The Role of Platelets in Atherothrombosis Kumar A et al. Exp Opin Invest Drugs. 1997;6:1257–1267. Adhesion Aggregation (GP IIb/IIIa Inhibitors) Fibrinogen Activated Gpllb/llla Activation (Clopidogrel) Platelets Lipidcore Collagen Gpla/lla bind von Willebrand Factor/Gplb bind Thrombin ADP 5 HT TXA 2 Platelet Plug PF4 CD 40 ligand thrombospondin TGF-B

PRISM7.1% 5.8% † PRISM-PLUS12.0% (*) 8.7% () 13.6% † PRISM-PLUS12.0% (*) 8.7% ( † ) 13.6% † PARAGON-A11.7% (l) 10.3% (h) 12.3% PURSUIT15.7% (l) 13.4% (h) 14.2% PURSUIT15.7% (l) 13.4% (h) 14.2% PARAGON-B11.4% 10.6% GUSTO-IV8.0% (24h) 8.2% (48h) 9.1% GUSTO-IV8.0% (24h) 8.2% (48h) 9.1% Overall11.8% 10.8% * Overall11.8% 10.8% * Odds Ratio PlaceboIV Gp IIb/IIIa 95% CI † without heparin, * with/ without heparin (l) = low dose, (h)= high-dose Boersma, E. et al. Lancet. 2002;359: IV Gp IIb/IIIa Inhibitors in ACS: Death or MI at 30 Days (N=31,402) Placebo BetterGp IIb/IIIa Better Odds Ratio (95% CI) Study P=.015 srm

CURE Prevalence N=31,402 Placebo Event Rate ORP Age <6035%7.3% %11.1%0.91  70 35%15.5%0.96 Sex Male65%11.3% Female35%11.1%1.15 ST dep -44%8.9% %13.1%0.98 CKMB <ULN54%9.6%  ULN 46%14.1%0.98 IV GP IIb/IIIa Inhibitors in ACS: Death or MI (at 30 d): Subgroup Results Boersma, E. et al. Lancet. 2002;359

CURE IV GP IIb/IIIa Antagonists in ACS Death or MI (at 30d) by PCI/CABG < 5 days P=0.001 P=NS N=5847 N=25,555 Boersma et al. Lancet 2002; 359: 189b Interaction p < 0.02

CURE Odds Ratio 95% CIStudyPlaceboIV Gp IIb/IIIa PRISM 1.2% 1.7% † PRISM-PLUS 2.0% 3.0% PARAGON-A 0.7% 1.3% PURSUIT 0.9% 1.1% PARAGON-B 1.0% 1.7% GUSTO-IV 2.8% 4.7% Overall 1.4% 2.4% * IV Gp IIb/IIIa Inhibitors in ACS: Major Bleeding at 30 Days † without heparin, * with/ without heparin major bleeding for all low dose treatment Boersma, E. et al. Lancet. 2002;359: srm

CURE Death During Follow-up Period p = Breslow-Day heterogeneity EXCITE0.3%0.7% Odds Ratio & 95% CI Trial PlaceboFiban Fiban Worse Fiban Better 7,232 N Xemilofiban 2.14 OPUS1.4%2.0% 10,302 Orbofiban 1.40 SYMPHONY1.8%2.0% 9,169 Sibrafiban 1.14 Pooled 1.3%1.7% 33,340 p = nd SYMPHONY 1.3%2.1% 6,637 Sibrafiban Chew DP, Bhatt DL, Sapp S, and Topol EJ. Circulation. 2001; 103:

CURE Platelet deposition (x10 -7 /cm 2 ) Ex vivo study of collagen-induced thrombus formation in 18 healthy volunteers at day 10 ** Synergistic Antithrombotic Effect of Clopidogrel Plus Aspirin in Humans ** p <0.01 vs ASA. Baseline ASA C75+ASA C300+ASA Baseline ASA 325mg C 75mg+ ASA 325mg C 300mg+ ASA 325mg Cadroy et al. Circulation. 2000;101:

Rapid Platelet Inhibition of Clopidogrel * 375 mg Loading Dose Day 1, 0hr Day 1, 0.5hr Day 1, 1.0hr Day 1, 2.0hr Day 1, 5.0hr Day 2Day 3Day 5Day 10 * Clopidogrel 75mg/d given on days Bachmann F et al. Eur Heart J. 1996;17(suppl):263. Abstract. Percent (%) Inhibition (5 ADP) Percent (%) Inhibition (5 mcM ADP)

P= ASA + Ticlopidine Better ASA alone Better HALL (1996) *STARS (1998) Total Study Odds Ratio 95% CI Death or MI Test for heterogeneity P=0.66 *STARS was a 3 arm trial. Data for aspirin + ticlopidine vs aspirin alone were used for this analysis. Mehta et al. for The CURE Study Investigators. Eur. Heart J. 21 ;24, Efficacy of Dual Antiplatelet Therapy vs ASA alone in Reducing Coronary Events after Stenting

Test for heterogeneity P=0.51 *STARS was a 3 arm trial. Data for aspirin + ticlopidine vs aspirin Mehta et al. for The CURE Study Investigators. Eur. Heart J. 21 ;24, Study Odds Ratio 95% CI P= ISAR (1996) *STARS (1998) MATTIS (1998) FANTASTIC (1998) Total ASA + Ticlopidine Better ASA + Oral Anticoagulation Better Death or MI Efficacy of Dual Antiplatelet Therapy vs Warfarin and ASA in Reducing Coronary Events after Stenting

CURE Hours After Randomization Cumulative Hazard Rates Within 24 hrs of Randomization RR= 0.66 p =0.003 Placebo + ASA Clopidogrel + ASA MI/Stroke/CV Death/Severe Ischemia 34% Relative Risk Reduction Mehta SR et al. AHA, 2002

CURE Interventions Associated with Refractory Ischemia in Hospital PlacClop # Patients # RFAs12685 Thromb Therapy53 Cath4035 PTCA4425 CABG1811 IABP103 Transfer for Cath2114 Missing20

Benefit of Clopidogrel stratified by TIMI Risk Score N=3276N=7297N=1989 ARR 1.6% 1.6% 4.8% P=0.03 P=0.02 P=0.003 Budaj et.al Circulation, In Press

CURE CV Death/MI/Stroke by Revascularization: Subgroup 2NPlac % Clop % RRCI H/O Revasc Others Post Rand Revasc + Post Rand Revasc

CURE Type of MI PlacClopRRCI # Patients % % All MI Q wave MI Other MI

CURE Prevention of large MI, thrombolytic use and new onset CHF after randomizaton Q-wave MI3.1%1.9%40%<0.001 Thrombolytics2.0%1.1%43%< Heart Failure ‡ 4.4%3.7%18%0.03 Heart Failure ‡ 4.4%3.7%18%0.03 Relative Risk Reduction P valueOutcome Placebo + ASA* N = 6303 Clopidogrel + ASA* N = 6259 ‡ ‡ Radiologically confirmed * In addition to other standard therapies

CURE During Initial Hospitalization PlacClopRR (95% CI)P % Refract Ang ( )0.007 Other Severe Ischemia ( ) Other Recurrent Angina ( )0.01 Heart Failure ( )0.026

CURE CV Death/MI Among Patients Undergoing Early PCI (< 72 Hrs) N=544N=2114 RRR 38%RRR 29% Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:

CURE CV Death or MI at Various Intervals RRR 31% 32% 34% 21% * *P=0.002 Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21: PCI- CURE

CURE Benefit/Risk Ratio % Events No. Placebo 6303 Clop 6259 RR (95% CI)P Primary + Life Threatening Bleed (0.76, 0.93)0.001 Primary + RFA + Major Bleeds ( )0.005 Yusuf, Mehta. N Eng J Med 2002; correspondence

CURE The CURE Trial Investigators The CURE Trial Investigators. N Engl J Med. 2001;345: CURE Study Definition of Bleeding Bleeding was defined as “Major” or “Minor” Major bleeding was defined as follows: requiring at least 2 units of blood, substantially disabling, or intraocular bleeding leading to vision loss Major Bleeding was sub-categorized as life-threatening if it was: fatal, symptomatic intracranial hemorrhage, leading to a drop in hemoglobin of at least 5 g/dL, significant hypotention requiring IV inotropes, requiring surgical intervention, or requiring transfusion of 4 or more units of blood Minor any other bleeds that led to interruption of study medication

CURE TIMI Major Bleeding / GUSTO Severe-Life-Threatening Bleeding Criteria PlacClopRR (95% CI) P # Patients TIMI Criteria73 (1.2%) 68 (1.1%) GUSTO Criteria70 (1.1%) 78 (1.2%)

CURE Life Threatening Bleeding PlacClop # Patients Percent Life Threatening Fatal0.2 5 g/L Drop Hemoglobin0.9 Hypotension-inotropes0.5 Surgery Required0.7 Hemorrhagic Stroke 4+ Blood Units

CURE All Major/LT Bleeding in Pts with CABG Surgery PlacClop %RRCI # Patients All Major Life Threatening Other Major TIMI Major GUSTO Severe/LT

CURE Major/Life-Threatening Bleeds within 7 Days of CABG Surgery PlacClopRRp Stopped < 5 days prior to CABG or continued N = 565N = 519 Pts with Maj/LT Bleeds5.7%8.5% Stopped > 5 days prior to CABG N = 454N = 456 Pts with Maj/LT Bleeds5.3%4.4%

CURE Bleeding by GP IIb/IIIa Use PlacClopRR GP IIb/IIIa Use All Major ( ) Minor ( ) No GP IIb/IIIa Use All Major ( ) Minor ( ) % Events

CURE Number and Proportion of Patients Undergoing Cardiac Procedures in ACS Trials CathPCICABG CURE5491 (44%) 2658 (21%) 2072 (16%) PURSUIT5625 (59%) 2253 (24%) 1558 (14%) PRISM PLUS--475 (69%) 365 (23%) PRISM2003 (62%) 698 (21%) 549 (17%) GUSTO IV5036 (49%) 1509 (19%) 859 (11%) SMR

CURE Relative Benefits of Different Interventions in ACS By Time (Death/MI) RRR < 30 days> 30 days ASA35%25% Clopidogrel21%20% Thrombin inhib20%0% IV GP IIb/IIIa inhib9%0% Invasive Strategy-35%40% Long term benefits from lipid lowering and ACE-inhibitor therapy

CURE Risk-Benefit Analysis of Clopidogrel versus IV GP IIb/IIIa in ACS ActivePlacebo ARR P value *Yusuf S, Mehta SR. N Engl J Med 2002 (correspondence) *Yusuf S, Mehta SR. N Engl J Med 2002 (correspondence). † Boersma, E. et al. Lancet. 2002;359: * †

CURE Benefit-Risk Comparison of Antithrombotic Therapies vs Placebo in UA/NSTEMI Treatment Major Duration N Death or MI Bleeding 1. Antithrombotic Trialists’ Collaboration. BMJ 2002;324: The CURE Trial Investigators. NEJM 2001;345: Frisc Investigators. Lancet 1996;347: Boersma E, et al. Lancet 2002;359: * In addition to aspirin † reported death or MI at 150 days Mehta SR. JACC 2002, In Press

CURE Active*DiffTrialNPlacebo* CURE: %2.0%+0.5% IV GP IIb/ IIIa Trials: PRISM-PLUS %1.4%+0.6% PURSUIT %10.6%+1.5% CAPTURE %3.8%+1.9% * In addition to other standard therapies including aspirin and heparin. The CURE Trial Investigators The CURE Trial Investigators. N Engl J Med. 2001;345: The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338: The PURSUIT Trial Investigators. N Engl J Med. 1998;339: The CAPTURE Investigators. Lancet. 1997;349: Major Bleeding in IV GP IIb/IIIa Antagonists ACS Trials vs CURE: Within 30 Days Mehta S. J Am Coll Cardiol. In Press

CURE Role Of Antiplatelet Therapies In ACS: Both ASA (RR of 40%) and clopidogrel (RR of add’l 20%) should be initiated early and continued long term, and are effective in addition to standard therapies (heparin, GP IIb/IIIa inhibitors and interventions) GP IIb/IIIa inhibitors (RR of 9% at 30 days) is best reserved for patients undergoing PCI All antiplatelet agents increase the risk of CABG related bleeds. Therefore an individualized approach (to the timing of CABG, continuation or discontinuation of the antiplatelet agents, the need for platelet transfusion) depending on the urgency of CABG and severity of CAD is needed Pre-treatment of patients with ASA and clopidogrel and periprocedural (PCI) use of IV GP IIb/IIIa inhibitors substantially reduces the risk of Death/MI

State of the Art Management of non-ST  ACS Acute ASA + Clopidogrel LMWH/UFH IV GP IIb/IIIa inhibitor during PCI for those undergoing an invasive strategy (moderate to high risk patients) Long Term ASA + Clopidogrel for at least one year Planned program of secondary risk factor modification including smoking cessation, lipid lowering therapy, ACE inhibitor, BP and diabetic control, weight reduction

CURE Implications of CURE and PCI CURE The results from both CURE and PCI CURE suggest that a broad range of patients with non-ST elevation ACS who present with ischemic ECG changes or positive enzymes will benefit with treatment with ASA and clopidogrel, in addition to other standard therapies, regardless of their baseline risk or management strategy