1. Clinical Trials of GP IIb/IIIa Inhibition Major Trials of GP IIb/IIIa Inhibitors in ACS GP IIb/IIIa Inhibitors in PCI GP IIb/IIIa Inhibition in Patients With Diabetes

2. Clinical Trials of GP IIb/IIIa Inhibition Major Trials of GP IIb/IIIa Inhibitors in ACS

3. VBWG Antman EM et al. Am Heart J. 2003;146:S18-S22. Death or MI at 30 days *Does not include 345 patients In the tirofiban only group, which was stopped prematurely Efficacy of GP IIb/IIIa inhibition on death or MI in PCI or ACS EPIC2099 IMPACT II4010 EPILOG2792 CAPTURE1265 RESTORE2139 EPISTENT2399 PRISM3231 PRISM-PLUS1570* PARAGON2282 PURSUIT10,948 Overall30,366 TrialN Odds ratio (95% CI) Favors GP IIb/IIIa Favors placebo 12 0.79 (0.73–0.85) P < 10 –9 Elective PCI ACS 0

4. VBWG PRISM-PLUS: Study design Tirofiban* n = 345 Heparin n = 797 Tirofiban + heparin n = 773 N = 1915 with unstable angina or non–Q-wave MI Randomized, double-blind study Infusion for 71.3 ± 20 hours Angiography + angioplasty during Tx after 48 hours (prn) Primary outcome: Death, MI, refractory ischemia ≤7 days PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-97. *Stopped prematurely due to high mortality at 7 days Platelet-Receptor Inhibition for ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS)

5. VBWG Morrow DA et al. Am J Cardiol. 2004;94:774-6.RI = recurrent ischemia 30 25 20 15 10 5 0 Heparin Death or MI 11.5 8.9 13.0 8.3 Tirofiban + heparin No PCI n = 1069 PCI n = 501 23%↓ 0.50–1.12 36%↓ 0.34–1.08 RRR (95% CI) 30 25 20 15 10 5 0 Death/MI/RI 21.3 18.7 24.7 18.1 No PCI n = 1069 PCI n = 501 12%↓ 0.63–1.15 27%↓ 0.44–1.04 Outcomes at 30 days PRISM-PLUS: Benefits at 30 days similar with/without PCI

6. VBWG H = heparin; T = tirofiban High risk = TIMI risk score ≥4 RI = refractory ischemia Morrow DA et al. Am J Cardiol. 2004;94:774-6. HT+HORP No PCI High risk (n = 664) Low risk (n = 405) High risk (n = 280) Low risk (n = 221) 0.04 0.1 0.06 0.9 0.69 1.6 0.60 0.98 21.9 13.6 22.2 13.4 28.2 8.7 32.4 13.7 0.1110 Favors tirofiban/heparin Favors heparin Odds ratio (95% CI) PCI Death/MI/RI PRISM-PLUS: Benefit of GP IIb/IIIa inhibition by risk profile

7. VBWG PURSUIT: Study design High-dose eptifibatide* 180-µg/kg bolus, then 2.0 µg/kg per min for 72 h (96 h with coronary intervention) n = 4722 Placebo n = 4739 N = 10,948 Chest pain ULN for hospital Randomized, double-blind study Primary outcome: Composite death/nonfatal MI ≤30 days *Lower-dose eptifibatide (n = 1487) stopped after safety of high-dose was shown PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-43. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy

8. VBWG HR = 0.29 P < 0.001 Kleiman NS et al. Circulation. 2000;101:751-7. Days from enrollment Pre-PCI MI (%) 1.7% 5.5% 5 10 0 0 1 2 3 Placebo Eptifibatide PURSUIT: Pre-PCI GP IIb/IIIa inhibition prevents early MI

9. VBWG Lincoff AM et al. Circulation 2000;102:1093-100. Early PCI: n = 450 No early PCI: n = 1316 % 96 Hours Early PCI15.39.2 No early PCI7.75.5 7 Days Early PCI16.09.9 No early PCI10.88.8 30 Days Early PCI16.711.2 No early PCI15.012.2 6 Months Early PCI19.8 15.1 No early PCI18.615.3 Favors eptifibatideFavors placeboPlaceboEptifibatide Death or myocardial reinfarction 0.5 12 OR (95% CI) PURSUIT: GP IIb/IIIa inhibition prevents death with/without early PCI

10. VBWG. Bhatt DL et al. JAMA. 2000;284:1549-58. 2.8 2.3 1.7 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Difference in rate of death or MI, eptifibatide vs placebo (%) <66–1212–24>24 Time to treatment (hours) PURSUIT: Importance of timing GP IIb/IIIa inhibition on outcomes N = 9471

11. VBWG TACTICS-TIMI 18: Study design Conservative approach ETT/cath/PCI for recurrent or demonstrated ischemia Invasive approach Cath within 4–48 hours with revascularization if anatomy suitable N = 2220 with unstable angina/NSTEMI ASA Unfractionated heparin Tirofiban 0.4 µg/kg per min over 30 min, then 0.1 µg/kg per min for 48 h, including 12 h post-PCI ETT = exercise tolerance test Cannon CP et al. N Engl J Med. 2001;344:1879-87. Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis In Myocardial Infarction Primary outcome: Death, MI, rehospitalization for ACS

12. VBWG Sabatine MS et al. Circulation. 2004;109:874-80. *Adjusted for baseline differences Deaths/MI/ACS at 6 months 38%  in death/MI/ACS in TACTICS-TIMI 18 vs TIMI IIIB (P < 0.0001) Events* (%) 22 23 39 12 18 24 0 10 20 30 40 Intermediate (3–4) Low (0–2) High (5–7) TIMI risk score category P < 0.0001 P = 0.005 P = 0.003 TIMI IIIBTACTICS-TIMI 18 TACTICS-TIMI 18 vs TIMI IIIB: Effects of early PCI GP IIb/IIIa inhibition

13. VBWG Longer infusion* TIMI myocardial perfusion grade 3: OR 0.52 (P = 0.012) TIMI flow grade 3: OR 0.61 (P = 0.054) Minimum diameter (P = 0.032) Gibson CM et al. Am J Cardiol. 2004;94:492-4.*Controlled for baseline troponin T TIMI myocardial perfusion grade 3 (%) Treatment duration (hours) P = 0.013 <21>21 10 30 50 0 20 40 29.9 43.4 TACTICS-TIMI 18: Duration of GP IIb/IIIa inhibitor pre-PCI influences TIMI flow

14. Clinical Trials of GP IIb/IIIa Inhibition GP IIb/IIIa Inhibitors in Planned PCI

15. VBWG ESPRIT: Study design Eptifibatide 180-µg/kg double-bolus 10 min apart + continuous infusion 2.0 µg/kg per min for 18–24 h Placebo Assess effect of novel, double-bolus dose eptifibatide in coronary stenting N = 2064 undergoing stent implantation Randomized, controlled study Primary outcome: Death, MI, urgent revascularization and thrombotic bailout after GP IIb/IIIa inhibitor ≤48 h Secondary outcome: Death/MI/urgent revascularization at 30 days Aspirin + heparin + thienopyridine ESPRIT Investigators. Lancet. 2000;356:2037-44. Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy

16. VBWG ESPRIT Investigators. Lancet. 2000;365:2037-44. N = 2064 UTVR = urgent target vessel revascularization EptifibatidePlaceboRRP Eptifibatide better Placebo better Primary endpoint Death/MI/UTVR Death/MI Death/Large MI Large MI All MI UTVR Thrombotic bailout 0.51.5012 Death 5.4 6.610.50.630.0015 6.09.30.650.0045 5.59.20.600.0013 3.45.10.670.053 5.49.00.600.0015 0.61.00.600.30 1.02.10.480.029 0.10.20.500.55 3.34.90.670.064 Relative Risk ESPRIT: Outcomes at 48 hours

17. VBWG Granada JF, Kleiman NS. Am J Cardiovasc Drugs. 2004:4:31-41. TVR = target vessel revascularization Death/MI/TVR/thrombotic bailout within 48 hours Placebo Eptifibatide RR = 0.76 (95% Cl 0.63–0.93) P = 0.0068 RR = 0.65 (95% Cl 0.49–0.87) P = 0.0034 RR = 0.65 (95% Cl 0.47–0.87) P = 0.0045 48 hours 30 days12 months Primary endpoint (%) 0 5 10 15 20 25 ESPRIT: Primary outcome over time

18. VBWG Lincoff AM et al. J Am Coll Cardiol. 2000;35:1103-15. B = bolus; B+I = bolus + infusion; LDH = low-dose heparin; SDH = standard-dose heparin Death, MI, or urgent revasc at 30 days P 0.430Abciximab B EPIC 0.008Abciximab B+I <0.001Abciximab LDH EPILOG <0.001Abciximab SDH <0.001Abciximab + stent EPISTENT 0.007Abciximab + PCI 0.063Eptifibatide 135/.5 IMPACT II 0.220Eptifibatide 135/.75 0.052Tirofiban RESTORE 0.030 Abciximab RAPPORT 0.251.04.0 Favors GP IIb/IIIaFavors placebo 0.012Abciximab CAPTURE Odds ratio (95% CI) Placebo (%) 12.8 11.7 10.8 11.4 10.5 11.2 15.9 GP IIb/IIIa (%) 11.4 8.3 5.2 5.4 5.3 6.9 9.2 9.9 8.0 5.8 11.3 GP IIb/IIIa inhibition in planned PCI

19. VBWG Ryan JW et al. Circulation. 2005;112:3049-57. N = 56,352 with UA/NSTEMI (CRUSADE) 60 50 40 30 20 10 0 061218243036 Time from admission (hours) Proportion undergoing cardiac catheterization (%) P < 0.001 by log-rank statistic 42485460667278 Weekend Weekday Timing of catheterization: Weekday vs weekend hospital admission

20. VBWG Weekend delay in catheterization does not increase adverse events Ryan JW et al. Circulation. 2005;112:3049-57. 1.00 (0.94–1.06)15.114.5Any adverse event 1.00 (0.93–1.08)9.28.6CHF 0.96 (0.86–1.07)0.8 Stroke 1.05 (0.92–1.21)2.82.6Cardiogenic shock 0.98 (0.91–1.07)6.6 Death or MI 0.96 (0.86–1.07)2.93.0Reinfarction 1.02 (0.92–1.13)4.44.1Death Adjusted OR (95% CI) Weekend patients (n = 10 804) Weekday patients (n = 45 548) In-Hospital Outcomes N = 56,352 with UA/NSTEMI (CRUSADE)

21. Clinical Trials of GP IIb/IIIa Inhibition GP IIb/IIIa Inhibition in Patients With Diabetes

22. VBWG CAD progression and/or worse outcomes post-PCI Roffi M, Topol EJ. Eur Heart J. 2004;25:190-8. RAGE = receptor for advanced glycation end-products (AGE) TSP-1 = thrombospondin-1 Accelerated CAD progression in diabetes Inflammation hsCRP , IL-6 . VCAM-1 , ICAM-1 , P-selectin , sCD40L , TNF- , TSP-1  Prothrombotic state GP IIb/IIIa receptors  Platelet factor 4  Fibrinogen , TF , vWf  PAI-1  Protein C  Associated conditions Renal dysfunction LV dysfunction Peripheral vascular disease Atherosclerotic burden Diffuse disease Multivessel disease Negative remodeling Restenosis Hyperinsulinemia RAGE/AGE  PPAR-  modulation TSP-1  Endothelial dysfunction Hyperglycemia Free fatty acids Insulin resistance RAGE/AGE  Dyslipidemia

23. VBWG Colwell JA, Nesto RW. Diabetes Care. 2003;26:2181-8. Altered platelet functions in diabetes  Membrane fluidity Altered Ca +2 and Mg +2 homeostasis  Arachidonic acid metabolism  Thromboxane A 2 synthesis  Prostacyclin production  NO production  Antioxidants  Activation-dependent adhesion molecules (eg, GP IIb/IIIa, P-selectin) These changes contribute to increased platelet aggregability and adhesiveness in diabetes

24. VBWG Lincoff AM et al. Circulation. 2000;102:1093-100. 30-day death or MI No diabetes Diabetes 0.331.03.0 Placebo betterEptifibatide better PURSUIT: Outcomes in diabetic vs nondiabetic US patients Odds ratio (95% CI)

25. VBWG Théroux P et al. Circulation. 2000;102:2466-72. Heparin (%) Tirofiban + heparin (%) 30-day outcomes Composite MI/Death Medical management CABG PCI All diabetic patients undergoing Medical management CABG PCI All diabetic patients undergoing 0.115100.5 25.4 22.5 44.9 12.7 26.5 11.2 21.2 17.7 25.6 1.9 2.6 7.6 Risk ratio (95% CI) PRISM-PLUS: Outcomes in diabetic NSTEMI patients by treatment strategy

26. VBWG Roffi M et al. Eur Heart J. 2004;25:190-8. Event rate* at 6 months (%) *Death, MI, rehospitalization for ACS Patients treated with aspirin, clopidogrel, and tirofiban 0 5 10 15 20 25 30 DiabetesNo diabetes 14.2 16.4 13% 27% 20.1 27.7 Invasive Conservative TACTICS-TIMI 18: Death/MI/ACS in ACS patients with/without diabetes

27. VBWG Lincoff AM. Circulation. 2003;107:1556-9. 1-year mortality (%) Evaluation of Platelet Inhibition in STENTing Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy 0 1 2 3 4 5 Diabetes 4.1 1.2 No diabetes EPISTENT (Abciximab) ESPRIT (Eptifibatide) 1.9 1.0 Diabetes 3.5 1.3 No diabetes 1.5 1.4 Placebo GP IIb/IIIa inhibitor EPISTENT, ESPRIT: Effect on 1-year mortality in planned PCI by diabetes status

28. VBWG Roffi M, Topol EJ. Eur Heart J. 2004;25:190-8. PCI in patients with ACS and diabetes Patients with ACS plus diabetes are at higher risk for recurrent events but derive greater benefit from aggressive therapy Mainstays of acute-phase therapy in diabetic ACS: –Triple antiplatelet therapy: Aspirin, clopidogrel, GP IIb/IIIa inhibition –Heparin or LMWH –Early invasive assessment and, if appropriate, stent-based PCI Despite sharp declines in restenosis rates with drug- eluting stents, patients with ACS plus diabetes remain at high risk for repeat revascularization