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  • 1. Prasugrel Compared to Clopidogrel in Patients with Acute Coronary Syndromes Undergoing PCI with Stenting: the TRITON - TIMI 38 Stent Analysis Stephen D. Wiviott, Elliott M. Antman, Ivan Horvath, Matyas Keltai, Jean-Paul R. Herrman, Frans van de Werf, William Downey, Benjamin M. Scirica, Sabina A. Murphy, Carolyn H. McCabe, Eugene Braunwald SCAI – ACCi2 2008 Chicago, Illinois Disclosure Statement : The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co. STENT ANALYSIS
  • 2. Main Trial 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 1 o endpoint: CV death, MI, Stroke 2 o endpoint: Stent Thrombosis Safety endpoints: TIMI major bleeds, Life-threatening bleeds Duration of therapy: 6-15 months N= 13,608 Wiviott SD, Antman EM et al AHJ 2006 STENT ANALYSIS
  • 3. Trial Organization Trial Leadership: TIMI Study Group Eugene Braunwald,Chairman, Elliott M. Antman, PI, Carolyn H. McCabe, Director, Stephen D. Wiviott, Gilles Montalescot, Sabina A. Murphy, Susan McHale Sponsors: Daiichi Sankyo and Eli Lilly J. Anthony Ware, Jeffrey Riesmeyer, William Macias, James Croaning, Govinda Weerakkody, Francis Plat, Tomas Bocanegra Data Center and Site Management: Quintiles Inc Data Safety Monitoring Board David Williams (Chair) , Christophe Bode, Spencer King, Ulrich Sigwart, David DeMets STENT ANALYSIS
  • 4. 0 5 10 15 0 30 60 90 180 270 360 450 HR 0.81 (0.73-0.90) P=0.0004 Prasugrel Clopidogrel Days Endpoint (%) 12.1 9.9 HR 1.32 (1.03-1.68) P=0.03 Prasugrel Clopidogrel 1.8 2.4 Main Trial: Primary Results CV Death / MI / Stroke TIMI Major NonCABG Bleeds Wiviott SD, Braunwald E, McCabe CH et al NEJM2007
  • 5. Goals of Stent Analysis
    • To compare the efficacy and safety of PRASUGREL and CLOPIDOGREL in 12,844 patients with at least one stent as part of the index procedure with respect to:
        • Stent Thrombosis (ARC definitions)
        • Ischemic Events, Bleeding
        • Overall and stratified by stent type received
    STENT ANALYSIS
  • 6. Patient Population Randomized 13,608 Stent Placed 12,844 (94%) STENT ANALYSIS BMS Only 6461 (47%) DES Only 5743 (42%) Both BMS/DES 640 (5%) PES Only 2766 (20%) SES Only 2454 (18%) Other/Mixed 523 (4%)
  • 7. Baseline Characteristics STENT ANALYSIS Any Stent (N=12844) 94 % UA/NSTEMI 75 STEMI 25 Age, median (IQR) > 75 y 60 (53,69) y 13 Female 26 Diabetes 23 Smoker 38 North America 32 Prior MI 17 CrCl (ml/min) > 60 <60 89 11
  • 8. Key Efficacy, Safety EP: Stratified by Stent Type
    • CVD/MI/CVA
    • Non-CABG TIMI Major Bleeding
    STENT ANALYSIS HR 0.80 (0.69-0.93) p=0.003 HR 0.82 (0.69-0.97) p=0.02 HR 1.37 (0.95-1.99) p=0.09 HR 1.19 (0.83-1.72) p=0.34 N=6461 N=5743 CLOPIDOGREL PRASUGREL % of Subjects
  • 9. ARC ST Definitions Blinded CEC review of using source documents incl imaging reports: Definite : total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of the stent AND a clinical syndrome <48 h. Probable : unexplained death < 30 days or MI in stented territory w/o angiographic confirmation ST AND w/o alternative cause Possible : unexplained death > 30 days following stenting Early: 0 – 30 days after randomization Late > 30 days after randomization (landmark analysis) Based on ARC Definitions Mauri L et al NEJM 2007 STENT ANALYSIS
  • 10. Death Following ST
    • Mortality During Follow up (%) Post-Stent Thrombosis
    STENT ANALYSIS N=210 N=12634 HR 13.1 (9.8 – 17.5) P<0.0001 % of Subjects
  • 11. Definite/Probable ST: Any Stent (N=12844) 0 0.5 1 1.5 2 2.5 0 50 100 150 200 250 300 350 400 450 % of Subjects HR 0.48 [0.36-0.64] P<0.0001 1 year: 1.06 vs 2.15% HR 0.48 [0.36-0.65], P<0.0001 2.35% 1.13% 52% STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL
  • 12. Definite/Probable ST: Any Stent (N=12844) % of Subjects HR 0.41 [0.29-0.59] P<0.0001 HR 0.60 [0.37-0.97] P=0.03 DAYS EARLY ST LATE ST STENT ANALYSIS 1.56% 0.64% 59% 0.82% 0.49% 40% CLOPIDOGREL PRASUGREL
  • 13. Stent Thrombosis By ARC Category (N=12844) STENT ANALYSIS DEF/PROB HR 0.48 (0.36-0.64) P<0.0001 DEFINITE HR 0.42 (0.31-0.59) P<0.0001 DEF/PROB/POSS HR 0.56 (0.43-0.73) P<0.0001 CLOPIDOGREL PRASUGREL % of Subjects
  • 14. Stent Thrombosis Subgroups STENT ANALYSIS PRASUGREL BETTER CLOPIDOGREL BETTER PRAS CLOP RISK (%) 1.6 2.8 42% 1.0 2.2 57% 1.4 2.9 53% 0.9 1.9 52% 1.1 2.2 50% 1.4 4.6 69% 1.1 2.1 51% 1.1 3.9 70% 1.2 2.1 45% 0.8 3.4 75% 0.9 2.0 54% 1.3 2.6 51% 2.0 3.6 48% 0.9 2.0 55% 1.8 3.4 44% 1.0 2.2 54% 0.9 2.3 61% 1.2 2.4 50%
  • 15. Definite/Probable ST: DES Only (N=5743) % of Subjects HR 0.36 [0.22-0.58] P<0.0001 1 year: 0.74% vs 2.05% HR 0.35 [0.21-0.58], P<0.0001 2.31% 0.84% 64% STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL
  • 16. Definite/Probable ST: DES Only (N=5743) % of Subjects HR 0.29 [0.15-0.56] P=0.0001 HR 0.46 [0.22-0.97] P=0.04 DAYS STENT ANALYSIS EARLY ST LATE ST 1.44% 0.42% 71% 0.91% 0.42% 54% CLOPIDOGREL PRASUGREL
  • 17. Stent Thrombosis DES Subtypes Trial Duration STENT ANALYSIS N=2454 N=2766 Sirolimus Only HR 0.33 (0.15-0.73) p=0.004 Paclitaxel Only HR 0.33 (0.16-0.68) p=0.002 CLOPIDOGREL PRASUGREL 67% 67% % of Subjects
  • 18. Definite/Probable ST: BMS Only (N=6461) 2.41% 1.27% % of Subjects HR 0.52 [0.35-0.77] P=0.0009 1 year: 1.22 vs 2.27% HR 0.53 [0.36-0.79], P=0.0014 48% STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL
  • 19. Definite/Probable ST: BMS Only (N=6461) % of Subjects HR 0.45 [0.28-0.73] P=0.0009 HR 0.68 [0.35-1.31] P=0.24 DAYS STENT ANALYSIS EARLY ST LATE ST 1.66% 0.75% 55% 0.78% 0.53% 32% CLOPIDOGREL PRASUGREL
  • 20. Summary
    • Intensive antiplatelet therapy with PRASUGREL in stented patients compared to CLOPIDOGREL :
    • Substantial reduction in ST:
      • Regardless of stent type or ST definition
      • Early and Late
      • A broad range of clinical/procedural characteristics
    • Fewer ischemic events, more major bleeding
    STENT ANALYSIS
  • 21. Balance of Efficacy and Safety (Stented Population) STENT ANALYSIS Stent Thrombosis CVD/MI/CVA w/o ST Events per 1000 patients treated
  • 22. Conclusions/Implications
    • Stent Thrombosis is a rare, but devastating complication of PCI associated with a high mortality. Efforts to reduce ST have focused on compliance w/ and duration of ASA/clopidogrel
    • Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a broad array of clinical procedural characteristics
    STENT ANALYSIS www.thelancet.com
  • 23. STENT ANALYSIS
  • 24. Clinical Endpoints
    • Net Clinical Benefit
    STENT ANALYSIS HR 0.88 (0.77-1.01) p=0.07 HR 0.86 (0.77-0.95) p=0.002 HR 0.84 (0.72-0.98) p=0.025 N=12844 N=6461 N=5743 % of Subjects
  • 25. Primary EP (D/MI/CVA) Not Related to ST % of Subjects 10.3% 8.7% 15% HR 0.85, P=0.005 STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL
  • 26. Key Efficacy, Safety EP: Stratified by Stent Type
    • CVD/MI/CVA
    • Major Bleeding
    STENT ANALYSIS HR 0.80 (0.69-0.93) p=0.003 HR 0.81 (0.72-0.90) p=0.0001 HR 0.82 (0.69-0.97) p=0.02 HR 1.37 (0.95-1.99) p=0.09 HR 1.27 (0.99-1.63) p=0.06 HR 1.19 (0.83-1.72) p=0.34 N=12844 N=6461 N=5743 CLOPIDOGREL PRASUGREL