1. The 90 Minute Wall: 60% Rates of TIMI Grade 3 Flow % TIMI 3 Flow

2. What Do We Need to Do to Achieve Another 1% Mortality Reduction in AMI? % TIMI Grade 3 Flow Mortality (%) A 20% improvement in TIMI Grade 3 flow led to a 1% improvement in mortality in GUSTO 1 54% 32% 6.3% 7.4%

3. Microvascular Dysfunction Following AMI Microvascular Obstruction Platelet microembolization Thrombosis Reperfusion Injury Neutrophil aggregation Complement activation Free radical generation Endothelial dysfunction, spasm, microvascular constriction Microvascular Obstruction Platelet microembolization Thrombosis Reperfusion Injury Neutrophil aggregation Complement activation Free radical generation Endothelial dysfunction, spasm, microvascular constriction

4. Paradoxical Activation of Coagulation Following Thrombolytic Administration Thrombin generation Clot bound thrombin exposed as lysis proceeds Plasmin activation Rapid flow through a narrow lumen increases shear force & activates platelets Activated platelets in turn activate plasminogen inactivator (PAI 1) Thrombin generation Clot bound thrombin exposed as lysis proceeds Plasmin activation Rapid flow through a narrow lumen increases shear force & activates platelets Activated platelets in turn activate plasminogen inactivator (PAI 1) CM Gibson Annals Int Med 1999

5. Motivation for the Development of Combination Therapy Improved lysis of thrombus (more rapid & more complete), better flow Reduced reocclusion Improved microvascular function Improved safety (reduced bleeding due to reduction in dose of thrombolytic agent) Improved lysis of thrombus (more rapid & more complete), better flow Reduced reocclusion Improved microvascular function Improved safety (reduced bleeding due to reduction in dose of thrombolytic agent) CM Gibson Annals Int Med 1999

6. ST Segment Acute MI Trials Involving GP 2b3a Inhibitors Combination Therapy With Thrombolytic Agents Combination Therapy With Thrombolytic Agents PCI Trials Full Dose Lytic + GP 2b3a Reduced Dose Lytic + GP 2b3a TAMI 8 Impact AMI Paradigm SK- Eptifibatide TAMI 8 Impact AMI Paradigm SK- Eptifibatide TIMI 14 SPEED INTRO AMI TIMI 14 SPEED INTRO AMI FASTER ENTIRE INTEGRITI FASTER ENTIRE INTEGRITI GRAPE RAPPORT ADMIRAL CADILLAC GRAPE RAPPORT ADMIRAL CADILLAC CM Gibson Annals Int Med 1999

7. ST , lytic eligible, < 12 h Group I tPA < 100 mg Group I tPA < 100 mg Group II  dose tPA Group II  dose tPA Group III  dose SK Group III  dose SK Group IV No lytic Group IV No lytic Angio (90 min), In Hospital Events, 30 day F/U Angio (90 min), In Hospital Events, 30 day F/U No ReoPro ReoPro: bolus 0.25 mg/kg inf 0.125  g/kg/min x 12 h ReoPro: bolus 0.25 mg/kg inf 0.125  g/kg/min x 12 h STD Heparin (70 U/kg ; 15 U/kg/h) STD Heparin (70 U/kg ; 15 U/kg/h) Low Dose Heparin (60 U/kg ; 7 U/kg/h) ASAASA TIMI 14 TIMI 14 Study Group, Circulation 1999; 99: 2720.

8. TIMI 14: TIMI 2/3 Flow (Core Lab): 90 min tPAtPA 50 mg tPA + ReoPro RP bolus 0.3 mg/kg RP bolus 0.3 mg/kg ReoProReoPro SK 1.5M U  SK + ReoPro % Pts 9494 7979 4848 TIMI 14 7979 5454 8181 6666 7575 8181 bb inf 30’ inf 60’ 14631429364947284636 N = 100 mg bolus 0.25 inf 0.125 500 K 750 K 1.25 M UU 34 8989 TIMI 1 + GUSTO 1 TIMI 14 Study Group, Circulation 1999; 99: 2720.

9. TIMI Frame Count: 90 min TIMI 14 0 0 10 20 30 40 50 60 70 80 90 100 0 0 10 20 30 40 50 60 70 80 90 100 % Patients Corrected TIMI Frame Count Normal Flow cTFC < 28 tPA 100 mg 37 tPA (bolus/60 m inf)+ ReoPro 31 ReoPro 100 ReoPro 100 SK + ReoPro 45 TFC Median TIMI 14 Study Group, Circulation 1999; 99: 2720.

11. TIMI-14: TIMI 3 Flow (Core Lab) at 90 Min t-PA 100 mg All Dose Conf. Dose Find  t-PA (50 mg*) + Abciximab Low-dose Heparin Very Low-dose Heparin 214 87 61 58 29 p < 0.02 *(bolus 15 mg; infusion 35 mg x 60 m) TIMI 14 Study Group, Circulation 1999; 99: 2720.

12. Abciximab Improves Myocardial Perfusion Complete (>70%) ST Resolution at 90 Min. Myocardial Perfusion Grade 2/3 at 90 Min. % Patients N=125 N=221 N=33 N=66 tPA rPA tPA + Abx rPA + Abx p<0.001 p<0.08 de Lemos AHA 1999 Gibson AHA 1999

13. TIMI Grade 3 Flow at 60–90 Min Angiographic Core Lab Reading n = 107n = 103n = 75n = 66 r-PA60 U Hep40 U HepAbciximab AloneAbciximabAbciximabAlone + r-PA 5 + 5+ r-PA 5 + 5 n = 107n = 103n = 75n = 66 r-PA60 U Hep40 U HepAbciximab AloneAbciximabAbciximabAlone + r-PA 5 + 5+ r-PA 5 + 5 Dose escalation and confirmation combined p = 0.2 p 0.06

14. Abciximab 0.25 mg/kg bolus 0.125  g/kg/min r-PA 5 + 5 U Heparin Abciximab 0.25 mg/kg bolus 0.125  g/kg/min r-PA 5 + 5 U Heparin Primary Endpoint: 30-Day Mortality 16,600 patients  Acute MI  ST elevation  Symptoms  6 hrs r-PA 10 + 10 U Heparin Heparin GUSTO-IV AMI: Protocol

15. INTRO AMI: TIMI Grade 3 Flow at 90 Minutes 33 30 31 30 48 Integrilin bolus 180 180180 180/90 180/90 Integrilin infusion 1.33 1.33 2.0 1.33 1.33 tPA bolus 25 15 15 25 15 tPA infusion 35 35 35 Integrilin bolus 180 180180 180/90 180/90 Integrilin infusion 1.33 1.33 2.0 1.33 1.33 tPA bolus 25 15 15 25 15 tPA infusion 35 35 35

16. Major Hemorrhage (Investigator) % Pts tPAtPA ReoP ro  SK + ReoPro  tPA + ReoPro Major Hemorrhage = ICH, Retroperitoneal, or  Hg > 5 gm/dL ICHICH InstrInstr SpontSpont N = 164 32323737494951516638384242505036365353373748483535 00 00 66 66 55 88 1414 6767 55 44 88 88 55 1515 500 K 750 K 1.25 M 1.5 M 2020353550506565 RP 0.3mg RP 0.3mg 100 mg b 0.25 inf 0.125 1212 ALL SK 66 143143339339 ALL tPA TIMI 14 Study Group, Circulation 1999; 99: 2720.

17. Advantages of Combination Pharmacotherapy Quick and easy to administer, no learning curve Widely available at all times of the night and day at all hospitals Achieves patency early Prejunctive therapy does not preclude mechanical intervention Quick and easy to administer, no learning curve Widely available at all times of the night and day at all hospitals Achieves patency early Prejunctive therapy does not preclude mechanical intervention CM Gibson Annals Int Med 1999

18. The New Time Dependent Open Artery and Open Microvascular Hypothesis The Five Laws : –Not all TIMI Grade 3 Flow is Created Equally –TIMI Grade 3 Flow is Necessary but not Sufficient –It is the Achievement of TIMI Grade 3 Flow in both the Epicardial Artery and the Microvasculature that Optimizes Clinical Outcomes –Faster is Better: The Faster Achievement of Faster Flow Optimizes Clinical Outcomes –Location, location, location: Drug efficacy and clinical outocmes must be interpreted in the context of infarct artery location The Five Laws : –Not all TIMI Grade 3 Flow is Created Equally –TIMI Grade 3 Flow is Necessary but not Sufficient –It is the Achievement of TIMI Grade 3 Flow in both the Epicardial Artery and the Microvasculature that Optimizes Clinical Outcomes –Faster is Better: The Faster Achievement of Faster Flow Optimizes Clinical Outcomes –Location, location, location: Drug efficacy and clinical outocmes must be interpreted in the context of infarct artery location CM Gibson 2000