1. Transfers, Facilitated and Rescue PCI for AMI Michael J Cowley, M.D., FSCAI Nothing to disclose

2. Primary PCI vs Lysis for STEMI Meta-analysis of 23 trials Keeley EC Lancet 2003; 361: 13-20 p=0.0003 p<0.0001 p=0.0004 p<0.0001 p<0.0001 Short Term Events %

3. Transfer for PCI is better than Lysis! (In a timely manner)

4. Lysis vs Transport for PCI Meta-analysis of 5 RCT Keeley EC Lancet 2003; 361: 13-20 p=0.057 p<0.0001 p<0.05 p=0.25 p<0.0001 % Average transfer time = 39 min

5. Transfer for Primary PCI vs Lysis Death, Re-MI, Stroke Dalby M et al: Circ; 2003; 108: 1809 Maastricht PRAGUE Air-Pami CAPTIM DANAMI 2 PRAGUE 2 8/75 14/75 8/101 23/99 6/71 9/66 26/421 34/419 63/790 107/782 36/429 64/421 147/1887 251/1863 Total OR: 0.58 p<0.001 - - - - - - - 0.1 0.2 0.3 0.5 0.7 1.0 1.4 Relative Risk PCI Lysis

6. DANAMI-2 Primary Endpoint (Death, re-MI, CVA) % Days 14.2% 8.5% NNT=18 20 10 0 0 5 15 20 25 30 Average transfer time = 68 min

7. Time Delay Is Important with Primary PCI

8. Transfers, Facilitated and Rescue PCI Primary PCI is the preferred reperfusion strategy for STEMI if it can be done in a timely manner Only 25% of US hospitals are capable of Primary PCI 82% of STEMI pts transferred from non-PCI hospitals for Primary PCI have Door to Balloon times > 120 min (ACC/NCDR ) Chakrabarti, JACC 2008 Primary PCI is the preferred reperfusion strategy for STEMI if it can be done in a timely manner Only 25% of US hospitals are capable of Primary PCI 82% of STEMI pts transferred from non-PCI hospitals for Primary PCI have Door to Balloon times > 120 min (ACC/NCDR ) Chakrabarti, JACC 2008 Delays due to Long Transfer Times are common

9. Primary PCI: Access in US Nallamothu et al: Circulation 2006;113:1189 * Weather permitting Pre-Hospital Time Period < 60 min > 60 min 42% PCI hospital is closest facility 79% within 60 min prehospital time*

10. # of Pts 2,230 5,734 6,616 4,461 2,627 5,412 Cannon CP, et al: JAMA 2000;283:2941–2947 p=0.35 p=0.29 p=0.01 p<0.001 p<0.001 Time (min) Relation Between D2B Times and In-Hospital Mortality in NRMI Multivariate Odds Ratio

11. Treatment Delays with 1° PCI Brodie B, et al: JACC 2006;47:289 100 – 90– 80– 70– 60– 50– 01234567891011 Cardiac Survival Door–to–Balloon Time 0 – 1.4 hr 1.5 – 1.9 hr 2.0 – 2.9 hr ≥ 3.0 hr p< 0.0001 Years n = 2,300 % – – – – – – – – – – – 0-90 min 90-120 min 120-180 min 180 min

12. % Transfer for Primary PCI Chakrabarti A: J Am Coll Cardiol 51:2442, 2008 Total door-to-balloon time (hrs) Only 36% <120 min

13. % Door-In Door-Out Time at Referring Hospital Ting HH: AHA 2009 (abstract) Door-in Door-Out time (min) Median DIDO (IQR) = 74 min (45-132) 40% had DIDO >90 min

16. p=0.01 Interhospital Delay in Transfer Door-to-Door Times 1 year Mortality (n=616 pts) % De Luca G: AJC 2005; 95: 1361

17. US Transfer Delay for Primary PCI (NRMI 3 / 4) % Nallamothu B: Circulation 2005; 111: 761 Total Door to Balloon Time (h) <16% < 2h52% > 3h

18. Rescue PCI

19. Rescue PCI is better than Lysis!

20. RESCUE PCI: REACT Trial REACT= Rescue Angioplasty versus Conservative Treatment or Repeat Thrombolysis Gershlick AH, et al: NEJM 2005; 353:2758-2768 1.00 0.90 0.80 0.70 0.60 0.00 020406080100120140160180200 Days After Randomization Probability of Event-Free Survival Rescue PCI Conservative Repeat Lysis p=0.004 84.6% 70.1% 68.7% Primary End Point (D, re-MI, severe CHF, CVA) at 6 mo

21. JACC 2007; 49: 422-430

22. % Meta-analysis of 3 RCT (n=700 pts) Wijeysundera HC: JACC 2007; 49:422-430 Rescue PCI vs Conservative Rx p=0.09 p=0.04 p=0.04 p=0.05 p=0.001

23. “Facilitated” PCI

24. Facilitated PCI Was inferior to pPCI with short transfer times Was harmful in ASSENT 4 Study had serious design flaws Did not address key question: Best Rx for pts with long transfer delays? Was inferior to pPCI with short transfer times Was harmful in ASSENT 4 Study had serious design flaws Did not address key question: Best Rx for pts with long transfer delays?

25. Reperfusion Options for Transfer Patients with Expected Delays Primary PCI (no matter how long it takes) Lysis; ischemia-guided transfer for rescue PCI Lysis with transfer for immediate (“early” PCI): Pharmaco-invasive strategy Primary PCI (no matter how long it takes) Lysis; ischemia-guided transfer for rescue PCI Lysis with transfer for immediate (“early” PCI): Pharmaco-invasive strategy

26. Facilitated or Pharmaco-invasive AMICO Registry CARESS-in-AMI TRANSFER-AMI NOR-DISTEMI AMICO Registry CARESS-in-AMI TRANSFER-AMI NOR-DISTEMI

27. AMICO: Alliance for Myocardial Infarction Care Optimization R McKay A Denktas, H Athar, S Sdringola, Vernon Anderson, R Smalling Timothy Henry, David Larson M Simons, N Niles H Thiele, G Schuler C Ahn, PhD

28. p=0.002 AMICO Registry: Pharmacoinvasive Rx 30 day Outcomes Henry T, et al: JACC 2008; 1: 504-510 % p=NS p=0.0006 p<0.0001

29. Early Invasive vs Ischemia-guided Rx after Lysis for STEMI: Meta-analysis Wijeysundera HC: AHJ 2008; 156: 564-572

30. % Borgia F: EHJ 2010; 31: 2156-2169 Early Routine PCI vs Standard Rx after Lysis p=ns 7 RCT (n=2961 pts) p=0.001 p=0.004 p=0.003 p=0.51 * Rescue PCI: 20% 30 Day Clinical Outcomes

31. CARESS in AMI: Design UFH (7 U/Kg/h) for transfer PCI: ACT adjusted to 200- 250” ;UFH stopped after PCI UFH (7 U/Kg/h) for transfer PCI: ACT adjusted to 200- 250” ;UFH stopped after PCI Reteplase UFH bolus (max 3000 + IV at 7 U/kg/h) Abciximab bolus + IV ASA 300-500 mg iv Reteplase UFH bolus (max 3000 + IV at 7 U/kg/h) Abciximab bolus + IV ASA 300-500 mg iv UFH (7 U/Kg/h for 24 hrs) If Rescue PCI: ACT adjust to 200 - 250”; UFH stopped after PCI Facilitated PCIMedical Treatment/ Rescue Clopidogrel for 1-12 mo after stenting (514 pts; 82%)

32. Primary Outcome at 30 days 4.1% 11.1% Death, re-MI, refractory ischaemia OR 0.34 (95%CI 0.17-0.68) p=0.001 ‘Facilitated’ CARESS IN AMI DiMario C: Lancet 2008; 371:559-568 RescueRescue

33. PCI Centre Cath Lab CommunityHospitalEmergencyDepartment Cath / PCI < 6 hrs (+ reperfusion) Cath + Rescue PCI  GPI TNK + ASA + UFH / Enoxaparin + Clopidogrel “Pharmacoinvasive Strategy” Urgent Transfer to PCI Centre Assess chest pain, ST  resolution at 60-90 min after Rx ‘High Risk’ STEMI < 12 hrs 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 pts within 24 hrs of PCI Randomization stratified by age (≤75 vs > 75) and by enrolling site Transfer-AMI

34. 0 2 4 6 8 10 12 14 16 18 051015202530 10.6 16.6 Days from Randomization % Standard (n=496) Pharmacoinvasive (n=508) Pharmacoinvasive vs Lysis for high risk STEMI OR=0.54 (0.37, 0.78) p=0.0013 N=1,004 pts *Primary EP: Death, re-MI, CHF, Severe re-Ischemia, Shock Primary Endpoint* at 30 Days

35. PCI in STEMI* CO R LOE Non-Primary PCI (Delayed PCI) Evidence of lytic failure or IRA reocclusionIIaB Patent IRA 3 - 24 h after lytic therapyIIaB GNL 2011 *Systems goal for primary PCI: < 90 min of first medical contact at hospital with PCI capability (Class I, LOE: B) <120 min when the pt presents to hospital without PCI capability (Class I, LOE: B) 2011 Guidelines Indications

36. Transfer, Facilitated and Rescue PCI Primary PCI is preferred for STEMI Primary PCI preferred if transfer times are short Pharmacoinvasive strategy is preferred for when transfer times are long Early “routine” PCI after lysis is preferred over rescue strategy (particularly in high risk pts) Includes rescue PCI for failed reperfusion Prevents early reocclusion after successful lysis Primary PCI is preferred for STEMI Primary PCI preferred if transfer times are short Pharmacoinvasive strategy is preferred for when transfer times are long Early “routine” PCI after lysis is preferred over rescue strategy (particularly in high risk pts) Includes rescue PCI for failed reperfusion Prevents early reocclusion after successful lysis Summary

38. 0 20 40 60 80 100 1361224 Extent of salvage (% of area at risk) Treatment objectives Time to treatment is critical Opening the IRA (PCI > lysis) Hours Relationship Between Myocardial Salvage and Survival Gersh, Stone, Holmes. JAMA 2005 Median U.S. Sx-ER: 2° Mortality reduction (%) 90’ DBT Goal U.S. PCI Sx-bal: 3.5° Modifying factors CollateralsIschemic preconditioning Collaterals Ischemic preconditioning MVO 2

39. 2012: Do whatever it takes to reduce time from symptom onset to ER arrival and time from ER arrival to PCI!  Public awareness of MI Sx Chest pain centers of excellence with lower DBTs and excellent outcomes Regional coordination Ambulance ECG telemetry Ambulance/ER CCL activation ICs sleep in hospital Continual QI

40. 0 20 40 60 80 100 1361224 Extent of salvage (% of area at risk) Treatment objectives Time to treatment is critical Opening the IRA (PCI > lysis) Hours Relationship Between Myocardial Salvage and Survival Gersh, Stone, Holmes. JAMA 2005 Median U.S. Sx-ER: 1.75° Modifying factors CollateralsIschemic preconditioning Collaterals Ischemic preconditioning MVO 2 Mortality reduction (%) Goal U.S. PCI Sx-bal: 2.75° 60’ DBT

41. Krumholz H M et al. Circulation 2011;124:1038-1045 44.2% 91.4% Median 96 mins Median 64 mins Door-to-balloon time <90 mins at CMS hospitals N pts48,97752,02851,29853,03253,68242,150

42. 0 20 40 60 80 100 1361224 Extent of salvage (% of area at risk) Treatment objectives Time to treatment is critical Opening the IRA (PCI > lysis) Hours Relationship Between Myocardial Salvage and Survival Gersh, Stone, Holmes. JAMA 2005 Mortality reduction (%) Median U.S. Sx-ER: 1.5° 45’ DBT Goal U.S. PCI Sx-bal: 2.25° Modifying factors CollateralsIschemic preconditioning Collaterals Ischemic preconditioning MVO 2

43. 0 20 40 60 80 100 1361224 Extent of salvage (% of area at risk) Treatment objectives Time to treatment is critical Opening the IRA (PCI > lysis) Hours Relationship Between Myocardial Salvage and Survival: The future? Mortality reduction (%) Median U.S. Sx-ER: 1.5° Goal U.S. PCI Sx-bal: 2.25° 45’ DBT Modifying factors Collaterals Collaterals Ischemic preconditioning Ischemic preconditioning MVO 2 Change the shape of the curve! Interventions to improve: Reperfusion injury Microcirculatory function Microcirculatory function

45. p=0.01 Interhospital Delay in Transfer Door-to-Door Times 1 year Mortality (n=616 pts) % De Luca G: AJC 2005; 95: 1361

46. p=0.01 Interhospital Delay in Transfer Door-to-Door Times 1 year Mortality (n=616 pts) % De Luca G: AJC 2005; 95: 1361

47. US Transfer Delay for Primary PCI (NRMI 3 / 4) % Nallamothu B: Circulation 2005; 111: 761 Total Door to Balloon Time (h) <16% < 2h52% > 3h

48. Reperfusion Options for Transfer Patients with Expected Delays Lysis; ischemia-guided transfer for rescue PCI Lysis, routine transfer for aggressive rescue PCI Primary PCI (no matter how long it takes) Lysis with transfer for immediate (“early” PCI): Pharmaco-invasive strategy Lysis; ischemia-guided transfer for rescue PCI Lysis, routine transfer for aggressive rescue PCI Primary PCI (no matter how long it takes) Lysis with transfer for immediate (“early” PCI): Pharmaco-invasive strategy

49. 7 RCT; n=2961 pts

51. AMICO: Alliance for Myocardial Infarction Care Optimization Raymond G. McKay, MD Ali. E. Denktas, MD, Haris Athar, MD, Stefano Sdringola, MD, H. Vernon Anderson, MD, Richard W. Smalling, MD, PhD Timothy D. Henry, MD, David M. Larson, MD Michael Simons, MD, Nathaniel W. Niles, MD Holger Thiele, MD Gerhard Schuler, MD Chul Ahn, PhD

52. 0 2 4 6 8 10 12 14 16 18 051015202530 10.6 16.6 Days from Randomization % Standard (n=496) Pharmacoinvasive (n=508) Primary Endpoint: 30-Day Death, re-MI, CHF, Severe Recurrent Ischemia, Shock OR=0.54 (0.37, 0.78) p=0.0013 N=1,004 pts

53. 0 2 4 6 8 10 12 14 16 18 051015202530 10.6 16.6 Days from Randomization % Standard (n=496) Pharmacoinvasive (n=508) n=496 n=508 422 468 415 466 415 463 414 461 414 460 412 457 Primary Endpoint: 30-Day Death, re-MI, CHF, Severe Recurrent Ischemia, Shock OR=0.54 (0.37, 0.78) p=0.0013 N=1,004 pts