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Do T irofiban A nd R eoPro G ive Similar E fficacy Outcomes T rial

Preliminary. Do T irofiban A nd R eoPro G ive Similar E fficacy Outcomes T rial. Presented at AHA Scientific Sessions Nov. 15, 2000. Preliminary. GP IIb/IIIa Inhibition in PCI. Consistent reduction in adverse events Optimal outcome when combined with stents

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Do T irofiban A nd R eoPro G ive Similar E fficacy Outcomes T rial

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  1. Preliminary Do Tirofiban And ReoPro Give Similar Efficacy Outcomes Trial Presented at AHA Scientific Sessions Nov. 15, 2000

  2. Preliminary GP IIb/IIIa Inhibition in PCI • Consistent reduction in adverse events • Optimal outcome when combined with stents • No comparative data between agents Presented at AHA Scientific Sessions Nov. 15, 2000

  3. 0.0 0.5 1.0 2.0 Preliminary Background 30-Day Death, MI, Urgent Revascularization % Odds Ratio Trial N Agent IIb/IIIa Control (95% CI) EPIC 2099 Abciximab 8.3 12.8 EPILOG 2792 Abciximab 5.3 11.7 EPISTENT 1603 Abciximab 5.3 10.8(stent arms only) IMPACT-II 4010 Eptifibatide 9.5 11.4 ESPRIT 2064 Eptifibatide 6.8 10.4 RESTORE 2141 Tirofiban 8.0 10.5 Presented at AHA Scientific Sessions Nov. 15, 2000

  4. Tirofiban non-peptide 495 dalton MW recovery of platelet function: hours specific for IIb/IIIa receptor Abciximab monoclonal antibody 47,615 dalton MW recovery of platelet function: days binds to IIb/IIIa, MAC-1, v3 Preliminary Characteristics of Tirofiban and Abciximab Presented at AHA Scientific Sessions Nov. 15, 2000

  5. Preliminary PrimaryHypothesis Tirofiban will have comparable efficacy to abciximab in reducing the incidence of adverse cardiac ischemic events during the first 30 days after intracoronary stent placement. Presented at AHA Scientific Sessions Nov. 15, 2000

  6. Preliminary Statistical Considerations Sample size provides 88% power to declare tirofiban non-inferior to abciximab, based on the relative efficacy of abciximab to placebo in EPISTENT* * the upper bound of the 1-sided 95% C.I. for the odds ratio (tirofiban relative to abciximab) must be below 1.47. Presented at AHA Scientific Sessions Nov. 15, 2000

  7. Preliminary PrimaryEndpoint 30 day composite of: • death • myocardial infarction • CK-MB > 3x ULN in two samples • new Q waves • urgent TVR • PCI or CABG Presented at AHA Scientific Sessions Nov. 15, 2000

  8. Study Design Preliminary Inclusion Criteria • stable CAD or ACS, scheduled to undergo PCI in native vessel and/or graft with planned stent • primary or rescue PCI for ST elevation MI • increased risk of bleeding • allergy, intolerance, or recent exposure to study medications • creatinine > 2.5 mg/dl • cardiogenic shock Exclusion Criteria Presented at AHA Scientific Sessions Nov. 15, 2000

  9. Preliminary Study Design Bolus + 18-24 hr infusion Tirofiban or Pbo 30 Days 6 Mos 1 Yr Abciximab or Pbo Bolus + 12 hr infusion PCI ASA Clopidogrel* Heparin Primary Endpoint Long term follow up * Investigator’s discretion Presented at AHA Scientific Sessions Nov. 15, 2000

  10. Preliminary Concomitant Medications Clopidogrel* • 300 mg 2-6 hours pre-PCI (or immediately pre-PCI in patients with unknown anatomy) • 75 mg daily for 29 days Heparin • 70 U/kg IV bolus • ACT target of 250 seconds Aspirin *Investigator’s discretion Presented at AHA Scientific Sessions Nov. 15, 2000

  11. Preliminary Study Drug Administration • Study drug boluses administered at start of procedure • Study drug infusions started immediately after completion of study drug boluses Presented at AHA Scientific Sessions Nov. 15, 2000

  12. Preliminary Enrollment • December 30, 1999 - August 25, 2000 • 151 sites; 18 countries • 5308 patients randomized • 4812 patients randomized and treated Presented at AHA Scientific Sessions Nov. 15, 2000

  13. Participating Sites Presented at AHA Scientific Sessions Nov. 15, 2000

  14. Preliminary Baseline Demographics Tirofiban Abciximab n = 2398 n = 2414 US (n) 1950 1963 Ex-US (n) 448 451 age (yr) 62.0 62.6 gender (M/F, %) 73/27 74/26 diabetes (%) 25 24 hypertension (%) 64 65 dyslipidemia (%) 73 72 smoking (%) 64 64 prior MI (%) 39 39 prior PCI (%) 29 30 prior CABG (%) 17 17 Presented at AHA Scientific Sessions Nov. 15, 2000

  15. Preliminary Indication for Procedure ACS (%) 63 63 Stable Angina (%) 22 21 Positive Stress Test (%) 11 12 Other (%) 4 5 Tirofiban Abciximab n = 2398 n = 2414 Presented at AHA Scientific Sessions Nov. 15, 2000

  16. Preliminary Procedural Characteristics Tirofiban Abciximab n = 2398 n = 2414 Patients with stent placed (%) 95 95 Stents/Patient 1.3 1.3 Patients with thrombus present(%) 10 9 Vein grafts (%) 5 5 Restenotic lesion(%) 5 5 Maximum ACT (median) 281 282 Presented at AHA Scientific Sessions Nov. 15, 2000

  17. Preliminary Medications Tirofiban Abciximab n = 2398 n = 2414 ASA pre-procedure (%) 99 99 Mean Heparin dose (U) 6355 6461 Clopidogrel any pre-procedure (%) 93.4 92.2 300 mg load pre-procedure(%) 87.2 85.6 Study drug infusion duration (hrs) 18.2 12.0 Presented at AHA Scientific Sessions Nov. 15, 2000

  18. Preliminary Primary Endpoint 30 day Death, MI, Urgent TVR Non-inferiority boundary RR = 1.26 Upper bound of 95% confidence interval = 1.52 p=0.037 RR = 1.26 1.47 Abciximab better 30 day Death, MI, Urgent TVR (%) 1.00 Tirofiban better Tirofiban Abciximab Presented at AHA Scientific Sessions Nov. 15, 2000

  19. 10 8 6 4 2 0 Preliminary Primary EndpointD/MI/Urgent TVR 7.55% 6.01% % Patients Tirofiban Abciximab 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (Days) Presented at AHA Scientific Sessions Nov. 15, 2000

  20. Preliminary Primary Endpoint Analysis p = 0.037 p = NS p = 0.043 p = 0.04 p = NS Event Rate % Composite Death MI Death/MI Urgent TVR Presented at AHA Scientific Sessions Nov. 15, 2000

  21. Preliminary Primary Endpoint Analysis Tirofiban Abciximab RR CI % % 7.55 6.01 1.26 1.05,1.52 7.17 5.72 1.26 1.01,1,58 6.88 5.43 1.27 1.01,1.60 0.50 0.41 1.21 0.52, 2.81 0.83 0.66 1.26 0.65, 2.44 Primary composite endpoint Death/MI MI Death Urgent TVR 1 Tirofiban better Abciximab better Presented at AHA Scientific Sessions Nov. 15, 2000

  22. Preliminary Time to MIMIs within the first 72 hrs 10 8 6 % Patients 4 Tirofiban Abciximab 2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 Time (Hours) Presented at AHA Scientific Sessions Nov. 15, 2000

  23. Tirofiban Abciximab RR CI % % 6.25 5.38 1.17 0.72, 1.90 7.94 6.20 1.29 1.01, 1.64 6.61 4.60 1.45 1.05, 2.01 8.71 7.84 1.11 0.82, 1.50 7.16 6.49 1.11 0.86, 1.43 8.66 4.69 1.85 1.19, 2.89 Preliminary Subgroup Analysis Diabetes No Diabetes Age < 65 Age > 65 Male Female 1 Tirofiban better Abciximab better Presented at AHA Scientific Sessions Nov. 15, 2000

  24. Preliminary Subgroup Analysis Tirofiban Abciximab RR CI % % • Pre-procedure Clopidogrel • Yes • No • ACS • non-ACS • U.S. • Ex-U.S. 7.19 5.75 1.26 1.00, 1.58 12.66 9.04 1.40 0.73, 2.68 9.31 6.27 1.49 1.15, 1.94 4.52 5.56 0.82 0.54, 1.24 7.69 6.72 1.15 0.91, 1.45 6.92 2.88 2.43 1.27, 4.64 1 Tirofiban better Abciximab better Presented at AHA Scientific Sessions Nov. 15, 2000

  25. Preliminary Planned Stenting in Non-ACSDeath / MI / Urgent TVR 30 Days • In patients with planned stenting or non-ACS patients ReoPro and Aggrastat have shown similar event rates. % of Patients with Event Presented at AHA Scientific Sessions Nov. 15, 2000; EPISTENT Investigators; ESPRIT - Presented ACC March, 2000

  26. Preliminary Substudy of U.S. vs International Primary Endpoint Results • The separation between Tirofiban and Abciximab in the U.S. was 18 events in 3913 patients treated • The separation outside the US was 18 events in the 899 patients treated % of Patients with Event Death / MI / Urgent TVR at 30 Days Presented at AHA Scientific Sessions Nov. 15, 2000

  27. 30 day Death, MI, Urgent TVR U.S. Cohort Non-inferiority boundary Upper bound of 95% confidence interval = 1.44 RR = 1.14 1.47 Abciximab better 1.00 Tirofiban better Preliminary U.S. - Primary Endpoint Presented at AHA Scientific Sessions Nov. 15, 2000

  28. Preliminary Safety Analysis Tirofiban Abciximab P % % • TIMI Major Bleeding • IC hemorrhage • TIMI Minor Bleeding • Any TIMI bleeding • Thrombocytopenia (< 100,000) • RBC Transfusion • Platelet Transfusion 1.17 0.95 0.467 0.04 0.04 3.54 5.59 0.001 4.59 6.50 0.54 2.44 <0.001 1.42 1.49 0.46 0.50 Presented at AHA Scientific Sessions Nov. 15, 2000

  29. Preliminary Conclusions • Abciximab was superior to tirofiban in reducing the incidence of the primary endpoint of the trial: The composite endpoint of death / MI / urgent target vessel revascularization at 30 days after intracoronary stent placement. • There were no differences in rates of TIMI major bleeding, but significant differences in minor bleeding and thrombocytopenia were observed favoring tirofiban. Presented at AHA Scientific Sessions Nov. 15, 2000

  30. Preliminary Preliminary Cost Analysis • The cost differential of Abciximab vs Tirofiban is on the average $1000 more per patient to use abciximab • Based on TARGET • No difference in mortality, no cost per year of life saved, although trial not adequately powered to assess mortality • 3 MIs are prevented per 200 patients with use of abciximab • Additional cost of treating 200 patients with abciximab instead of Aggrastat would be $200,000 • Cost per MI prevented: $66,666 (I.e. $200,000 / 3 pts)

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