1. EXPERTS WORKSHOP ON EARLY TREATMENT STRATEGIES FOR ACUTE MYOCARDIAL INFARCTION FOR THE MIDDLE EAST COUNTRIES FEBRUARY 26 TH -28 TH 2005 / DUBAI, UAE SPONSORED BY BOEHRINGER INGELHEIM SUNDAY, 27 th FEBRUARY – SESSION 2 A rationale for pre-hospital thrombolytic therapy Patrick Goldstein

6. “ Time is Muscle” Cross-sections of left ventricle after experimental coronary artery occlusion (Reimer KA, et al. Circulation. 1977;56:786-794). Duration of occlusion 3 h Area supplied by occluded artery x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x XXXX Necrosis Ischemic but viable Non-ischemic 24 h 40 min

8. “ Time is muscle” MITI 4.9 11.2 14 12 10 8 6 4 2 0 Infarct Size (%) < 70 min 70-180 min

9. Estimated benefit (lives saved at 35 days) per 1000 patients Time from onset (hours) Mortality Reduction Depends on the Delay “Onset of Pain - Thrombolytic Treatment” Eric Boersma’s meta-analysis (22 trials from 83 to 93 - 50 246 patients) BOERSMA, E. et al Early thrombolytic in acute myocardial treatment infarction : reappraisal of the golden hour - Lancet 1996 ; 771 - 775 0 12 18 24 6 0 20 40 60 80 11% 30 to 50 lives saved for 1000 patients 1 to 3 hours 60 to 80 lives saved for 1000 patients 30 to 60 min 1- month benefit Delay

11. Delay pain – treatment French experience 1.60 1.59 2.10 2.10 2.35 3.03 3.03 2.50 3.03 2002 2001 1997 2001 2002 2001 2000 1995 1990 ESTIM Nord ESTIM IdF STIM SAMU CAPTIM A3+ A3 A2 G3 GI

13. ASSENT-3 Plus (Pre-hospital Treatment) Early treatment (ambulance-car) of AMI patients <6 hrs ASA RANDOMIZATION 1:1 TNK-tPA full dose 0.53 mg/kg bolus Unfractionated heparin 60 IU/kg bolus (max. 4000 IU) 12 IU/kg/hr infusion (max 1000 IU/ hr) target aPTT 50-70 sec Patients’ outcome will be compared with matched pairs extracted from the corresponding arm of the ASSENT-3 main study. The same exploratory endpoints (single and composite) as in the ASSENT-3 main study will be evaluated; the influence of time to treatment will be analyzed. (500) TNK-tPA full dose 0.53 mg/kg bolus Enoxaparin 30 mg i.v. bolus 1 mg/kg s.c. twice a day (500)

14. Hours to treatment (median) 3+ 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 ENOX UFH TNK TNK Symptom - call Call - arrival Arrival - Rand. Rand. - first drug First drug - ER ASSENT-3 In-hospital Symptom – TNK 45 min

15. Thrombolysis or PTCA still a debate ?

21. DANAMI-2 DENMARK 5.4 mill. inhabitants 5 PCI centers 24 referral hospitals 62% of Danish population Transport distance up to 95 US miles (mean 35 miles) 100 US miles

25. Preventing Reinfarction : IIb/IIIa Inhibitors, Enoxaparin, or Primary PCI PRAGUE-2 30-day deaths 6.8 v 10.0 % , p = 0.12 * 6-month data in press, Simes AHU 2002 ** Pre-hospital administration p < 0.05 reMI, death (PCAT only) ; stroke (PCAT only) CAPTIM 840 PCI t - PA** DANAMI - 2 1.572 PCI t - PA C - PORT* 451 PCI t - PA PCAT* 2.725 PCI lytic Death 4.6% 3.7% 6.6% 7.6% 6.2% 7.1% 6.2% 8.2% ReMI 1.7% 3.7% 1.6% 6.3% 5.3% 10.6% 4.8% 9.8% Stoke 0 1.0% 1.1% 2.0% 2.2% 4.0% 0.7% 1.9%

26. DANAMI-2 vs CAPTIM vs ASSENT-3 Mortality at 30 days % (TNK + ENOX) ESSAI TOTAL 6.6 4.8 7.6 3.8 5.4 5.8 0 2 4 6 8 DANAMI-2 CAPTIM ASSENT-3 ASSENT3+ PCI TT

27. CAPTIM 1-Year Results Pre-Hospital Lysis Primary PCI Death GW Symposium, AHA 2002 Death Pre-Hospital Lysis Primary PCI Sx < 2 hours Sx > 2 hours P=0.057 P=0.47 2.2% 5.7% 0% 5% 5.9% 3.7% 0% 10%

28. CAPTIM 1 Year Results Pre-Hospital Lysis Primary PCI P=0.032 Shock Randomization to DC GW Symposium, AHA 2002 P=0.0007 Shock Randomization to Adm Pre-Hospital Lysis Primary PCI Sx < 2 hours Sx < 2 hours 1.3% 5.3% 0% 5% 0.0% 3.6% 0%

29. All presented periods are median Beginning of pain 65 min Emergency call at SAMU 19 min PEC SMUR Beginning of thrombolysis 35 min 66 min Arrival at hospital 84 min Puncture According to ATLS: 32 min 120 min 185 min E-MUST Comparable periods

31. The Lille Experience 4h55 3h 3h 1h49 1h42 0 1 2 3 4 5 6 Thr. pre-hosp. Thr. pre-hosp. + angioplasty Thr. hosp. Thr. hosp.+ angioplasty Angioplasty

33. One-month Mortality in Patients with Reperfusion Therapy: USIC 2000 n = 428 370 108 47 % 41 % 12 % 7.9 7.8 4.6 0 1 2 3 4 5 6 7 8 9 Primary PTCA IV lysis Lysis + PTCA

34. USIC 2000: One-month Mortality in Patients with Reperfusion Therapy n = 370 108 428 41% 12% 47% 7.1 9.6 3.0 5.8 3.6 7.9 0 2 4 6 8 10 12 Hosp. lysis no PCI Pre-hosp. lysis no PCI Hosp. lysis + PCI Pre-hosp. lysis + PCI Primary PCI

35. Combined Strategy of reperfusion

36. The Combined Strategies of Reperfusion J.M. Julliard : A matched comparison of the combination of prehospital thrombolysis and stand bye rescue angioplasty with primary angioplasty. Am.J. Cardiol. 1999 ; 83 - 305-310. 170 patients in Paris city Pre-hospital Thrombolysis Angiography at 80 min TIMI 3 108 (64%) TIMI 2 12 (7%) TIMI 0 50 (29%) angioplasty TIMI 3 91% TIMI 2 7%

39. 131 patients Angiography 95 min after TT 64 (49%) TIMI 3 54 (84%) PTCA 65 (50%) TIMI 0 - 2 PTCA 119 (91%) PTCA 114 stent 120/131 TIMI 3 (92%) 9/131 TIMI 2 2 TIMI 0-1 no emergency surgery From C. Loubeyre

41. Early PCI versus Guided PCI after Lytics in the Modern Era Death Relative risk, fixed model Bilateral CI, 95% for trials, 95% for MA SIAM III 0.44 [0.14;1.37] GRACIA-1 0.57 [0.26;1.26] CAPITAL-AMI 0.67 [0.11;3.89] Total 0.54 [0.29;0.99] 0.047 Cochran Q het. p=0.91 Rel. Risk 0 1 2 3 4 0.538, p=0.047 RR CI p

42. Rescue PCI after Lytics RESCUE 0.53 [0.16;1.75] REACT 0.51 [0.24;1.10] MERLIN 1.14 [0.59;2.20] LIMI 0.84 [0.27;2.65] Belenkie et al 0.19 [0.02;1.47] Total 0.73 [0.48;1.11] 0.138 Cochran Q het. P=0.33 Death 6 weeks Relative risk, fixed model Bilateral CI, 95% for trials, 95% for MA Rel. Risk 0.4 1.0 1.6 2.2 RR CI p