  10%) Low responders (Platelet inhibition 10-29%) Responders (Platelet inhibition >30%) 56% 6% 38% 0 20 40 60 80 Platelet aggregation (%) p=0.002 p<0.0001 ADP 20  M ADP 6  M DM No-DM DM No-DM
  • 28. Marqueurs de mauvaise réponse au clopidogrel #1 Génétique x3 #2 Diabète x2 Hochholzer et al. J Am Coll Cardiol 2010 Phase aigue (600mg LD) n=760
  • 29. CYP 2C19 Chromosome 10 Cytogenetic band : 10q23.33 Position : chr10:96,512,453-96,602,661
  • 30. Est-ce que l’hyperéactivité plaquettaire et la résistance aux antiagrégants ont un impact clinique ?
  • 31. Platelet reactivity after ACS Predicts 5-Year Outcomes Trip MD, et al. N Engl J Med. 1990;322:1549-1554. Avant les stents Platelet Aggregability Status 0 10 20 30 40 50 Death Cardiac Events 10.3 6.4 14.9 24.1 46.2 34.6 Patients (%) Negative (n=94) Intermediate (n=29) Positive (n=26)
  • 32. Platelet response after PCI (DES) Predicts 6-Months Outcomes P < 0.001 P < 0.001 P < 0.001 Antoniucci D et al. JACC 2008. Depuis les stents Double résistance ASA +Plavix ? Thrombose de stent x 3.18 (1.14 to 8.83, p = 0.027) Mortalité CV x 2.94 (1.16 to 7.41, p = 0.022)
  • 33. Solutions pour diminuer la non réponse ?
  • 34. OPTIMUS-1 n = 20 n = 20 p <0.0001 Late ADP Induced (20 µmol/L) Platelet Aggregation Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716. 75 mg 150 mg 150 mg 75 mg Augmentation des doses de Clopidogrel
  • 35. Clopidogrel: Double vs. Standard Dose Primary Outcome and Components Standard Double HR 95% CI P CV Death/MI/Stroke Overall (2N=25,087) 4.4 4.2 0.95 0.84-1.07 0.370 MI Overall (2N=25,087) 2.2 1.9 0.86 0.73-1.03 0.097 CV Death Overall (2N=25,087) 2.2 2.1 0.96 0.81-1.14 0.628 Stroke Overall (2N=25,087) 0.5 0.5 0.99 0.70-1.39 0.950 Bleedings TIMI Major 1 0.95 1.04 1.09 0.85-1.40 0.50 CURRENT Major 2 2.0 2.5 1.25 1.05-1.47 0.01 CURRENT Severe 3 1.5 1.9 1.23 1.02-1.49 0.03 Fatal 0.11 0.13 1.15 0.56-2.35 0.71 ICH 0.05 0.03 0.67 0.19-2.37 0.53 RBC transfusion ≥ 2U 1.76 2.21 1.26 1.06-1.51 0.01
  • 36. 0.50 1.50 Overall NSTEMI/UA STEMI Male Female Age <= 65 yrs Age > 65 yrs Non-Diabetic Prev Diabetic No Inhosp GPIIb/IIIa GPIIb in hosp No Prot Pump Inhib Prot Pump Inhib Non-smoker Current Smoker ASA Low ASA High 17232 10886 6346 13009 4223 10975 6257 13400 3831 12288 4936 7675 5557 10845 6380 8620 8612 4.5 4.2 5.0 4.1 5.8 3.0 7.1 4.2 5.6 3.9 6.0 3.8 5.7 4.9 3.8 4.2 4.8 3.9 3.6 4.2 3.6 4.6 2.7 6.0 3.6 4.9 3.5 4.7 3.2 4.2 4.6 2.6 4.3 3.5 0.805 0.419 0.702 0.836 0.465 0.408 0.045 0.024 0.50 1.50 3.7 3.6 4.0 3.5 4.6 2.9 5.2 3.6 4.1 3.1 5.2 3.1 4.8 3.9 3.4 3.6 3.8 3.0 3.1 2.8 3.0 3.0 2.2 4.4 2.8 3.6 2.5 4.1 2.3 3.3 3.5 2.1 3.2 2.7 0.248 0.148 0.418 0.567 0.894 0.613 0.050 0.191 CV Death, MI or Stroke MI or Stent Thrombosis Clopidogrel: Double vs Standard Dose PCI Cohort Subgroups Std % Double % Std % Double % Intxn P Intxn P Double Dose Better Double Dose Better Std Dose Better Std Dose Better 2N
  • 37. Le cilostazol ? (Inhibiteur des PDE3)
  • 38. Withdrawal due to side effects N=4 (migraine, GI symptoms, tachycardia) Withdrawal due to side effects N=1 (GI symptoms) OPTIMUS-2 Cilostazol N=13 Placebo N=12 20 patients Randomized N=25 Crossover Placebo N=9 Cilostazol N=11 Side effects not leading to withdrawal of study medication: cilostazol (N=3) and placebo (N=1) T2DM patients with coronary disease on : aspirin (81 mg) + clopidogrel (75 mg) Angiolillo, et al. Eur Heart J. 2008 Sep;29(18):2202-11. CILOSTAZOL PLACEBO p=0.0002 Primary Endpoint % P2Y12 reactivity Index (VASP) 20 40 60 0 100 80
  • 39. Les nouveaux antiagrégants ? (inhibiteur du P2Y12)
  • 40. Biotransformation and mode of action P2Y12 Inhibitors
  • 41. 90 80 70 60 50 40 30 20 10 0 300mg 100 600mg 900mg 90mg 10mg 60mg Clopidogrel Ticagrelor Prasugrel TRITON CURRENT CURE 180mg PLATO Meilleur inhibition plaquettaire ALBION Platelet Aggregation at 4 hours ISAR-CHOICE – Von Beckerhat et al .Circulation 2005 ALBION – Montalescot et al. JACC 2007 RELOAD – Collet et al. Circulation 2008 DIPSERSE 2 – Storey et al. JACC 2007 PRINCIPLE TIMI-44 – Wiviot et al. Circulation 2007
  • 42. 0 30 60 90 180 270 360 450 days 5 10 15 Endpoint (%) 0 9.8 11.7 Ticagrelor 90mg x2 HR 0.84 (0.77–0.92) p=0.0003* TRITON and PLATO Primary endpoint = CV Death / MI / Stroke 12-15 months Meilleur Inhibition = Meilleur efficacité n= 13,608 n= 18,624 12.1 9.9 Prasugrel 10mg Clopidogrel 75mg HR 0.81 (0.73-0.90) p=0.0004*
  • 43. p=0.03* p=0.025* K-M estimated rate 6 5 4 3 2 1 0 2.8 2.2 Safety = TIMI Major Non-CABG Bleeds 1.8 2.4 p=0.001* 2.7 3.7 450 days 360 days 360 days +27% +25% +22% Meilleur Inhibition = Plus de saignements Ticagrelor Clopidogrel 75 Prasugrel TRITON PLATO CURE
  • 44. Diabetics in TRITON (n=3 146) 0 2 4 6 8 10 12 14 16 18 0 30 60 90 180 270 360 450 HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 21 N=3146 17.0 % 12.2 % Prasugrel Clopidogrel Prasugrel Clopidogrel 2.6 2.5 TRITON – Circulation 2008 Bleedings Ischemia (death/MI/stroke)
  • 45. Efficacité des nouvelles approches pour améliorer le pronostic du SCA du diabétique TRITON-TIMI 38 17.0 12.2 0.70 (0.58 – 0.85)* PLATO 16.2 14.1 0.88 (0.76 – 1.03) CURRENT OASIS 7 5.6 4.9 0.87 (0.66 – 1.15) (PCI Cohort) Ferreiro JL, Angiolillo DJ. Circulation. 2010. In press. Study % of Events Hazard Ratio (95% confidence interval) Standard New Drug/Approach New Drug/Approach Better Standard Clopidogrel Better 0 0.5 1 1.5 Prasugrel Ticagrelor Clopidogrel X2
  • 46. Adapter le traitement selon la réponse ?
  • 47.
  • 49.
  • 50.
  • 51.
  • 52. Dr Johanne SILVAIN Pr Jean-Philippe COLLET Pr Gilles MONTALESCOT GH Pitié-Salpêtrière Institut de Cardiologie - INSERM 937 Pharmacogénétique - INSERM 621 Merci

Notes de l'éditeur

  1. Background: previous data suggest that biological platelet resistance to low dose aspirin occurs frequently in diabetic patients in secondary prevention. The higher platelet turn over described in this population could contribute to shorten the duration of aspirin effect. We therefore aimed to assess the rate of biological aspirin resistance in diabetic patients soon after aspirin intake (peak effect) as compared to 24 hours after the last aspirin intake. Methods: 52 type-2 diabetic patients with stable coronary artery disease and treated with 75 mg (n=21) or 100 mg (n=31) aspirin daily for at least 10 days were studied. Platelet aggregation to arachidonic acid and closure time on the platelet function analyzer-100 (PFA-100) were performed 2 hours and 24 hours after the last aspirin intake. Aspirin resistance was defined as a residual aggregation ≥20% with 0.5mg/ml arachidonic acid. Results: all the patients were sensitive to aspirin at 2h after ingestion but 16 patients (31%) were aspirin resistant 24 h after the last aspirin intake: 48% in the 75 mg group and 23% in the 100 mg group. Concordant results were found concerning PFA-100 especially with the collagen-epinephrine cartridge. Moreover, in the resistant group, PFA 100 was increased (mean &gt;300sec) as compared to sensitive patiens (mean 152 sec). In patients with aspirin resistance, a trend towards a higher platelet volume (10.8± 0.9 in aspirin resistant vs. 10.2±0.7)) and a higher plasma factor VIII level were found (163±54 IU/dl in aspirin resistant vs 132± 61 IU/dl). Aspirin resistance was not related to the presence or absence of metabolic syndrome (IDF) nor other clinical or to biological parameters. Conclusion: low dose aspirin does not offer a 24-hour biological protection in a high proportion of diabetic patients in secondary prevention. Further studies are needed to define the optimal aspirin dose and regimen in this population.
  2. DC ou DC+MI
  3. Among diabetic patients undergoing elective PCI and pretreated with high-dose clopidogrel, treatment with abciximab was not associated with a difference in the primary endpoint of death or MI at 12 months compared with placebo, but was associated with a lower rate of binary restenosis and target lesion revascularization. These data are similar to the ISAR REACT trial, which showed no difference in 30 day major cardiac events with abciximab compared with placebo in low-risk patients undergoing PCI who were pretreated with 600 mg clopidogrel. While there was no difference in the primary endpoint of death or MI in the present trial, it should be noted that the trial was powered to detect a 50% reduction with abciximab, a relatively large improvement in clinical events that may have been over-estimated
  4. In the CAPRIE study, 3866 patients had co-existing diabetes 1 Patients without diabetes treated with clopidogrel were at lower risk of MI, ischemic stroke, vascular death or rehospitalization for ischemic events/bleeding than those treated with ASA (11.8 vs 12.7%; p=0.096; 9 events prevented per 1000 patients per year with clopidogrel versus ASA) 1 Similarly, patients with diabetes treated with clopidogrel were at lower risk of MI, ischemic stroke, vascular death or rehospitalization for ischemic events/bleeding than those treated with ASA (15.6 vs 17.7%; p=0.042) 1 The benefits of clopidogrel over ASA were even further amplified in the higher risk, insulin-dependent patients (17.7 vs 21.5%; p=0.106; 38 events prevented per 1000 patients per year with clopidogrel versus ASA) 1 Reference 1. Bhatt DL et al. Am Heart J 2002; 148: 67–73.
  5. In CHARISMA, major atherothrombotic risk factors were as follows: 1 Type 1 or 2 diabetes currently under drug therapy Diabetic nephropathy ABI  0.9 Asymptomatic carotid stenosis  70% Presence of at least one carotid plaque evidenced by intima–media thickness In CHARISMA, minor atherothrombotic risk factors were as follows: 1 SBP  150 mmHg, despite therapy for at least 3 months Primary hypercholesterolemia Currently smoking  15 cigarettes per day Male aged  65 years or female aged  70 years Reference 1. Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
  6. The primary efficacy endpoint in CHARISMA was a cluster of the first occurrence of fatal or nonfatal MI, or fatal or nonfatal stroke (of any cause), or cardiovascular death (including haemorrhagic death). There was no statistical difference in the primary endpoint between the two treatment arms. An analysis of the population with documented atherothrombotic disease (symptomatic) and that with multiple atherothrombotic risk factors (asymptomatic) was pre-specified in the CHARISMA statistical analysis plan. In the 12,153 patients with documented atherothrombosis, there was a significant 12.5% RRR in the primary endpoint (CV death/MI/stroke) from 7.9% in the placebo + ASA group to 6.9% clopidogrel+ ASA group (p=0.046, 95% CI: 0.2%, 23.2%). At the end of follow-up, the event rate in the multiple risk factor population (N=3284) for the primary outcome in the clopidogrel plus ASA arm was 6.57% as compared to 5.48% in the placebo plus ASA arm (RRR -20.0% [-58.8%, 9.3%])
  7. Figure 1. Roles in Clopidogrel Activity of Proteins with Known Genetic Polymorphisms. Intestinal absorption of the prodrug clopidogrel is limited by an intestinal efflux pump P-glycoprotein coded by the ABCB1 gene. The majority of the prodrug is metabolized into inactive metabolites by ubiquitous esterases. The minority is bioactivated by various cytochrome P450 (CYP) isoforms into active metabolites. These metabolites irreversibly antagonize the adenosine diphosphate (ADP) receptor (coded by the P2RY12 gene), which in turn inactivates the fibrinogen receptor (the glycoprotein [GP] IIb/IIIa receptor coded by the ITGB3 gene) involved in platelet aggregation.
  8. Platelet aggregation offers useful prognostic information after myocardial infarction (MI). Investigators assessed platelet aggregation in 149 patients post-MI within 3 months of the index event. Spontaneous platelet aggregation (SPA) was graded as negative when there was no aggregation within 20 minutes of the addition of a platelet intermediate when aggregation occurred between 10 and 20 minutes and positive when aggregation occurred within 10 minutes. Clinical outcomes, including cardiac events—nonfatal recurrent MI or cardiac death (defined as death occurring in hospital post-MI or death occurring suddenly without previous symptoms or within 24 hours of the onset of new symptoms of heart disease)—were recorded over 5 years. A total of 14.9% SPA-negative patients experienced at least 1 cardiac event over 5 years vs 24.1% of SPA-intermediate patients and 46.2% of SPA-positive patients. The relative risk (RR) for a cardiac event was 1.6 (95% CI range: 0.7-3.5) in patients in the SPA-intermediate group and 3.1 (95% CI range: 1.6-5.8) in those in the SPA-positive group. Mortality was also highest in the SPA-positive group (34.6%) compared with the SPA-intermediate and SPA-negative groups (10.3% and 6.4%, respectively). Compared with patients in the SPA-negative group, the RR for death was 1.6 (95% CI range: 0.5-5.5) in patients in the SPA-intermediate group and 5.4 (95% CI range: 2.2-13.4) in those in the SPA-positive group. Overall, a positive association between platelet hyperreactivity and both cardiac events and mortality was demonstrated in post-MI patients over 5 years. References Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med . 1990;322:1549-1554.
  9. OBJECTIVES: This study sought to determine the incidence of aspirin nonresponsiveness in addition to clopidogrel nonresponsiveness and whether this association identifies patients at an increased risk of drug-eluting stent (DES) thrombosis. BACKGROUND: Nonresponsiveness to clopidogrel is a predictor of DES thrombosis. No prospective data exist about the possible association of dual nonresponsiveness to clopidogrel and aspirin with DES thrombosis. METHODS: Platelet function was assessed after a loading dose of 600 mg clopidogrel in 746 patients who had successful DES implantation followed by 6-month dual-antiplatelet therapy. Platelet reactivity was assessed by light transmittance aggregometry using adenosine 5&apos;-diphosphate, arachidonic acid, and collagen. The primary end point was definite/probable DES thrombosis at 6 months. The secondary end point was the composite of cardiac mortality and DES thrombosis. RESULTS: The incidence of dual nonresponsiveness to aspirin and clopidogrel was 6%. Definite/probable DES thrombosis was significantly higher in dual aspirin and clopidogrel nonresponders (11.1%) than in clopidogrel and aspirin responders (2.1%, p &lt; 0.001), isolated clopidogrel nonresponders (2.2%, p &lt; 0.05), or aspirin nonresponders (2.3%, p &lt; 0.05). The incidence of the secondary end point was 4.4% in isolated clopidogrel nonresponders, 2.3% in isolated aspirin nonresponders, and 13.3% in dual aspirin and clopidogrel nonresponders. Dual clopidogrel and aspirin nonresponsiveness was an independent predictor of. CONCLUSIONS: Dual nonresponsiveness to aspirin and clopidogrel is a relatively infrequent condition that identifies patients at a very high risk of DES thrombosis or death.