1. Time Is Myocardium and the Wavefront of Necrosis CM Gibson 2002

2. The DANAMI-2 Trial Danish Trial in Acute Myocardial Infarction-2 Presented at the American College of Cardiology 51st Annual Scientific Session Atlanta, GA Dr. Henning Rud Andersen for the DANAMI-2 investigators Danish Trial in Acute Myocardial Infarction-2 Presented at the American College of Cardiology 51st Annual Scientific Session Atlanta, GA Dr. Henning Rud Andersen for the DANAMI-2 investigators

3. High-risk ST elevation MI patients (>4 mm elevation), Sx < 12 hrs 5 PCI centers (n=443) and 22 referring hospitals (n=1,129), transfer in < 3 hrs High-risk ST elevation MI patients (>4 mm elevation), Sx < 12 hrs 5 PCI centers (n=443) and 22 referring hospitals (n=1,129), transfer in < 3 hrs Lytic therapy Front-loaded tPA 100 mg (n=782) Lytic therapy Front-loaded tPA 100 mg (n=782) Death / MI / Stroke at 30 Days DANAMI-2: Study Design Primary PCI with transfer (n=567) Primary PCI with transfer (n=567) Primary PCI without transfer (n=223) Primary PCI without transfer (n=223) Stopped early by safety and efficacy committee

4. DANAMI-2: Centers

5. Death / MI / Stroke (%) Lytic Primary PCI P=0.0003 P=0.002 Combined Transfer Sites P=0.048 Non-Transfer Sites DANAMI-2: Primary Results RRR 45% Lytic Primary PCI Lytic Primary PCI RRR 40% RRR 45%

6. P=0.033 P=NS GUSTO-IIb Angioplasty Substudy Investigators. N Engl J Med. 1997;336:1621-1628. Trials Comparing Primary PTCA With Fibrinolytic Therapy: GUSTO-IIb Cohort Composite Outcome (%)

7. Lytic Primary PCI P=0.35 Death DANAMI-2: Results Lytic Primary PCI P=0.15 Stroke Lytic Primary PCI P<0.0001 Recurrent MI

8. DANAMI-2: Commentary on Low Rate of Rescue/Adjunctive PCI The benefit in the primary composite endpoint result is driven predominantly by a lower rate of recurrent MI among patients treated with fibrinolysis compared with primary PCI Rescue PTCA for failed fibrinolysis was carried out infrequently in DANAMI 2, in only 2.5% of cases. The trial confirms what has been observed in the past: fibrinolytic monotherapy when administered with unfractionated heparin is associated with a significant rate of recurrent myocardial infarction if not accompanied by either rescue, facilitated or delayed PCI. It could be speculated that the incidence of recurrent MI may be reduced with a more aggressive strategy of performing rescue or adjunctive PCI soon after fibrinolytic administration. The benefit in the primary composite endpoint result is driven predominantly by a lower rate of recurrent MI among patients treated with fibrinolysis compared with primary PCI Rescue PTCA for failed fibrinolysis was carried out infrequently in DANAMI 2, in only 2.5% of cases. The trial confirms what has been observed in the past: fibrinolytic monotherapy when administered with unfractionated heparin is associated with a significant rate of recurrent myocardial infarction if not accompanied by either rescue, facilitated or delayed PCI. It could be speculated that the incidence of recurrent MI may be reduced with a more aggressive strategy of performing rescue or adjunctive PCI soon after fibrinolytic administration. Gibson CM, 2002

9. DANAMI-2: Commentary on Biases Inherent in the Assessment of the Recurrent MI Endpoint Among patients treated with fibrinolysis: Recurrent MI may be secondary to reocclusion of a patent infarct vessel following thrombolysis or may occur following delayed PCI after thrombolytic administration Among patients treated with fibrinolysis: Recurrent MI may be secondary to reocclusion of a patent infarct vessel following thrombolysis or may occur following delayed PCI after thrombolytic administration Gibson CM, 2002 Among patients treated with primary PCI: Recurrent MI may be secondary to stent thrombosis or late vessel occlusion several days following the procedure Because of the inability to detect recurrent MI during the index primary PCI (unlike during the performance of a later delayed PCI), this limits the number of post PCI CK MIs detected in this strategy Among patients treated with primary PCI: Recurrent MI may be secondary to stent thrombosis or late vessel occlusion several days following the procedure Because of the inability to detect recurrent MI during the index primary PCI (unlike during the performance of a later delayed PCI), this limits the number of post PCI CK MIs detected in this strategy

10. DANAMI-2: Commentary on Low Rate of Rescue/Adjunctive PCI Thus, the detection of post PCI CK elevations may be limited to only those patients enrolled in the fibrinolytic arm of the study Determination of the timing of the recurrent MI is critical: did the recurrent MI occur before or after the PCI Lower rates of GP 2b3a inhibitor use may be associated with higher rates of post PCI CK elevations, and it is critical to understand the proportion of patients treated with adjunctive GP 2b3a inhibition during elective or late PCI Thus, the detection of post PCI CK elevations may be limited to only those patients enrolled in the fibrinolytic arm of the study Determination of the timing of the recurrent MI is critical: did the recurrent MI occur before or after the PCI Lower rates of GP 2b3a inhibitor use may be associated with higher rates of post PCI CK elevations, and it is critical to understand the proportion of patients treated with adjunctive GP 2b3a inhibition during elective or late PCI Gibson CM, 2002

11. Thrombus Remains Following Thrombolysis Van Belle et al. Circulation. 1998;97:26-33.

12. Clinical Impact of Reocclusion: Data from the TAMI trials: 810 patients, cath 90 min & 7 days later: 810 patients, cath 90 min & 7 days later: 12.4% reocclude 12.4% reocclude 58% symptomatic 58% symptomatic In-hospital mortality 11.0% vs 4.5% (P=0.01). In-hospital mortality 11.0% vs 4.5% (P=0.01). Ohman et al. Circulation. 1990;82:781-791.

13. Recent Efforts to Reduce Reocclusion / Reinfarction In order to reduce the risk of reocclusion, several strategies have been employed in recent thrombolytic trials –Mechanical Adjunctive / Rescue / and delayed PCI –Pharmacologic GP 2b3a inhibition Treatment with the antithrombotic agent enoxaparin In order to reduce the risk of reocclusion, several strategies have been employed in recent thrombolytic trials –Mechanical Adjunctive / Rescue / and delayed PCI –Pharmacologic GP 2b3a inhibition Treatment with the antithrombotic agent enoxaparin CM Gibson 2002

14. 2 Year Survival Following Rescue PCI Survival was Improved in patients with 90 minute TIMI Grade 0/1 Flow after TNK who underwent rescue PCI in the TIMI 10B trial CM Gibson, AHA 2001 Survival Years No PCI Log rank p=0.006 Rescue PCI

15. DANAMI 2: Commentary on Low Rate of Rescue / Adjunctive PCI Use In recent large scale thrombolytic trials in which rescue / adjunctive PCI has been performed more aggressively, lower rates of recurrent MI have been observed In the setting of ST segment elevation MI treated with thrombolytic monotherapy, the administration of enoxaparin has been associated with a reduced rate of reinfarction when compared to unfractionated heparin. Would the use of Rescue / Adjunctive PCI and enoxaparin have been associated with a lower rate of reinfarction in the DANAMI 2 study? In recent large scale thrombolytic trials in which rescue / adjunctive PCI has been performed more aggressively, lower rates of recurrent MI have been observed In the setting of ST segment elevation MI treated with thrombolytic monotherapy, the administration of enoxaparin has been associated with a reduced rate of reinfarction when compared to unfractionated heparin. Would the use of Rescue / Adjunctive PCI and enoxaparin have been associated with a lower rate of reinfarction in the DANAMI 2 study? Gibson CM, 2002

16. Rate of Rescue / Adjunctive PCI Use in DANAMI 2 Compared with Other Recent Trials % Recurrent MI 11.9% 9.1% 14.4% 17.4% 19.4% 16.5% 8.6% 5.6% rPA + Hep rPA + Abx TNK + Enox TNK + Abx 44.4%* TNK + Hep TNK + Enox 2.5% tPA + Hep Urgent PCI Non-Urgent PCI Non-Urgent PCI * Urgent & non-urgent combined CM Gibson 2002

17. ENTIRE TIMI 23: 30 Day Death/MI ENTIRE TIMI 23: 30 Day Death/MI N = 82160 77 164 % Pts FULL Dose TNK HALF Dose TNK + Abx P=0.003 Death MI 15.9 4.4 6.5 5.5 P=0.005 11.3 4.9 P=0.01 P=0.002 159 324

18. ENTIRE TIMI 23: Recurrent MI In Patients NOT Undergoing PCI (N=259) % Pts 41 FULL Dose TNK HALF Dose TNK + Abx 103 38 77 N= 79 180

19. DANAMI-2 Commentary on Door to Balloon Times In DANAMI 2, door-to-balloon times were approximately 114 minutes for those patients transferred to another facility Based upon the data presented by Cannon et al, a door- to-balloon time of 114 minutes was not associated with a significant increase in mortality in the NRMI 2 database when compared to a door-to-balloon time of < one hour If transfer for primary PCI is elected, then door to balloon times should be similar to those observed in DANAMI 2 In NRMI 4, the current median door to balloon time among patients transferred to another facility in the US for primary PCI is much longer at 198 minutes In DANAMI 2, door-to-balloon times were approximately 114 minutes for those patients transferred to another facility Based upon the data presented by Cannon et al, a door- to-balloon time of 114 minutes was not associated with a significant increase in mortality in the NRMI 2 database when compared to a door-to-balloon time of < one hour If transfer for primary PCI is elected, then door to balloon times should be similar to those observed in DANAMI 2 In NRMI 4, the current median door to balloon time among patients transferred to another facility in the US for primary PCI is much longer at 198 minutes Gibson CM, 2002

20. Community Hospital Thrombolysis (n=782) Community Hospital Thrombolysis (n=782) PCI, non-transported patients (n=223) PCI, non-transported patients (n=223) PCI, transported patients (n=567) PCI, transported patients (n=567) DANAMI 2: Door to Balloon Times

21. Cannon CP et al, JAMA 2000

22. N=27,080 P < 0.00001 N=27,080 P < 0.00001 NRMI-2: Primary PCI Door-to-Balloon time vs. Mortality Door-to-Balloon Time (minutes)

23. Door to Balloon Times Among Patients Transferred in NRMI 4 NRMI 4 Transfer-In Annual Data Report 2002 Door to Data: 50 th : 8 Min. 25 th : 4 Min. 75 th : 16 Min. Door to Data: 50 th : 8 Min. 25 th : 4 Min. 75 th : 16 Min. Data to Cath Lab Arrival: 50 th : 137 Min. 25 th : 87 Min. 75 th : 220 Min. Data to Cath Lab Arrival: 50 th : 137 Min. 25 th : 87 Min. 75 th : 220 Min. Cath Lab to Balloon: 50 th : 39 Min. 25 th : 29 Min 75 th : 53 Min. Cath Lab to Balloon: 50 th : 39 Min. 25 th : 29 Min 75 th : 53 Min. 8 8 137 39 Total Door to Balloon Time: 198 minutes (25 th : 137; 75 th : 281) Percent of Patients with Door to Balloon Time < 90 Min.: 4.8% Total Door to Balloon Time: 198 minutes (25 th : 137; 75 th : 281) Percent of Patients with Door to Balloon Time < 90 Min.: 4.8% Sample Size: 1,292; Time Period: October 2000 – September 2001 Gibson CM, 2002

24. Importance of Operator Experience and Volume in Primary PCI Outcomes A significant proportion of the DANAMI operators had little prior experience with primary PCI. Is operator and hospital volume associated with PCI outcomes in larger series? A significant proportion of the DANAMI operators had little prior experience with primary PCI. Is operator and hospital volume associated with PCI outcomes in larger series? Gibson CM, 2002

25. NRMI 2-3: Primary PCI vs. Thrombolysis: 1996-2000 N=62,000 Patients Volume% HospTlysisPrim PCIP value < 16 /yr25%5.96.2NS 17-48/yr50%5.94.5<0.001 >48/yr25%5.43.4<0.001 Non-fatal stroke1.10.4<0.001 Volume% HospTlysisPrim PCIP value < 16 /yr25%5.96.2NS 17-48/yr50%5.94.5<0.001 >48/yr25%5.43.4<0.001 Non-fatal stroke1.10.4<0.001 In-hospital Mortality Magid et al. JAMA 2000

26. N=27,080 P < 0.00001 N=27,080 P < 0.00001 NRMI-2: Primary PCI Institutional Volume vs. Mortality NRMI-2: Primary PCI Institutional Volume vs. Mortality Institutional Monthly Volume of Primary Angioplasty Cases

27. Door-to-Balloon Time (minutes) <1 / month N=4,740 P = 0.0008 <1 / month N=4,740 P = 0.0008 1-3 / month N=14,078 P < 0.0001 1-3 / month N=14,078 P < 0.0001 >3 / month N=14,078 P < 0.0001 >3 / month N=14,078 P < 0.0001 Primary PCI: Door-to-Balloon time vs. Mortality Stratified by Institutional Volume

28. Hospital Volume of Primary PTCA vs. Mortality 0.87 0.72 0.83 P value for trend < 0.001 Canto. NEJM 2000 N: Pt = 2,825 5,245 9,303 19,162 Hosp =113 112 113 112

29. Randomized Trial Results Versus Community-Setting Results: NRMI-2 Cohort Tiefenbrunn AJ, et al. J Am Coll Cardiol. 1998;31:1240-1245. P=NS Percent n=2,958, lytic eligible, no shock at presentation

30. Time After Discharge (years) Every NR, et al. N Engl J Med. 1996;335:1253-1260. P=0.80 Trials Comparing Primary PTCA With Fibrinolytic Therapy: MITI Cohort Thrombolytic therapy Primary angioplasty

31. DANAMI-2 Commentary: Facilitated PCI Not Evaluated This trial tested the efficacy of thrombolytic therapy with very little use of rescue/adjunctive PCI (2.5%) versus “primary PCI” without significant pharmacologic therapy before the PCI The trial provides no data regarding the efficacy of “facilitated PCI” in which a thrombolytic agent or GP 2b3a inhibitor would be administered prior to rescue or adjunctive PCI. The concept of “facilitated PCI” will be tested in upcoming trials. This trial tested the efficacy of thrombolytic therapy with very little use of rescue/adjunctive PCI (2.5%) versus “primary PCI” without significant pharmacologic therapy before the PCI The trial provides no data regarding the efficacy of “facilitated PCI” in which a thrombolytic agent or GP 2b3a inhibitor would be administered prior to rescue or adjunctive PCI. The concept of “facilitated PCI” will be tested in upcoming trials. Gibson CM, 2002

32. Time (minutes) Relative Speed and Magnitude of Patency  ED arrival  ED arrival  Drug administration  Drug administration Adapted from Gibson CM. Am Interm Med. 1999;130:841-847. Lytic + 2b3a: 94% by 60 min. Lytic 2 hour Door to Balloon 2 hour Door to Balloon  Pre Hospital Drug administration  Pre Hospital Drug administration Pre Hospital Lytic + 2b3a Pre Hospital Lytic + 2b3a

33. Placebo tPA Adapted from Ross AM, et al. J Am Coll Cardiol. 1999;34:1954-1962. PACT % TIMI 2/3 flow pre PCI PRAGUE* Placebo SK Fibrinolytic Therapy Pre-PCI * Patients transferred for PCI Adapted from Widimsky P, et al. J Eur Heart J. 2000;21:823-831.

34. Adapted from Ross AM, et al. J Am Coll Cardiol. 1999;34:1954-1962. % Convalescent LVEF Convalescent LV Function by Patency Group: Global Ejection Fraction P=0.004

35. Relationship of TIMI 3 Flow Before PCI to 6 Month Survival Stone et al. Circ 2001; 104: 636-641

36. Preliminary Designs of Upcoming Facilitated PCI Trials ASSENT 4 TNK Heparin / ASA ADVANCE TNK + Integrilin Integrilin TIGERTNK TITAN Integrilin in ER Integrilin in Cath Lab FINESSErPA rPA + abciximab in ER vs CCL CM Gibson 2002

37. DANAMI 2 Conclusions Among patients transferred for primary PCI with a median door to balloon time of 114 minutes, the incidence of the composite endpoint of death, recurrent MI, and stroke is reduced compared with the administration of tPA and heparin when used in conjunction with a rescue / adjunctive PCI rate of 2.5%. CM Gibson 2002

38. DANAMI 2 Conclusions The median US door to balloon time for transfer patients is 198 minutes, and is not as rapid as in DANAMI 2 (114 minutes) The composite endpoint was driven primarily by a lower rate of recurrent MI among PCI patients Current strategies that employ higher rates of rescue and adjunctive PCI after fibrinolysis and higher rates of enoxaparin use have been associated with lower rates of recurrent MI than that reported in DANAMI 2 The median US door to balloon time for transfer patients is 198 minutes, and is not as rapid as in DANAMI 2 (114 minutes) The composite endpoint was driven primarily by a lower rate of recurrent MI among PCI patients Current strategies that employ higher rates of rescue and adjunctive PCI after fibrinolysis and higher rates of enoxaparin use have been associated with lower rates of recurrent MI than that reported in DANAMI 2 CM Gibson 2002

39. DANAMI 2 Conclusions As an endpoint, recurrent MI may more often be detected among patients treated with fibrinolysis who undergo delayed or late PCI because post PCI CK release may not be detected during primary PCI DANAMI 2 trial was performed in a dedicated network of centers. Larger hospital / and operator volumes are associated with improved outcomes and the ability to implement this strategy in smaller volume hospital systems with less experienced operators is not yet tested To this end, US community hospital registry experience suggests no benefit of primary PCI over fibrinolysis As an endpoint, recurrent MI may more often be detected among patients treated with fibrinolysis who undergo delayed or late PCI because post PCI CK release may not be detected during primary PCI DANAMI 2 trial was performed in a dedicated network of centers. Larger hospital / and operator volumes are associated with improved outcomes and the ability to implement this strategy in smaller volume hospital systems with less experienced operators is not yet tested To this end, US community hospital registry experience suggests no benefit of primary PCI over fibrinolysis CM Gibson 2002

40. DANAMI 2 Conclusions DANAMI 2 did not assess the effectiveness of “facilitated PCI” in which pharmacologic and mechanical strategies are combined. Upcoming trials will test the effectiveness of “facilitated PCI” DANAMI 2 did not assess the effectiveness of “facilitated PCI” in which pharmacologic and mechanical strategies are combined. Upcoming trials will test the effectiveness of “facilitated PCI” CM Gibson 2002