1. MULTIcentre evaluation of Single high-dose bolus TiRofiban versus Abciximab with sirolimus eluting sTEnt or bare metal stent in acute myocardial infarction studY MULTIcentre evaluation of Single high-dose bolus TiRofiban versus Abciximab with sirolimus eluting sTEnt or bare metal stent in acute myocardial infarction studY MULTISTRATEGY M. Valgimigli, MD, PhD On behalf of Multistrategy Investigators ClinicalTrials.gov number, NCT00229515

2. Background There is limited data on the comparison between Abciximab vs. Tirofiban at high bolus dose (HDB: 25  g/kg over 3 min) 4 RCTs have so far contrasted these two drugs in 719 pts undergoing PCI of whom less than 300 were recruited in the setting of STEMI 1,2 The use of DES in the setting of STEMI is currently discouraged due to partially conflicting results on efficacy from MC-RCTs 3,4 and safety concerns from registries 5,6 1: Valgimigli et al. JAMA 2005; 2: Danzi et al. Am J Cardiol 2004; 3: Spaulding et al. NEJM 2006 4: Laarman et al. NEJM 2006; 5: Spertus et al. Circulation 2006; Steg PG et al. ESC 2007

3. INCLUSION CRITERIA: Chest pain for >30 min with ST- segment elevation ≥1 mm in two or more contiguous leads, or with a new left bundle-branch block Admission either within 12 h of symptom onset or between 12 and 24 h after onset with evidence of continuing ischemia EXCLUSION CRITERIA: Those related to controindications to the use of glycoprotein IIb/IIIa inhibitors INCLUSION CRITERIA: Chest pain for >30 min with ST- segment elevation ≥1 mm in two or more contiguous leads, or with a new left bundle-branch block Admission either within 12 h of symptom onset or between 12 and 24 h after onset with evidence of continuing ischemia EXCLUSION CRITERIA: Those related to controindications to the use of glycoprotein IIb/IIIa inhibitors Trial Design Aspirin 160-325 mg orally or 250 mg intravenously, followed by 80-125 mg orally indefinitely Clopidogrel 300 mg orally and then 75 mg/day for at least 3 months Unfractioned Heparin (40-70 U/kg) Target ACT of at least 200 secs Aspirin 160-325 mg orally or 250 mg intravenously, followed by 80-125 mg orally indefinitely Clopidogrel 300 mg orally and then 75 mg/day for at least 3 months Unfractioned Heparin (40-70 U/kg) Target ACT of at least 200 secs No exclusion criteria based on: Haemodynamic Status Angiographic Findings

4. STEMI all-comer Patients Aspirin + Clopidogrel + UFH Before Arterial Sheath Insertion Aspirin + Clopidogrel + UFH Before Arterial Sheath Insertion Tirofiban*Tirofiban*AbciximabAbciximab SESSESBMSBMS Trial Design SESSESBMSBMS 1:1 Clinical FU only @ 1, 4, 8 ms, 1yr and then yearly up to 5 Coronary Angiography±PCI Stenting was the default strategy in pts with a RVD≥ 2.5 mm at visual estimation *: given as a bolus of 25  g/kg, followed by an 18-24 hour infusion at 0.15  g/kg/min

5. Study Primary Endpoints Pharmacology Arm ≥50%  ST segment elevation resolution within 90’ after last balloon inflation @ tt-EKG Non-inferiority basis Stent Arm Cumulative rate of MACE, defined as overall death, Reinfarction or TVR within 8 months Superiority basis

6. Assumed event rates Endpoint Test Abciximab Tirofiban SES BMS  Power ≥  50% N-Inf. 85% 85% ─ ─ 9%* >85% STR MACE Sup. ─ ─ 16% 27% ─ 80% Study Primary Endpoints Power Analysis Study Primary Endpoints Power Analysis With 600 pts randomized and type I error set @2.5% *: ~50% of previously reported  ≥  50% STR between Abciximab vs. placebo in the ACE trial (Antoniucci et al. J Am Coll Cardiol 2003)

7. Study Organization Sponsor: University of Ferrara, Italy Data Management: Medical Trial Analysis, Switzerland Site and data monitoring: Medical Trial Analysis, Italy ; Sermes C.R.O., Spain Clinical Events Committee: P. Agostoni (Chair), Belgium, E. Meliga, The Netherlands. ECG core lab: MTA, C. Arcozzi (Chair) Angiographic core lab: MTA, P. Malagutti (Chair) DSMB: P. Vranckx, (Chair), Belgium

8. G Campo Ferrara R Moreno Madrid G Percoco Lagosanto T Piva Ancona M Anselmi Verona I Sheiban Torino L Bolognese Arezzo G Pasquetto Mirano S Colangelo Torino F Prati Rome N de Cesare Zingonia M Nazzaro Rome A Rodriguez B. Aires J Fernández Huelva M Ferrario Pavia J Mieres B Aires MULTISTRATEGY P.I.s and Sites

9. 745 Randomized Abciximab and Uncoated Stent (n=186) Abciximab and Uncoated Stent (n=186) 1:1:1:1 1030 Patients Assessed for Eligibility 285 Excluded 153 Not Meeting Inclusion Criteria 132 Refused to Participate Abciximab and Sirolimus-Stent (n=187) Abciximab and Sirolimus-Stent (n=187) Tirofiban and Uncoated Stent (n=186) Tirofiban and Uncoated Stent (n=186) Tirofiban and Sirolimus-Stent (n=186) Tirofiban and Sirolimus-Stent (n=186) N=186 N=186 N=186 N=186 8 month Follow-up Study N=179 N=182 N=184 N=177 ST Segment Resolution Study 1 pt withdrew consent 99% received Abciximab 97% received PCI 90% received Abc+BMS 99% qualified as STEMI 3% non-interpretable ECG 100% received Abciximab 99% received PCI 87% received Abc+BMS 100% qualified as STEMI 2% non-interpretable ECG 100% received Tirofiban 98% received PCI 95% received Tir+BMS 99% qualified as STEMI 1% non-interpretable ECG 100% received Tirofiban 98% received PCI 89% received Abc+BMS 99.5% qualified as STEMI 4% non-interpretable ECG 72% 97% 100%

10. Abciximab Tirofiban P BMS SES BMS SES Age (yr) 64.1 (55-74) 63.4 (55-70) 66.3 ( 57-75) 64.1 (54-74) 0.29 Male Sex (%)73.1 72.679.5 78.5 0.26 BMI (kg/m 2 ) 27 (25-29) 27 (25-29) 27 (24-29) 27 (24-29) 0.27 Diabetes (%) 12.4 14 17 14.5 0.26 Hypertension (%) 60.2 52.6 58 58 0.84 CrCl (ml/min) 78.8 79.8 78.6 81.3 0.78 Prior MI (%) 6.4 9.1 9.1 5.9 0.54 Prior PCI (%) 6.4 7.5 2.7 4.8 0.18 Prior CABG (%) 0.5 0.5 2.1 1 0.42 Prior CVA (%) 3.7 2.7 9.1 3.2 0.05 Systolic Pres (mmHg) 135 130 135 135 0.85 Heart Rate (bpm) 75 75 74 74.50.70 LVEF (%) 45 45 45 450.78 Killip class >1 (%)16.1 19.3 15.6 12.30.38 Symptoms to H (min) 105 90 107 100 0.47 Door to balloon (min) 97 91.5 100 95 0.78 Abciximab Tirofiban P BMS SES BMS SES Age (yr) 64.1 (55-74) 63.4 (55-70) 66.3 ( 57-75) 64.1 (54-74) 0.29 Male Sex (%)73.1 72.679.5 78.5 0.26 BMI (kg/m 2 ) 27 (25-29) 27 (25-29) 27 (24-29) 27 (24-29) 0.27 Diabetes (%) 12.4 14 17 14.5 0.26 Hypertension (%) 60.2 52.6 58 58 0.84 CrCl (ml/min) 78.8 79.8 78.6 81.3 0.78 Prior MI (%) 6.4 9.1 9.1 5.9 0.54 Prior PCI (%) 6.4 7.5 2.7 4.8 0.18 Prior CABG (%) 0.5 0.5 2.1 1 0.42 Prior CVA (%) 3.7 2.7 9.1 3.2 0.05 Systolic Pres (mmHg) 135 130 135 135 0.85 Heart Rate (bpm) 75 75 74 74.50.70 LVEF (%) 45 45 45 450.78 Killip class >1 (%)16.1 19.3 15.6 12.30.38 Symptoms to H (min) 105 90 107 100 0.47 Door to balloon (min) 97 91.5 100 95 0.78 Baseline Characteristics

11. Abciximab Tirofiban P BMS SES BMS SES 1-VD 40.3 45.7 45.2 48.4 0.72 2-VD 36.6 34.9 32.8 32.2 0.73 3-VD 20.4 18.3 21.5 17.7 0.78 LAD-culprit 43.4 45.9 41.8 43.1 0.88 RCA-culprit 35.1 39.3 42.9 40.3 0.48 LMCA-culprit 1.6 1.6 0 0.5 0.14 SVG-culprit 0 0 1.1 0 0.13 Interventions 96.8 98.4 97.8 98.7 0.67 De Novo culprit 96.8 95.7 97.3 96.8 0.79 No. Stents 1 1 1 1 0.47 Stent Length 20 23 19 23 0.18 Max Stent Size 3.07±0.4 3.05±0.4 3.14±0.5 3.05±0.5 0.06 Stent post-dil 18.9 21.6 20.3 21.7 0.91 Max Pressure 14.1±4.3 14.6±3.6 13.6±4.4 14.7±3.6 0.039 GP2b/3a infusion 12 (12-12) 12 (12-12) 24 (16-24) 24 (17-24) <0.001 ACT at peak 225 250 229 231 0.87 (191-307) (250-303) (194-284) (188-286) Abciximab Tirofiban P BMS SES BMS SES 1-VD 40.3 45.7 45.2 48.4 0.72 2-VD 36.6 34.9 32.8 32.2 0.73 3-VD 20.4 18.3 21.5 17.7 0.78 LAD-culprit 43.4 45.9 41.8 43.1 0.88 RCA-culprit 35.1 39.3 42.9 40.3 0.48 LMCA-culprit 1.6 1.6 0 0.5 0.14 SVG-culprit 0 0 1.1 0 0.13 Interventions 96.8 98.4 97.8 98.7 0.67 De Novo culprit 96.8 95.7 97.3 96.8 0.79 No. Stents 1 1 1 1 0.47 Stent Length 20 23 19 23 0.18 Max Stent Size 3.07±0.4 3.05±0.4 3.14±0.5 3.05±0.5 0.06 Stent post-dil 18.9 21.6 20.3 21.7 0.91 Max Pressure 14.1±4.3 14.6±3.6 13.6±4.4 14.7±3.6 0.039 GP2b/3a infusion 12 (12-12) 12 (12-12) 24 (16-24) 24 (17-24) <0.001 ACT at peak 225 250 229 231 0.87 (191-307) (250-303) (194-284) (188-286) Baseline Characteristics

12. Abciximab Tirofiban P BMS SES BMS SES RVD (mm) before PCI 2.81 2.88 2.90 2.85 0.43 2.52-3.16 2.55-3.14 2.58-3.23 2.61-3.06 after PCI 2.87 2.91 2.90 2.86 0.79 2.57-3.24 2.62-3.17 2.58-3.26 2.61-3.14 MLD (mm) before PCI 0 0 0 0 0.34 0-0.77 0-0.56 0-0.73 0-1.00 after PCI 2.68 2.662.65 2.61 0.64 2.34-2.96 2.42-2.91 2.41-3.00 2.42-2.91 % stenosis before PCI 100 100 100 100 0.57 71-100 79-100 76.5-100 70-100 after PCI 6.5 7 6 8 0.89 2-13 2-13 1-13 2-13.5 Abciximab Tirofiban P BMS SES BMS SES RVD (mm) before PCI 2.81 2.88 2.90 2.85 0.43 2.52-3.16 2.55-3.14 2.58-3.23 2.61-3.06 after PCI 2.87 2.91 2.90 2.86 0.79 2.57-3.24 2.62-3.17 2.58-3.26 2.61-3.14 MLD (mm) before PCI 0 0 0 0 0.34 0-0.77 0-0.56 0-0.73 0-1.00 after PCI 2.68 2.662.65 2.61 0.64 2.34-2.96 2.42-2.91 2.41-3.00 2.42-2.91 % stenosis before PCI 100 100 100 100 0.57 71-100 79-100 76.5-100 70-100 after PCI 6.5 7 6 8 0.89 2-13 2-13 1-13 2-13.5 QCA Analysis

13. ST Segment Resolution Rationale for choosing this endpoint in STEMI Circulation 2004;110(21):e506-10. Jama 2005;293(9):1063-72. Eur Heart J. 2007 Jun;28(12):1433-9. ST segment resolution correlates with infarct size and infarct transmurality as assessed at MRI or SPECT ST segment resolution has strong and independent prognostic implications in terms of both death or the composite of death or MI Interventions in STEMI which improve ST segment resolution have a consistent effect on outcomes and viceversa Lancet 1997;350(9078):615-9 N Engl J Med. 2008 Feb 7;358(6):557-67 J Am Coll Cardiol 2003;42(11):1879-85 Jama 2005;293(9):1063-72.

14. ST Segment Resolution Internal Validity Assessment of the Chosen 1° Endpoint P=0.023 at Log Rank test ST-Res ≥50% ST-Res <50%

15. ST Segment Elevation P=0.78 P=0.62  ST segment (mm) Number of ECG leads with ST Abciximab Tirofiban

16. Primary Endpoint ≥50%  ST segment resolution Abciximab Tirofiban 0 10 20 30 40 50 60 70 80 90 100 H0: 85% 83.6% 85.3% P<0.001 for non-inferiority

17. Tirofiban Better Abciximab Better 1 1 0.9 0.8 0.7 0.6 0.5 1.1 1.2 1.3 1.4 1.5 Prespecified Non-inferiority Limit Overall < 65 yr ≥ 65 yr Male Female Diabetes No Diabetes Killip class 1 Killip class ≥2 Single-vessel disease Double-vessel disease Triple-vessel disease Anterior Myocardial infarction Non Anterior Myocardial infarction Time to Tx ≤ 4 hr Time to Tx > 4 hr Creatinine Clearance ≥ 60 ml/min Creatinine Clearance < 60 ml/min RISK RATIO (95% CI) PRIMARY END POINT Tirofiban Abciximab % 85.3 83.6 86.6 84.6 84.5 82.3 86.0 81.9 82.4 88.5 84.6 80.0 85.2 84.2 86.5 84.9 77.0 78.9 85.2 85.8 87.2 86.7 84.2 72.8 79.6 71.9 89.4 92.1 84.7 88.4 86.0 82.0 85.6 85.1 85.8 76.3 P-VALUE 0.74 0.57 0.86 0.89 0.10 0.11 0.26 0.95 0.37 0.89 0.11 0.55 0.53 Non-inferiority Superiority 0.001 Bare Metal Stent Sirolimus-Eluting Stent 85.9 84.60.74 84.8 82.70.59 1° Endpoint: ≥50% ST segment resolution Subgroup Analysis 0.002 0.003 <0.001 0.37 0.059 <0.001 0.22 0.002 0.003 0.02 0.01 0.002 <0.001 0.01 0.004 0.002 0.001 <0.001

18. ECG Analysis Core Lab Evaluation ECG Analysis Core Lab Evaluation N=722

19. 30-Day Outcomes Efficacy Endpoints (CEC adjudicated) MACE Death/MI uTVR Definite Def/Prob Stent Thrombosis (ARC) Stent Thrombosis (ARC) P=0.85 P=0.98 P=0.59 P=0.56 P=0.22 Abciximab Tirofiban 4% 1% 2.5%

20. 30-Day Outcomes Safety Endpoints (DSMB adjudicated) Major Minor RBC Tranfusion RBC Tranfusion Severe Any Thrombocytopenia P=0.44 P=0.40 P=0.82 P=0.03 P=0.004 Abciximab Tirofiban TIMI-Bleeding 2% 6% 4% 8% 0%

21. 8 Month Outcomes MACE (CEC adjudicated) No. at Risk Abciximab 372 351 343 331 325 Tirofiban 372 355 350 342 336

22. 8 Month Outcomes Death/MI (CEC adjudicated) No. at Risk Abciximab 372 355 349 347 345 Tirofiban 372 358 354 352 349

23. 8 Month Outcomes Target Vessel Revascularization (CEC adjudicated) No. at Risk Abciximab 372 355 349 338 332 Tirofiban 372 357 353 344 340

24. 8 Month Outcomes MACE (CEC adjudicated) No. at Risk Uncoated Stent 372 351 342 326 318 Sirolimus-Stent 372 355 351 347 343 Adjusted HR: 0.53 (97.5%CI: 0.33-0.83); p=0.006

25. 8 Month Outcomes Target Vessel Revascularization (CEC adjudicated) No. at Risk Uncoated Stent 372 355 347 331 322 Sirolimus-Stent 372 357 355 351 350

26. 8 Month Outcomes Death/MI (CEC adjudicated) *: % SES patients taking dual antiplatelet treatment 82%*82%* 39%*39%* 32%*32%*

27. Uncoated Stent Sirolimus Stent Definite Definite/Probable Possible Definite/Probable Possible ARC Stent Thrombosis (CEC adjudicated) P=0.65 P=0.31 P=0.45 0% 1.5% 3% 4.5% 6%

28. Summary Our study provides evidence that in a broad population of largely unselected patients undergoing angioplasty for ST- elevation myocardial infarction: Tirofiban enables non-inferior STR within 90’ after intervention and similar outcomes at 8 months than Abciximab The MACE rate was approximately halved by the use of SES compared to BMS