1. A H Gershlick University Hospital of Leicester UK A H Gershlick University Hospital of Leicester UK AA 2008 Who should we rescue ?

2. Thrombolysis Tissue Plasminogen activator

3. 150 000 patients 53% early reperfusion 52% thrombolysis Thrombolysis studied in 45 000 pt 20-30 lives saved / 1000 Thrombolysis studied in 45 000 pt 20-30 lives saved / 1000

4. Acute MI CatchmentsTertiary PCI Catchments Is P-PCI deliverable everywhere

5. While there is still lysis, there will be lytic failure Failure ? : “TIMI 3” In the real world ? ST segment resolution @ 60/ 90 min Failure ? : “TIMI 3” In the real world ? ST segment resolution @ 60/ 90 min X Normal Flow 60% 40%

6. Who should we Rescue ?  - ? markers of lytic failure o Pain - insensitive - MERLIN 43% R-PCI (ECG) pain free - TAMI -5 – clinical variables not predictive o Biomarkers –sensitivity 92% specificity 56% Stewart JACC 1998 31 1499

8. Schroder R et al. JACC 1995;26:1657-1664

9. Peak CK values in relation to the sum of ST-segment resolution (100%, 70% or 30% cut-offs) 3 hours following start of thrombolytic therapy Schroder R et al. JACC 1995;26:1657-1664

10. The Data :

11. 2004

14. Cumulative Event-free Survival following R-PCI versus Conservative Therapy REACT MERLIN Gershlick AH et al NEJM 2005;353:2758-2768Sutton AGC et al JACC 2004;44:287-296

15. Differing Methodology: REACT versus MERLIN Centres 35 5 ST Resolution 50% at 90mins 50% at 60 mins 10% had TIMI III at angios 40% TIMI III at angio SK 58% 96% Stents 69% 50% GP IIb-IIIa use 43% 3% PCI arm- PCI mandated not mandated completed in 96.5% completed in 66% PCI within 30 days 2% of conservative group 20% conservative group Recruitment 3.3 patients /centre/ year 30.7 patients/centre/year Heart failure “NYHA III or IV” Diuretics

16. Outcome MERLIN versus REACT @ 1 year Outcome MERLIN versus REACT @ 1 year

17. 12 month & Long term 12 month & Long term REACT Trial

19. Mortality – to a median 4 ½ years

20. death death/reAMI

22. RESCUE PCI – HOW DO THE OUTCOMES FROM ‘REAL-WORLD’ PATIENTS COMPARE TO THE PUBLISHED TRIALS ? 185 Consecutive Rescue PCI patients April 2005- August 2007 @ glenfield Clinical follow-up via PCI database, case-note review and ONS, at a mean of 4.5months Mean (SD) delay from symptom onset to PCI =501 (229) minutes [8.35 hours], range 145-2240 min Kelly DJ, Siddiqui N, Holt M, Gershlick AH-Submitted to BCS

23. 2007 R-PCI Registry vs REACT Trial * Mean 4.5month Follow-up **6/12 Follow-up 7 2.2 0.5 10.3 6.2 2.1 4.9 15.3 0 2 4 6 8 10 12 14 16 % 2007 Registry*REACT Trial** Death Re-AMI CVA Heart Failure MACE

24. Local vs Transfer Patients p=0.322 p=0.42 Mean Delay 438minMean Delay 525min 3.7 9.3 8.4 11.5 0 2 4 6 8 10 12 % Local PCI Centre Patients Transferred Patients Mortality MACE 7.3 hrs 8.75 hrs Mean Delay S-B

25. When ? : Timing issues

26. GRACE REGISTRY- Relationship between door-to-needle time and 6-month mortality among1786 patients undergoing fibrinolytic therapy for AMI Nallamothu B et al Heart 2007;93:1552-5

27. Time (hrs) Lytic to R- PCI Symptom to R-PCI 4.6 hours6.9 hours

28. REACT delay after symptom onset 1

29. Mortality versus Tertile of Delay (Symptom onset to R-PCI) *Mean Delay from Symptom Onset to R-PCI (all patients) p=0.09 3.2 4.8 13.1 0 2 4 6 8 10 12 14 All-cause Mortality (%) Shortest 290 min* Mid tertile 485 min Longest 694 min Registry

30. Rescue PCI : o All failed lytic (25%-30%) failure to resolve max St  to > 50% at 90 mins o As soon as possible ( Sympt - balloon < 3 hrs) Who not to “rescue”

31. 1082 PCI 1084 OMT 3–28 days post AMI

33. “Mm… shall I give repeat thrombolysis ?” REACT – Bleeding Outcomes REACT – Bleeding Outcomes 5 15 20 10 4.9 2.1 18.7 3.5 8.58.4 % % MAJOR ( > 3g/dl) MAJOR ( > 3g/dl) Lysis C RPCI Lysis C RPCI OVERT Bld No OVERT Bld 22/27 (82%) sheath 22/27 (82%) sheath 3 HPericard 1 Death 3 HPericard 1 Death 1 H thorax 1 Death 1 H thorax 1 Death

34. What can Rescue –PCI do for you ?

35. Pre-Hospital Lysis @ 4.30 am ECG @ 6 am Angio @ 6.45 Pre-Hospital Lysis @ 4.30 am ECG @ 6 am Angio @ 6.45

36. RESCUE–PCI should be mandated & be part of AMI protocols Repeat lytic may be dangerous RESCUE–PCI should be mandated & be part of AMI protocols Repeat lytic may be dangerous

37. Conservative Rescue (n=154) (n=153) Death 11.0 9.8 Re-AMI 10.4 7.2 Stroke 0.6 4.6 Heart failure 29.9 24.2 10.6 7.8 2.1 12.1 4.9 0.7 1.4 7.6 REACT 30 day MERLIN

38. 1 2 3 4 5 6 7 Time hrs 1 2 3 4 5 6 7 Time hrs L 1 – L 2 190 (3.2 hrs) L 1 -RPCI 274 (4.6 hrs) 84 mins 1.4 hrs 1.4 hrs 84 mins 1.4 hrs 1.4 hrs R Pain D Door to 1 st lytic 27 mins (0-3736) Pain to 1 st lytic 140 mins (15-1990) 113 Pain to 2 nd lytic 330 mins (160-2145) 2 nd lytic Pain to R-PCI 414 mins (188-4220) MEDIAN TIMES

39. REACT delay after symptom onset 2

40. REACT delay after randomisation

41. R-PCI trials

42. *1 st anterior ‘failed reperfusion’ **1 st anterior ‘occluded LAD’ Adapted from Kunadian B, et al. J Invasive Cardiol 2007 Sep;19(9):359-68

43. MERLIN: 30-day Mortality according to ST-segment resolution 6 hours after initiation of fibrinolytic therapy Sutton et al JACC 2004;44:287-96

44. Timing of AMI Rx

45. Absolute Reduction in 35-day Mortality versus Delay from Symptom Onset to Randomization Among 45000 Patients with ST-segment elevation or LBBB Fibrinolytic Therapy Trialists’ Collaborative Group. Lanct 1994;343:311-322

46. Use of reperfusion therapy in 376,753 patients from NRMI-4 with STEMI or LBBB within 12 hours of symptom onset Curtis JP et al JACC 2006;47:1544-52

47. GRACE REGISTRY- Relationship between door-to-needle time and 6-month mortality among 2173 patients undergoing Primary PCI for AMI Nallamothu B et al Heart 2007;93:1552-5

48. Wiviott SD et al JACC 2004;44:783-9) Mortality versus NRMI-4 Risk Index following AMI

49. Curtis JP et al JACC 2006;47:1544-52

50. Thrombolysis Primary PCI

52. Denmark Czech Republic

54. Management of acute myocardial infarction in patients presenting with ST-segment elevation Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology Frans van der Werf EHJ 2003 ‘Rescue PCI’ is defined as PCI performed on a coronary artery which remains occluded despite fibrinolytic therapy. Limited experience from two randomised trials suggest a trend towards clinical benefit…. Class IIa Level of evidence B Weight of evidence in favour of usefulness Data from limited number of randomised trials involving small numbers of patients or from careful analysis of registry/observational Management of acute myocardial infarction in patients presenting with ST-segment elevation Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology Frans van der Werf EHJ 2003 ‘Rescue PCI’ is defined as PCI performed on a coronary artery which remains occluded despite fibrinolytic therapy. Limited experience from two randomised trials suggest a trend towards clinical benefit…. Class IIa Level of evidence B Weight of evidence in favour of usefulness Data from limited number of randomised trials involving small numbers of patients or from careful analysis of registry/observational

55. Intuitive to perform PCI But Rescue PCI is not Primary  Why did lysis fail ?  clot burden, disrupted vessel,  PCI in the setting lytic administration (activation platelets, release thrombin)  Time delay  Patients sicker Intuitive to perform PCI But Rescue PCI is not Primary  Why did lysis fail ?  clot burden, disrupted vessel,  PCI in the setting lytic administration (activation platelets, release thrombin)  Time delay  Patients sicker

56. Late 1990s

57. RESCUE I Trial Results Randomised Evaluation of Salvage Angioplasty with Combined Utilization of Endpoints Ellis et al. Circulation 90(5) 1994 5 10 1 7 6 17 0 2 4 6 8 10 12 14 16 18 % DeathSevere heart failure Death or severe heart failure Angioplasty 78 Conservative 73 p=0.18 p=0.11 p=0.05 Background

58. 2004

59. REACT ( RE scue A ngioplasty v C onservative treatment or repeat T hrombolysis ) ECG 90 min post (any incl SK) thrombolytic ST < 50 % resolution (with or without pain) CONSENT & RANDOMISE Conservative 2 nd thrombolytic Coronary Angio 24 iv heparin Accelerated tPA or +/- PCI Reteplase primary end point: 6/12 ~death/re-infarction/severe HF/CVA REACT ( RE scue A ngioplasty v C onservative treatment or repeat T hrombolysis ) ECG 90 min post (any incl SK) thrombolytic ST < 50 % resolution (with or without pain) CONSENT & RANDOMISE Conservative 2 nd thrombolytic Coronary Angio 24 iv heparin Accelerated tPA or +/- PCI Reteplase primary end point: 6/12 ~death/re-infarction/severe HF/CVA 2000

60. Inclusion Criteria uAcute Myocardial Infarction uAspirin + Thrombolytic within 6 hours uAge 21yrs - 85 yrs uAbility to perform intervention within 12hrs of onset symptoms uFailed reperfusion (ECG < 50% resolved) uAcute Myocardial Infarction uAspirin + Thrombolytic within 6 hours uAge 21yrs - 85 yrs uAbility to perform intervention within 12hrs of onset symptoms uFailed reperfusion (ECG < 50% resolved)

61. Exclusion Criteria Safety pre-requisites pre randomisation (thrombolytic) Safety pre-requisites pre randomisation (thrombolytic) a. Hb, Hct & platelet count b. Weight (< 65 kg) c. Age (> 85 y) d. Any evidence bleeding e. Hypertension during admission (after administration first lytic; age ) f. CGS {g. LMW heparin} {g. LMW heparin} Safety pre-requisites pre randomisation (thrombolytic) Safety pre-requisites pre randomisation (thrombolytic) a. Hb, Hct & platelet count b. Weight (< 65 kg) c. Age (> 85 y) d. Any evidence bleeding e. Hypertension during admission (after administration first lytic; age ) f. CGS {g. LMW heparin} {g. LMW heparin}

62. Demographics slide 1 n=427 Group A (n=142) R -LYSIS Group B (n=141) CONSERVATIVE Group C (n=144) R-PCI Male80.3%78.7%78.5%79.2% Age61.3 (10.3) y61.0 (10.7) y61.1 (11.9) y61.1 (11.0) y H/o angina 22.5%20.6%22.2%21.8% H/o AMI n=426 16.2%12.1%9.8% (p= 0.1) 12.7% H/o PCI4.2%2.8%4.2%3.7% H/o CABG4.9%2.8%4.9%4.2% H/o Diabetes16.2%11.3%14.6%14.1% H/o HT42.3%37.6%32.6%37.5% SmokingCurr 49.6% Prev 29.1% Curr 46.1% Prev 29.8% Curr 47.2% Prev 27.8% Curr 47.7% Prev 28.9% RESULT S All patients

63. Demographics n=427* AnteriorInferior Post/Lateral Totals First lytic First Lytic rPA67432112(26%) SK771725 ( 60% ) TNK73010 (2%) tPA3118150(12%) Total Regions 182(43%) (55%)8(2%) 426 (*1 unknown)

64. 6 month data REACT Trial

65. Primary composite endpoint: (death and non-fatal re-AMI, CVA, Severe HF) Primary composite endpoint: (death and non-fatal re-AMI, CVA, Severe HF) RESULTS No. of subjects with a component of the Composite Primary End Point @ any time within 6 months N=142 R-LYSIS N=142 R-LYSIS N=141 Conservative N=141 Conservative N=144 R-PCI N=144 R-PCI 44 ( 31.0%) 44 ( 31.0%) 42 (29.8%) 42 (29.8%) 22 (15.3%) 22 (15.3%) R-PCI v Repeat lytic p< 0.001 R-PCI v Conservative p< 0.01 Repeat lytic v Conservative NS

66. R-PCI R-lysis C

67. Group Group 00.20.40.60.811.21.41.61.82 (Death, AMI, CVA or Severe Heart Failure) Comparative Group vs Reference Group Favours Comparative Favours Reference Hazard Ratio R-PCI vs Conservative Repeat Lysis vs Conservative R-PCI vs Repeat Lysis HR=0.47 95% CI 0.28 to 0.79 HR=0.45 95% CI 0.27 to 0.75 HR=1.04 95% 0.68 to 1.59 n=285 n=286 n=283 COMPOSITE END POINT Hazard Ratios and 95% CI at 6 Months p=0.80 p=0.002 p=0.004

69. R-PCI leads to a consistently lower event rate within each age group For all patients, increasing age had an adverse effect upon 1 o endpoint (HR=1.05, 95% CI 1.03-1.07 (p<0.0001) Relative incremental risk of an event increased by 5% per year of age Impact of age on 6 month 1 o endpoint (ITT analysis) ARR: 14-17%7-10%22-30%29-34% Absolute risk reduction of R-PCI appears greater in patients >70 Characteristics similar across age ranges within and between groups

70. R-PCIRpt LysisConser 91% F-up

72. 18 2 18 3 9 2 18 2 14 0 4 1 0-6 months 6-12 months 3 0 4 0 1 0 21 3 22 2 13 1 0-6 months 6-12 months 33 5 29 14 19 5 Re-vasc

73. 0.08 R-PCIRpt LysisConser

74. Secondary End Point Hazard Ratio R-PCI vs Repeat Lysis vs Conservative R-PCI vs Repeat Lysis 00.20.40.60.811.21.41.61.82 Hazard Ratios and 95% CI of Revascularisation at 6 Months Comparative Group vs Reference Group Favours Comparative Favours Reference Group Group HR=0.61 95% CI 0.34 to 1.09 HR=0.53 95% CI 0.30 to 0.93 HR=1.16 95% 0.70 to 1.90 n=285 n=286 n=283 p=0.57 p=0.03 p= 0.10

75. R-PCIRpt LysisConser NS

76. Mortality REACT Trial

77. 0.13

78. Hazard Ratios and 95% CI of Mortality at 6 Months R-PCI vs Conservative Repeat Lysis vs Conservative R-PCI vs Repeat Lysis 00.20.40.60.811.21.41.61.82 Favours Comparative Favours Reference Group Group Hazard Ratio HR=0.48 95% CI 0.21 to 1.06 HR=0.48 95% CI 0.21 to 1.06 HR=1.00 95% 0.52 to 1.92 n=285 n=286 n=283 Comparative Group vs Reference Group p= 0.07

79. Longer term mortality ONS Patient specific NHS No.

81. Mortality for 416 /427 patients at median 4.4 years R PCI 19 % C 28 % R lysis 24 %

82. REACT trial Longer term outcome Events and difference in outcome happens early Benefit is maintained out to 12 months Late (4.4) year data indicates longer term mortality benefit In general R-PCI Where lysis is still a reperfusion strategy Failed lysis (< 50% ST segment resolution @ 90 mins) should be treated with Rescue – PCI R-PCI should be part mandated reperfusion protocols timing issues are unresolved ASAP (within 3 hours of ECG  ) REACT trial Longer term outcome Events and difference in outcome happens early Benefit is maintained out to 12 months Late (4.4) year data indicates longer term mortality benefit In general R-PCI Where lysis is still a reperfusion strategy Failed lysis (< 50% ST segment resolution @ 90 mins) should be treated with Rescue – PCI R-PCI should be part mandated reperfusion protocols timing issues are unresolved ASAP (within 3 hours of ECG  )

83. Numbers at risk R-PCI1441321311198440140 Repeated thrombolysis142119117104663580 Conservative141118112100723380

86. REACT delay after symptom onset 1

87. REACT delay after symptom onset 2

88. REACT delay after randomisation

89. MERLIN REACT Time sypmt to hospital 10 6 Pain to lysis 180 mins 140 mins ECG 6o mins 90 mins SK 96% 60% Stents 50.3% 68.5% GP IIbIIIa 3.3% 43.4% Pain to cath lab 320 mins 420 mins Local v National Definitions (HF) MERLIN REACT Time sypmt to hospital 10 6 Pain to lysis 180 mins 140 mins ECG 6o mins 90 mins SK 96% 60% Stents 50.3% 68.5% GP IIbIIIa 3.3% 43.4% Pain to cath lab 320 mins 420 mins Local v National Definitions (HF)

90. Conservative Rescue p value (n=154) (n=153) Death 11.0 9.8 0.7 Re-AMI 10.4 7.2 0.3 Stroke 0.6 4.6 0.03 Heart failure 29.9 24.2 0.3 Re-vasculascularisation 20.1 6.5 < 0.01 COMPOSITE 72 37.3 0.02 MERLIN 30 day JACC 2004,4, 287-96 10.6 7.8 2.1 12.1 14.9 47.5 4.9 0.7 1.4 7.6 8.3 22.9 REACT 30 day

92. Thrombolysis :(+ APT) tested in 100 000 pts  Saves 20-30 lives per thousand  Easy to administer  It is where the patients attend  No extra training  Starting to understand its limitations  Using pharmacology on way to cath lab not appropriate (ASSENT 4 FINESS) Thrombolysis :(+ APT) tested in 100 000 pts  Saves 20-30 lives per thousand  Easy to administer  It is where the patients attend  No extra training  Starting to understand its limitations  Using pharmacology on way to cath lab not appropriate (ASSENT 4 FINESS) Achieving recommended time lines for P-PCI may be difficult

93. Schroder R et al. JACC 1995;26:1657-1664

96. Admission Lysis 90 min repeat ECG Admission Lysis 90 min repeat ECG Giving lytic and going to bed is not enough !!! Primary Strategy