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M. Valgimigli, MD, PhD On behalf of Multi strategy Investigators

MULTI centre evaluation of S ingle high-dose bolus T iRofiban versus A bciximab with sirolimus eluting s TE nt or bare metal stent in acute myocardial infarction stud Y. M. Valgimigli, MD, PhD On behalf of Multi strategy Investigators. Potential Conflicts of interest.

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M. Valgimigli, MD, PhD On behalf of Multi strategy Investigators

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

  2. Potential Conflicts of interest • Speaker’s bureau: Merck, Medicure • Research grant: Merck,

  3. 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 Background • 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

  4. 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 • 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 • No exclusion criteria based on: • Haemodynamic Status • Angiographic Findings

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

  6. Study Primary Endpoints Pharmacology Arm Non-inferiority basis ≥50%  ST segment elevation resolution within 90’ after last balloon inflation @ tt-EKG Stent Arm Superiority basis Cumulative rate of MACE, defined as overall death, Reinfarction or TVR within 8 months Valgimigli et al. Am Heart J. 2007 Jul;154(1):39-45

  7. Study Primary Endpoints Power Analysis Assumed event rates Endpoint Test Abciximab Tirofiban SES BMS  Power ≥50% N-Inf. 85% 85% ── 9%* >85% STR MACE Sup. ─ ─ 16% 27% ─ 80% 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)

  8. 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

  9. MULTISTRATEGY P.I.s and Sites 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 FernándezHuelva M Ferrario Pavia J MieresB Aires

  10. 285 Excluded • 153 Not Meeting Inclusion Criteria • 132 Refused to Participate 1030 Patients Assessed for Eligibility 72% 745 Randomized 1:1:1:1 Abciximab and Uncoated Stent (n=186) Abciximab and Sirolimus-Stent (n=187) Tirofiban and Uncoated Stent (n=186) Tirofiban and Sirolimus-Stent (n=186) 1 pt withdrew consent 100% received Tirofiban 98% received PCI 89% received Abc+BMS 99.5% qualified as STEMI 4% non-interpretable ECG 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 97% N=179 N=182 N=184 N=177 ST Segment Resolution Study 100% N=186 N=186 N=186 N=186 8 month Follow-up Study

  11. Baseline Characteristics AbciximabTirofibanP BMSSESBMSSES Age (yr) 64.1(55-74) 63.4(55-70) 66.3 (57-75) 64.1(54-74) 0.29 Male Sex (%) 73.1 72.6 79.5 78.5 0.26 BMI (kg/m2) 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 74.5 0.70 LVEF (%) 45 45 45 45 0.78 Killip class >1 (%) 16.1 19.3 15.6 12.3 0.38 Symptoms to H (min) 105 90 107 100 0.47 Door to balloon (min) 97 91.5 100 95 0.78

  12. Baseline Characteristics AbciximabTirofibanP BMSSESBMSSES 1-VD 40.3 45.7 45.2 48.4 0.72 2-VD 36.6 34.9 32.8 32.20.73 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)

  13. QCA Analysis AbciximabTirofibanP BMSSES BMS SES RVD (mm) before PCI 2.81 2.88 2.90 2.850.43 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 PCI2.68 2.66 2.65 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 PCI6.5 7 6 8 0.89 2-13 2-13 1-13 2-13.5

  14. ST Segment ResolutionRationale for choosing this endpoint in STEMI • 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 Circulation 2004;110(21):e506-10. Jama 2005;293(9):1063-72. Eur Heart J. 2007 Jun;28(12):1433-9. 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.

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

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

  17. Primary Endpoint≥50%  ST segment resolution Tirofiban Abciximab P<0.001 for non-inferiority* 100 85.3% 83.6% 90 H0: 85% 80 70 60 50 40 30 20 10 0 *: at ITT and PP Analysis (Heterogeneity: 2 6.22, P=0.718)

  18. 1° Endpoint: ≥50% ST segment resolution Subgroup Analysis PRIMARY END POINT RISK RATIO (95% CI) P-VALUE Non-inferiority Tirofiban Abciximab Superiority % Overall 85.3 83.6 0.001 0.53 0.002 < 65 yr 0.55 86.6 84.6 84.5 82.3 0.55 0.003 ≥ 65 yr Male 86.0 81.9 <0.001 0.55 Female 0.37 82.4 88.5 0.059 Diabetes 84.6 80.0 0.74 <0.001 No Diabetes 85.2 84.2 Killip class 1 <0.001 86.5 84.9 0.57 Killip class ≥2 0.22 77.0 78.9 Bare Metal Stent 0.002 84.8 82.7 0.59 Sirolimus-Eluting Stent 0.003 85.9 84.6 0.74 Single-vessel disease 0.86 85.2 85.8 0.02 Double-vessel disease 0.01 87.2 86.7 0.89 Triple-vessel disease 0.002 0.10 84.2 72.8 Anterior Myocardial infarction <0.001 79.6 71.9 0.11 Non Anterior Myocardial infarction 0.01 89.4 92.1 0.26 Prespecified Non-inferiority Limit Time to Tx ≤ 4 hr 0.004 84.7 88.4 0.95 Time to Tx > 4 hr 86.0 82.0 0.37 0.002 Creatinine Clearance ≥ 60 ml/min 0.001 85.6 85.1 0.89 Creatinine Clearance < 60 ml/min <0.001 85.8 76.3 0.11 1.5 1.4 1.3 1.1 1 0.9 0.8 0.7 0.6 0.5 1.2 Tirofiban Better Abciximab Better

  19. ECG Analysis Core Lab Evaluation N=722

  20. 30-Day OutcomesEfficacy Endpoints (CEC adjudicated) Tirofiban Abciximab P=0.85 P=0.98 Stent Thrombosis (ARC) 4% P=0.22 P=0.59 2.5% P=0.56 1% Death/MI MACE uTVR Definite Def/Prob

  21. 30-Day OutcomesSafety Endpoints (DSMB adjudicated) 8% Tirofiban Abciximab P=0.40 6% P=0.004 4% P=0.82 P=0.44 P=0.03 2% 0% Major Minor RBC Tranfusion Severe Any Thrombocytopenia TIMI-Bleeding

  22. 8 Month OutcomesMACE (CEC adjudicated) No. at Risk Abciximab 372 351 343 331 325 Tirofiban 372 355 350 342 336

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

  24. 8 Month OutcomesTarget Vessel Revascularization (CEC adjudicated) No. at Risk Uncoated Stent 372 355 347 331 322 Sirolimus-Stent 372 357 355 351 350

  25. 8 Month OutcomesDeath/MI (CEC adjudicated) 82%* 39%* 32%* *: % SES patients taking dual antiplatelet treatment

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

  27. 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

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