1. The Evolving Role of LMWH in ACS James J. Ferguson, MD Texas Heart Institute Houston, TX James J. Ferguson, MD Texas Heart Institute Houston, TX

2. 2 Objectives Assist peers in overcoming gaps in awareness of LMWH therapy in ACS Review emerging data for ACS NICE-3 GUSTO-IV Discuss strategies for increasing early administration of LMWH therapy Discuss future directions for LMWH therapy in ACS Assist peers in overcoming gaps in awareness of LMWH therapy in ACS Review emerging data for ACS NICE-3 GUSTO-IV Discuss strategies for increasing early administration of LMWH therapy Discuss future directions for LMWH therapy in ACS

3. 3 TIMI 11B-ESSENCE Meta-Analysis Death/MI 0.5120.60.70.80.9 Odds Ratio Enox Better UFH Better Day OR p N UFH (%) Enox (%) OVERALL ESSENCE 8 0.77 (0.62-0.96) 23 0.02 7081 3910 3171 B B 5.34.1 OVERALL ESSENCE 14 0.79 (0.65-0.96) 210.02 7081 3910 3171 B B 6.55.2 OVERALL ESSENCE43 0.82 (0.69-0.98) 180.02 7081 3910 3171 B B 8.67.1 % TIMI 11B

4. 4 The ESSENCE Trial: 1-Year Time to First Triple Endpoint 0 5 10 15 20 25 30 35 40 02468101214 Months Cumulative event rate (%) Heparin Enoxaparin

5. 5 Paradox We have data strongly supporting a better form of therapy We are still not using it widely Why? We have data strongly supporting a better form of therapy We are still not using it widely Why?

6. Unfractionated Heparin LMW Heparin IIaAT IIaAT XaATXa AT UpstreamUpstream DownstreamDownstream

7. 7 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2610141822263034 Time (h) Anti-Xa activity (IU/ml) 1.0 mg/kg 1.25 mg/kg 1.5 mg/kg 2.0 mg/kg Plasma Anti-Xa Activity after Ascending Single Doses of Subcutaneous Enoxaparin in Healthy Volunteers Subcutaneous Enoxaparin in Healthy Volunteers

8. % Pts Hours from Randomization 0 1 2 3 4 5 6 7 8 9 081624324048566472 UFH ENOX 5.2 % 4.2 % RRR 18% P=0.21 % Pts Hours from Randomization 0 1 2 3 4 5 6 7 8 9 0 816243240 48 5664 72 7.3 % 5.5 % RRR 24% P=0.03 UFH ENOX ESSENCE TIMI 11B Death/MI/Urgent Revasc Early Rx Phase Early Benefit Aventis Parsippany, NJ

9. 9 TIMI 11B Triple Endpoint at Day 43

10. 10 Discussion How are you currently using LMWHs? What are you using? When are you using it? Why? Why not? How are you currently using LMWHs? What are you using? When are you using it? Why? Why not?

11. 11 CAPTURE GUSTO IV † PRISM PRISM-Plus PURSUIT PARAGON Trial (LMWH) ESSENCE TIMI 11B TESSMA ‡ Trial (IIb/IIIa) Placebo IIb/IIIa 1252 7800 3231 1570 10,948 2282 3171 3910 7,081 N 9.0 8.0 7.0 11.9 15.7 11.7 Heparin 7.7 8.3 8.6 4.8 ~8.6 5.7 8.7 14.2 10.3 Enoxaparin 6.2 7.4 7.1 BetterWorse 0.1 1 10 Clinical Event Rates in Unstable Angina Trials Death / MI at 30 days Odds Ratio & 95% CI N † Preliminary results - placebo vs abciximab bolus plus 24 and 48 hr infusion ‡ Meta-analysis of TIMI 11B and ESSENCE at Day 43 (%)

12. 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

13. 13 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)

14. 14 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

15. 15 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

16. 16 NICE-3 Protocol Study Initiated January 2000 Study Initiated January 2000 46 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

17. 17 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

18. 18 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 0.1-3.9% 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 0.1-3.9% A 150 patient sample size has a 95% CI of approx 0-4.2%

19. 19 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%

20. 20 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

21. 21 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

22. 22 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)

23. 23 NICE-3 All Major Bleeding (%) 1 4.8 3.6 4.8 3.1 0.9 4.3 1.7 0 2 4 6 AbciximabEptifibatideTirofibanAll IIb/IIIa Patients undergoing PCI Patients not undergoing PCI or CABG

24. 24 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

25. 25 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

26. 26 NICE-3 Clinical Implications Real-world study Broad distribution of patients and institutions Safety data for all 3 commercially available IIb/IIIa antagonists Addresses safety concerns about combining enoxaparin and a IIb/IIIa antagonist Addresses logistical concerns about transition to cath lab Foundation for future investigations Real-world study Broad distribution of patients and institutions Safety data for all 3 commercially available IIb/IIIa antagonists Addresses safety concerns about combining enoxaparin and a IIb/IIIa antagonist Addresses logistical concerns about transition to cath lab Foundation for future investigations

27. 27 Is it safe to combine enoxaparin with IIb/IIIa blockers? How do we make the transition from the floor to the cath lab? Is it safe to combine enoxaparin with IIb/IIIa blockers? How do we make the transition from the floor to the cath lab? No safety issues at present Potential synergism Good regimen for PCI No safety issues at present Potential synergism Good regimen for PCI Carefully but confidently, within the limits of our experience Issues for Enoxaparin in ACS

28. 28 Discussion How does NICE-3 help you? What questions doesn’t it answer? Is it going to affect your practice? What additional information do we need? How does NICE-3 help you? What questions doesn’t it answer? Is it going to affect your practice? What additional information do we need?

29. 29 NICE-1 NICE-4 NICE-3 ? ? ? PI: Cindy Grines Enoxaparin (1 mg/kg iv) for PCI PI: Cindy Grines Enoxaparin (1 mg/kg iv) for PCI PI: Dean Kereiakes Enoxaparin (0.75 mg/kg iv) with abciximab for PCI PI: Dean Kereiakes Enoxaparin (0.75 mg/kg iv) with abciximab for PCI PI: James Ferguson Enoxaparin (1 mg/kg sq) with IIb/IIIa blocker for ACS (including PCI) PI: James Ferguson Enoxaparin (1 mg/kg sq) with IIb/IIIa blocker for ACS (including PCI) The NICE Trials Together

30. 30 Discussion Patient management strategies when an ACS patient, who is a candidate for LMWH, proceeds to the cath lab

31. 31 Future Data GUSTO-IV ACS A to Z ACUTE-2INTERACTCRUISE [Pilot trial LMWH vs combo Rx] [Efficacy trial LMWH vs UFH] GUSTO-IV ACS A to Z ACUTE-2INTERACTCRUISE [Pilot trial LMWH vs combo Rx] [Efficacy trial LMWH vs UFH]

32. 32 GUSTO-IV ACS Simoons, ESC 2000 Multicenter study (458 sites in 24 countries) ACS patients not undergoing revascularization Treated with ASA and UFH Scandanavian subset got LMWH 7800 patients randomized to abciximab (24 hours) abciximab (48 hours) placebo Primary Endpoint: Death or MI at 30 days Multicenter study (458 sites in 24 countries) ACS patients not undergoing revascularization Treated with ASA and UFH Scandanavian subset got LMWH 7800 patients randomized to abciximab (24 hours) abciximab (48 hours) placebo Primary Endpoint: Death or MI at 30 days

33. 33 GUSTO-IV ACS Simoons, ESC 2000 Definition of ACS: Rest angina with ST-segment  (1/2 mm) or (+) troponin Coronary angiography only for recurrent ischemia ~ 28% had evolving MI 14% from US, 48% from Western Europe ~80% had ST-segment  ~59% had + troponin ~32% had both Revasc performed in ~30% by day 30 Only 1.4% revasc in first 48 hours Definition of ACS: Rest angina with ST-segment  (1/2 mm) or (+) troponin Coronary angiography only for recurrent ischemia ~ 28% had evolving MI 14% from US, 48% from Western Europe ~80% had ST-segment  ~59% had + troponin ~32% had both Revasc performed in ~30% by day 30 Only 1.4% revasc in first 48 hours

34. GUSTO-IV ACS 48 Hours 7 Days 30 Days

36. 36 GUSTO-IV ACS ICH Ischemic Stroke LMWH Substudy

39. 39