1. The Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction (ASSENT-4 PCI) Trial ASSENT- 4 PCI Trial Presented at The European Society of Cardiology Hot Line Session 2005 Presented by Dr. Frans Van de Werf

2. www. Clinical trial results.org Full-dose TNK + Primary PCI 60 IU/kg, maximum 4000 IU n=829 GP IIb/IIIa inhibitors allowed only for bail out use Full-dose TNK + Primary PCI 60 IU/kg, maximum 4000 IU n=829 GP IIb/IIIa inhibitors allowed only for bail out use ASSENT- 4 PCI Trial 1667 patients age > 18 years with ST elevation myocardial infarction (summed ST deviation > 6 mm); time from symptom onset within 6 hrs; intent to perform primary PCI Randomized Mean follow-up: 6 mos (30 days reported to date) 63% of patients received clopidogrel/ticlopidine during PCI Additional UFH was given to 67.4% in the TNK + PCI group and 70.1% in the PCI alone group 1667 patients age > 18 years with ST elevation myocardial infarction (summed ST deviation > 6 mm); time from symptom onset within 6 hrs; intent to perform primary PCI Randomized Mean follow-up: 6 mos (30 days reported to date) 63% of patients received clopidogrel/ticlopidine during PCI Additional UFH was given to 67.4% in the TNK + PCI group and 70.1% in the PCI alone group Presented at ESC 2005 Primary PCI 70 IU/kg, no maximum dose n=838 GP IIb/IIIa inhibitors allowed at physician discretion Primary PCI 70 IU/kg, no maximum dose n=838 GP IIb/IIIa inhibitors allowed at physician discretion  Primary Endpoint: Composite of death, shock, or congestive heart failure at 90 days.  Secondary Endpoint: Composite of death, shock, or congestive heart failure at 30 days; shock or CHF at 90 days; single components of the composite endpoint.  Primary Endpoint: Composite of death, shock, or congestive heart failure at 90 days.  Secondary Endpoint: Composite of death, shock, or congestive heart failure at 30 days; shock or CHF at 90 days; single components of the composite endpoint.

3. www. Clinical trial results.org ASSENT- 4 PCI Trial: PCI Patients undergoing PCI among two treatment groups (%) p=0.01 Patients undergoing PCI with stent (%) Presented at ESC 2005 p=0.02 p=0.97 PCI was performed at a median of 104 minutes following TNK bolus administration PCI was performed at a median of 104 minutes following TNK bolus administration Median time from symptom onset to randomization was 140 minutes in the combined therapy group and 135 minutes in the PCI alone group Median time from symptom onset to randomization was 140 minutes in the combined therapy group and 135 minutes in the PCI alone group 19% of patients were randomized in the ambulance 19% of patients were randomized in the ambulance

4. www. Clinical trial results.org GP IIb/IIIa inhibitor administration prior to and during PCI (%) p<0.001 GP IIb/IIIa inhibitors were given more often prior to PCI in the PCI alone treatment groupGP IIb/IIIa inhibitors were given more often prior to PCI in the PCI alone treatment group GP IIb/IIIa inhibitors were given more often during PCI in the PCI alone treatment groupGP IIb/IIIa inhibitors were given more often during PCI in the PCI alone treatment group ASSENT- 4 PCI Trial: GP IIb/IIIa Inhibitors

5. www. Clinical trial results.org Presented at ESC 2005 ASSENT- 4 PCI Trial: TIMI Flow Grade TIMI grade 3 flow prior to PCI and TIMI grade 2/3 flow post-PCI (%) p<0.001 TIMI grade 3 flow prior to PCI was present more frequently in the TNK + PCI arm (43.6% vs 15.0%)TIMI grade 3 flow prior to PCI was present more frequently in the TNK + PCI arm (43.6% vs 15.0%) TIMI grade 2/3 post-PCI was slightly higher in the PCI alone group (95.3% vs 97.6%)TIMI grade 2/3 post-PCI was slightly higher in the PCI alone group (95.3% vs 97.6%) p=0.03

6. www. Clinical trial results.org Presented at ESC 2005 ASSENT- 4 PCI Trial: Abrupt Closure, Re-infarction, and Repeat TVR Analysis of in-hospital abrupt closure, re- infarction, and repeat TVR (%) p<0.001 In-hospital abrupt closure occurred more often in the TNK + PCI treatment group (1.9% vs 0.1%) In-hospital abrupt closure occurred more often in the TNK + PCI treatment group (1.9% vs 0.1%) Re-infarction occurred more often in the TNK + PCI treatment group (4.1% vs 1.9%) Re-infarction occurred more often in the TNK + PCI treatment group (4.1% vs 1.9%) Repeat TVR occurred more often in the TNK + PCR treatment group (4.4% vs 1.0%)Repeat TVR occurred more often in the TNK + PCR treatment group (4.4% vs 1.0%) p<0.001 p=0.01

7. www. Clinical trial results.org Presented at ESC 2005 ASSENT- 4 PCI Trial: Pericarditis, Tamponade, and Cardiac Rupture Analysis of in-hospital pericarditis, tamponade, and cardiac rupture (%) p=0.07 Pericarditis occurred more often in the TNK + PCI treatment group (0.7% vs 0.1%) Pericarditis occurred more often in the TNK + PCI treatment group (0.7% vs 0.1%) Presence of tamponade did not differ significantly between the two treatment groups Presence of tamponade did not differ significantly between the two treatment groups Cardiac rupture occurred more often in the TNK + PCR treatment group (0.9% vs 0.2%)Cardiac rupture occurred more often in the TNK + PCR treatment group (0.9% vs 0.2%) p=0.11 p=0.50

8. www. Clinical trial results.org Presented at ESC 2005 ASSENT- 4 PCI Trial: EM Dissociation, Pulmonary Edema, and VF Analysis of in-hospital EM dissociation, pulmonary edema, and VF (%) p=0.20 Presence of EM dissociation did not differ significantly between the two treatment groups Presence of EM dissociation did not differ significantly between the two treatment groups Presence of pulmonary edema did not differ significantly between the two treatment groups Presence of pulmonary edema did not differ significantly between the two treatment groups VF occurred more often in the TNK + PCR treatment group (5.6% vs 3.7%)VF occurred more often in the TNK + PCR treatment group (5.6% vs 3.7%) p=0.08 p=0.78

9. www. Clinical trial results.org ASSENT- 4 PCI Trial: Mortality at 30 days The primary endpoint of mortality was higher in the TNK + PCI treatment group compared with the PCI alone group (6.0% vs 3.8%, p=0.04) at 30 days Analysis of mortality at 30 days (%) p = 0.04 Presented at ESC 2005 n=50n=32

10. www. Clinical trial results.org ASSENT- 4 PCI Trial: Mortality Subgroup Analysis The greatest mortality difference by treatment group was seen in hospitals with on- site PCI (7.3% vs 3.8%), with less difference in community hospitals (6.0% vs 4.0%), and a shift in direction for patients enrolled in the ambulance (3.1% vs 3.7%) Subgroup analysis of mortality based on site of randomization (%) Presented at ESC 2005 n=754 n=588n=325

11. www. Clinical trial results.org ASSENT- 4 PCI Trial: Total Stroke and ICH at 30 days Total stroke occurred more often in the TNK + PCI group (1.81% vs 0%), as did ICH (0.97% vs 0%) at 30 days Analysis of total stroke and ICH at 30 days (%) Presented at ESC 2005 p<0.001 p=0.004

12. www. Clinical trial results.org ASSENT- 4 PCI Trial: Ischemic Stroke, Haemorrhagic Conversion, and Unclassified Stroke Rates at 30 days Ischemic stroke occurred more often in the TNK + PCI group (0.60% vs 0%), as did haemorrhagic conversion (0.12% vs 0%) at 30 days Analysis of ischemic stroke, haemorrhagic conversion, and unclassified stroke rates at 30 days (%) Presented at ESC 2005 p=0.03 p=0.50 p=0.25

13. www. Clinical trial results.org ASSENT- 4 PCI Trial: Bleeding Events at 30 days No difference in the frequency of major bleed existed between the two treatment groups (5.7% vs 4.4%) at 30 days The presence of any bleeding event (major + minor bleeding) was more common in the TNK+ PCI treatment group (31.3% vs 23.4%) at 30 days (p<0.001) Analysis of bleeding events at 30 days (%) Presented at ESC 2005 p=0.26 p<0.001

14. www. Clinical trial results.org ASSENT- 4 PCI Trial: Transfusions at 30 days The percentage of transfusions administered was greater in the TNK + PCI treatment group 93.8% received no transfusion in the TNK + PCI treatment group; 95.8% received no transfusion in the PCI alone treatment group (p=0.21) Analysis of transfusions at 30 days (%) Presented at ESC 2005

15. www. Clinical trial results.org ASSENT- 4 PCI Trial: Comparison with Previous ASSENT Trials (TNK in MI patients) Outcomes in the TNK + PCI treatment group did not differ from previous ASSENT trials Outcomes in the PCI alone treatment group showed a significant decrease in percentage of deaths at 30 days Analysis of 30-day death among other ASSENT trials (%) Presented at ESC 2005

16. www. Clinical trial results.org ASSENT- 4 PCI Trial: Comparison with Previous ASSENT Trials (TNK in MI patients) Outcomes in the TNK + PCI treatment group did not differ from previous ASSENT trials Outcomes in the PCI alone treatment group showed a significant decrease in percentage of ICH cases Analysis of ICH across all ASSENT trials (%) Presented at ESC 2005

17. www. Clinical trial results.org ASSENT- 4 PCI Trial: Comparison with Previous ASSENT Trials (TNK in MI patients) Outcomes in the TNK + PCI treatment group did not differ significantly from previous ASSENT trials Outcomes in the PCI alone treatment group showed a significant decrease in percentage of total stroke Analysis of total stroke across all ASSENT trials (%) Presented at ESC 2005

18. www. Clinical trial results.org ASSENT- 4 PCI Trial: Comparison with Previous ASSENT Trials (TNK in MI patients) Outcomes in the TNK + PCI treatment group did not differ significantly from previous ASSENT trials Outcomes in the PCI alone treatment group showed a significant decrease in percentage of re-infarction cases Analysis of re-infarction among other ASSENT trials (%) Presented at ESC 2005

19. www. Clinical trial results.org ASSENT- 4 PCI Trial: Comparison with Previous ASSENT Trials (TNK in MI patients) Outcomes in the TNK + PCI treatment group differed significantly from the ASSENT-3 and ASSENT 3+ Trials results Outcomes in the PCI alone treatment group did not differ from the ASSENT-2 Trial, but were more significant in comparison to the ASSENT-3 and ASSENT 3+ Trials Analysis of major bleed among other ASSENT trials (%) Presented at ESC 2005

20. www. Clinical trial results.org ASSENT- 4 PCI Trial: Comparison with Those in Primary-PCI Overview Outcomes in the TNK + PCI treatment group did not differ significantly compared with the primary-PCI overview Outcomes in the PCI alone treatment group were significantly lower than those in the primary-PCI overview Analysis of 30-day death among ASSENT-4 and those in the primary-PCI overview (%) Presented at ESC 2005

21. www. Clinical trial results.org ASSENT- 4 PCI Trial: Comparison with Those in Primary-PCI Overview Outcomes in the TNK + PCI treatment group were significantly higher compared with the primary-PCI overview Outcomes in the PCI alone treatment group did not differ from the primary-PCI overview Analysis of ICH among ASSENT-4 and those in the primary-PCI overview (%) Presented at ESC 2005

22. www. Clinical trial results.org ASSENT- 4 PCI Trial: Comparison with Those in Primary-PCI Overview Outcomes in the TNK + PCI treatment group were higher compared with the primary-PCI overview Outcomes in the PCI alone treatment group were significantly lower compared with the primary-PCI overview Analysis of total stroke among ASSENT-4 and those in the primary-PCI overview (%) Presented at ESC 2005

23. www. Clinical trial results.org ASSENT- 4 PCI Trial: Comparison with Those in Primary-PCI Overview Outcomes in the TNK + PCI treatment group were higher compared with the primary-PCI overview Outcomes in the PCI alone treatment group did not differ with the primary-PCI overview Analysis of re-infarction among ASSENT-4 and those in the primary-PCI overview (%) Presented at ESC 2005

24. www. Clinical trial results.org ASSENT- 4 PCI Trial: Comparison with Those in Primary-PCI Overview Outcomes in the TNK + PCI treatment group were lower compared with the primary-PCI overview Outcomes in the PCI alone treatment group were significantly lower compared with the primary-PCI overview Analysis of major bleed among ASSENT-4 and those in the primary-PCI overview (%) Presented at ESC 2005

25. www. Clinical trial results.org ASSENT- 4 PCI Trial: Summary The trial intended to enroll 4,000 patients, but was discontinued early after enrollment of 1,667 patients. Among patients with ST elevation MI intended for primary PCI, administration of full-dose fibrinolytic (TNK) immediately prior to PCI was associated with increased mortality and stroke at 30 days compared with primary PCI alone. Primary endpoint data are not yet available. Further evaluation of the clinical benefit of fibrinolytics among patients undergoing early PCI for STEMI appears warranted (FINESSE). The trial intended to enroll 4,000 patients, but was discontinued early after enrollment of 1,667 patients. Among patients with ST elevation MI intended for primary PCI, administration of full-dose fibrinolytic (TNK) immediately prior to PCI was associated with increased mortality and stroke at 30 days compared with primary PCI alone. Primary endpoint data are not yet available. Further evaluation of the clinical benefit of fibrinolytics among patients undergoing early PCI for STEMI appears warranted (FINESSE). Presented at ESC 2005