1. Thrombolysis assisted PCI Bonnie H. Weiner MD MSEC MBA FSCAI Past President SCAI Professor of Medicine Director Interventional Cardiology Research St Vincent Hospital @ Worcester Medical Center Bonnie H. Weiner MD MSEC MBA FSCAI Past President SCAI Professor of Medicine Director Interventional Cardiology Research St Vincent Hospital @ Worcester Medical Center

2. Disclosure I am an Interventional Cardiologist I believe every STEMI patient should have PCI I deal with reality and recognize that this may not be possible everywhere today General Disclosures Ownership Imaging Core Lab Services Davol AtheroMed Consulting Boston Biomedical Associates CR Bard Labcoat Therox Cormend Research Medtronic Boston Scientific Abbott Honoraria SCAI I am an Interventional Cardiologist I believe every STEMI patient should have PCI I deal with reality and recognize that this may not be possible everywhere today General Disclosures Ownership Imaging Core Lab Services Davol AtheroMed Consulting Boston Biomedical Associates CR Bard Labcoat Therox Cormend Research Medtronic Boston Scientific Abbott Honoraria SCAI

3. PCI in STEMI Primary PCI PCI immediately following successful fibrinolysis Rescue PCI in failed fibrinolysis Facilitated PCI Primary PCI PCI immediately following successful fibrinolysis Rescue PCI in failed fibrinolysis Facilitated PCI

4. Repeat Thrombolysis Accelerated tPA or reteplase n=142 Primary Endpoint: Composite of death, reinfarction, CVA, or severe heart failure at 6 months REACT: 6 month results NEJM 2005;353:2758 427 Acute MI patients with failed thrombolysis aspirin thrombolytic therapy (60% received streptokinase) within 6 hours of chest pain onset, <50% resolution of ST changes on ECG at 90 minutes 42% anterior infarctions Conservative Treatment IV Unfractionated Heparin for 24 hours n=141 Rescue PCI Angiography with or without Revascularization n=144

5. REACT: 6 Month Results Primary Composite Endpoint at 6Months (Death, MI, CVA, or severe heart failure) The primary composite endpoint of death, MI, CVA or severe heart failure at 6 months was significantly lower in the rescue PCI group compared with either the repeat thrombolysis group or the conservative management group Repeat Thrombolysis Rescue PCI Conservative Management p<0.001 p=0.002

6. Facilitated PCI a strategy of planned immediate PCI after administration of an initial pharmacological regimen intended to improve coronary patency before the procedure. These regimens have included high- dose heparin, platelet glycoprotein (GP) IIb/IIIa inhibitors, full-dose or reduced dose fibrinolytic therapy, and the combination of a GP IIb/IIIa inhibitor with a reduced-dose fibrinolytic agent (e.g., fibrinolytic dose typically reduced 50%). *ACC/AHA 2007 Focused update STEMI Guidelines

7. Rational Primary PCI appears superior to thrombolysis but not all patients have the required prompt (DTB < 90 minutes) access to the cath lab. Treatment delays are common and reduce the true benefit of PCI TIMI 3 flow prior to PCI is an important predictor of success and clinical outcome Primary PCI appears superior to thrombolysis but not all patients have the required prompt (DTB < 90 minutes) access to the cath lab. Treatment delays are common and reduce the true benefit of PCI TIMI 3 flow prior to PCI is an important predictor of success and clinical outcome

8. Facilitated PCI A number of small studies suggested a benefit to several approaches CAPITAL-AMI 170 patients with STEMI randomized to TNK vs. TNK facilitated PCI Primary endpoint: death, re MI, recurrent unstable ischemia or stroke at 6 months A number of small studies suggested a benefit to several approaches CAPITAL-AMI 170 patients with STEMI randomized to TNK vs. TNK facilitated PCI Primary endpoint: death, re MI, recurrent unstable ischemia or stroke at 6 months

9. CAPITAL-AMI % With Composite Endpoint Days form Randomization JACC 2005;46:417 p=0.04 24.4% 11.6%

10. A D M I R A L bciximab before irect Angioplasty and Stenting in yocardial nfarction egarding cute and ong term follow-up ADMIRAL Study NEJM 2001;334:1895

11. Aim of the Study To demonstrate the superiority of abciximab over placebo in primary PTCA with stenting in acute myocardial infarction ESC

12. Design AMI < 12 hours randomized Abciximab + Heparin, ASA, Ticlopidine Placebo + Heparin, ASA, Ticlopidine First Coronary Angiography PTCA + Stent First Coronary Angiography PTCA + Stent Coronary Angiography at 24 h and 6 Months Coronary Angiography at 24 h and 6 Months Clinical evaluation (24 h, 30 Days and 6 Months

13. Primary Endpoint (6 months) 7.4 15.9 0 5 10 15 20 % of Patients p = 0.02 - 52.3 % Death, Recurrent MI, Urgent TVR Placebo n = 150 Abciximab n = 150

14. Primary Endpoint Components (6 Months) 7.3 3.4 4.0 6.6 2.0 0 5 10 DeathRecurrent MIUrgent TVR % of Patients PlaceboAbciximab p = 0.33 - 54.8% - 35.0% p = 0.02

15. Secondary Endpoint (6 Months) Death, Recurrent MI, Any Revascularization 22.8 33.8 0 20 30 40 % of Patients p = 0.03 - 39.5 % Placebo n = 150 Abciximab n = 150

16. Bleeding Events (30 Days) 3.3 12.1 0 0.7 0 2 4 6 8 12 MajorMinor % of Patients PlaceboAbciximab p = 0.50 p = 0.004

17. Facilitated PCI: Limits of the Data Conflicting studies: Currently is Class IIb, abciximab, anterior location, < 75 years old, no risk factors for bleeding, + planned PCI* Most show improved TIMI flow rates or less reinfarction Other harder endpoints such as death have been harder to prove Several recently presented larger trials: ASSENT 4: Negative study, stopped prematurely FINESSE: Reported at the ESC 2007 Conflicting studies: Currently is Class IIb, abciximab, anterior location, < 75 years old, no risk factors for bleeding, + planned PCI* Most show improved TIMI flow rates or less reinfarction Other harder endpoints such as death have been harder to prove Several recently presented larger trials: ASSENT 4: Negative study, stopped prematurely FINESSE: Reported at the ESC 2007 *ACC/AHA 2004 STEMI Guidelines

18. ASSENT-4: Full Dose Fibrinolytic with PCI vs. PCI Alone Full dose tenecteplase N=4000 Primary endpoint: death or CHF or cardiogenic shock at 90 days Study stopped at 1667 patients by the DSMB due to superiority of the PCI only arm Full dose tenecteplase N=4000 Primary endpoint: death or CHF or cardiogenic shock at 90 days Study stopped at 1667 patients by the DSMB due to superiority of the PCI only arm

19. Lancet 2006;367:569 ASSENT- 4: Outcomes at 90 days (primary end point) End pointTNK+PCI (%) PCI alone (%) p Death/CHF/ cardiogenic shock 18.813.70.0055

20. ASSENT- 4: Outcomes at 90 days Lancet 2006;367:569 End pointTNK+PCI (%) PCI alone (%) p Death6.75.00.141 Cardiogenic shock 6.14.80.273 CHF12.19.40.078

21. ASSENT- 4 secondary end points at 90 days Lancet 2006;367:569 End pointTNK+PCI (%) PCI alone (%) p Re-MI6.13.50.020 Repeat TVR6.63.60.006 Stroke2.650.10<0.0001 Intracranial hemorrhage 1.090.10<0.05 Major bleeds (in hospital) 5.64.40.3118

22. 3000 pts STEMI Chest pain <6 h ASA (150-325 mg) Heparin (40 U/kg, 3000) or Enoxaparin (.5/.3 mg/kg iv/sc) FACILITATED PCI Abciximab (.25/.125) Reteplase (5 IU + 5 IU) in the ED (single bolus for age>75) PCI 60-120 mins PRIMARY PCI Angio/PCI 60-120 minutes Abciximab during PCI in CCL 1° Endpoint 90 day death, CHF,VF, shock Double-blind, randomized, triple-dummy placebo-controlled ABCIXIMAB FACILITATED PCI Abciximab in ER Angio/PCI 60-120 minutes

23. Ellis S. European Society of Cardiology Congress 2007; September 3, 2007; Vienna, Austria. *All-cause mortality; rehospitalization or emergency department treatment for CHF; resuscitated ventricular fibrillation occurring >48 hours after randomization; cardiogenic shock ED=emergency department FINESSE End pointPrimary PCI (%) Abciximab- facilitated (%) Combination (abciximab/ reteplase)- facilitated (%) p, combination- facilitated vs primary PCI p, combination- facilitated vs abciximab- facilitated Primary end point* 10.710.59.8NS All-cause mortality 4.55.55.2NS Complications of MI 8.97.57.4NS CHF requiring hospital/ED visit 2.22.91.9NS Death4.55.55.2NS

24. Ellis S. European Society of Cardiology Congress 2007; September 3, 2007; Vienna, Austria. Primary, Secondary, and Bleeding End Points in FINESSE End pointPrimary PCI (%) Abciximab- facilitated (%) Combination (abciximab/ reteplase)- facilitated (%) p, combination- facilitated vs primary PCI p, combination- facilitated vs abciximab- facilitated Cardiogenic shock 6.84.85.3NS VF0.40.20.6NS TIMI major bleeding 2.64.14.80.025NS TIMI minor bleeding 4.36.09.7<0.0010.006 TIMI major or minor bleeding 6.910.114.5<0.0010.008 *All-cause mortality; rehospitalization or emergency department treatment for CHF; resuscitated ventricular fibrillation occurring >48 hours after randomization; cardiogenic shock VF=ventricular fibrillation

25. Ellis S et al. N Engl J Med 2008;358:2205-2217 FINESSE

26. Transfer-MI Randomized trial of pharmacoinvasivestratagy Routine transfer within 6 hours vs Rescue PCI for high risk STEMI Randomized trial of pharmacoinvasivestratagy Routine transfer within 6 hours vs Rescue PCI for high risk STEMI

27. Results

30. Level 1 MI Treatment Times Minutes (median) In door 1 outdoor 1 Transport time In door 2 - balloon Total In door to balloon Zone I (n=775) Zone II (n=557) AN (n=360) DANAMI (n=567) 49 (36,66) 60 (48,83) NA 50 (39-65) 22 (16,31) 35 (26,49) NA 32 (20-45) 21 (16,28) 19 (15,25) 65 (47,83) 26 (20-38) 95 (82,116) 122 (101,151) 65 (47,83) 108

31. Adair Adams Allamakee Appanoose Audubon Benton Black Hawk Boone Bremer Buchanan Buena Vista Butler Calhoun Carroll Cass Cedar Cerro Gordo Cherokee Chickasaw Clarke Clay Clayton Clinton Crawford Dallas Davis Decatur Delaware Des Moines Dickinson Dubuque Emmet Fayette Floyd Franklin Fremont Greene Grundy Guthrie Hamilton Hancock Hardin Harrison Henry Howard Humboldt Ida Iowa Jackson Jasper Jefferson Johnson Jones Keokuk Kossuth Lee Linn Louisa Lucas Lyon Madison Mahaska Marion Marshall Mills Mitchell Monona MonroeMontgomery Muscatine O'Brien Osceola Page Palo Alto Plymouth Pocahontas Polk Pottawattamie Poweshiek Ringgold Sac Scott Shelby Sioux Story Tama Taylor Union Van Buren Wapello Warren Washington Wayne Webster Winnebago Winneshiek Woodbury Worth Wright Primary Secondary Tertiary

32. Level 1 Heart Attack Program Report Card – February 1, 2004 to June 30, 2007Report Card – February 1, 2004 to June 30, 2007 MercyZone 1Zone 2 N=848N=509N=187N=152 Median D-B (min)60100134 30 Day Mortality(4.2%)4.5%2.1%5.9%

33. Blue = 30 miles- 15 min flight time (each way) Red= 60 miles- 23 min flight time (each way) GEISINGER: RURAL PENNSYLVANIA

34. GEISINGER RESULTS Patients Transferred to GMC 2004 (n = 110) 2005 (n = 134) 2006 (n = 143) 2007 (n = 63) D2B (Minutes) 18911310596

35. 10 PCI centers 16 Transfer for PCI 28 Lytics 11 Mixed RACE Centers and Regions 65 hospitals (10 PCI, 55 non PCI) Asheville Winston-Salem Durham-Chapel Hill- Greensboro Charlotte East Carolina Each non-PCI center was assessed for reperfusion designation based on resources, transfer ability, and transfer time to PCI center

36. Adair Adams Allamakee Appanoose Audubon Benton Black Hawk Boone Bremer Buchanan Buena Vista Butler Calhoun Carroll Cass Cedar Cerro Gordo Cherokee Chickasaw Clarke Clay Clayton Clinton Crawford Dallas Davis Decatur Delaware Des Moines Dickinson Dubuque Emmet Fayette Floyd Franklin Fremont Greene Grundy Guthrie Hamilton Hancock Hardin Harrison Henry Howard Humboldt Ida Iowa Jackson Jasper Jefferson Johnson Jones Keokuk Kossuth Lee Linn Louisa Lucas Lyon Madison Mahaska Marion Marshall Mills Mitchell Monona MonroeMontgomery Muscatine O'Brien Osceola Page Palo Alto Plymouth Pocahontas Polk Pottawattamie Poweshiek Ringgold Sac Scott Shelby Sioux Story Tama Taylor Union Van Buren Wapello Warren Washington Wayne Webster Winnebago Winneshiek Woodbury Worth Wright Primary Secondary Tertiary

37. Level 1 Heart Attack Program Report Card – February 1, 2004 to June 30, 2007Report Card – February 1, 2004 to June 30, 2007 MercyZone 1Zone 2 N=848N=509N=187N=152 Median D-B (min)60100134 30 Day Mortality(4.2%)4.5%2.1%5.9%

38. Blue = 30 miles- 15 min flight time (each way) Red= 60 miles- 23 min flight time (each way) GEISINGER: RURAL PENNSYLVANIA

39. GEISINGER RESULTS Patients Transferred to GMC 2004 (n = 110) 2005 (n = 134) 2006 (n = 143) 2007 (n = 63) D2B (Minutes) 18911310596

40. 10 PCI centers 16 Transfer for PCI 28 Lytics 11 Mixed RACE Centers and Regions 65 hospitals (10 PCI, 55 non PCI) Asheville Winston-Salem Durham-Chapel Hill- Greensboro Charlotte East Carolina Each non-PCI center was assessed for reperfusion designation based on resources, transfer ability, and transfer time to PCI center

41. Focused Update

42. Already out of sync with available data

43. Conclusions Large randomized trials of facilitated PCI (fibrinolytics+IIb/IIIa agents) have failed to show a positive benefit and but recent data have at least shown no harm The latest ACC/AHA (2007) consider facilitated PCI as a class IIb indication but with the more recent data from ASSENT-4 and FINESSE did not change substantially New Class III recommendation is out of sync with Transfer-MI data and network data (which both AHA and ACCF endorse) and fails to provide an option for patients without access to Primary PCI within 90 minutes Large randomized trials of facilitated PCI (fibrinolytics+IIb/IIIa agents) have failed to show a positive benefit and but recent data have at least shown no harm The latest ACC/AHA (2007) consider facilitated PCI as a class IIb indication but with the more recent data from ASSENT-4 and FINESSE did not change substantially New Class III recommendation is out of sync with Transfer-MI data and network data (which both AHA and ACCF endorse) and fails to provide an option for patients without access to Primary PCI within 90 minutes

44. Facilitated PCI should not be first line therapy if primary PCI is available within 90 minutes It is a reasonable alternative however when it is not possible to provide primary PCI because of: Distances Transfer times Resources Cost If done correctly mortality may approach that seen for primary PCI and will provide more patients with reperfusion therapy

45. Thank You