1. S TANFORD Tirofiban Given in the Emergency Room Before Primary Angioplasty (TIGER-PA) Pilot Study David P. Lee, MD, Alan C. Yeung, MD, Donald Schreiber, MD, Michelle Huston, MD Donald Schreiber, MD, Michelle Huston, MD

2. S TANFORD GP IIb/IIIa Inhibitors in Acute MI Key questions regarding new adjuvant therapiesKey questions regarding new adjuvant therapies –Can we improve reperfusion times? –Can we improve flow after reperfusion? –Can we limit infarct size and thus complications?

3. S TANFORD GP IIb/IIIa Inhibitors in Acute MI Why a GP IIb/IIIa inhibitor could workWhy a GP IIb/IIIa inhibitor could work –Early potent antiplatelet therapy –Adjunctive use in PCI improves outcomes –May improve flow –Relatively safe to use

4. S TANFORD N=483N=483 Abciximab in the ER or cath labAbciximab in the ER or cath lab –30-day MACEAny drug Int to treat (n=409) (n=483) Control12.011.2 Abciximab4.65.8 P value0.0050.038 6-month MACE: no difference6-month MACE: no difference RAPPORT ReoPro in Acute myocardial infarction and Primary PTCA Organization Randomized Trial

5. S TANFORD ADMIRAL Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up Event*AbciximabPlacebo (n=150)(n=150) P Death, MI, urgent TVR at 30 d10.7%20.0%0.03 TIMI-3 initial21%10%<0.01 24 h86%78%<0.03 LVEF24 h55%51% 30 d63%55% *26% received in ambulance or ER

6. S TANFORD GRAPE Glycoprotein Receptor Antagonist Patency Evaluation Pilot (N=60) GRAPE (n=60) 45 min SPEED (n=26) 60 min TIMI-14A (n=31) 90 min All Abciximab (n=117) GUSTO-IIb (n=510) 115 min angio at P < 0.0001 18% 23% 32% 23% 8% Patients With TIMI-3 Flow

7. S TANFORD Improved TIMI-grade Flow with Early IIb/IIIa in Acute MI % with TIMI-3 flow N 60 300 888

8. S TANFORD TIGER-PA Pilot GoalsGoals –To test the safety and efficacy of tirofiban in the setting of an acute MI –To compare early adjunctive use of tirofiban before primary PCI with peri-PCI use

9. S TANFORD TIGER-PA Pilot TargetsTargets –100 patients –40% power to detect a 15% difference in the TIMI frame count and flow

10. S TANFORD TIGER-PA Pilot Inclusion criteriaInclusion criteria –Chest pain within 12 hours of onset –  1 mm ST-elevation in 2 or more contiguous leads or new LBBB

11. S TANFORD TIGER-PA Pilot Exclusion criteriaExclusion criteria –Age <18 –Major surgery, GI or GU bleed within 30 days –CVA within 1 year or with residual deficit –Known bleeding diathesis –Known intracranial disease –Cardiogenic shock

12. S TANFORD TIGER-PA Pilot Exclusion criteriaExclusion criteria –Uncontrolled HTN (SBP > 180, DBP > 100) –Prolonged CPR –Thrombolysis within 24 hours –Concomitant use of a GP IIb/IIIa inhibitor –Hemorrhagic retinopathy –PLTs < 150K

13. S TANFORD TIGER-PA Pilot Study designStudy design –1:1 open-label randomization to tirofiban in the ER (early) or in the cath lab (delayed) –No PTCA in early arm if culprit lesion <50% –Delayed tirofiban if PTCA to be performed

14. S TANFORD Final angiogram Acute myocardial infarction Meets inclusion criteria AngiogramAngiogram Final angiogram TIGER-PA Pilot Tirofiban in ER No tirofiban in ER PTCA/stent No PTCA if lesion <50% No PTCA Tirofiban if PTCA to be performed

15. S TANFORD TIGER-PA Pilot DosingDosing –Tirofiban: 10 µg/kg over 3 minutes, then 0.15 µg/kg/min x 24 hours –Heparin Early: 70 U/kg IV bolus, then 7.5 U/kg/hEarly: 70 U/kg IV bolus, then 7.5 U/kg/h Delayed: 100 U/kg IV bolus, then 10 U/kg/hDelayed: 100 U/kg IV bolus, then 10 U/kg/h –All other medications including NTG,  -blockers at the investigator’s discretion

16. S TANFORD TIGER-PA Pilot LaboratoriesLaboratories Baseline6 h12 h18 h24 h HbX-X-X HctX-X-X PLTX-X-X CPKXXXXX CPK-MBXXXXX

17. S TANFORD TIGER-PA Pilot EndpointsEndpoints –Primary endpoint TIMI flowTIMI flow TIMI frame countsTIMI frame counts –Secondary endpoint BleedingBleeding –Minor: Hct  10% or Hb  3 g/dL –Major: Hct  15% or Hb  5 g/dL –Thrombocytopenia (PLTs< 90000)

18. S TANFORD TIGER-PA Pilot EndpointsEndpoints –Tertiary endpoint (30 days) Repeat coronary revascularizationRepeat coronary revascularization –Urgent vs nonurgent Death (from any cause)Death (from any cause) New MI (CPK >2x normal)New MI (CPK >2x normal) Hospitalization for refractory ischemiaHospitalization for refractory ischemia

19. S TANFORD TIGER-PA Pilot Adjuvant therapyAdjuvant therapy –If a stent is placed, ticlopidine 250 mg po bid or clopidogrel 75 mg po qd x  14 d –Heparin may be stopped temporarily for early sheath removal

20. S TANFORD TIGER-PA Pilot Data analysisData analysis –Primary endpoint Blinded observers for TIMI frame count, myocardial perfusion and flow at baseline and after PTCABlinded observers for TIMI frame count, myocardial perfusion and flow at baseline and after PTCA –Secondary endpoint Data monitoring for CBC and CPKsData monitoring for CBC and CPKs Safety monitor for bleeding eventsSafety monitor for bleeding events –Tertiary endpoint Clinical follow-up by chart review and telephoneClinical follow-up by chart review and telephone

21. S TANFORD TIGER-PA Pilot N=100 50 ER, 50 cath labN=100 50 ER, 50 cath lab Patients screened157Patients screened157 – Declined enrollment 32 – Shock/IABP 9 – Signif comorbities 14 – Recent IIb/IIIa 2 Demographics

22. S TANFORD TIGER-PA Pilot CharacteristicEarlyLatep Age (y) 63.5 12.6 63.5  12.6 66.4 14.3 66.4  14.3NS Gender (%male) 6064NS %Diabetes2424NS %HTN3640NS %Hyperlipidemia3232NS %Prev CAD 1210NS Demographics

23. S TANFORD TIGER-PA Pilot CharacteristicEarlyLatep CP duration (h) 3.0 2.0 3.0  2.0 3.0 1.8 3.0  1.8NS Door-to-tirofiban (min) 55.7 18.0 55.7  18.0 81.8 17.7 81.8  17.7<0.001 Door-to-balloon (min) 88.9 20.7 88.9  20.7 82.7 20.0 82.7  20.0NS Demographics 33 minute mean from drug-to-balloon

24. S TANFORD TIGER-PA Pilot CharacteristicEarlyLatep Culprit Vessel (%) LAD4036NS LCX2020NS RCA4044NS Initial TGF (%) 332100.007 2148 1102 04480 Angiographic Outcomes

25. S TANFORD TIGER-PA Pilot CharacteristicEarlyLatep Initial CTFC 44 20 44  20 66 + 23 0.005 % Initial TMPG-3 3260.001 % Final TGF-3 9292NS Final CTFC 18 8 18  8 16 8 16  8NS % Final TMPG-3 5040NS Angiographic Outcomes

26. S TANFORD Initial TIMI-Grade Flow 0 10 20 30 EarlyLate 40 TIMI-0 or 1 TIMI-2 TIMI-3 * P < 0.007 # Patients 32% 50 14% 8% 10% TIGER-PA Pilot

27. S TANFORD Initial CTFC 0 20 40 60 Early Late CTFC 80 * P = 0.005 44  20 66  23 TIGER-PA Pilot

28. S TANFORD Initial TIMI-Myocardial Perfusion Grade 0 10 20 30 EarlyLate 40 TMPG-0 or 1 TMPG-2 TMPG-3 * P < 0.001 # Patients 32% 50 16% 12 % 6% TIGER-PA Pilot

29. S TANFORD TIGER-PA Pilot Clinical OutcomesEarlyLatep Peak CPK 1924 1699 1924  1699 2260 1959 2260  1959NS Time-to-peak 10.0 7.1 10.0  7.1 11.1 6.5 11.1  6.5NS 30-d Composite 6%10%NS Death2%2%NS Re-MI02%NS Rehosp4%6%NS Urgent TVR 0%2%NS

30. S TANFORD TIGER-PA Pilot ERCath Lab p *Minor bleeding10%6%NS *Major bleeding2%2%NS Transfusions10%8%NS PLT < 100K4%0%NS Clinical Outcomes * TIMI-defined

31. S TANFORD 10 patients in the Cath Lab group underwent measurements of platelet inhibition with the Accumetrics Ultegra RPFA while in the Cath Lab Time points: baseline, 20m, 40m, EOC TIGER-PA Pilot Platelet Substudy

32. S TANFORD % platelet inhibition 0 20 40 60 80 100 BaselinePost Bolus20 min40 minEOC TIGER-PA Pilot Platelet Substudy

33. S TANFORD SummarySummary –Pilot study to determine safety and efficacy of tirofiban given in the ER before primary PTCA –Tirofiban given early in the ER may lead to further improvement in TIMI flow, frame count, and blush when compared with tirofiban given in the cath lab –Earlier reperfusion may translate into better clinical outcomes TIGER-PA Pilot

34. S TANFORD Summary GP IIb/IIIa receptor inhibitors may be beneficial as an adjunct in acute MI with primary angioplastyGP IIb/IIIa receptor inhibitors may be beneficial as an adjunct in acute MI with primary angioplasty Safe and well toleratedSafe and well tolerated Further large-scale trials are needed to better delineate a long-term benefitFurther large-scale trials are needed to better delineate a long-term benefit TIGER-PA Pilot