Nouveaux Antiplaquettaires, Nouveaux Risques? Poitiers le 19 septembre 2009 [email protected] Institut de Cardiologie – Inserm 937 Pitié-Salpêtrière University Hospital 75013 Paris.
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Nouveaux Antiplaquettaires, Nouveaux Risques? Poitiers le 19 septembre 2009 [email protected] Institut de Cardiologie – Inserm 937 Pitié-Salpêtrière University Hospital 75013 Paris Traitements antiagrégants en France Traitement-années (millions) 2,5 2 200 000 traitementsannées 2 1,5 Aspirine à faible dose Clopidogrel 840 000 traitementsannées 1 0,5 0 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Rapport AFSSAPS juillet 2005, Données GERS Platelet Activation Mechanisms ASPIRIN C18886 x Thromboxane Coagulation A2 SCH530348 Thrombin 5HT Collagen x GPVI TPa PAR4 5HT ADP 5HT2A ADP ATP ADP TICLOPIDINE CLOPIDOGREL PRASUGREL ATP P2Y1 P2X1 ACTIVE METABOLITE PAR1 Thrombin generation Shape change PLATELET ACTIVATION Dense granule x P2Y12 AZD6140 CANGRELOR Amplification Alpha granule aIIb b3 Coagulation factors Inflammatory mediators Storey RF. Curr Pharm Des. 2006;12:1255-59. aIIb b3 Fibrinogen Aggregation x aIIb b3 GP IIb/IIIa ANTAGONISTS Une success Story Clopidogrel vs Ticlopidine on 30-day MACE Trial n CLASSICS Clop. Ticl. 1,020 1.3% 0.9% TOPPS 941 2.6% 3.5% Müller 700 3.1% 2.0% CCF 2,369 5.7% 8.9% Lenox Hill 2,565 2.4% 3.8% Mayo 2,827 0.6% 1.6% N. Memorial 1,378 0.8% 2.2% S. Illinois 875 2.1% 1.4% Wash. Hosp. 844 2.0% 0.5% Wessex 361 2.3% 5.3% 2.0% 4.0% Overall 13,880 Odds ratios & 95% CI 0.50 (0.40, 0.61) p = 0.001 0.1 Clopidogrel better 1 Ticlopidine better 10 Bhatt DL et al. J Am Coll Cardiol 2002;39:9–14 Plavix Robust Clinical Research Program More than 100,000 patients in the clinical program… .... and more than 70 million of patients treated to date Ongoing Trials Indication in STEMI patients Published Trials ACTIVE ACTIVE CASPAR CASPAR CASPAR CHARISMA CHARISMA CHARISMA CHARISMA COMMIT CCS2 COMMIT CCS2 COMMIT CCS2 COMMIT CCS2 COMMIT CCS2 CLARITY CLARITY CLARITY CLARITY CLARITY CLARITY CARESS CARESS CARESS CARESS CARESS CARESS CARESS MATCH MATCH MATCH MATCH MATCH MATCH MATCH MATCH CREDO CREDO CREDO CREDO CREDO CREDO CREDO CREDO Indication in UA/NSTEMI patients Indication in patients after MI, IS, or with established PAD CREDO CURRENT CURE CURE CURE CURE CURE CURE (PCI-CURE) (PCI-CURE) (PCI-CURE) (PCI-CURE) (PCI-CURE) (PCI-CURE) CURE (PCI-CURE) CURE CURE (PCI-CURE) (PCI-CURE) CURE (PCI-CURE) CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE 1996 2000 2001 2002 2004 2004 2005 2005 2006 2007 2009 Publication Date 2009 Expected Date of Results Primary Outcome 0 .3 HR=0.89 (0.81-0.98) p=0.014 0 .2 Placebo+Aspirin 0 .1 Clopidogrel+Aspirin 0 .0 C um ulat iv e H az ard R at es 0 .4 (Stroke, MI, non-CNS Systemic Embolism, Vascular Death) 0 No. at Risk C+ A 3772 ASA 3782 1 2 3 4 3456 3426 3180 3103 2522 2460 1179 1156 Years 1000 patients treated for 3 years: – Prevent 28 strokes (17 fatal or disabling) and 6 myocardial infarctions – Cost 20 (non-stroke) major bleeds (3 fatal) Indications Maladie Coronaire Stable 1. Poursuivre l’aspirine à faibles doses (75 à 162 mg/j)(Grade 1A). Il est suggéré de le poursuivre indéfiniment (Grade 2C) 2. Si maladie coronaire symptomatique= associer aspirine (75– 100mg/j) et clopidogrel (75 mg/j) [Grade 2B] 3. Si DES, apirine (75–100mg/j) plus clopidogrel (75 mg/j pour au moins 12 mois) [Grade 1A pour 3 à 4 mois; Grade 1B pour 4 à 12 mois]. Après 1 an, poursuivre l’association indéfiniment en l’absence de saignement et si bonne tolérance (Grade 2C) (CHEST 2008; 133:71S–105S) Bénéfice Clinique Net après 1 an de bithérapie Aspirine seul TS: 0.5% Décès, IDM, AVC (TS exclus): 4% Saignement majeur: 0.5% 5% Dual OAT (aspirin and clopidogrel) TS: 0.35% Décès, IDM, AVC (TS exclus): 3% Saignement majeurr: 0.6% 4% Les Enjeux Pratiques non Résolus La résistance aux AAP La place des nouveaux Interruption de la bithérapie Interruption prématurée But : éliminer l’interruption prématurée des AAP 1. Chez les patients chez qui on suspecte une mauvaise compliance au plavix la première année, éviter le stent actif 2. En cas de chirurgie programmée la première année, éviter le stent actif 3. L’éducation sur la compliance et le risque d’interruption prématurée est une priorité 4. Les tutelles doivent être mises en garde sur le risque d’interruption prématuré, en particulier le coût ne doit pas être une cause d’arrêt prématuré 5. Différer toute intervention jusqu’à au moins 1 an après le mise en place d’un stent actif et 1 mois en cas de stent nu 6. En cas de stent actif, poursuivre aspirine et reprende clopidogrel le plus rapidement Circulation 2007; 115 Discontinuation of Single/Dual OAT • 161 cases of late or very late stent thrombosis (84 articles) Eisenberg et al. Circulation In press Discontinuation of Single/Dual OAT Eisenberg et al. Circulation In press Aspirin Compliance Cuisset el al. Am H Journal In Pre Interruption après 1 an Primary Endpoint (MI/Stroke/CV Death) in Patients with Previous MI, IS, or PAD “CAPRIE-like Cohort” Primary outcome event rate (%) 10 N=9,478 Placebo + ASA 8.8 % 8 Clopidogrel + ASA 7.3 % 6 4 RRR: 17.1 % [95% CI: 4.4%, 28.1%] p=0.01 2 0 0 6 12 18 24 Months since randomization Bhatt DL et Al., JACC 2007 30 Long-term Bleeding Risk? Hazard function per day 0.00008 Placebo + ASA Clopidogrel + ASA 0.00007 0.00006 0.00005 0.00004 0.00003 0.00002 0.00001 0 15 60 135 270 450 Days since randomization Bhatt DL et al. J Am Coll Cardiol 2007;49:1982–1988. 630 810 KM from Time of Discontinuation to first Event* Placebo vs Clopidogrel *Primary Efficacy Endpoint (death/MI/Stroke) Average time from drug discontinuation to primary endpoint was 228 days (95% CI 197-258) 100 ----Clopidogrel Placebo 90 80 log-rank test, p=0.029 70 clopidogrel was an independent correlate for survival (HR 0.75; 95% CI 0.59-0.95, p=0.016) 60 0 180 360 540 720 900 Arch Cardiovasc Dis. 2009 Jun-Jul;102(6-7):485-96 Conlcusions 1. Bithérapie indéfiniment chez tous (principe de précaution) 2. Monothérapie après 1an chez la majorité − Arrêt clopidogrel ? (principe économique) − Arrêt aspirine ? (principe de réalisme) 3. « A la carte » (principe de bon sens) − − − − − − − − Multitronculaires Multistentés Petites artères Post infarctus Diabètiques SAT ou nouvel évènement ischémique Polyvasculaires … 4. Aide à la décision ARCTIC; ISAR-SAFE La résistance: un enjeu Effect of 900mg of Clopidogrel LD RELOAD Study The ALBION trial (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) (“REload with cLOpidogrel before coronary Angioplasty in subjects treated long term with Dual antiplatelet therapy”)” Inhibition of RPA 4 hours after the first reloading dose Maximum Inhibition of Platelet Aggregation (ADP 20 µmol/L) 600 mg 300 mg 600 mg LD (%) Inhibition 35 30 25 20 15 10 P<.05 vs 300 mg LD 5 0 1 2 3 4 5 6 p=0.0008 120 900 mg LD 24 IRPA (20 µMol ADP, %) 40 300 mg LD 900 mg p=0.017 100 p=0.34 80 60 40 20 Time (hours) The ALBION study (J ACC 2006;48:931– 8) 0 First reloading dose Circulation. 2008 ;118(12):1225-33 The RECLOSE Study: 6 Month Outcomes After DES Implantation Stratified By Post-Plavix ADPmediated Platelet Reactivity Overall (n=804) Responders (n=699) 8,6% Non-Responders (n=105) 10,5% 8,6% p<0.001 p<0.001 p<0.001 3,1% 2,4% 3,5% 2,4% 2,7% Stent Thrombosis Cardiac Death and ST 1,4% Cardiac Death Non-responders defined as >70% aggregation by LTA 12 hours after 600-mg plavix load Buonamici, J Am Coll Cardiol 2007;49:2312-7 « VASP-Guided » PCI after a first 600mg LD of clopidogrel MACE: CV death, MI, revasc. 1 Log rank p =0.007 0.95 0.90 (10 vs 0%, p=0.004) 0.85 0.80 • Each LD by 35 to 49% suboptimal response •14% patients remained suboptimal responders 0 5 days 10 15 20 25 30 • Average LD 1600 mg J Am Coll Cardiol 2008;51:1404–11 Benefit of High Loading Dose vs Standard Loading Dose Death and MI within the first month of PCI Study or subcategory High loading Standard loading n/N n/N Peto OR 95% CI Peto OR 95% CI Year 01 Randomized trials ALBION ARMYDA-2 CLEAR PLATELETS Cuisset et al Gurbel et al ISAR-CHOICE Muller et al Subtotal (95% CI) 2/68 5/126 1/60 7/146 0/52 0/40 0/10 502 1/35 15/129 3/60 15/146 0/138 0/20 0/10 1.03 0.35 0.36 0.46 538 [0.09, [0.14, [0.05, [0.19, 11.50] 0.87] 2.61] 1.09] 2006 2005 2005 2006 2005 2005 2001 0.42 [0.23, 0.75] Total events: 15 (High loading), 34 (Standard loading) Test for heterogeneity: Chi² = 0.75, df = 3 (P = 0.86), I² = 0% Test for overall effect: Z = 2.93 (P = 0.003) 02 Non-randomized studies Angiolillo et al Seyfarth et al Wolfram et al Subtotal (95% CI) 0/23 0/11 13/319 353 0/27 0/21 4/126 1.28 [0.44, 3.74] 1.28 [0.44, 3.74] 174 2004 2003 2006 Total events: 13 (High loading), 4 (Standard loading) Test for heterogeneity: not applicable Test for overall effect: Z = 0.45 (P = 0.66) Total (95% CI) 855 Total events: 28 (High loading), 38 (Standard loading) Test for heterogeneity: Chi² = 3.94, df = 4 (P = 0.41), I² = 0% Test for overall effect: Z = 2.36 (P = 0.02) 712 0.54 [0.32, 0.90] 0.1 0.2 0.5 1 Favours high loading 2 5 10 Favours low loading Aucune augmentation du risque d’hémorragie majeure ou mineure (p=0.55 et p=0.98). Interaction significative entre le taux d’événement ischémique et le bénéfice clinique des fortes doses de charge (p=0.005), suggérant que plus le risque est élevé et plus l’intérêt de forte de charge est important La thrombose de stent : situation complexe Facteurs multiples Risque de récidive Prévalence de la résistance élevée A Thombose de stent sous clopidogrel % RPA (20µM ADP) 80 p=0.0032 (Krukal Wallis) 60 40 20 0 75 Efficacité du Prasugrel 150 225 Clopidogrel MD dose (mg) 300 10 900 Prasugrel Clopidogrel MD dose (mg) RD dose (mg) Circulation. 2009 Jun 2;119(21):2854-7 La résistance: les causes Sources de Variabilité de la Réponse aux Médicaments Dose Prescrite – Non-observance – Erreur d’administration Dose administrée Absorption Distribution Elimination Pharmacocinétique Concentration au site d’action Récepteur Effecteur – Facteurs pathologiques et physiologiques – Facteurs environnementaux Pharmacodynamique – Facteurs génétiques Effet Déterminisme génétique du métabolisme des médicaments Clopidogrel metabolism O OCH3 Esterases ~85% Inactive Metabolites N S Cl CYP2C19 CYP1A2 CYP2B6 O OCH3 N O S Cl CYP3A4 CYP2C19 CYP2C9 CYP2B6 O OCH3 N HOOC HS N Engl J Med 2008 Cl CYP2C19*2 681 G A Exon 4 *1 (sauvage)G Intron 68 Exon 5 1 4 Exon 4 *2 (muté) A681 Intron Exon 5 4 Épissage aberrant Exon 4 Exon 5 Exon 4 Exon 5 Perte de 40bp dans l’exon 5 Décalage du cadre de lecture Protéine complète et fonctionnelle Protéine tronquée et non-fonctionnelle Codon stop prématuré AFIJI Registry (STEMI<45yrs, n=259) death/non fatal MI /urgent revascularization 1.0 0.0 0.8 CYP 2C19 *1/*1 *1/*2 or *2/*2 0.7 0.6 0.5 HR=3.66; 95%CI (1.69-8.05) p=0.0005 Stent thrombosis3.31 [1.05-10.47]; p=0.04 0.2 0.1 0.0 0 1 2 3 4 *1/*1 *1/*2 *2/*2 11/186 (5.9%) 13/64 (20.3%) 2/9 (22.2%) 5 years STENT THROMBOSIS (n=4905) Odds Ratio, fixed model Bilateral CI, 95% for trials, 95% for MA 2C19*2 2C19*1 Mega et al. (0.26) 10/375 8/1014 Collet et al. (0.15) 8/73 4/186 Giusti et al. (0.34) 13/247 11/525 Sibbing et al. (0.24) 10/680 7/1805 41/1375 30/3530 2C19*2 better 2C19*2 worse Total OR 3.45 95% CI: 2.14-5.57, p<0.001, phet=0.78 0 Odds Ratio 1 2 3 4 5 10 20 events / size Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome Neither clopi nor PPI PPI without clopi Clopi+PPI Clopi without PPI Death or Rehosp for ACS % 0.7 0.6 0.5 0.4 0.3 0.3 AOR=1.25; 95% CI (1.11-1.41) 0.1 0 0 90 180 270 360 450 540 630 Period since discharge in days 810 900 900 JAMA. 2009;301(9):937-944 What We Do Not Know, Precisely Platelet resistance Genetic resistance (2C19*2) (low response on a functional test) Clinical Resistance (thrombotic event) Assessment with a double Randomization of 1) a monitoring-adjusted antiplatelet treatment vs. a Common antiplatelet Treatment for DES implantation, and 2) Interruption vs. Continuation of double antiplatelet therapy one year after stenting Randomisation avant implantation d’un stent actif Groupe 1 : Bras Monitoré Groupe 2 : Bras Conventionnel 1-Evaluation systématique de la réponse biologique à l’aspirine et au clopidogrel avant la mise en place de l’endoprothèse active. 1- Pas d’évaluation de la réponse biologique au traitement antiplaquettaire 2-Adaptation du traitement antiplaquettaire chez les hyporépondeurs au moment de l’angioplastie 2- La stratégie antiplaquettaire orale est laissée à la discrétion de l’investigateur en fonction des pratiques habituelles 3-Réévaluation chez tous les patients à J30±3 de la réponse au traitement antiplaquettaire oral et ajustement du de la dose d’entretien Evaluation du critère primaire de jugement tous les 6 mois (6 jusqu’à 18 mois) 1. 2. 3. 4. Toute cause de mortalité Infarctus du myocard Toute revascularisation urgente PHAO 2008 ARCTIC (Essai P080403)- Promoteurou non Thrombose de stent nécessitant unen°revascularisation AP-HP 36 Algorithme d’ajustement de la dose Patient prévu pour angioplastie élective avec DES et prétraité par aspirine et clopidogrel (pratiques locales) et randomisés dans le “bras monitoring” VerifyNow avant PCI : TM-Aspirin &Clopidogrel %inh≤15% ou PRU≥235 ( cartouche P2Y ARU≥550 (cartouche ASA) Recharge avec 500 mg ASA doses d’entretien au choix 12) Inhibiteurs de la GPIIb/IIIa + recharge en clopidogrel (300-900mg) et dose d’entretien à 150 mg VerifyNow @ J30 TM-Aspirin & Clopidogrel tous les patients ARU≥550 (cartouche ASA) Aspirine à 200 mg et fractionner %inh≤15% ou PRU≥235(cartouche P2Y12) clopidogrel sans limite supérieure Les nouveaux Biotransformation and mode of action Platelet Aggregation at 4 hours 100 90 ISAR-CHOICE – Von Beckerhat et al .Circulation 2005 ALBION – Montalescot et al. JACC 2007 DIPSERSE 2 – Storey et al. JACC 2007 PRINCIPLE TIMI-44 – Wiviot et al. Circulation 2007 RELOAD – Collet et al. Circulation 2008 300mg 80 600mg 900mg 70 60 50 10mg 40 90mg 60mg 0 Clopidogrel Ticagrelor TRITON 180mg PLATO 10 CURE 20 CURRENT 30 Prasugrel Study Design, Flow and Compliance 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d) Angio 24,769 (99%) No PCI 7,855 (30%) PCI 17,232 (70%) No Sig. CAD 3,616 Compliance: Clop in 1st 7d (median) 7d Efficacy Outcomes: Safety Outcomes: Key Subgroup: 7d CABG 1,809 2d CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Bleeding (CURRENT defined Major/Severe and TIMI Major) PCI v No PCI CAD 2,430 7d Complete Followup 99.8% PLATO study design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) 6–12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack Prasugrel LD 60mg + MD 10mg TRITON Angiograpy n= 13,608 R PCI 99% 100% Clopidogrel LD 300mg + MD 75mg Ticagrelor 180mg + MD 90mgx2 PLATO n= 18,624 R Angiograpy 81% PCI 64.3% Clopidogrel LD 300mg + MD 75mg Clopidogrel LD 600mg (16%) Clopidogrel LD 600mg + MD 150mg CURRENT n= 25,087 R Angiograpy 99% PCI 70% Clopidogrel LD 300mg + MD 75mg Baseline and index event characteristics CURE (n=12,562) TRITON (n=13,608) PLATO (n=18,624) CURRENT (n=25,087) Median age, years 64.2 61.0 62.0 - Women, % CV risk factors, % Habitual smoker Hypertension Dyslipidaemia Diabetes mellitus BMI History, % Myocardial Infarction Percutaneous coronary intervention Coronary-artery bypass grafting Clinical Presentation % Unstable angina or NSTEMI STEMI TIMI Risk Score >3 TIMI Risk Score >5 38.5 26 28.4 24.5 60.8 59 na 22.6 na 38 64 56 23 28 35.8 65.4 46.6 25.0 27 37 22.2 - 32.2 17.7* * 18 13.1 7.5 20.5 13.3 6.0 - 74.9 25.1 33.3 33.3 74 26 - 62.3 37.7 44.6 20.6 70.8 29.2 - na 42.2 25.3 na ? - 37.6 51.0 85.7 81.0 40 - Characteristic ECG at entry, % Persistent ST-segment elevation ST-segment depression Troponin-I positive (all population) % Troponin-I positive (UA or NSTEMI) % Study medication CURE (n=12,562) TRITON (n=13,608) PLATO (n=18,624) CURRENT (n=25,087) - - 11.3 - Premature discontinuation of study drug - - 23.4 - Premature discontinuation of control - - 21.5 - Clopidogrel in hospital before randomisation - - 46.1 - Loading dose of clopidogrel ≥ 600mg 0 0 16.6 0 Study-drug administration before PCI - 25.5 ?* ? GP IIbIIIa Inhibitor - 54.5 26.6 28.6 Planned invasive treatment - 100 72.0 - Coronary angiography - 100 81.5 99 PCI during index hospitalisation - 99 61.0 70 Cardiac surgery - 2.5 4.5 10 Start of randomised treatment Time after start of chest pain, h, median Compliance, % Concomitent antithrombotic, % Invasive procedures at index hospitalisation, % Benefits of Antiplatelet Therapy in ACS are Greater in Patients Undergoing PCI Relative Risk Reduction PCI No PCI CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI) 30%1 19%2 STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI) 46%3 9%4 TRITON: Prasugrel v Clopidogrel 300/75mg (CVD/MI/Stroke) 19%5 Not evaluated PLATO : Ticagrelor v Clopidogrel 300/75mg (CVD/MI/Stroke) 16%6 15%*NS deleterious CURRENT : Clopidogrel 600/150 v 300/75mg (CVD/MI/Stroke) 15%7 ?+17%*p=0.1 4 1. Mehta SR, et al. Lancet 2001; 358(9281):527-33. 6. Wallentin L et al. N Engl J Med 2009 2. Fox KAA, et al. Circulation 2004;110:1202-8 7. Metha et al. presented at the ESC09 3. Sabatine MS, et al. JAMA 2005; 294(10):1224-32. 4. Chen ZM Lancet 2005;366:1607-21 4. Boersma E et al. Lancet 2002; 359:189 5. Wiviott S et al. N Engl J Med 20072007; 357: 2001–15. TRITON and PLATO 15 Primary endpoint = CV Death / MI / Stroke 12-15 months 12.1 11.7 Endpoint (%) Clopidogrel 75mg 9.9 10 9.8 Prasugrel 10mg HR 0.84 (0.77–0.92) p=0.0003* HR 0.81 (0.73-0.90) p=0.0004* 5 Ticagrelor 90mg x2 0 0 30 60 90 180 270 360 450 days TRITON, PLATO and CURRENT EARLY CV Death / MI / Stroke (30days) 8 Clopidogrel 300mg + 75mg 5.6% (Prasugrel 5.6% Prasugrel 60mg + 10mg 6 4.7% Cumulative incidence (%) 7.1% (Clopidogrel 75 TRITON) TRITON) 5.4 % (Clopidogrel 75 PLATO) 4.8 % (Ticagrelor PLATO) 4.4 % (Clopidogrel 75 CURRENT) 4.2 % (Clopidogrel 150 CURRENT) 4 Ticagrelor 180mg + 90mg x2 2 Clopidogrel 600mg + 150mg 0 0 10 20 30 days Clopidogrel 75mg vs Prasugrel 10mg HR 0.77 (95% CI 0.67–0.88), p<0.001* Clopidogrel 75mg vs Ticagrelor 90mg x2 HR 0.88 (95% CI 0.77–0.95), p=0.045* Clopidogrel 75mg vs Clopidogrel 150mg HR 0.96 (95% CI 0.85-1.08), p=0.47 - 23% - 12% - 4% TRITON and PLATO LATE CV Death / MI / Stroke (30- 360 days) Prasugrel 10mg Clopidogrel 75mg 8 Cumulative incidence (%) 6.6 6 Ticagrelor 90mg x2 5.3 6.9 5.6 4 HR 0.80 (95% CI 0.70–0.91), p=0.003* (TRITON) HR 0.80 (95% CI 0.70–0.91), p<0.001 (PLATO) 2 0 31 90 150 210 270 330 390 450 All cause Mortality (12-15 months) 9 p=0.62 p<0.001 -9% - 5% -22% 7 6.2 5.9 5.8 6 4.5 5 p=0.6 4 3.0 3.2 - 4% 3 2 1 Prasugrel Ticagrelor Clopidogrel 150 Clopidogrel 75 2.1 2.2 ASA only K-M estimated rate 8 p=NS 0 CURE TRITON PLATO CURRENT 360 days 450 days 360 days 30 days and CV deaths only ! Stent Thrombosis (12-15 months) Hazard Ratio 2.4% vs 1.1% (142/68) 2.3% vs 1.6% (199 vs 136) 2.8% vs 2.1 (158/118) Significant reductions both with BMS, DES Significant reductions in early and late stent thromboses Safety = TIMI Major Non-CABG Bleeds (12-15 months) 9 Prasugrel Ticagrelor Clopidogrel 150 Clopidogrel 75 8 6 5 4 3 2 1 p=0.001 * p=0.03* p=0.025* +27% +25% +22% 3.7 30 days ! 2.8 2.7 2.4 ASA only K-M estimated rate 7 2.2 1.8 1.04 0.95 0 CURE TRITON PLATO 360 days 450 days 360 days CURRENT Safety = (12-15 months) 9 Prasugrel Ticagrelor Clopidogrel 150 Clopidogrel 75 8 K-M estimated rate 7 6 Fatal Bleeds Intracranial Bleeds 5 4 3 p=NS +0% p=0.002* p=0.66 p=0.74 +0% +0% +75% p=0.06 +33% 2 1 0.2 0.2 0.4 0.3 0.3 0.1 450 days TRITON 0.3 0.3 0.2 ? 0 CURE 0.3 PLATO CURE TRITON PLATO Safety = Life-threatening Bleeds (12-15 months) 9 8 p=0.7 +0% K-M estimated rate 7 Prasugrel Ticagrelor Clopidogrel 150 Clopidogrel 75 5.8 5.8 6 p=0.13 p=0.01* 5 +19% +55% 4 DEFINITION Rate of CABG! 3 2.2 2 1.8 1.4 0.9 1 0 CURE 360 days TRITON 450 days PLATO 360 days Le futur proche Les Enjeux Pratiques du Futur Le switch Le préhospitalier La place des anti-IIb/IIIa? Le NSTEMI Les sujets fragiles Les coûts The ACAPULCO Study A Randomized, Double-Blind, Crossover Study Comparing the Pharmacodynamic Response in Subjects with Acute Coronary Syndrome Receiving 14 Days of 10-mg Maintenance Dose Prasugrel versus 14 Days of 150-mg Maintenance Dose Clopidogrel After Using a 900-mg Loading Dose of Clopidogrel to Reduce Ongoing Platelet Activation Maximal Platelet Aggregation (%) (20 µM ADP) 90 80 70 Pre-LD Clopidogrel Clopidogrel 150 mg 150 mg 60 50 (n = 32) p = 0.016 40 30 p = 0.001 Prasugrel Clopidogrel n = 19 Clopidogrel 900 mg * Clopidogrel Prasugrel n = 18 20 10 0 * p = 0.003 vs. clopidogrel 900 mg Pre-LD Post-LD Prasugrel 10 mg Visit 3 (day 15) Prasugrel 10 mg Visit 4 (day 29) Net Clinical Benefit Bleeding Risk Subgroups Post-hoc analysis Risk (%) Prior Stroke / TIA Age Yes + 37 No Pint = 0.006 -1 >=75 Pint = 0.18 < 75 Wgt -16 < 60 kg -16 +3 >=60 kg Pint = 0.36 -14 -13 OVERALL 0.5 1 Prasugrel Better HR 2 Clopidogrel Better TRITON-TIMI 38: Patients Age<75 and Weight ≥60 and no history of TIA/stroke 16 Hazard Ratio, 0.745 (95% CI, 0.657-0.84) P<0.001 14 Endpoint (%) 12 11% Clopidogrel 10 8 8.4% Prasugrel 6 Hazard Ratio, 1.240 (95% CI, 0.911-1.687) P=0.170 4 2 0 0 30 CI=confidence interval 90 180 270 Days From Randomization 360 Prasugrel 1.95% Clopidogrel 1.50% 450 Net Clinical Benefit after 1 year Aspirin alone ST: 0.5% Death, MI, stroke (ST not considered): 4% Major bleed: 0.5% 5% ST: 0.35% Death, MI, stroke (ST not considered): 3% Major bleed: 0.6% 4% Dual OAT (aspirin and clopidogrel) Dual OAT (apirin and prasugrel) ST: 0.20% Death, MI, stroke (ST not considered): 2.5% Major bleed: 0.8% 3.5%