2. Intravenous GP IIb/IIIa Inhibitors Abciximab (c7E3 Fab, ReoPro) = Human- murine chimeric monoclonal Fab antibody fragment Eptifibatide (Integrilin) = A cyclic heptapeptide based on the Lys-Gly-Asp (KGD) amino acid sequence Tirofiban (Aggrastat) = Tyrosine derivative non-peptide mimetic inhibitor

3. Intravenous GP IIb/IIIa Inhibitors Abciximab (ReoPro) Has a rapid, high affinity to platelets within minutes Dissociation slowly from GP IIb/IIIa receptor Clears rapidly from plasma but remains bound to circulating platelets up to 21 days Binding to IIb/IIIa receptor is non-specific and has equal affinity for the vitronectin receptor which appears to play a role in cell adhesion, migration and proliferation

4. Intravenous GP IIb/IIIa Inhibitors ReoproIntegrilinAggrastat StructureMonoclonal antibody PeptideNon-peptide Tyrosine derivative Specificity to IIb/IIIa receptor Also binds to vitronectin Very Platelet bound t 1/2 HoursSeconds Platelet recovery12-36 Hrs4 Hrs Plasma t 1/2 Minutes2.5 Hrs1.8 Hrs % of dose in bolus75%<2-16%<2-5%

5. IV IIb/IIIa Inhibitors and Time course of Action on Platelets

10. N = 2099 N = 2792 N = 1265

19. EPISTENT

20. EPISTENT Placebo/Stent Abx /Stent Abx /Balloon No. Patients Stent Placed (%) No. Stents/Pt (%) 1 1 2 2 3 3   4 4 Maximum Balloon Inflation Pressure (mm) 809 95.3 69.6 21.9 5.7 2.7 16.0 794 96.9 73.8 20.2 4.5 1.6 16.0 796 19.1 66.4 23.0 7.2 3.3 16.0 Stent Placement

21. EPISTENT o 1Endpoint: Death, MI, or Urgent Intervention 10.8 12.1 5.3 6.4 6.8 9.2 0 3 6 9 12 15 30 day6 months Incidence (%) Placebo/StentAbciximab/StentAbciximab/PTCA p < 0.001 p = 0.051 p < 0.001 p = 0.007 Reduction vs Stent Only Abciximab + Stent Abciximab Only 47% 24% 51% 37%

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30. World Wide Effect of Reopro if Used in All PTCA Procedures - Extrapolation from EPISTENT No. of Lives Saves:>2500 No. of MIs Prevented:>40,000 No. of emergency Revascularisation>6500 Prevented:

32. RESTORE Trial - Tirofiban for Patients with UA or acute MI undergoing PTCA R = Revascularisation. 10.5 8 Treatment Arms 0 2 4 6 8 10 12 Composite Endpoint % (Death, MI, Urgent R Placebo Tirofibin p=0.052 24% N = 2139 Treatment was given for 36 hrs Baseline characteristics or risk stratification were not predictive of treatment effect The differences in death and MI rates was maintained over 6 months but the rate of revascularisation remained unchanged Subgroup angiography study of 600 pts should no effect on restenosis ) ) ) ) )

33. Overview of Randomised Trials of GP IIb/IIIa Inhibitors During Coronary Intervention

34. RAPPORT TRIAL - Reopro For Primary PTCA Endpoint A= Death, recurrent MI, urgent repeat TVR at 30 days. B= Death, recurrent MI, any repeat TVR (inc elective ones) at 6 month 11.2 28.2 9.5 5.8 28.1 16.6 Endpoint AEndpoint BBleeding Complications 0 5 10 15 20 25 30 35 Event Rate (%) Placebo Reopro p= 0.038 48% 0.02 N = 483

35. GP IIb/IIIa Inhibitors for Coronary Intervention In >15,000 patients GP IIb/IIIIa blockade shown to reduce risk of important acute ischaemic events by >50-60% during coronary intervention The treatment effect extends to each of the components of the composite clinical endpoints (Death, MI, and emergency revascularisation) The inhibition of ischaemic events is achieved early (12-48 hrs) and maintained up to 3 yrs

36. All patients regardless of their demographics, clinical, angiograhic, or procedural characteristic benefit Patients with UAP and Diabetics obtain the greatest benefit There may be heterogeneity among the different IIb/IIIa inhibitors. The greatest impact has been shown with Reopro. This may be due to its non-specific binding ability and its different pharmocokinetic profile GP IIb/IIIa Inhibitors for Coronary Intervention

37. Reopro may be specially effective in reducing TVR and therefore restenosis in diabetes in association with coronary stenting but influence of GP IIb/IIIa inhibitors on restenosis in other groups remain unclear Safety of these drugs is increased by keeping ACT ~200 during procedure and avoiding post-procedural heparin with early sheath removal Economical aspects of this therapy needs to be evaluated GP IIb/IIIa Inhibitors for Coronary Intervention

38. Who should have Reopro during Coronary Intervention Patients with UAP at rest with ECG changes, or Refractory angina or Post MI angina particularly if: –Diabetic –Clot present –TIMI 3 flow not achieved –Troponin level is raised ? In Rescue / Salvage PTCA

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