1. Optimal Angioplasty Pharmacology in 2006 : is there a continuing need for GP IIbIIIa inhibitors? Tony Gershlick Leicester UK AA 2006 Optimal Angioplasty Pharmacology in 2006 : is there a continuing need for GP IIbIIIa inhibitors? Tony Gershlick Leicester UK AA 2006 Advisory Board :Speakers Bureau : Meeting sponsorships Eli Lilly :The Medicines Company: BMS : Sanofi No direct financial conflicts of interest Advisory Board :Speakers Bureau : Meeting sponsorships Eli Lilly :The Medicines Company: BMS : Sanofi No direct financial conflicts of interest

2. Stable / ACS: Planned /unplanned, Stable / ACS: Planned /unplanned, Diabetic/Elderly Immediate MEDIUM LONG TERM Lesion Safe & Effective Outcome

3. Pre 1996 stent thrombosis rates 10 - 15% (50% death /AMI ) Pre 1996 stent thrombosis rates 10 - 15% (50% death /AMI ) Since operators improved stents improved high pressure came and went Routine IVUS came and went antiplatelet therapy introduced routine stenting became “routine” now stent thrombosis rates <1-2% Since operators improved stents improved high pressure came and went Routine IVUS came and went antiplatelet therapy introduced routine stenting became “routine” now stent thrombosis rates <1-2%

4. 40 30 20 10 0 0 1 2 3 % of CD62 positive platelets Day after intervention PTCA * * * * * * * * Stent Activation of platelets : stenting v PTCA

5. MACE in patients treated with antiplatelet v anti-coagulants MACE in patients treated with antiplatelet v anti-coagulants 12 0 0 4 4 8 8 warfarin + ASA Ticlopidine + ASA 6.26.2 0.50.5 1111 5.65.6 1.61.6 8.68.6 5.75.7 2.72.7 Clopidogrel + ASA 0.90.9 1.51.5 1 Hall P. et al. Circulation. 1996;93:215-222. 2 Schömig A. et al. N Engl J Med. 1996; 334:1084-1089. 3 More R. et al. Lancet. 1997;349:146-147. 4 Urban P et al. Lancet. 1997; 340:146-147 Abstract. ISAR FANTASTIC STARS MATTIS CLASSICS (n= 517) (n=485) (n=1653) (n=350) (n=1020) ISAR FANTASTIC STARS MATTIS CLASSICS (n= 517) (n=485) (n=1653) (n=350) (n=1020)

7. Abciximab in PTCA 0 0 2 2 4 4 6 6 8 8 10 12 14 16 % Death or non-fatal MI at 30 days Placebo Abciximab 12.8 8.3 11.7 5.2 15.9 11.3 p=0.008 p<0.001 p=0.012 2099 2792 1265 EPIC EPILOG CAPTURE

8. Clopidogrel : Is it enough? Do we still need GP IIbIIIa? {Anti-thrombins?} When start How much Which patients How long What trying to prevent Clopidogrel : Is it enough? Do we still need GP IIbIIIa? {Anti-thrombins?} When start How much Which patients How long What trying to prevent Stent thrombosis/ enzyme rise { bumps or micro-infarcts } Stent thrombosis/ enzyme rise { bumps or micro-infarcts } Stable ACS BMS or DES Diabetics Stable ACS BMS or DES Diabetics

9. Effect of Timing of Loading Dose on MACE at 30d 0.40.60.81.01.2 Hazard ratio (95% CI) 3 to <6 hrs7.97.0893 6 to 24 hr5.89.4 851 RRR -13.4 P=NS RRR 38.6 P=0.05 RRR 18.5 P=0.23 Overall CREDO Results N Clopidogrel pre* Clopidogrel pre*No-pre* Events (%) No-preBetter Clopidogrel pre Better UTVR= urgent target vessel revascularization * Plus ASA and other standard therapies CREDO Steinhubl S, et al. JAMA. 2002;288:2411-20 300 mg

10. Clopidogrel Loading Dose and Clinical Outcome Patti Circulation 2005;111:2099-2106 N=255 300mg/600 mg 4-8 hours pre

11. Clopidogrel Loading Kastrati et al Circulation 2004;110:1916-19

13. 0.15 0.10 0.05 0.0 0100200300400 Days of follow-up 12.6% 8.8% 31% RRR P = 0.002 N = 2658 Clopidogrel + ASA* Placebo Cumulative Hazard Rate Composite of CV death or MI from randomization to end of follow-up Overall Long-Term Results PCI-CURE

14. Clopidogrel in PCI Loading dose of 600mg - > 6 hours pre ACS Continue maintenance dose for 12 months Top up to 600 mg ?? BMS – 1 month What about Drug-Eluting Stents? Credo and PCI-CURE – Bare metal stents Ravel – 8 weeks Ticlopidine or clopidogrel Sirius – 3 months Clopidogrel TAXUS– 6 months Clopidogrel After complex PCI in addition to aspirin, clopidogrel 75 mg for at least 9 to 12 months”

15. Clopidogrel Resistance in AMI Matetzky et al. Circulaion 2004;109:3171-75

16. Clopidogrel Resistance in non Emergent PCI High ex vivo platelet reactivity to ADP and rapid generation of fibrin are risk factors for ischaemic events in 6 months post PCI. 1 MACE rates varied between 10% to 32% at 6 months according to quartiles defined by platelet aggregation assays Gurbel et al JACC 2005;46:1820-26

17. Lau et al. Circulation 2004;109:166-71 Clopidogrel Response is Variable

19. Contribution of Hepatic P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance Lau et al. Circulation 2004;109:166-71 Clopidogrel response is variable In contrast, rifampin, a CYP3A4 inducer, increased clopidogrel efficacy.

20. *Antiplatelet Therapy disc Prior Brachy Renal failure BifurcationsULMDiabetesUA * Premature discontinuation Thrombosis Rates According to Selected Patient Characteristics % 29 8.7 5.5 3.5 3.2 2.6 1.3 0 5 10 15 20 25 30 35

21. Outstanding Issues for Oral Antiplatelet Therapy Post PCI  How long to continue dual antiplatelet therapy post PCI with DES…….? > 12 months  Need to screen for Plavix resistance ?  Use increased maintenance doses of plavix in some cases ?  How can we maximise drug compliance ?

22. Anfeathers.jpg “I don’t know about you, but I still take 75 mg Plavix daily whether I need it or not” “I don’t know about you, but I still take 75 mg Plavix daily whether I need it or not”

23. ASA Resistance Important NOT ASA alone 3-6 /12 Never - NO MEDICATION – Dual till when ? AHG Website for Stent thrombosis ASA Resistance Important NOT ASA alone 3-6 /12 Never - NO MEDICATION – Dual till when ? AHG Website for Stent thrombosis

25. Limitations of Clopidogrel Variable response - Resistance Time of onset of action Irreversible GP IIbIIIa Inhibitors GP IIbIIIa Inhibitors Prasugrel (Lilly/Sankyo) Rapid onset Higher and more consistent level of platelet inhibition TRITON – TIMI 38 trial (Prasugrel vs Clopidogrel PCI in ACS)

26. 0 0 2 2 4 4 6 6 8 8 10 12 14 16 EPIC EPILOG CAPTURE % % Death or non-fatal MI at 30 days Placebo Abciximab 12.8 8.3 11.7 5.2 15.9 11.3 p=0.008 p<0.001 p=0.012 2099 2792 1265 GP IIb/IIIa improve outcome in PCI

29. Across Study Comparism PRISM/CURE Clopidogrel is no alternative for the high risk ACS patient 0 5 10 15 0 5 10 15 PRISM n.s. PRISM Event Rate [%] P<0.001 Control Tirofiban Heeschen et al., Lancet 1999 Positive MarkersNegative Markers CURE P<0.05 CURE P<0.05 Clopidogrel CURE, ACC 2001 RR 67% RR 19% Event Rate [%] RR 21%

30. Are both necessary Is there sufficient effect with clopidogrel (upfront) Are both necessary Is there sufficient effect with clopidogrel (upfront) GP IIbIIIa in the era of Clopidogrel pre-treatment GP IIbIIIa in the era of Clopidogrel pre-treatment

31. Tc

32. Stone, Circulation 2002;105:2347-54

33. JACC 2004 Jan 21;43(2):162-8. Dalby et al, 48% inhibition Clopidogrel 80% GP IIbIIIa (p<0.0001)

34. Who doesn’t need GP IIbIIIa ? Clopidogrel is a potent anti-platelet agent

35. ISAR-REACT Abciximab in Low to Intermediate Risk PCI after Plavix loading Kastrati et al NEJM 2004;350:232-38.

36. ISAR-REACT Safety % of patients Major TIMI bleed Minor TIMI bleed ThrombocytopeniaTransfusions P=0.37P=0.38P=0.002P=0.007 Kastrati A, et.al. NEJM 2004; 350 (3): 232-238.

37. ISAR-REACT Primary Endpoint at 30 Days Composite of Death, MI or Urgent TVR % of Patients CompositeMIUrgent TVRDeath/MIDeath P=NS for all Kastrati A, et.al. NEJM 2004; 350 (3): 232-238.

38. ISAR-REACT Primary Endpoint at 30 Days Incidence and Relative Risk of the Primary Endpoint Kastrati A, et.al. NEJM 2004; 350 (3): 232-238.

39. Enhanced Survival Benefit of Abciximab in Diabetics 1 Year Mortality in Diabetics Following PCI with and without Abciximab EPIC, EPILOG, and EPISTENT - Meta-Analysis 030120150210270300360 0 1 2 3 4 Days of Randomization Death (%) 5 6 6090180240330  2.0% p = 0.031 4.5 2.5 JACC 2000; 35:922-28 Placebo Abciximab n = 574 n = 888 Diabetics

40. * AMI

41. *in hospital *

43. Who GP IIb/IIIa Inhibitors in setting of pre-PCI 600mg clopidogrel Who GP IIb/IIIa Inhibitors in setting of pre-PCI 600mg clopidogrel AMI as early as possible Inadequate stent deployment Evidence I.C thrombus COMPLEX PCI Clopidogrel resistance Diabetics ACS Stenting as perfect as possible reduces complications

45. Who GP IIb/IIIa Inhibitors in setting of pre-PCI 600mg clopidogrel Who GP IIb/IIIa Inhibitors in setting of pre-PCI 600mg clopidogrel AMI as early as possible Inadequate stent deployment Evidence I.C thrombus COMPLEX PCI Clopidogrel resistance Diabetics - BVR Which studies ? Which studies ? Stenting as perfect as possible reduces complications

46. ISAR-REACT 2 Abciximab in High {ACS} Risk PCI after Clopidogrel loading Patients with ACS (Trop+ or ST-depression) undergoing PCI (STEMI excluded). Primary endpoint: composite of death, MI, urg. Revasc within 30 days. Ones to watch for at ACC

47. ACUITY Design ACS patients (N~13,800) with troponin or CPK-MB elevation or ECG changes or demographic and cardiac risk factors or history of documented coronary artery disease ASA + clopidogrel per local practice A: EnoxaparinB: BivalirudinC: Bivalirudin YesNoYesNo Upstream GPIIB/IIIA Diagnostic cath within 72 hours Yes No (bailout only) GPIIB/IIIA during PCI Bleeding Death/MI/Unplanned revascularization Composite of the above PCI, surgical, or medical management Patients Main groups Angiography Definitive treatment Aspirin, clopidogrel loading 30 day endpoints

48. HORIZONS 3 400 STEMI ASA 300mg Clopidogrel 300-600mg UH Bivalirudin GP IIb/IIIa {bail-out IIbIIIa} Cath Lab TAXUS BMS CABG 3 : 1 [ 2250 : 750] 1,6 mo 3 400 STEMI ASA 300mg Clopidogrel 300-600mg UH Bivalirudin GP IIb/IIIa {bail-out IIbIIIa} Cath Lab TAXUS BMS CABG 3 : 1 [ 2250 : 750] 1,6 mo The independently adjudicated 30- day rates of a. Primary - The composite of major adverse ischaemic events and major bleeding (net clinical benefit) b. Major Secondary - Major adverse ischaemic events (death, reinfarction, stent thrombosis, disabling stroke or ischaemic target vessel revascularisation) c. Major secondary - Major bleeding

49. Summary & Conclusions “Optimal Angioplasty Pharmacology in 2006 : is there a continuing need for GP IIbIIIa inhibitors?” “YES” We understand better how best to administer APT –clopidogrel Concerns regarding Clopidogrel resistance BVR role unclear Prasugrel Until there is data definitively showing that standard treatment with Clopidogrel (600 mg 6 hours pre) in high risk /complex patients is equal to GP IIbIIIa IH and against a background of increased utility of Primary PCI We understand better how best to administer APT –clopidogrel Concerns regarding Clopidogrel resistance BVR role unclear Prasugrel Until there is data definitively showing that standard treatment with Clopidogrel (600 mg 6 hours pre) in high risk /complex patients is equal to GP IIbIIIa IH and against a background of increased utility of Primary PCI

51. Prasugrel Phase 3 Stent Trial Design Clopidogrel 75 mg/day + ASA Prasugrel 10 mg/day + ASA Last pt followed for 6 m (med =12m, max =15 m) 2 0 EPs (30, 90 d): CVD/MI/CVA; CVD/MI/uTVR Clopidogrel 300 mg LD / 75 mg MD + ASA Prasugrel 60 mg LD/ 10 mg MD + ASA Mod - Hi Risk UA/NSTEMI STEMI Antithrombin GP IIb/IIIa at MD discretion 1 0 Endpoint(end of FU): CVD/MI/CVA 2 0 EP (end of FU): CVD/MI/CVA/Hosp for Rec Isch Stratified Randomization: UA/NSTEMI vs STEMI Planned PCI for ACS

52. Heart Care Centers of Illinois Clinical Outcomes, Comparison to CADILLAC BIAMI (N=201) Abciximab/Stent (N=524) 30 Days, % Death Reinfarction Disabling stroke* Ischemic TLR COMPOSITE 2.0 0.5 1.0 1.5 3.6 2.7 0.8 0.2 1.6 4.4 Subacute thrombosis1.00.0 Blood product transfusion 2.05.0 Intracranial hemorrhage0.00.2 Thrombocytopenia2.54.0 * 2 Strokes Post CABG *

53. JUMBO -TIMI 26 Study Design Study Drug in Lab Prior to PCI; Stratify Based on IV GP IIb/IIIa Maintenance Rx for 30 days Double-blind, Double Dummy Elective or Urgent PCI w stent ASA 325 mg900 patients Parallel Randomization Prasugrel Loading Dose 40 mg Maint. Dose 7.5 mg N=200 Prasugrel Loading Dose 60 mg Maint. Dose 10 mg N=200 Clopidogrel Loading Dose 300 mg Maint. Dose 75 mg N=250 1 o endpoint: Significant (non-CABG) bleeding through 30 d 2 o endpoints:Major bleeding (non-CABG) through 30 d CV MACE through 30 d Component clinical endpoints Prasugrel Loading Dose 60 mg Maint. Dose 15 mg N=250 26

54. Clinical Target Vessel Thrombosis P= NS 6/2544/6502/1991/2001/251 Target Vessel Revasc or Documented Total Occlusion 26 R/N RR=0.25 [0.1, 0.9] P = 0.03 Prasugrel LD/MDTreatment Group

55. JUMBO -TIMI 26 Study Design Study Drug in Lab Prior to PCI; Stratify Based on IV GP IIb/IIIa Maintenance Rx for 30 days Double-blind, Double Dummy Elective or Urgent PCI w stent ASA 325 mg900 patients Parallel Randomization Prasugrel Loading Dose 40 mg Maint. Dose 7.5 mg N=200 Prasugrel Loading Dose 60 mg Maint. Dose 10 mg N=200 Clopidogrel Loading Dose 300 mg Maint. Dose 75 mg N=250 1 o endpoint: Significant (non-CABG) bleeding through 30 d 2 o endpoints:Major bleeding (non-CABG) through 30 d CV MACE through 30 d Component clinical endpoints Prasugrel Loading Dose 60 mg Maint. Dose 15 mg N=250 26

56. Clinical Target Vessel Thrombosis P= NS 6/2544/6502/1991/2001/251 Target Vessel Revasc or Documented Total Occlusion 26 R/N RR=0.25 [0.1, 0.9] P = 0.03 Prasugrel LD/MDTreatment Group

58. How important are the enzyme leaks ? represent micro infarcts unimportant < x3 adverse prognosis markers only any rise is dangerous small percent avoid at all cost surgeons are worse unpredictable interventionist knows immediacy not good select patients (?) ‘everyone’ should have GP IIb/IIIa RB only a (small) percent patients ++??

60. The CAPTURE trial of ReoPro 18 hrs before … PCI

62. ISAR-2 - Outcomes through 30 Days Primary PCI for AMI 10.5 6.0 4.5 1.5 5.0 2.5 2.0 0.5 3.0 0 5 10 15 20 25 % of Patients p = 0.038 p = 0.30 Usual Care (n = 200) Abciximab (n = 201) p = 0.16 Death, MI or Any TVR DeathTVR  52%  40%  56% p = 0.08  58% p = 0.62  67% Death or Re-MI JACC 2000: 35:915-21

63. ADMIRAL - Angiographic Analysis TIMI 3 Flow Prior To PCITIMI 3 Flow Post PCI 5.4 10.8 16.8 25.8 0 20 40 60 80 100 % of Patients p = 0.01 p = 0.006 TIMI 3 FlowTIMI 2/3 Flow NEJM 2001; 341:1895-1903 86.7 92.6 82.8 95.1 95.9 94.3 p = 0.04p = 0.33p = 0.04 Immediately Post-PCI 24 hour Post-PCI 6 month Post-PCI Abciximab (n = 101) Placebo (n = 92) Primary PCI for AMI

64. ADMIRAL - 1° Endpoint through 6 Months Death, re-MI or Urgent TVR NEJM 2001; 341:1895-1903 15.9 7.4 0 4 8 12 16 050100150 200  53% p = 0.02 Days % of Patients Placebo Abciximab Primary PCI for AMI

65. ADMIRAL - Place/Time of Administration 26 73 0 20 40 60 80 100 178 266 238 0 50 100 150 200 250 300 350 % of Patients Time between symptom onset and study drug (min) p = 0.002 p = 0.02 n = 78n = 222 MICU/ ED ICU/ Cath Lab Place of Study Rx Admin.Time to Study Rx NEJM 2001; 341:1895-1903 MICUEDICU/ Cath Lab Primary PCI for AMI

66. PCI:Which Antiplatelet Therapy ? Dr. Niall Mulvihill St. James’s Hospital and Trinity College, Dublin

67. Aggregation of platelets into a thrombus Platelets Endothelial cells Subendothelial space Platelets adhering to subendothelial space Platelet thrombus Platelet Adhesion and Activation Normal platelets in flowing blood Platelets adhering to damaged endothelium and undergoing activation

68. Platelet Activation Pathways Platelet Aggregation Fibrinogen TxA 2 Fibrinogen Binding Site ADP Thrombin Platelet Herbert. Exp Opin Invest Drugs 1994;3:449-455.

69. Aspirin in PCI

70. Antithrombotic Trialists’ Collaboration: Reduction in Risk of Vascular Deaths Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86. Category% odds reduction Acute MI Acute stroke Prior MI Prior stroke/TIA Other high risk * All trials 15% ±2 (p < 0.0001) 1.00.50.01.52.0 Control better Antiplatelet better *Coronary artery disease, peripheral arterial disease, high risk of embolism and other high risk conditions (including hemodialysis, diabetes mellitus, carotid disease)

71. Chen et al. J Amer Coll Cardiol 2004;43:1122-6 ASA/clopidogrel (n=151), 19.2% ASA resistant ASA Resistance in PCI ASA resistant  ASA sensitive

72. Aspirin Resistance Do patients who suffer a thrombotic event while taking aspirin exhibit aspirin resistance ? Reports of aspirin resistance vary from 5-40% Aspirin inhibits COX1 - but resistance assays do not measure activity of this enzyme Most resistance assays are strongly affected by pathways of platelet activation other than COX1

73. Aspirin Resistance Recent report suggests aspirin (325mg) resistance is <1% (1 of 223 patients) when measured by methods directly dependant on platelet COX 1 1 Pseudoresistance is more common (3%) and reflects non compliance which is probably a more significant clinical problem. Tantry et al JACC 2005;46:1705

74. ADP Receptor Antagonists in PCI

75. Antithrombotic effects after 3 hours of high-dose clopidogrel 5 5 4 4 3 3 2 2 1 1 0 0 0 0 10 20 30 40 50 60 Platelet Deposition (x10 9 ) Time Controls (6) 2mg/kg Clopidogrel 20mg/kg Clopidogrel

76. Efficacy of Aspirin and ADP-Receptor Antagonist Combinations in Reducing Death, MI and Revascularization in Stent Patients 1 Hall P. et al. Circulation. 1996;93:215-222. 2 Schömig A. et al. N Engl J Med. 1996; 334:1084-1089. 3 More R. et al. Lancet. 1997;349:146-147. 4 Urban P et al. Lancet. 1997; 340:146-147 Abstract. ASA + TIC ASA only ASA + Warfarin 2.4 6.2 3.6 3.9 0.6 1.6 0.8 03.05.08.012 STARS (1997) 3 ISAR (1997) 2 MATTIS (1997) 4 Hall (1996) 1 N = 226 N = 350 N = 517 N = 1652 11.0 5.6 Cumulative Event Rate (%)

77. Advantages of Clopidogrel over Ticlopidine Ticlopidine Neutropenia, Thrombocytopenia TTP, HUS Twice a day

78. PCI PLACEBO + ASA * CLOPIDOGREL + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Open-label thienopyridine Pretreatment Open-label thienopyridine Pretreatment N = 2,658 patients undergoing PCI * In combination with standard therapy N = 1345 N = 1313 CURE PCI-CURE R

79. PCI PLACEBO + ASA * CLOPIDOGREL 300 mg 3-24h pre-PCI + ASA * 30 days post PCI End of follow-up Up to 12 months after randomization Clopidogrel 75 QD Pretreatment Clopidogrel 75 QD Pretreatment N = 2,116 patients undergoing elective PCI * In combination with standard therapy N = 1345 N = 1313 R CREDO

80. CREDO Study: Long-Term (1 Year) Benefits of Clopidogrel in PCI MI, Stroke, or CV Death * Plus ASA and other standard therapies Combined Endpoint Occurrence (%) Months From Randomization 27% RRR P=0.02 Placebo*Clopidogrel* 0 5 10 15 8.5% 11.5% 036912 Steinhubl S, et al. JAMA. 2002; 288:2411-20

81. Time after Administration (hours) 042448 100 60 20 0 Muller I et al. Heart. 2001;85:92-3 Ticlopidine 2x 500mg, then 250mg BID Clopidogrel 300mg, then 75mg QD Clopidogrel 600mg, then 75mg BID % of 20µM ADP-induced aggregation Clopidogrel Loading Dose

82. Addressing Clopidogrel Resistance Higher loading dose Higher maintenance dose Additional antiplatelet agents ? Adding cytochrome P450 inducers

83. Time after Administration (hours) 042448 100 60 20 0 Muller I et al. Heart. 2001;85:92-3 Ticlopidine 2x 500mg, then 250mg BID Clopidogrel 300mg, then 75mg QD Clopidogrel 600mg, then 75mg BID % of 20µM ADP-induced aggregation Clopidogrel Loading Dose

84. Clopidogrel Loading and Clincal Outcome Patti et al Circulation 2005;111:2099-2106

85. Triple Antiplatelet Therapy Cilostazol is a phosphodiesterase III inhibitor with similar antiplatelet effects to clopidogrelCilostazol is a phosphodiesterase III inhibitor with similar antiplatelet effects to clopidogrel Addition of cilostazol to aspirin and clopidogrel provided additional supression of P-selectin (marker of platelet activation)Addition of cilostazol to aspirin and clopidogrel provided additional supression of P-selectin (marker of platelet activation) Lee et al JACC 2005;46:1833-37

86. Dual versus Triple Therapy Dual (n=1,597) Triple (n=1,415) P-value Stent Thrombosis 0.5%0.1%0.024 Acute Stent thrombosis 0.2%0%Ns Subacute stent thrombosis 0.3%0.1%ns Primary EP: Death, MI or ST 0.8%0.3%0.085 Lee et al JACC 2005;46:1833-37

87. Prasugrel Phase 3 Stent Trial Design Clopidogrel 75 mg/day + ASA Prasugrel 10 mg/day + ASA Last pt followed for 6 m (med =12m, max =15 m) 2 0 EPs (30, 90 d): CVD/MI/CVA; CVD/MI/uTVR Clopidogrel 300 mg LD / 75 mg MD + ASA Prasugrel 60 mg LD/ 10 mg MD + ASA Mod - Hi Risk UA/NSTEMI STEMI Antithrombin GP IIb/IIIa at MD discretion 1 0 Endpoint(end of FU): CVD/MI/CVA 2 0 EP (end of FU): CVD/MI/CVA/Hosp for Rec Isch Stratified Randomization: UA/NSTEMI vs STEMI Planned PCI for ACS

88. Clopidogrel Nonresponders: A Comparison With Prasugrel (CS-747, LY640315), a Novel Thienopyridine P2Y12 Receptor Antagonist

90. Outstanding Issues for Oral Antiplatelet Therapy Post PCI Do we need to consider triple antiplatelet therapy +/- higher maintenance dose of clopidogrel for high risk PCI ? – AMI – LM stenting – Multivessel stenting

91. GP IIb/IIIa Receptor Antagonists in PCI

92. Platelet Activation Pathways Platelet Aggregation Fibrinogen TxA 2 Fibrinogen Binding Site ADP Thrombin Platelet Herbert. Exp Opin Invest Drugs 1994;3:449-455.

95. Data on file, Centocor

96. Is Reopro necessary in Elective PCI when patients are appropriately loaded with Clopidogrel ?

97. TARGET: Clopidogrel pre-treatment Chan et al. J Amer Coll Cardiol 2003; 42:1196 Clopidogrel pre-treatment: RR = 0.61 (0.44-0.84) P=0.003

98. ISAR-REACT Abciximab in Low to Intermediate Risk PCI after Plavix loading Kastrati et al NEJM 2004; 350:232-38.

99. ISAR-REACT Abciximab in Low to Intermediate Risk PCI after Plavix loading Kastrati et al NEJM 2004;350:232-38.

100. ISAR-REACT Abciximab in Low to Intermediate Risk PCI after Plavix loading Kastrati et al NEJM 2004; 350:232-38.

101. Low to Intermediate Risk PCI Aspirin 300mg bolus and 75mg daily maintenance Clopidogrel 600mg bolus Clopidogrel 75mg maintenance x 12 months

102. Moderate to High Risk PCI Aspirin 300mg bolus and 75mg daily maintenance Clopidogrel 600mg bolus Clopidogrel 75mg (150mg) maintenance x 12 months Reopro bolus and infusion periprocedure

103. Future of Antiplatelet therapy for PCI New ADP receptor antagonists Higher maintenance doses of ADP receptor antagonists in high risk cases Triple antiplatelet therapy