Randomized Trial to Evaluate the Relative PROTECTion against Post-PCI Microvascular Dysfunction and Post-PCI Ischemia among Anti-Platelet and Anti-Thrombotic Agents PROTECT – TIMI 30 Trial

Unresolved Issues Among UA / NSTEMI Patients Undergoing PCI What is the magnitude of the incremental benefit provided by the addition of an intravenous antiplatelet agent (a GP IIb-IIIa inhibitor) to antithrombotic agents?What is the magnitude of the incremental benefit provided by the addition of an intravenous antiplatelet agent (a GP IIb-IIIa inhibitor) to antithrombotic agents? What is the magnitude and importance of ongoing ischemia, myonecrosis and inflammation following PCI and how do antiplatelet and antithrombin agents affect these processes?What is the magnitude and importance of ongoing ischemia, myonecrosis and inflammation following PCI and how do antiplatelet and antithrombin agents affect these processes? How do we balance the risks (bleeding) and benefits (reduced myonecrosis) of these agents? How do we balance the risks (bleeding) and benefits (reduced myonecrosis) of these agents?

PROTECT: Goals (Continued) Efficacy:Efficacy: –Myocardial perfusion –Myonecrosis –Recurrent ischemia –Inflammation –Rebound thrombin production –Clinical outcomes Safety:Safety: –Bleeding Efficacy:Efficacy: –Myocardial perfusion –Myonecrosis –Recurrent ischemia –Inflammation –Rebound thrombin production –Clinical outcomes Safety:Safety: –Bleeding

TIMI 30: The PROTECT Trial High-risk UA/NSTEMI for PCI of a native coronary artery with either DM; or + Troponin; or ST   0.5 mm; or TRS > 3 Bivalirudin 0.75 mg/kg IVB mg/kg/h Eptifibatide 180/180  g/kg + 2  g/kg/min Low Dose UFH 50 U/kg IVB ACT Low Dose Enoxaparin 0.5 mg/kg IV + TRANSFER TO CATH LAB, DIAGNOSTIC ANGIOGRAM CONFIRM ELIGIBLE FOR PCI OF CULPRIT IN NATIVE ARTERY N = 857 Randomization stratified by Clopidogrel pretreatment >6 h and ≤6 h If not pretreated, then 300 mg Clopidogrel immediately prior to stenting. All tx’d with ASA

Primary Efficacy Endpoint Primary Efficacy Endpoint: –Coronary Flow Reserve (CFR) The acceleration in blood flow after adenosine TIMI Frame Count PRE-adenosine TIMI Frame Count POST-adenosine Interpreted by TIMI Angiographic Core Lab Blinded to treatment and clinical outcomes Primary Efficacy Endpoint: –Coronary Flow Reserve (CFR) The acceleration in blood flow after adenosine TIMI Frame Count PRE-adenosine TIMI Frame Count POST-adenosine Interpreted by TIMI Angiographic Core Lab Blinded to treatment and clinical outcomes Higher CFR means greater improvement in blood flow after adenosine e.g. a CFR of 2 would mean blood flow was twice as fast after adenosine

Other Angiographic Efficacy Endpoint: TIMI Myocardial Perfusion (TMP) Grades 6.2% 4.4% 2.0% n = 203 n = 46 n = 434 TMP Grade 3 p = 0.05 Mortality (%) n = % Gibson et al, Circulation 2000 Normal ground glass appearance of blush Dye mildly persistent at end of washout Normal ground glass appearance of blush Dye mildly persistent at end of washout Dye strongly persistent at end of washout Gone by next injection Dye strongly persistent at end of washout Gone by next injection Stain present Blush persists on next injection Stain present Blush persists on next injection No or minimal blush TMP Grade 2 TMP Grade 1 TMP Grade 0