2. Pathophysiology of Combination Therapy in AMI *Gibson et al. J Am Coll Cardiol. 1995;25:582-589. Gibson et al. Circulation. 2001;103:2550-2554. Combination Therapy  Thrombus  % Stenosis  Minimum Diameter  Epicardial Flow  Myocardial Blush  ST Resolution  Myocardial Flow Facilitates PCI Reduces Reinfarction*

3. Recent Clinical Trials Unfractionated heparin Enoxaparin Unfractionated heparin Enoxaparin Abciximab None ENTIRE ACC/AHA heparin dose Low-dose heparin Enoxaparin None Abciximab None ASSENT-3 Standard-dose heparin Low-dose heparin None Abciximab 50% TNK-tPA 100% TNK-tPA 50% TNK-tPA 100% TNK-tPA 100% r-PA 50% r-PA GUSTO-V Anticoagulant GP IIb/IIIa Receptor Inhibitor LyticTrial

4. Clinical Trials: Ongoing Low-dose heparin Eptifibatide 50% TNK-tPA 75% TNK-tPA 100% TNK-tPA INTEGRITI Low-dose heparin Tirofiban 50% TNK-tPA 75% TNK-tPA 100% TNK-tPA FASTER Anticoagulant GP IIb/IIIa Receptor Inhibitor LyticTrial

5. 54% 32% GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is Needed to Yield a 1% Mortality Reduction The GUSTO Angiographic Investigators. N Engl J Med. 1993;329:1615-1622. 0 30 50 60 40 20 % TIMI Grade 3 Flow t-PASK 10 t-PA 5 7.4% 6.3% SK 876

6. TIMI Grade 3 Flow – Pooled Data From Dose Confirmation Phases of Recent Trials 0 40 80 100 60 20 % Patients With TIMI Grade 3 Flow GUSTO-I 90 min T14 t-PA 90 min T14 r-PA 90 min SPEED 60-90 min INTRO-AMI 60 min Pooled 60-90 min 54 73 70 47 40 56 78 73 54 56 64 29263879881329588810075321 Lytic alone Combination

7. SPEED: Results of Dose-Confirmation Phase There was a 7.4% improvement in the rate of TIMI Grade 3 flow If a 20% improvement is required to improve mortality by 1%, then a 7.4% improvement would be predicted to improve mortality by 0.3% The SPEED Study Group. Circulation. 2000;101:2788-2794. 0 40 80 100 r-PA 10+10 Ur-PA 5+5 U + Abx 60 20 Patency (%) TIMI-2 TIMI-3 n=109n=115 21.6 54.9 47.5 28.7

8. GUSTO-V: Study Design The GUSTO-V Investigators. Lancet. 2001;357:1905-1914. ST , lytic eligible, < 6 h (n=16,588) ASA No Abciximab 2 x 10 U bolus (30’) Full-dose r-PA 2 x 10 U bolus (30’) Full-dose r-PA Abciximab Low-dose Heparin: 60 U/kg bolus followed by 7 U/kg/h infusion Low-dose Heparin: 60 U/kg bolus followed by 7 U/kg/h infusion 1º end point: mortality at 30 days 2º end point: clinical and safety events at 30 days 2 x 5 U bolus (30’) Half-dose r-PA 2 x 5 U bolus (30’) Half-dose r-PA Standard Heparin: 5000 U bolus followed by 800 U/h (< 80 kg) or 1000 U/h (  80 kg) infusion Standard Heparin: 5000 U bolus followed by 800 U/h (< 80 kg) or 1000 U/h (  80 kg) infusion

9. Primary End Point: 30-Day Mortality The GUSTO-V Investigators. Lancet. 2001;357:1905-1914. 0 % Mortality Days 051015202530 P=.43 for superiority Non-Inferiority RR 0.95 (95% CI, 0.84-1.08) Std. Reteplase (n = 8260) Abx +  Dose Reteplase (n = 8328) 4 6 2 5.9% 5.6%

10. GUSTO-V: Noninferiority Analysis Adapted with permission from the GUSTO-V Investigators. Lancet. 2001;357:1905-1914. Non-Inferiority RR 0.95 (95% CI, 0.84-1.08) 1.11 OR and 95% CI 0.02.01.0 Abciximab + Half-dose r-PA superior Full-dose r-PA superior Upper Boundary of 95% CI for Noninferiority

11. A Comparison of the Outcomes With r-PA Monotherapy in GUSTO-III vs GUSTO-V Trials The GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123. The GUSTO-V Investigators. Lancet. 2001;357:1905-1914. 0 3 7 8 5 1 2 6 4 GUSTO IIIGUSTO V 7.4% 5.9%10,1388,260 Death P<.001 0 40 50 20 30 10 GUSTO IIIGUSTO V 48% 37% 10,1388,260 Anterior MI 0 0.5 0.9 1.0 0.7 0.3 0.4 0.8 0.6 0.2 GUSTO IIIGUSTO V 0.91% 0.59% 10,1388,260 ICH P=.015 0.1

12. 0.2 1.2 1.7 2.3 GUSTO-V: Causes of Reinfarction *Unblinded, unadjudicated The GUSTO-V Investigators. Lancet. 2001;357:1905-1914. 0 1 3 4 2 Myocardial Infarction (%) AnyQ-waveEnzymaticIschemic ST Change* 3.5 0.5 1.6 2.7 r-PA r-PA + Abx P<.0001

13. Non-Intracranial Bleeding Through Discharge/Day 7 The GUSTO-V Investigators. Lancet. 2001;357:1905-1914. 0 % of Patients 15 25 30 20 r-PA r-PA + Abx 10 Severe Bleeding Moderate Bleeding Mild Bleeding Any Bleeding Receiving Transfusions 5 0.5 1.1 1.8 3.5 11.4 20.0 13.7 24.6 4.0 5.7

14. ICH by Age Group *Significant treatment interaction for the age 75 dichotomy; P=.033. The GUSTO-V Investigators. Lancet. 2001;357:1905-1914. 0 1 3 2 % of Patients  70 yrs > 70 yrs  75 yrs > 75 yrs 0.4 1.2 0.5 1.1 1.5 0.4 2.1 r-PA (n=8260) r-PA + Abx (n=8328) 0.3 P=.66 P=.53 P=.27* P=.069* 12/108824/114928/7179 37/7172 25/203031/2135 21/619324/6230

15. * * * * GUSTO-V: PCI Within 6 Hours (Urgent) and Through Day 7 *P<.0001. The GUSTO-V Investigators. Lancet. 2001;357:1905-1914. 5.6 25.4 27.9 8.6 0 15 25 30 20 10 PCI (%) Urgent Through Day 7 5 r-PAr-PA + Abx

16. 2.8 9.0 5.4 GUSTO-V: Event Rates in Those Requiring Urgent PCI Heartwire News. September 2, 2001. GUSTO-V: Combination half-dose fibrinolytic plus IIb/IIIa blocker. An Alternative approach to MI? 6.7 4.8 9.6 0 4 10 12 8 Myocardial Infarction (%) r-PA r-PA + Abx n=1173 DeathRepeat MIDeath Plus Repeat MI 2 6

17. GUSTO-V: Conclusions Compared with r-PA monotherapy, combination therapy with r-PA and abciximab resulted in –A mortality rate that was not inferior to r-PA monotherapy –Fewer nonfatal reinfarctions (primarily a reduced incidence of recurrent ST elevation) –A lower rate of urgent revascularization –More noncerebral bleeding complications, transfusions, and thrombocytopenia –A higher rate of ICH in elderly patients over the age of 75 years

18. ASSENT-3: Rationale for Use of Enoxaparin TNK-tPA plus enoxaparin –Favorable effects of LMWHs in recent small-scale thrombolysis trials –Higher late patency:HART-2 ASSENT-Plus AMI-SK –Less reocclusion:HART-2 –Fewer reinfarctions:ASSENT-Plus AMI-SK Wilson, et al. ASSENT-3 is the first large-scale trial to test LMWH

19. ASSENT-3: Study Design ST-Segment Elevation AMI (n=6095 patients) 150 to 325 mg ASA (daily) Randomized Full-dose TNK-tPA Plus Enoxaparin Half-dose TNK-tPA Plus Abciximab Plus Low-dose Heparin Full-dose TNK-tPA Plus Weight- adjusted UFH The ASSENT-3 Investigators. Lancet. 2001;358:605-613.

20. ASSENT-3: Primary End Points Primary Efficacy End Point: Composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia. Primary Efficacy Plus Safety End Point: Composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia plus in-hospital intracranial haemorrhage or in-hospital major bleeding other than intracranial.

21. ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia 0 5 10 15 20 % Risk of 30-Day D/MI/Ref Isch TNK-tPA + EnoxTNK-tPA + Abx TNK-tPA + UFH *P-values are the Bonferroni P-values after correcting for multiple comparisons. The uncorrected P-values were P=.0002 for the enox vs UFH comparison, and P<.0001 for the abx vs UFH comparison. 11.4 11.1 15.4 3-way P=.0001 P=.0002* P=.0009*

22. ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia, Major Bleeding and ICH % Risk of 30-Day D/MI/ Ref Isch/Maj Bleed/ICH *P-values are the Bonferroni P-values after correcting for multiple comparisons. The uncorrected P-values were P=.0037 for the enox vs UFH comparison, and P=.0142 for the abx vs UFH comparison. 0 5 10 15 20 TNK-tPA + EnoxTNK-tPA + Abx TNK-tPA + UFH 13.8 14.2 17.0 3-way P=.0062 P=.057* P=.0146*

23. Kaplan-Meier Curves UFH Abx* 51015202530 0 2 4 6 8 10 12 14 16 20 18 0 Enox* log-rank P=.0001 *vs UFH Days to death, reinfarction, or refractory ischemia Primary Efficacy End Point Probability (%) Reprinted with permission from the ASSENT-3 Investigators. Lancet. 2001;358:605-613. 51015202530 0 2 4 6 8 10 12 14 16 20 18 0 log-rank P=.0062 *vs UFH + Abx Days to death, reinfarction, refractory ischemia, ICH, or major bleeding Primary Efficacy Plus Safety End Point Probability (%) UFH Abx Enox*

24. ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients >75 Years of Age *There was a statistically significant interaction between treatment with abciximab and age such that patients over the age of 75 had poorer outcomes with abciximab (P=.001). % Risk of 30-Day Efficacy and Safety End Point 0 15 25 35 45 TNK-tPA + EnoxTNK-tPA + Abx TNK-tPA + UFH 25.5 36.9 28.0 P=.001* 5 20 30 40 10

25. ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients with Diabetes *There was a statistically significant interaction between treatment with abciximab and diabetes, such that diabetics had poorer outcomes with abciximab therapy (P=.0007). % Risk of 30-Day Efficacy and Safety End Point 0 15 25 30 TNK-tPA + EnoxTNK-tPA + Abx TNK-tPA + UFH 13.9 22.3 16.5 P=.0007* 5 20 10

26. ASSENT-3: 30-Day Mortality 0 4 8 10 TNK-tPA + EnoxTNK-tPA + Abx TNK-tPA + UFH 5.4 6.6 6.0 3-way P=.25 6 2 % Risk of 30-Day Mortality

27. ASSENT-3: 30-Day Death or MI % Risk of 30-Day Death or MI 0 4 8 10 TNK-tPA + EnoxTNK-tPA + Abx TNK-tPA + UFH 6.8 7.3 9.1 3-way P=.0198 6 2

28. ASSENT-3: In-Hospital Recurrent MI % Risk of In-Hospital Recurrent MI 0 2 4 5 TNK-tPA + EnoxTNK-tPA + Abx TNK-tPA + UFH 2.7 2.2 4.2 3-way P=.0009 3 1

29. ASSENT-3: In-Hospital Refractory Ischemia % Risk of 30-Day Refractory Ischemia 0 4 8 10 TNK-tPA + EnoxTNK-tPA + Abx TNK-tPA + UFH 4.6 3.2 6.5 3-way P<.0001 6 2

30. ASSENT-3: Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Complications *While 3-way P-value is significant, Enox vs UFH comparison P=NS EnoxAbxUFHP-Value (n=2040) (n=2017)(n=2038)3-way Any thrombocytopenia1.23.21.3<.0001 Thrombocytopenia<.0001 <20,000 cells/µL0.10.50.2 20,000 to 50,000 cells/µL0.20.60.2 50,000 to 100,000 cells/µL0.92.01.0 Bleeding episodes Total25.6*39.721.1<.0001 Major3.0*4.32.2.0005 Minor22.6*35.418.8<.0001 Blood transfusion3.4*4.22.3.0032

31. ASSENT-3: In-Hospital Stroke Rates *Including hemorrhagic conversion Unclassified Hemorrhagic conversion Ischemic stroke* Intracranial hemorrhage Total strokes 0.15 0.07 0.400.64 0.940.88 1.491.62 Abx (n=2017) Enox (n=2040) 0.590.05 0.770.00 0.570.54 0.980.93 0.941.52 P-Value UFH (n=2038)

32. Patients Undergoing PCI: Mortality ASSENT-3: In-Hospital PCI GUSTO-V: Urgent PCI 0 5 7 8 6 3 Mortality (%) 4 2 1 2.5 3.7 2.7 5.4 6.7 TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH r-PA + UFH r-PA + Abx

33. How Does Actual Weight Compare to Estimated Weight? Reprinted with permission from Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A. Correlation Between Estimated and Actual Patient Weight in TIMI 10B 40.5 36.4 188.5 Actual Patient Weight (kg) Estimated Patient Weight (kg) R 2 =0.93, P<.0001 181

34. Weight-Based Dosing of Thrombolysis: How Well Do We Estimate Weight? How Often Would This Translate Into Errors With Administration of Thrombolytic Drugs and Adverse Outcomes? 1.Errors in estimating weight are uncommon, especially those that would lead to a dose change (1.3% or 49/3730 for TNK-tPA and 4.5% or 13/290 for t-PA). 2.No adverse outcomes were seen among patients who received an incorrect dose, suggesting a broad safety profile for the new single-bolus agent TNK-tPA. Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.

35. ASSENT-3: Study Group Conclusions Regarding TNK-tPA + Abciximab Therapy “The results obtained with half-dose tenecteplase plus abciximab are very similar to those with half-dose reteplase and abciximab seen in GUSTO-V.” “In both trials, these benefits are obtained at the cost of a higher rate of major bleeding complications and blood transfusions.” “No benefit and perhaps even harm was observed in patients above 75 years and in diabetics.” “Taken together they suggest that caution should be exercised regarding the use of conjunctive therapy with abciximab in elderly patients with an acute myocardial infarction treated with a fibrinolytic agent.” The ASSENT-3 Investigators. Lancet. 2001;358:605-613.

36. ASSENT-3: Study Group Conclusions Regarding Enoxaparin “In view of the present data and the ease of administration, enoxaparin might be considered an attractive alternative anticoagulant treatment when given in combination with tenecteplase.” The ASSENT-3 Investigators. Lancet. 2001;358:605-613.

37. ENTIRE TIMI-23: Study Design ST  MI <6h (n=461) UFH 60 U/kg bolus 12 U/kg/h infusion  36 h ENOX varying doses +/- IV bolus Index Hosp (  8 d) ASA  ENOX varying doses +/- IV bolus Index Hosp (  8 d) Combination Reperfusion: Half-dose TNK-tPA + Abx (0.27 mg/kg) Combination Reperfusion: Half-dose TNK-tPA + Abx (0.27 mg/kg) Standard Reperfusion: Full-dose TNK-tPA (0.53 mg/kg) Standard Reperfusion: Full-dose TNK-tPA (0.53 mg/kg) Antman E, et al. Eur Heart J. 2001;22:15. Abstract 145.  UFH 40 U/kg bolus 7 U/kg/h infusion  36 h

38. Outstanding Issues Should enoxaparin replace UFH as the optimal antithrombin agent for AMI? Will similar improvements in efficacy and safety occur if enoxaparin is combined with a less fibrin-specific agent such as r-PA? Will physicians accept the use of enoxaparin in selected patients with ST-elevation MI who may require rescue PCI? Will trials of TNK-tPA plus the small molecule GP IIb/IIIa receptor inhibitors produce results similar to ASSENT-3? What is the optimal strategy for facilitated PCI?

39. Future Trials: Potential Downstream Targets Large embolii: Filters Small embolii (thrombii): Filters & GP IIb/IIIa inhibitors, p-selectin inhibitors Vasoconstrictor release: GP IIb/IIIa inhibitors Spasm: Adenosine, Ca channel blockers, alpha blockers, avoid over sizing with PCI, high pressure inflations, serotonin inhibitors, endothelin inhibitors Endothelial & Myocardial swelling: Myocardial cooling, Ca channel blockers, DHEA, Na / H pump inhibitors, anti-inflammatory approaches