NICE-3 National Investigators Collaborating on Enoxaparin XXII nd Congress of the European Society of Cardiology August 30, 2000 Amsterdam, The Netherlands XXII nd Congress of the European Society of Cardiology August 30, 2000 Amsterdam, The Netherlands

2 NICE-3 Objectives To assess the safety profile (primarily with respect to bleeding) of enoxaparin and a IIb/IIIa antagonist (abciximab, eptifibatide or tirofiban) in patients with ACS To assess the feasibility and safety of bringing patients to the cath laboratory on combination therapy (without the use of UFH) To assess the safety profile (primarily with respect to bleeding) of enoxaparin and a IIb/IIIa antagonist (abciximab, eptifibatide or tirofiban) in patients with ACS To assess the feasibility and safety of bringing patients to the cath laboratory on combination therapy (without the use of UFH)

3 NICE-3 Inclusion Criteria Recent (w/in 24 hours) unprovoked or rest angina Documented ischemic CAD ECG changes Abnormal biomarkers Previously documented CAD Patients on prior UFH could be included Recent (w/in 24 hours) unprovoked or rest angina Documented ischemic CAD ECG changes Abnormal biomarkers Previously documented CAD Patients on prior UFH could be included

4 NICE-3 Exclusion Criteria Evolving Q-wave MI Fibrinolytic Rx w/in 48 hours Cardiogenic shock Left main disease Valvular disease CABG w/in 2 mos.; revasc w/in 1 week Thrombocytopenia Evolving Q-wave MI Fibrinolytic Rx w/in 48 hours Cardiogenic shock Left main disease Valvular disease CABG w/in 2 mos.; revasc w/in 1 week Thrombocytopenia

5 NICE-3 Protocol Study Initiated January 2000 Study Initiated January clinical sites in US/Canada In-hospital, 14-day, and 30-day follow-up 661 patients enrolled [Enoxaparin alone] (n=45) Data available August 2000 Data available August 2000 All IIb/IIIa patients (n=616) Enrollment Completed May 2000 Enrollment Completed May 2000 Abciximab(n=147)Eptifibatide(n=252) Tirofiban(n=217) All treated with Enoxaparin If patients went to the cath lab, combination Rx continued; no UF heparin used If within 8 hrs of last enoxaparin, no additional Rx If > 8 hrs from last dose, 0.3 mg/kg enoxaparin iv

6 NICE-3 Protocol Primary Endpoint Non-CABG major bleeding (TIMI criteria) during hospitalization Secondary Endpoints Minor bleeding (TIMI criteria) Clinical efficacy Composite of death, MI, ischemia-driven TVR Primary Endpoint Non-CABG major bleeding (TIMI criteria) during hospitalization Secondary Endpoints Minor bleeding (TIMI criteria) Clinical efficacy Composite of death, MI, ischemia-driven TVR

7 NICE-3 Sample Size Primary Hypothesis The 95% CI for major bleeding will not exceed the historical rate Agents examined as a whole and separately Example (Assuming major bleed rate of 2%): A 200 patient sample size has a 95% CI of approx % A 150 patient sample size has a 95% CI of approx 0-4.2% Primary Hypothesis The 95% CI for major bleeding will not exceed the historical rate Agents examined as a whole and separately Example (Assuming major bleed rate of 2%): A 200 patient sample size has a 95% CI of approx % A 150 patient sample size has a 95% CI of approx 0-4.2%

8 NICE-3 Demographics Age62.9  12.2 years Weight83.9  18.5 kg M/F approx 2:1 LOS5.9  4.2 days Age62.9  12.2 years Weight83.9  18.5 kg M/F approx 2:1 LOS5.9  4.2 days History History HTN63.5%Prior PCI30.7% DM30.0%Prior CABG20.9% Smoking28.1%Prior MI36.2% CHF (on admin) 4.5%

9 NICE-3 Bleeding (%) Abciximab(n=147)Eptifibatide(n=252)Tirofiban(n=217) Enoxaparin [Enoxaparin alone] (n=45) All IIb/IIIa (n=616) All 17.8 Major 6.7 non-CABG 4.4 Minor 13.3 Xfusion 8.9 All 27.2 Major 5.1 non-CABG 1.4 Minor 24.0 Xfusion 10.6 All 30.6 Major 4.4 non-CABG 3.2 Minor 27.2 Xfusion 10.3 All 24.5 Major 4.1 non-CABG 0.7 Minor 22.4 Xfusion 10.9 All 27.9 Major 4.5 non-CABG 1.9 Minor 25.0 Xfusion 10.5

10 NICE-3 In-Hospital Clinical Outcomes (%) Abciximab(n=147)Eptifibatide(n=252)Tirofiban(n=217) [Enoxaparin alone] (n=45) All IIb/IIIa (n=616) Death 0 MI 2.2 uTVR 2.2 D/MI/uTVR 4.4 D/MI 2.2 Death 0.3 MI 3.4 uTVR 2.1 D/MI/uTVR 5.7 D/MI 3.6 Death 0.5 MI 4.1 uTVR 3.2 D/MI/uTVR 7.8 D/MI 4.6 Death 0.4 MI 3.2 uTVR 2.0 D/MI/uTVR 5.2 D/MI 3.2 Death 0 MI 2.7 uTVR 0.7 D/MI/uTVR 3.4 D/MI 2.7 Enoxaparin

11 NICE-3  30%  in Platelet Count 0<100K0.85%<100K 1.44%<100K 0.86%<100K (n=138)(n=235)(n=208)(n=581)(n=38)

12 NICE-3 All Major Bleeding (%) AbciximabEptifibatideTirofibanAll IIb/IIIa Patients undergoing PCI Patients not undergoing PCI or CABG

13 NICE-3 PCI Patients (n=292) Tirofiban0.9% Eptifibatide2.4% Abciximab 0 All IIb/IIIa1.0% Tirofiban0.9% Eptifibatide2.4% Abciximab 0 All IIb/IIIa1.0% Non-CABG Major Bleeding

14 NICE-3 Conclusions Combination of enoxaparin and IIb/IIIa Does not result in excess major bleeding Events (non-CABG) Patients on combination Rx can safely undergo PCI Clinical outcomes in NICE-3 were comparable to those noted in prior studies Therefore, not necessary to use UFH in: UA/NSTEMI patients undergoing coronary intervention who are treated with enoxaparin and an IV IIb/IIIa antagonist Combination of enoxaparin and IIb/IIIa Does not result in excess major bleeding Events (non-CABG) Patients on combination Rx can safely undergo PCI Clinical outcomes in NICE-3 were comparable to those noted in prior studies Therefore, not necessary to use UFH in: UA/NSTEMI patients undergoing coronary intervention who are treated with enoxaparin and an IV IIb/IIIa antagonist