9803mo01, 1 Trial of Routine ANgioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction The TRANSFER-AMI trial Warren J. Cantor, David Fitchett, Bjug Borgundvaag, Michael Heffernan, Eric A. Cohen, Laurie J. Morrison, John Ducas, Anatoly Langer, Shamir Mehta, Charles Lazzam, Brian Schwartz, Vladimir Dzavik, Amparo Casanova, Paramjit Singh, Shaun G. Goodman on behalf of the TRANSFER-AMI Investigators

9803mo01, 2 Trial Sponsors Canadian Institute of Health Research (CIHR) Hoffman LaRoche, Canada Stents provided by Abbott Vascular Canada Consulting Fees & Speakers Honoraria received by Hoffman Laroche Canadian Institute of Health Research (CIHR) Hoffman LaRoche, Canada Stents provided by Abbott Vascular Canada Consulting Fees & Speakers Honoraria received by Hoffman Laroche Disclosures

9803mo01, 3 Background Treatment delays can reduce or eliminate benefits of primary PCI STEMI pts presenting to non-PCI centres often cannot undergo primary PCI in timely manner, and therefore receive thrombolysis The role and optimal timing of routine early PCI after fibrinolysis remains controversial Treatment delays can reduce or eliminate benefits of primary PCI STEMI pts presenting to non-PCI centres often cannot undergo primary PCI in timely manner, and therefore receive thrombolysis The role and optimal timing of routine early PCI after fibrinolysis remains controversial

9803mo01, 4 Objective To compare: Pharmacoinvasive strategy (transfer to PCI centre for routine early PCI within 6 hrs) with Standard treatment (early transfer only for failed reperfusion, otherwise cath > 24 hrs) for high-risk STEMI patients receiving thromboysis at non-PCI centres. To compare: Pharmacoinvasive strategy (transfer to PCI centre for routine early PCI within 6 hrs) with Standard treatment (early transfer only for failed reperfusion, otherwise cath > 24 hrs) for high-risk STEMI patients receiving thromboysis at non-PCI centres.

9803mo01, 5 PCI Centre Cath Lab CommunityHospitalEmergencyDepartment Cath / PCI within 6 hrs regardless of reperfusion status Cath and Rescue PCI  GP IIb/IIIa Inhibitor TNK + ASA + Heparin / Enoxaparin + Clopidogrel “PharmacoinvasiveStrategy” Urgent Transfer to PCI Centre Assess chest pain, ST  resolution at minutes after randomization at minutes after randomization ‘High Risk’ ST Elevation MI within 12 hours of symptom onset Failed Reperfusion* Successful Reperfusion Elective Cath  PCI > 24 hrs later “Standard Treatment” * ST segment resolution < 50% & persistent chest pain, or hemodynamic instability Repatriation of stable patients within 24 hrs of PCI Randomization stratified by age (≤75 vs. > 75) and by enrolling site

9803mo01, 6 Inclusion Criteria Within 12 hrs of symptom onset ≥ 2 mm ST-segment elevation in 2 anterior leads OR ≥ 1 mm ST-segment elevation in 2 inferior leads and at least one of the following: l SBP < 100 l HR > 100 l Killip Class II-III l ≥ 2mm ST-segment depression in anterior leads l ≥ 1 mm ST-segment elevation in V 4 R Within 12 hrs of symptom onset ≥ 2 mm ST-segment elevation in 2 anterior leads OR ≥ 1 mm ST-segment elevation in 2 inferior leads and at least one of the following: l SBP < 100 l HR > 100 l Killip Class II-III l ≥ 2mm ST-segment depression in anterior leads l ≥ 1 mm ST-segment elevation in V 4 R

9803mo01, 7 Selected Exclusion Criteria Cardiogenic Shock PCI within 1 month Previous CABG Primary PCI available with DTB < 60 minutes Use of Enoxaparin in last 12 hours in patient > 75 years of age Consent not obtained within 30 minutes of TNK Cardiogenic Shock PCI within 1 month Previous CABG Primary PCI available with DTB < 60 minutes Use of Enoxaparin in last 12 hours in patient > 75 years of age Consent not obtained within 30 minutes of TNK

9803mo01, 8 PCI for Pharmacoinvasive Group PCI of culprit lesion at time of cath if ≥ 70% stenosis or 50-70% stenosis with high-risk features (thrombus, ulceration, spont dissection) regardless of coronary flow Stents used whenever technically possible, use of Abbott vascular stents (ML Vision, Mini Vision) encouraged GP IIb/IIIa inhibitors left to operator’s discretion PCI of culprit lesion at time of cath if ≥ 70% stenosis or 50-70% stenosis with high-risk features (thrombus, ulceration, spont dissection) regardless of coronary flow Stents used whenever technically possible, use of Abbott vascular stents (ML Vision, Mini Vision) encouraged GP IIb/IIIa inhibitors left to operator’s discretion

9803mo01, 9 Endpoints 1 o Efficacy Endpoint: 30-day composite of Death, Reinfarction, Recurrent Ischemia, CHF, shock * 2 o Efficacy Endponts: Death / Reinfarction at 6 months and 1 Year Safety Endpoints: Bleeding (GUSTO Severe, TIMI Major) Endpoints adjudicated by clinical events committee blinded to treatment group 1 o Efficacy Endpoint: 30-day composite of Death, Reinfarction, Recurrent Ischemia, CHF, shock * 2 o Efficacy Endponts: Death / Reinfarction at 6 months and 1 Year Safety Endpoints: Bleeding (GUSTO Severe, TIMI Major) Endpoints adjudicated by clinical events committee blinded to treatment group * Endpoint definitions – Cantor WJ, Am Heart J 2008; 155: 19-25

9803mo01, 10 Baseline Characteristics Age (years) Age > 75 (%) Sex (% female) Medical History (%) Prior Angina Prior MI Prior PCI Prior Stroke/TIA * HypertensionHyperlipidemia Current smoker Diabetes StandardTreatment(n=508) 56 (49, 66) PharmacoinvasiveStrategy(n=522) 57 (51, 66) * p< 0.05

9803mo01, 11 Presenting Characteristics Weight (kg) Heart rate (beats/min) Systolic BP (mm Hg) Diastolic BP (mm Hg) Killip Class IIIIII Anterior ST-elevation Inferior ST-elevation Symptom Onset to TNK (hrs) StandardTreatment(n=508) 80 (70, 91) 77 (66, 90) 145 (130, 160) 84 (74, 95) (1, 3) 2 (1, 3)PharmacoinvasiveStrategy(n=522) 80 (70, 91) 74 (63, 88) 146 (130, 165) 84 (73, 95) (1, 3)

9803mo01, 12 Procedures Cardiac Cath performed (%) Time- TNK to Cath (hrs) Time- TNK to Cath (hrs) PCI performed (%) Stent used (% of PCI cases) Stent used (% of PCI cases) Time- TNK to PCI (hrs) Time- TNK to PCI (hrs) PCI within 6 hrs of TNK (%) PCI within 6 hrs of TNK (%) PCI within 12 hrs of TNK (%) PCI within 12 hrs of TNK (%) GP IIb/IIIa inhibitor use (%) GP IIb/IIIa inhibitor use (%) Time- TNK to GP IIb/IIIa inhib. (hrs) Time- TNK to GP IIb/IIIa inhib. (hrs) IABP use (%) CABG performed (%) StandardTreatment(n=508)82 27 (4, 69) (4, 73) (4, 63) 68PharmacoinvasiveStrategy(n=522)97 3 (2, 4) (3, 5)

9803mo01, 13 Selected Medications Used ASA 1 st 6 hrs Clopidogrel 1 st 6 hrs * HeparinEnoxaparin Beta Blocker 1 st 6 hrs ASA at discharge Clopidogrel at discharge Beta Blocker at discharge ACE Inhibitor at discharge Lipid Lowering at discharge StandardTreatment(n=508) PharmacoinvasiveStrategy(n=522) * p< 0.05

9803mo01, Days from Randomization % of Patients Standard PCI > 24 hrs (n=496) Invasive < 6 hrs (n=508) n=496n= Primary Endpoint: 30-Day Death, re-MI, CHF, Severe Recurrent Ischemia, Shock OR=0.537 (0.368, 0.783); p=0.0013

9803mo01, 15 Components of Primary Endpoint DeathReinfarction Recurrent Ischemia Death/MI/Ischemia New / worsening CHF Cardiogenic Shock StandardTreatment(n=498) PharmacoinvasiveStrategy(n=512) P-Value

9803mo01, 16 Safety Endpoints - Bleeding Intracranial hemorrhage TIMI scale Major Major (non-CABG-related) GUSTO scale ModerateSevere Severe (non-CABG-related) Transfusions StandardTreatment(n=498) PharmacoinvasiveStrategy(n=512) P-Value

9803mo01, 17 Summary Compared with ‘Standard Treatment’, a ‘Pharmacoinvasive Strategy’ of routine early PCI within 6 hrs after thrombolysis is associated with a 6% absolute (46% relative) reduction in the composite of death, reinfarction, recurrent ischemia, heart failure and shock The pharmacoinvasive strategy is not associated with any increase in transfusions, severe bleeding or intracranial hemorrhage despite high use of GP IIb/IIIa inhibitors during PCI In contrast to older trials, routine early PCI after thrombolysis using stents and contemporary pharmacotherapy is safe and effective l Benefit seen despite high cath/PCI rates in Standard Treatment group (including ~40% rescue PCI) Compared with ‘Standard Treatment’, a ‘Pharmacoinvasive Strategy’ of routine early PCI within 6 hrs after thrombolysis is associated with a 6% absolute (46% relative) reduction in the composite of death, reinfarction, recurrent ischemia, heart failure and shock The pharmacoinvasive strategy is not associated with any increase in transfusions, severe bleeding or intracranial hemorrhage despite high use of GP IIb/IIIa inhibitors during PCI In contrast to older trials, routine early PCI after thrombolysis using stents and contemporary pharmacotherapy is safe and effective l Benefit seen despite high cath/PCI rates in Standard Treatment group (including ~40% rescue PCI)

9803mo01, 18 Conclusions For high-risk STEMI patients receiving thrombolysis at non-PCI centres, urgent transfer and PCI within 6 hours is associated with significantly less ischemic complications and no excess in bleeding Transfers to PCI centres should be initiated immediately after thrombolysis without waiting to see whether reperfusion is successful Regional systems should be developed to ensure timely transfers of STEMI patients to PCI centres For high-risk STEMI patients receiving thrombolysis at non-PCI centres, urgent transfer and PCI within 6 hours is associated with significantly less ischemic complications and no excess in bleeding Transfers to PCI centres should be initiated immediately after thrombolysis without waiting to see whether reperfusion is successful Regional systems should be developed to ensure timely transfers of STEMI patients to PCI centres