1. 1 The GRACIA – 2 Trial (GRupo de Análisis de la Cardiopatía Isquémica Aguda) Randomised trial comparing Primary PCI versus Facilitated Intervention (TNK + Stenting) in patients with STEMI Francisco F. Avilés (on behalf on the GRACIA group)

2. 2 GRACIA – 2 BACKGROUND  Thrombolysis is widely available and easily applicable, but strongly limited by reopening failure and reocclusion  Less than 50% of pts with STEMI achieve optimal arterial reopening plus effective myocardial reperfusion because of the still limited use, availability and efficacy of current therapies  Primary PCI is highly effective, but available for less than 20% of pts with STEMI in Europe (Euro Heart Survey ACS). Few pts receive primary PCI within 2 hours of onset (6% in the PAMI trial)

3. 3 GRACIA – 2 RATIONALE FOR FACILITATION (pharmacological reperfusion therapy + early planned PCI) GRACIA – 2 RATIONALE FOR FACILITATION (pharmacological reperfusion therapy + early planned PCI)  Pharmacological reopening prolongs time-window for definitive mechanical repair of the culprit artery (PCI more available) (1) Stone GW. Circulation 2001; (2) Lundergan CF. Am Heart J 2002; (3) Ross AM. JACC1999; (4) Hermann HC. JACC 2000; (4) Simoons ML. Lancet 1998; (6) Aviles FF. Eur Heart J 2003  Unlike in previous attempts 4, in the era of stents and modern antiplatelets, early posthrombolysis PCI seems to be feasible, safe and beneficial (PACT 3, SPEED 5, GRACIA – 1 6 )  TIMI 3 flow before primary PCI increases technical success and benefits prognosis by enhancing myocardial salvage and preserving LV function 1  TIMI 3 flow before primary PCI increases technical success and benefits prognosis by enhancing myocardial salvage and preserving LV function 1,2,3

4. 4 HYPOTHESIS In pts with STEMI, the strategy of performing immediate thrombolysis followed by routine early catheterization and appropriate intervention is as available as thrombolysis and as effective as primary PCI HYPOTHESIS GRACIA – 2

5. 5 PURPOSE To compare the safety and efficacy of optimal primary PCI versus a combined reperfusion strategy designed to be easily applicable and widely available PURPOSE GRACIA – 2

6. 6 “OPTIMAL PRIMARY PCI” (N=108) DIRECT PTCA – IRA** (stent / abciximab) < 180 min GRACIA-2 (*) Adequate revascularization: revascularization of culprit artery or non-culprit arteries with severe stenosis threatening large areas of myocardium (**) IRA: Infarct Related Artery TNK + Enoxaparin Immediately ADEQUATE REVASCULARIZATION* (stent / CABG) 3 – 12 hours “ FACILITATED INTERVENTION” (N=104) AMI / ST+ (<12 hours) RANDOMISATION CLINICAL AND ANGIOGRAPHIC FOLLOW- UP AT 6 WEEKS & 6 MONTHS 3 deaths 6 deaths N = 103 N = 102

7. 7 GRACIA – 2 CO – PRIMARY ENDPOINTS  Infarct size (area under the CK-MB mass curve and cTnT release curve)  Myocardial reperfusion (% of pts with complete ∑STe resolution at 1, 3 and 6 hours)  LV angiographic evolution at 6 weeks (volumes, LVEF, Wall Motion Index) CO – PRIMARY ENDPOINTS  Infarct size (area under the CK-MB mass curve and cTnT release curve)  Myocardial reperfusion (% of pts with complete ∑STe resolution at 1, 3 and 6 hours)  LV angiographic evolution at 6 weeks (volumes, LVEF, Wall Motion Index)

8. 8 GRACIA-2 SECONDARY ENDPOINTS  Combined incidence of death, non-fatal myocardial infarction, or ischaemia-driven revascularization at 6 weeks and 6 months  Incidence of bleeding complications and non-cardiac events at 6 weeks and 6 months SECONDARY ENDPOINTS  Combined incidence of death, non-fatal myocardial infarction, or ischaemia-driven revascularization at 6 weeks and 6 months  Incidence of bleeding complications and non-cardiac events at 6 weeks and 6 months

9. 9 GRACIA – 2 212 patients July 2002 – March 2003 15 Centres (Spain & Portugal) 212 patients July 2002 – March 2003 15 Centres (Spain & Portugal) H. Clínico-Universitario, Valladolid (FF Avilés) H. P. Del Río Hortega, Valladolid (J Blanco, JJ Sanz) H. Río Carrión, Palencia (J López Mesa) H. Juan Canalejo, A Coruña (A Castro, N Vázquez) H. Meixoeiro (MEDTEC), Vigo (J Golicolea) H. Miguel Servet, Zaragoza (I Calvo) Complejo Hospitalario, León (F Fernández V) H. Clínico de San Carlos, Madrid (R A Hernández) H. Virgen de la Salud, Toledo (J Moreu) H. U. Virgen del Rocío, Sevilla (L Díaz de la Llera) H. U. V. de la Victoria, Málaga (J Alonso B) H. Rafael Méndez, Lorca-Murcia (S. Nicolás) H. C. U. Valencia (J Sanchís) H. Los Arcos, San Javier-Murcia (F.Martinez) H. Fernando Fonseca, Amadora, Portugal (P. Abreu) H. Clínico-Universitario, Valladolid (FF Avilés) H. P. Del Río Hortega, Valladolid (J Blanco, JJ Sanz) H. Río Carrión, Palencia (J López Mesa) H. Juan Canalejo, A Coruña (A Castro, N Vázquez) H. Meixoeiro (MEDTEC), Vigo (J Golicolea) H. Miguel Servet, Zaragoza (I Calvo) Complejo Hospitalario, León (F Fernández V) H. Clínico de San Carlos, Madrid (R A Hernández) H. Virgen de la Salud, Toledo (J Moreu) H. U. Virgen del Rocío, Sevilla (L Díaz de la Llera) H. U. V. de la Victoria, Málaga (J Alonso B) H. Rafael Méndez, Lorca-Murcia (S. Nicolás) H. C. U. Valencia (J Sanchís) H. Los Arcos, San Javier-Murcia (F.Martinez) H. Fernando Fonseca, Amadora, Portugal (P. Abreu) RecruitmentRecruitment

10. 10 MAIN SPONSORS  Spanish Ministry of Health*  Guidant**  Lilly** MAIN SPONSORS  Spanish Ministry of Health*  Guidant**  Lilly** GRACIA – 2 (*) Cooperative Network for Cardiovascular Research [Instituto de Salud Carlos III]; (**) Unrestricted grant

11. 11 GRACIA – 2 Primary PCI (108 pts) Facilitated PCI (104 pts) pAge 63+13 62+12 0.3 Male82%78%0.6 Prior Angina 25%15%0.1 Prior PCI 9%2%0.06 DiabetesHypertensionHyperlipidaemia Smoking Family history 27%39%40%45%18%23%34%41%50%15%0.490.750.410.480.51 Anterior MI 50%45%0.47 Baseline Clinical

12. 12 GRACIA – 2 85% 89% 75% 79% 66% 68% 91% 97% 87% Adjunctive medical treatment 64% 67% 23% Thienopyridines AspirinACE Inh.StatinsAbciximab B - Blockers p = 0.001Primary Facilitated

13. 13 GRACIA – 2 Time intervals (mean) Primary Facilitated Hours 3.18+1.9 hh3.20+2.05 hh 1.08+3.7 hh 5.89+3.7 hh 4.19+9.06 hh 9.06+4.19 hh p = 0.82 p = 0.001

14. 14 GRACIA – 2 Baseline culprit artery flow TIMI flow grade (TFG) & Corrected TIMI Frame Count (CTFC) 1 Primary (4.2+9.1 hh from onset) p=0.005 p=0.047 p=0.008 p=0.034 20.9+13.0 30.6+20.5 14% 15% 23% 73% 8% 59% Facilitated (9.1+4.2 hh from onset) (1) Gibson CM et al. Circulation 1996

15. 15 IRA location 47%44% 44% 45% 5% 11% 2% 0% CAD extension (vessels with >50% QCA stenosis) GRACIA – 2 Baseline Angiography Primary Facilitated (P=0.82) (P=0.37) (P=0.08) (P=0.01)

16. 16 GRACIA – 2 Angiography (culprit lesion) PRIMARY (4.19+9.1 hh from onset) FACILITATED (4.19+9.1 hh from onset) p Reference Pre 2.58+0.9 mm 2.67+0.82 mm 0.52 MLD pre 0.44+0.67 mm 1.06+0.66 <0.001 % stenosis Pre 84.8+59.7% 59.7+23.8% <0.01 Lesion Length 8.2+3.7 mm 7.9+3.4 mm 0.68 Calcification6%2%0.48 Thrombus70%43%0.001 Success (angio) 85%89%0.60 Reference Post 3.09+0.62 mm 3.37+2.03 mm 0.24 MLD Post 2.99+2.9 mm 2.96+1.67 0.94 % Stenosis Post 16.3+19.8% 11.4+5.7% 0.034

17. 17 GRACIA – 2 Final treatment (*) Conservative treatment due to non-significant CAD or CAD unsuitable for revascularization Primary Facilitated 3% 1% 8% 16% 89% 83% 9% 20% CABGCULPRIT PCI ASSOCIATED NON-CULPRIT PCI NO MECHANICAL INTERVENTION* p = 0.64 p = 0.07 p = 0.02 p = 0.19

18. 18 GRACIA – 2 ST – Segment Elevation Recovery Percentage of pts with “Complete” * ∑STe Recovery P= 0.19 P= 0.83 P= 0.03PrimaryFacilitated (*) [Schroeder R. JACC 1994]: > 70% reduction of the pre-reperfusion total deviation (∑STe)

19. 19 GRACIA – 2 Infarct size 0,19 0,59 4,15 3,19 3,36 4,17 2,98 2,61 4,5 ng/dl 0.0 3,06 2,23 Primary Facilitated days 01234 cTnT release CK-MB mass 253,92 171,91 106,11 17,62 211,06 27,57 12,42 20,08 34,62 58,56 229,12 91,68 160,87 15,51 21,96 35,03 56,96 229,94 Primary Facilitated 300 0 hours 01224 48 Area under the curve PRIMARYFACILITATEDpcTnT 275.5+211.4 241.8+155.5 0.52 CK-MB mass 4768.30+3734.0 4602.01+3371.2 0.76

20. 20 GRACIA – 2 LV evolution at 6 weeks PRIMARYFACILITATEDPLVEFBaseline 6-week FU 6-week FU∆ 52.5+14.3% 55.6+13.4% 3.2+11.8 53.4+9.9% 56.1+12.4% 3.4+11.8 0.70.90.9 Wall Motion Index (SD/chord) Baseline 6-week FU ∆ -1.50+0.4 -1.10+0.6 0.42+0.67 -1.47+0.4 -1.24+0.46 0.24+0.50 0.70.10.09 EDLV volume index ( ml/m 2 ) Baseline 6-week FU 6-week FU∆ 126.5+41 139.8+57.9 11.21+37.76 122.01+47 129.8+54.0 13.23+11.8 0.400.350.69 ESLV volume index ( ml/m 2 ) Baseline 6-week FU 6-week FU∆ 56.43+25.02 62.32+35.7 5.28+21.087 57.62+25.87 56.23+31.91 -2.07+28.30 0.920.350.16

21. 21 GRACIA – 2 6-week clinical outcome Cardiac Events PrimaryPrimaryFacilitatedFacilitated Combined clinical endpoint* (10.5%) Surgery (1%) Ischaemia driven PCI (6.5%) Re-admission (4.5%) Death (4.5%) **** **** **** **** ** p = NS **** **** Re-infarction (1.5%) (*) Combined clinical EP: death, nonfatal MI, or ischemia-driven revascularization

22. 22 GRACIA – 2 6-week clinical outcome Bleeding & vascular complications (*) Major bleeding or vascular complication: intracranial haemorrhage, or any complications that prolonged stay or needed surgery / transfusion PrimaryPrimary FacilitatedFacilitated Any Complication Major Complications (ICH included)* Intracranial Haemorrhage (ICH) p=0.45 p=0.97 p=0.99

23. 23  Catheterization plus adequate revascularization within 3 – 12 hours of immediate facilitation with TNK seems to be as safe as optimal primary PCI (stent & GP IIb/IIIa inhibitors) GRACIA – 2 CONCLUSIONSCONCLUSIONS  These results suggest that both strategies are similarly effective in restoring myocardial perfusion, preserving left ventricular size & function and beneficing clinical outcome  If this equivalence is confirmed in large studies clinically focused, the proportion of patients with STEAMI who can benefit from early PCI could increase dramatically

24. 24 GRACIA – 2 Hospital stay PRIMARYFACILITATED Days 7.4±5.6 p = 0.22 6.4±3.3