M. Valgimigli University of Ferrara Italy

1. MultiStrategy Study design M. Valgimigli University of Ferrara Italy

2. Background • Primary angioplasty is the current preferred therapeutic option for patients with ST-segment elevation myocardial infarction (STEMI). • Routine coronary stent implantation in patients with STEMI decreases the need for target vessel revascularization (TVR). Grines CL, et al. N Engl J Med 1999; 341: 1949 Stone G, et al. N Engl J Med 2002; 346: 957

3. STEMI: Stent and Mortality

4. STEMI: Stent and Reintervention 6 months 30 days

5. What about external validity? • Mostly excluded patients: • Shock • Diffusely diseased or small coronary vessel • Large thrombus burden • Severe coronary calcification or tortuosity • Bifurcated lesions • In some of these trials randomization occurred after angiography before PCI • In some of these studies randomization occurred after balloon angioplasty • In none of these studies patients were recruited without prior knowledge of coronary anatomy Ideal or good stent candidates

6. 25 20 15 Stent Balloon 10 5 0 N=1683 Heart 2005;91:641–645. Participants:All Patients with STEMI randomly assigned to stenting or balloon Angioplasty. No exclusion criteria were applied. RR 0.98 (95%CI: 0.78-1.22) Death or Reinfarction TVR (%)

7. Lessons from the BMS Era • BMS in the setting of STEMI is far from being the perfect solution for restenosis and TVR may remain high • New devices are needed which have to be tested in unselected (no angiographic selection bias) patient population

8. GP IIb/IIIa inhibitorsThe word to the …Guidelines • Primary PCI: • Class IIA indication • Class IIA indication with Stent • Class I indication without Stent • Class IIB for tirofiban and eptifibatide Abciximab

9. Study design • Inclusion Criteria: STEMI all comers: shock, elderly included • Exclusion Criteria: Contraindications to Gp IIb/IIIa Tirofiban SHDB Cypher STEMI UFH - ASA Clopidogrel BMS Abciximab stand. regimen CCU Cath-Lab Valgimigli et al. Cardiovasc Drugs Ther 04; 18: 225-30

10. 84 PTCA 3 POBA 74 SES 7 BMS Study Profile 219 Assessed for Eligibility • 44 Excluded • 34 Not Meeting Inclusion Criteria • 10 Refused to Participate 175 Randomized 1:1 SHDB Tirofiban (n=87) Abciximab (n=88) 88% 85% 83 PTCA 5 No PCI 3 No PCI 4 POBA 77 BMS 2 SES Clinical Follow-up Angiographic Follow-up Pts not eligible Refused to participate 3 4 3 74 7 77 2 5 1 1 0 62 4 64 1 0 77% 75% 2 3 3 6 0 4 0 5 0 0 0 6 3 9 1 0 Valgimigli et al. JAMA 2005; 293: 2109-2117

11. 30-Day Outcomen=175 Abciximab+BMS Tirofiban+SES P=0.33 % P=0.62 P>0.99 P=0.62 P=>0.99 Valgimigli et al. JAMA 2005; 293: 2109-2117

12. Death/MI at 8 Months p=0.4 HR 0.71 [95% CI: 0.34-1.5] JAMA 2005; 293: 2109-2117

13. Death/MI/TVR at 8 Months p=0.043 HR 0.53 [95% CI: 0.28-0.92] JAMA 2005; 293: 2109-2117

14. 50% 19% 8-Month Outcomen=175 P=0.005 Abciximab+BMS P=0.043 P=0.004 Tirofiban+SES % P=0.01 P=0.8 P=0.6 P>0.99 MACE Death MI TVR CVA BR 1° EndPoint Valgimigli et al. JAMA 2005; 293: 2109-117

15. Università degli Studi di Ferrara - Cattedra di Cardiologia MULTI-STRATEGY Trial Design STEMI All Comers Patients Aspirin + Clopidogrel +UFH Intent-to-stent N ~ 730 1:1 Tirofiban Abciximab 1:1 1:1 SES BMS SES BMS Valgimigli M. et al Am Heart J. 2007 Jul;154(1):39-45.

16. Università degli Studi di Ferrara - Cattedra di Cardiologia MULTI-STRATEGY Primary objectives • 1.Whether tirofiban administered at high bolus dose is non inferior to abciximab on the degree of cumulative ST-segment resolution, expressed as the proportion of patients reaching ≥ 50% recovery, at 90’ after the mechanical intervention. • 2. Whether SES implantation –based on the intention-to-treat principle– is superior to BMS on the incidence of major adverse cardiovascular events (MACE) within 8 months, defined as the composite of death, nonfatal myocardial infarction and clinically-driven target vessel revascularization (TVR). Valgimigli M. et al Am Heart J. 2007 Jul;154(1):39-45.

17. MULTI-STRATEGY Major Secondary objectives • The effect of tirofiban infusion or SES implantation on the MACE either singularly considered or as a composite and on the incidence of stent thrombosis. • The effect of tirofiban on the rate of TIMI 3 flow before and after intervention and on partial (≥50%) or complete (≥70%) cumulative ST segment resolution or in the single lead with greatest ST changes. • The effect of SES implantation on the rate of major cardiovascular events either singularly considered or as a composite after thienopyridines discontinuation • The cost-effectiveness profile in STEMI of SES implantation or tirofiban infusion • The effect of tirofiban on the rate of bleeding and thrombocytopenia

18. Università degli Studi di Ferrara - Cattedra di Cardiologia MULTI-STRATEGY 16 Participating centers Argentina Italy Spain Ferrara, M.Valgimigli Valle Oppio, GF Percoco Arezzo. L. Bolognese Verona, M. Anselmi Bergamo, N. De Cesare Mirano, GP Pasquetto Pavia, E. Bramucci Ancona, R. Piva Torino, I. Sheiban Torino, S. Colangelo Roma, F. Prati Roma, R. Violini Buenos Aires, A. Rodriguez Otamendi Hospital Madrid, R. Moreno Huelva, José Díaz Valgimigli M. et al Am Heart J. 2007 Jul;154(1):39-45.

19. Università degli Studi di Ferrara - Cattedra di Cardiologia MULTI-STRATEGY Trial Design STEMI All Comers Patients Aspirin + Clopidogrel +UFH Intent-to-stent ACC 2008 N ~ 730 1:1 Tirofiban Abciximab 1:1 1:1 SES BMS SES BMS Valgimigli M. et al Am Heart J. 2007 Jul;154(1):39-45.