Learning from the Recently Completed Oral Glycoprotein IIb/IIIa Receptor Antagonist Trials Christopher Cannon, M.D. Brigham and Women’s Hospital Boston, MA

Need for Long-Term Antiplatelet Therapy Markers of platelet activation persist at 1 month post ACS –Ault K, et al. P selectin in the TIMI 12 trial. J Am Coll Cardiol 1999;33: Events persist beyond acute period: In the TIMI 3 Registry, Death/MI/Rec Ischemia –In-hospital = 10.5% –One year = 28.3% Benefit of IIb/IIIa inhibition achieved only during IV infusion period (PURSUIT, PRISM-PLUS)

1. Platelet Adhesion 2. Platelet Activation Platelet GP Ib Plaque rupture Activated Platelet GP IIb/IIIa 3. Platelet Aggregation ASA, Clopidogrel/Ticlopidine ASA, Clopidogrel/Ticlopidine GP IIb/IIIa Inhibitors

GP IIb/IIIa Inhibitors in PCI and ACS Odds Ratio & 95% CI Placebo BetterIIb/IIIa Better TrialPlaceboIIb/IIIa N Overall 30, %9.0% 0.79 (0.73, 0.85) p < IMPACT-II EPIC 4,010 2, % 10.1% 7.1% 7.0% RESTORE CAPTURE 2,139 1, % 9.0% 5.1% 4.8% EPILOG 2, %4.0% PURSUIT 10, %14.2% PRISM 3, %5.7% PRISM PLUS 1, %8.7% PARAGON 2, %11.3% Topol EJ Lancet 1999;353: Death/MI at 30 Days EPISTENT 2, % 5.2%

TIMI-12: Oral IIb/IIIa Inhibition in ACS n= Patients (%) mg bidmg qd Cannon et al. Circulation 1998;97:340 Major or Minor Bleeding

6 Study Design ASA mg daily Orbofiban 50 mg BID Orbo 50 mg BID x 30 days then Orbo 30 mg BID Placebo BID Other Meds, Cath/Revasc per MD F/U Day 14, Day 30 Follow-up visit every 3 months Primary endpoint to 30 days + follow-up Death, MI Urgent Revasc, Ischemia -> Rehosp, or Stroke Randomize 1:1:1 Patient with Unstable Coronary Syndrome <72 hours N= 10,302

Primary Endpoint - Through F/U (300 days) No. Pts Composite (%) Death MI Urg revasc Rehosp Stroke Placebo Orbo 50/30* Orbo 50/ P values Each Dose vs. Placebo Data as of Jun NS / 0.03 NS / NS *Orbofiban 50mg bid x 30 days, then 30mg bid

Cause of Deaths within 30 Days (Preliminary Review) Data as of Jun No. Deaths reviewed Progressive Sudden Non-Ischemic Bleeding New Thrombotic Event Orbo 50/50PlaceboOrbo 50/30

Bleeding Events and Thrombocytopenia (F/U) No. Pts Severe ICH Major Major/Sev Platelets 50-80, ,000 <20,000 Placebo Orbo 50/ Orbo 50/ P value Each Dose vs. Placebo Data as of Jun / 0.04 NS NS / < / /0.01

Safety (Mean 2 year F/U) CAPRIE GI hemorrhage2.0%2.7%P < 0.05 Hospitalization due to GI hemorrhage0.7%1.1%P = GI ulcers 0.7%1.2%P < Intracranial hemorrhage0.4%0.5%P = NS Severe Neutropenia 0.04%0.02%P = NS *Patients with a history of GI bleed and peptic ulcers were excluded from CAPRIE. ClopidogrelAspirin* (n = 9599)(n = 9586) ClopidogrelAspirin* (n = 9599)(n = 9586)

Primary Endpoint to F/U Patients-> PCI on study drug Time (days) % Patients placebo mg mg F/U pl v : p=0.14 pl v : p= d pl v : p=0.73 pl v : p=0.08 Data as of Jun

Summary l First large global trial in ACS of oral IIb/IIIa inhibitor l Orbofiban: minimal efficacy benefit with small excess in mortality l Major bleeding and thrombocytopenia rates were low but higher than placebo l Greater benefit and no harm was seen in subgroups with normal renal function and without heart failure. l 30% benefit in PCI patients on study drug

Xemilofiban 10 mg TID Xemilofiban 20 mg TID Placebo TID RandomizationRandomization Xemilofiban 20 mg Placebo PTCR 30 to 90 min prior to PTCR Stented patients were assigned to receive either ticlopidine (if assigned to the placebo arm) or ticlopidine placebo (if assigned to an active therapy arm ) for 2 to 4 weeks. ASA was taken by all patients at doses between mg per day 6 Month Follow-up The EXCITE Trial

Primary Efficacy Analysis (Death, MI, and Urgent Revascularization)

TIMI 12 / Symphony I Trials Sibrafiban 6 weeks3 months D/MI/RIDeath/MI

IV vs. Oral GP IIb/IIIa inhibition h12h24h % inhibition (ADP) 36h IV infusion: (Eptifibatide 180 ug/kg ug/kg/min) (mean +/- Std. Dev) N=48 IntravenousOral Data on File, COR/Key Ferguson et al JACC 1998;31:185A (abstract) h6h 0h 6h 80 Oral : (Orbofiban 50 mg BID) = Mean = Mean

ADP-Inducted Activation of Platelets from Patients Treated with Orbofiban Platelet Degranulation/P Selectin 2.0 µM ADP Randomization1 Month P-selectin Expression (percentage of platelets) p < 0.05 _ _ Fibrinogen Binding 0.2 µM ADP Randomization1 Month Fibrinogen Binding (percentage of platelets) p < 0.01 _ _ Holmes et al. Am J Cardiol (in press)

Fibrinogen Binding and Platelet Aggregation with IIb/IIIa Inhibitor P=0.001 Fibrinogen BindingPlatelet Aggregation Peter et al, Blood 1998;92:

Hypothesis: Intrinsic Activating Property of IIb/IIIa Inhibition GP IIb/IIIa Receptor IIb/IIIa inhibitor ActivatedUnactivated Platelet Adapted: Peter et al., Blood 1998;92: Dissociation of competitive inhibitor FGN FGN Binding IIb/IIIa inhibitor Allows Binding of Fibrinogen + Plt Aggreg Activation of IIb/IIIa receptor “Outside-In Signaling  Platelet Activation FGN FGN

Exploratory Analyses: Lessons Learned Fixed-dosing with a competitive oral IIb/IIIa inhibitor: è Peaks/troughs in % inhibition and high inter-patient variability è Low blood levels at some time periods è Too low to prevent events è ? Proaggregatory effects (Peter et al, Blood 1998) è High blood levels in some patients (  creat.) è Potential for excess bleeding è ? Plaque hemorrhage -> increased events

Scorecard - Comparing Oral Agents Roxifiban Orbofiban SibrafibanXemilofiban Trial Rocket OPUS-TIMI16SymphonyEXCITE IIb/IIIa selective Binding Tightly CompetitiveCompetitive Competitive bound “Off rate” 7 mins secondssecondsseconds Peak of Onset 3-6h4-6h4-6h2-3h Half-life 24 h8-10h 11h 4-5h Excretion Plt. Dissoc.RenalRenalRenal Dosing QD BIDBIDTID Low Peak/trough Intra-pt variability Inter-pt variability Plts < 50,000 <0.5% 0.6%<0.5%0.5% Plts Pro-aggreg. NoYes- Yes 2nd Generation1st Generation Oral IIb/IIIa inhibitors

Conclusions - Oral Antiplatelet Therapy at the End of the Millennium l Future Directions - Oral IIb/IIIa inhibitors: 1. Need to optimize dosing è Mimic stable effect of IV drugs è Reduce inter- and intra-patient variability è ? Use bedside platelet test to adjust dose 2. Test “second generation” drugs (tight IIb/IIIa binding) l ASA and ADP antagonists l Proven benefit in large trials l Both decrease platelet activation l Combination ASA/Clopidogrel being tested