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

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?

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

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) Control Abciximab P value month MACE: no difference6-month MACE: no difference RAPPORT ReoPro in Acute myocardial infarction and Primary PTCA Organization Randomized Trial

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%< h86%78%<0.03 LVEF24 h55%51% 30 d63%55% *26% received in ambulance or ER

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 < % 23% 32% 23% 8% Patients With TIMI-3 Flow

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

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

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

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

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

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

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

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

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

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)

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

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

S TANFORD TIGER-PA Pilot Data analysisData analysis –Primary endpoint Blinded observer for TIMI frame count and flow at baseline and after PTCABlinded observer for TIMI frame count 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

S TANFORD TIGER-PA Pilot N=54 30 ER, 24 cath labN=54 30 ER, 24 cath lab Patients to date 54 (registry=83)Patients to date 54 (registry=83) Average age 65 ± 13 yearsAverage age 65 ± 13 years Male:female 7:2Male:female 7:2 Anterior 22, lateral 7, inferior 25Anterior 22, lateral 7, inferior 25 Mean time from ER to cath lab: 83 minutesMean time from ER to cath lab: 83 minutes Mean time for tirofiban to cath lab: 34 minutesMean time for tirofiban to cath lab: 34 minutes INTERIM

S TANFORD Initial CTFC ER Cath Lab ER CTFC TGF * P=0.002 * P=0.01 Mean = 34 min TIGER-PA Pilot TGF INTERIM

S TANFORD Initial TGF ER Cath Lab TGF 40 TIMI-0 or 1 TIMI-2 TIMI-3 * * P=0.002 # Patients TIGER-PA Pilot INTERIM

S TANFORD 30-day MACE include 1 patient in each group admitted for chest pain and 1 patient who had SAT and repeat PCI at 6 days in the cath lab group with no deaths. TIGER-PA Pilot ComplicationsComplications ERCath Lab Minor bleeding42 Major bleeding11 30 d MACE12 INTERIM

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 INTERIM

S TANFORD % platelet inhibition BaselinePost Bolus20 min40 minEOC TIGER-PA Pilot Platelet Substudy

S TANFORD TIGER-PA 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 and frame count compared with tirofiban given in the cath lab

S TANFORD Summary GP IIb/IIIa receptor inhibitors may be beneficial as an adjunct in acute MIGP IIb/IIIa receptor inhibitors may be beneficial as an adjunct in acute MI 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