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Recent advances in anti platelet therapy in ACS

Recent advances in anti platelet therapy in ACS. Damien Coisne. WWW:cœur.plus.fr. Oasis 6 Oasis 5 Horizon. Clarity Cure Acuity Oasis 5 Early ACS Aboard On Time Triton Plato. Extract Caress Finesse Eurotransfer. Overview. New paradigm: Bleeding and coronary efficacy

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Recent advances in anti platelet therapy in ACS

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  1. Recent advances in anti platelet therapy in ACS Damien Coisne WWW:cœur.plus.fr

  2. Oasis 6 Oasis 5 Horizon Clarity Cure Acuity Oasis 5 Early ACS Aboard On Time Triton Plato Extract Caress Finesse Eurotransfer

  3. Overview • New paradigm: Bleeding and coronary efficacy • Lesson from recent clinical trials (acuity, oasis) • Main issues in anti platelets treatement for ACS • Early ACS, ABoard , • New antiplatelets agents : • Triton, Plato, Acapulco, Current, Brave.

  4. Coronary efficacy Bleeding Net clinical result

  5. Predictive factors GRACE Registry : 24 045 patients with ACS (29 % angioplasty) Major predictors (NSTEMI) 7 Moscucci M, et al. Predictors of major bleeding in acute coronary syndromes: the Glogal Registry of Acute Coronary Events (GRACE). Eur Heart J 2003 ; 24 : 1815-23.

  6. Intra Hosp mortality related to major bleeding Impact on mortality ? 8 Moscucci M, et al. Predictors of major bleeding in acute coronary syndromes: the Glogal Registry of Acute Coronary Events (GRACE). Eur Heart J 2003 ; 24 : 1815-23.

  7. Overview • New paradigm: Bleeding and coronary efficacy • Lesson from recent clinical trials (acuity, oasis) • Main issues in anti platelets treatement for ACS • Early ACS, ABoard , • New antiplatelets agents. • Triton, Plato, Acapulco, Brave, Current

  8. Prise en charge du STEMI Reperfusion en urgence Angioplastie primaire avec/sans thrombo-aspiration Thrombolyse/angioplastie de sauvetage Angioplastie après thrombolyse réussie (3-24 heures) Traitement antithrombotique Aspirine + clopidogrel Anti-GPIIb/IIIa (si angioplastie) Anticoagulant ESC Guidelines for the Management of STE-ACS 10 Van de Werf.F, et al. The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. European Heart Journal 2008 ; 29:2909-45.

  9. ESC 2008

  10. Prise en charge des AI/NSTEMI Stratification du risque Traitement anti-ischémique : β-bloquant, dérivés nitrés et antagonistes calciques Traitement antiagrégant plaquettaire adapté selon le risque initial Aspirine + clopidogrel chez tous les patients dans la mesure où il n’y a pas de contre-indication Anti-GPIIb/IIIa pour les patients à risque intermédiaire ou à haut risque Traitement anticoagulant recommandé chez tous les patients en association au traitement antiagrégant plaquettaire Revascularisation pour les patients à risque intermédiaire ou à haut risque (délai d’intervention selon sévérité initiale) Le niveau de preuve est variable selon les différents traitements ESC Guidelines for the Management of NSTE-ACS 12 Bassand JP, et al. The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. European Heart Journal 2007, 28:1598-1660

  11. Antiplatelets Strategy in ACS What’s new Quel est l’impact de fortes doses de P2Y12 (Clopidogrel) sur la stratégie et les traitements adjuvants dans le cadre des SCA STEMI (PPPCI), STEMI(Lysis), NSTEMI Quid des nouvelles molécules?

  12. NSTEMI Leçons de 2 échecs relatifs Early ACS et Aboard

  13. Study Design High-risk NSTE ACSn = 10,500 2 of 3 high-risk criteria: 1. Age > 60 years 2. + CKMB or TnT/I 3. ST  or transient ST  (Or age 50-59, h/o CVD and + CKMB or TnT/I) Double bolus Routine, early eptifibatide(180/2/180) Placebo / delayed provisional eptifibatide pre-PCI Randomize within 12 hours of presentation Invasive strategy: 12 to 96 hours after randomization Primary Endpoint: 96-hr Death, MI, Recurrent ischemia requiring urgent revascularization, or Thrombotic bailout Key Secondary Endpoint: 30-d Death or MI

  14. Kaplan-Meier Curves for Primary Endpoint 15 10.0% 10 Delayed provisional eptifibatide 9.3% Death, MI, RIUR or TBO (%) P = 0.23 (stratified for intended early clopidogrel use) 5 Routine early eptifibatide 0 0 8 16 24 32 40 48 56 64 72 80 88 96 Time Since Randomization (Hours) RIUR, recurrent ischemia requiring urgent revascularization; TBO, thrombotic bailout

  15. Primary and Key Secondary Efficacy ResultsBy Clopidogrel Strata at Randomization Real life or Impact of Clopidogrel pre treatment 96-hr Death, MI, RIUR, TBO Clopidogrel intended 8.8 9.5 0.92 (0.78-1.08) No Clopidogrel intended 10.8 11.5 0.93 (0.72-1.20) 30-day Death / MI Clopidogrel intended 10.3 12.0 0.85 (0.73-0.91) No Clopidogrel intended 13.7 13.4 1.03 (0.81-1.31) Routine EarlyEptifibatide Delayed ProvisionalEptifibatide OR(95% CI) Need for Clopidogrel early treatment

  16. Background Randomized trials have demonstrated that an invasive strategy is superior to a conservative strategy in NSTE-ACS The optimal timing of intervention remains a matter of debate A “primary PCI” approach of NSTE-ACS has not been tested yet

  17. ABOARD study design NSTE-ACS 2 of 3 Criteria: Ischemic symptom, ST-T change, troponin rise with TIMI score > 3 IVRS RANDOMIZATION Next day cath Immediate cath All PCIs on abciximab 1-month Follow-up

  18. % P=0.08 P=0.09 P=0.32 P=0.57 P=0.28 P=0.62 Individual Ischemic Endpoints at 1 month

  19. In-hospitalmedications Optimal adjunctive therapy

  20. STEMI/NSTEMI Clopidogrel 300 or 600 mg?

  21. Impact of clopidogrel loading dose on the safety and effectiveness of bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction: The HORIZONS AMI trial George Dangas, Giulio Guagliumi, Bernhard Witzenbichler, Deepak Bhatt, Frederick Feit, Magnus Ohman, S. Chiu Wong, Helen Parise, Roxana Mehran, Gregg W. Stone

  22. JACC Sept 2009

  23. Baseline Characteristics Dangas et al, SCAI-ACCi2 2008

  24. Overall: Primary Outcomes (ITT) P<.0001 P=0.002 P=0.001 • *NACE = MACE or major bleeding • **Not related to CABG • ***MACE = All cause death, reinfarction, ischemic TVR or stroke Dangas et al, SCAI-ACCi2 2008

  25. 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) vsStandard dose (300 mg then 75 mg/d) ASA: High Dose (300-325 mg/d) vsLow dose (75-100 mg/d) Angio 24,769 (99%) PCI 17,232 (70%) No PCI 7,855 (30%) No Sig. CAD 3,616 CABG 1,809 CAD 2,430 Efficacy Outcomes: CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI

  26. Clopidogrel: Double vs Standard DosePrimary Outcome and Components

  27. Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients CV Death, MI or Stroke Clopidogrel Standard 15% RRR 0.04 Clopidogrel Double 0.03 Cumulative Hazard 0.02 HR 0.85 95% CI 0.74-0.99 P=0.036 0.01 0.0 0 3 6 9 12 15 18 21 24 27 30 Days

  28. ConclusionsASA Dose Comparison No significant difference in efficacy or bleeding between ASA 300-325 mg and ASA 75-100 mg.

  29. ClinicalTrials.gov Identifier: NCT00133250 Abciximab in Patients with AMI Undergoing Primary PCI After Clopidogrel Pretreatment BRAVE-3 Trial Bavarian Reperfusion AlternatiVes Evaluation-3 Trial J. Mehilli, A. Kastrati, K. Huber, S. Schulz, J. Pache, C.Markwardt, S. Kufner, F. Dotzer, K. Schlotterbeck, J. Dirschinger, A. Schömig.

  30. Background • Glycoprotein IIb/IIIa inhibitors (GPI) may improve the results of primary PCI in acute STEMI • Pretreatment with a 300mg loading dose of clopidogrel improved the outcome of patients undergoing PCI in the setting of the CLARITY trial • A higher, 600mg loading dose of clopidogrel further enhances and accelerates platelet inhibition

  31. Myocardial perfusion % 0% 100% 50% Endpoints Primary endpoint: • SPECT study (5-7days after • randomization) • Final infarct size • (% of the left ventricle) Secondary endpoints: • Death • Myocardial reinfarction • Urgent revascularization • Stroke • Major and minor bleedings (TIMI criteria) • Profound thrombocytopenia

  32. Study Therapy (randomized, double-blind, multicenter) Clopidogrel 600 mg oral Aspirin 500 mg i.v. or oral Unfractionated Heparin 5000 IE Abciximab n=401 Placebo n=399 Aspirin 200mg/day indefinitely Clopidogrel 2 x 75mg/day for 3 days Clopidogrel 75mg/day for at least 4 weeks

  33. Reperfusion Strategy P =.80 100 Drug-eluting stents % Bare metal stents PTCA 60 Medical treatment 20 Abciximab Placebo

  34. Primary Endpoint Final infarct size Mean Final infarct size Median[25th; 75th percentile] 40 P =.76 P = .47 % LV % LV 30 20 10 10 9 0 Abciximab Placebo Abciximab Placebo

  35. Conclusion In patients with acute STEMI undergoing primary PCI after pre-treatment with a 600mg loading dose of clopidogrel, the additional use of abciximab is notassociated with further reduction in infarct size

  36. Healthy VolunteerCrossover Study 100 N=66 80 InterpatientVariability 60 IPA at 24 hours (%) 40 InterpatientVariability 20 Clopidogrel Responder 0 Clopidogrel Non-responder -20 Response to Prasugrel 60 mg Response to Clopidogrel 300 mg From Brandt JT AHJ 153: 66e9,2007

  37. Balance of Efficacy and Safety 15 138 events Clopidogrel HR 0.81(0.73-0.90)P=0.0004 12.1 CV Death / MI / Stroke 9.9 10 NNT = 46 Prasugrel Endpoint (%) 5 35 events TIMI Major NonCABG Bleeds Prasugrel 2.4 HR 1.32(1.03-1.68)P=0.03 1.8 Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 Days

  38. Net Clinical BenefitDeath, MI, Stroke, Major Bleed (non CABG) 15 Clopidogrel 13.9 ITT= 13,608 12.2 HR 0.87P=0.004 Prasugrel 10 Endpoint (%) All CauseMortality 5 Clop 3.2%Pras 3.0 %P=0.64 0 0 30 60 90 180 270 360 450 Days

  39. CV Death, MI, StrokeMajor Subgroups Reduction in risk (%) 18 UA/NSTEMI B 21 STEMI 21 Male 12 Female 25 <65 14 Age 65-74 6 >75 14 No DM 30 DM 20 BMS 18 DES 21 GPI 16 No GPI 14 CrCl < 60 20 CrCl > 60 Pinter = NS 19 OVERALL 0.5 1 2 Prasugrel Better Clopidogrel Better HR

  40. 15 12.1 Clopidogrel 9.9 10 P<0.001 Prasugrel CV Death, MI, Stroke (%) 5 HR 0.81 (0.73-0.90) NNT= 46 0 0 30 60 90 180 270 360 450 Days Wiviott et al. New Engl J Med 2007;357:2001-2015 TRITON-TIMI 38 STEMI cohort P=0.002 P=0.03 P=0.01 • TRITON allowed recruitment of STEMI patients undergoing primary PCI when they presented < 12 hours of symptom onset or secondary PCI when they presented late

  41. STEMI cohort Clopidogrel Prasugrel 15 12.4 p=0.02 RRR=21% 10.0 10 9.5 p=0.002 RRR=32% Proportion of patients (%) 6.5 5 HR=0.79 (0.65–0.97) NNT=42 0 Age-adjusted HR=0.81 (0.66-0.99) 0 50 100 150 200 250 300 350 400 450 Time (Days) Primary EP (CV death, MI and stroke at 15 months) Montalescot et al. ESC 2008

  42. PLATO Lars Vallentin Perspective Clopidogrel Prasugrel Ticagrelor Rapidité d’action Variabilité interindividuelle Reversibilité Risque hémorragique Efficacité clinique Albert Schoming Editorial NEJM 2009, 361,11, 1108

  43. PLATO study design NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624) Clopidogrel-treated or -naive; randomized <24 hours of index event At randomization, 13,408 (72%) of patients were specified by the Investigator: intent for invasive strategy Clopidogrel (n=6,676) 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 (n=6,732) 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) 6–12 months treatment Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator

  44. Primary endpoint: CV death, MI or stroke 15 Clopidogrel 10.65 10 9.02 K-M estimated rate (% per year) Ticagrelor 5 HR: 0.84 (95% CI = 0.75–0.94), p=0.0025 0 0 300 360 60 120 180 240 Days after randomization No. at risk Ticagrelor 6,732 6,236 6,134 5,972 4,889 3,735 3,048 Clopidogrel 6,676 6,129 6,034 5,881 4,815 3,680 2,965 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

  45. Primary safety event: Major bleeding* 15 Clopidogrel 11.6 Ticagrelor 11.5 10 K-M estimated rate (% per year) 5 HR 0.99 (95% CI = 0.89–1.10), p=0.88 0 0 60 120 180 240 300 360 Days after randomization No. at risk Ticagrelor 6,651 5,235 4,947 4,755 3,726 2,741 2,503 Clopidogrel 6,585 5,215 4,984 4,786 3,753 2,754 2,496 * PLATO definitions

  46. CURE TRITON PLATO En perspective Albert Schoming Editorial NEJM 2009, 361,11, 1108

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