1. Prof. Federico Piscione Federico II University Naples, Italy Oclusões crônicas: Impacto da intervenção percutânea na evolução clínica de longo prazo Federico II University of Naples

2. OPEN ARTERY HYPOTHESIS TIME-DEPENDENT COMPONENT TIME-INDEPENDENT COMPONENT IRA LATE RECANALIZATION IRA EARLY RECANALIZATION BENEFITS INDEPENDENT OF MYOCARDIAL SALVAGE IMPROVED SURVIVAL MYOCARDIAL SALVAGE LV FUNCTION PRESERVATION IMPROVED SURVIVAL Indisputably shown! Never convincingly shown! Federico II University of Naples

3.  Collateral Vessels  Electrical Stability  Anti-Remodeling Effects  Time-independent Myocardial Salvage Potential Benefits by Time-Independent Mechanisms OPEN ARTERY HYPOTHESIS Federico II University of Naples

4. BENEFITS OF LATE PATENCY LINKED TO A TIME- INDEPENDENT MYOCARDIAL SALVAGE  Restoration of blood flow to ischemic myocardium adjacent to endocardial scar  Perfusion of hibernating myocardium  Preservation of an epicardial rim of myocardium Federico II University of Naples

5. LATE REPERFUSION AND ANTIREMODELING EFFECTS  Extracellular matrix remodeling  Reduced collagen breakdown  Accelleration of scar formation  Stiffer and firmer infarcted tissue  Scaffolding effect of the blood Federico II University of Naples

7. Olivari Z, Rubartelli P, Piscione F et al. JACC 2003

8. Federico II University of Naples

10. Improved LVF after Recanalization of CTO Piscione et al., Heart 2005 65 pts with CTO ≥ 6 months Group 1: 35 TIMI 3 Group 2: 30 TIMI 0-2

11. Federico II University of Naples

12. Olivari Z, Rubartelli P, Piscione F et al. JACC 2003

13. Federico II University of Naples Hoye et al. EHJ 2005

14. Federico II University of Naples

15. Three years Kaplan-Meier curves for cardiac death and MI, survival, and all MACE (cardiac death, AMI, TVR) Piscione et al., Heart 2005

16. Olivari Z, Rubartelli P, Piscione F et al. JACC 2003 Federico II University of Naples

18. J. Moses CTO Summit 2011 Federico II University of Naples

21. J. Moses CTO Summit 2011 Federico II University of Naples

25. Thanks Federico II University of Naples

27. Olivari Z, Rubartelli P, Piscione F et al. JACC 2003

28. Federico II University of Naples Kirschbaumet al, Am J Cardiol 2008

33. What factors, if any, may have masked the benefit of late IRA recanalization?

34. THE SCIENTIFIC BACKGROUNG OF THE OPEN ARTERY HYPOTHESIS  EXPERIMENTAL STUDIES  OBSERVATIONAL RETROSPECTIVE STUDIES  OBSERVATIONAL PROSPECTIVE STUDIES  RANDOMIZED STUDIES

35. Federico II University of Naples Jeffrey W. Moses, CTO Summit 2008

36. Federico II University of Naples

37. Jeffrey W. Moses, CTO Summit 2008

38. Federico II University of Naples “OAT” patients in the real world (data from CUMC) Jeffrey W. Moses, CTO Summit 2008

39. POWER of the STUDY Estimated sample size 3200 pts 90% power to detect 25% reduction in PE rate assuming PE rate of 25% with med Rx, 25% cross-over rate and a 5% loss at FU New estimated sample size 2400 pts Recruitment challenges and cross-over rate less than expected Final enrollment 2166 pts 90% target population 94% power to detect anticipated difference in PE

40. The actual event rate in the medical arm at 3 years was 14.8% not 25% !!! The number of observed events required was nearly 508. The study includes only 301 study events (60% of the expected rate) POWER of the STUDY 79%

41. The PCI succes rate was relatively low considering subacute occlusions (NOT CTO!) The definition of anatomic success after PCI was too liberal in OAT given it included patients with less than TIMI 3 epicardial flow and even those with grade 1 antegrade flow perceived to be exclusively related to suboptimal microvascular coronary flow. Successful PCI 87% TIMI Flow 0-218% Stent utilization87%

42. To have lasting benefit, late reperfusion of an occluded IRA must result in sustained long-term patency Reocclusion rate 17% Restenosis rate45.7% Stent utilization99% TOSCA-2 Trial

43. The secondary end-point of changes in LVEDVI was drawn from a subset of a subset since only 42% of the TOSCA-2 cohort underwent volume determination studies. This subset of patients is enriched by patients who survive for 1 year and may reflect a lower risk population

44. Coronary and LV angiography was performed one year after randomization. Since much of the healing and remodelling after infarction occurs within the first week, a quicker ascertainment and intervention might well have yielded a different result as has been the case with angiotensin inhibitors.

45.  Mechanical reperfusion of chronically occluded vessels is not without hazards. Thus, the overall risk-benefit ratio may be not favourable  IRA closure may be the result of poor flow caused by high microvascular resistance, which in turn is caused by severe ischemic injury. Thus, it conceivable that IRA patency does not improve LV remodelling but that minor infarction and improved ventricular remodeling enhance patency  Late reperfusion may be detrimental because collateral vessels may be forced to regress, thus, precipitating further ischemia and reinfarction Does late mechanical recanalization confer the same benefits of spontaneous late recanalization?

46. The OAT trial found a non-significant but disturbing trend toward more new infarcts in the PCI group. A potential benefit of attenuation of left ventricular remodeling may be countered by excess nonfatal reinfarctions.  Microvascular damage may occur when the artery is reopened  Delayed recanalization of the infarct related artery in this setting will lead to loss of previously recruited collateral flow, reexposing the once-protected distal vascular bed and viable myocardium to future upstream vascular events  The majority of patients (>85%) in this trial had collaterals at baseline, a finding presumably responsible for the high prevalence of viability of the infarct zone (69% of patients in the viability substudy)

47. Federico II University of Naples

48. R. Moreno et al. J Invas Cardiology 2006

49. Federico II University of Naples Bates and HochmanHochmanAHJ 2007

50. Federico II University of Naples Shaw for the COURAGE investigators Circ 2008

51. Federico II University of Naples

52. Shaw for the COURAGE investigators Circ 2008

53. Federico II University of Naples

54. Hachamovitchet al Circulation. 2003

55. Federico II University of Naples Abbate et al, JACC 2008

56. Federico II University of Naples Abbate et al, JACC 2008

57. Federico II University of Naples Abbate et al, JACC 2008

58. Federico II University of Naples Jeffrey W. Moses, CTO Summit 2008

59. Federico II University of Naples

61. Late mechanical reperfusion of the IRA in stable asymptomatic post-MI patients is dead Biological plausibility of the “late” open artery hypothesis might be still alive CONCLUSIONS

62. TOSCA-2 Trial: Study Design  Primary Endpoints: 1) Change in LVEF and 2) infarct-related artery patency  Secondary Endpoints: Change in LVEDVI, LVESVI, and regional wall motion score  Primary Endpoints: 1) Change in LVEF and 2) infarct-related artery patency  Secondary Endpoints: Change in LVEDVI, LVESVI, and regional wall motion score PCI with stenting n=195 PCI with stenting n=195 381 patients with the same characteristics of the OAT Trial Medical Therapy n=186 Medical Therapy n=186 1-year repeat coronary and LV angiography

63. TOSCA-2 Trial IRA Patency at One Year p<0.001 83% 25% % Dzavik et al. Circulation 2006; 114:2449

64. TOSCA-2 Trial Changes in LVEF Dzavik et al. Circulation 2006; 114:2449

65. TOSCA-2 Trial Changes in LVEDVI and LVESVI Dzavik et al. Circulation 2006; 114:2449

66. OPEN ARTERY HYPOTHESIS CLINICAL IMPLICATIONS OF TIME- INDEPENDENT COMPONENT THE FIRST VERSIONTHE LAST VERSION IRA RECANALIZATION FROM 6 TO 24 HRS AFTER AMI IRA RICANALIZATION DAYS AFTER AMI LATE THROMBOLYSIS RESCUE THROMBOLYSIS PrImary and RESCUE PCI ELECTIVE PTCA OF THE OCCLUDED IRA

67. Federico II University of Naples

68.  The available nonrandomized and randomized data on very late reperfusion (>24 h) was inconclusive  The epidemiologic link between late patency and survival might reflect an epiphenomenon  There were no large randomized trial data that had convincingly shown the long-term benefit of very late reperfusion What did we know on late reperfusion before the OAT study?

69. No systematic evaluation of residual viability and/or ischemia

70. Primary Endpoint Covariate adjusted and “as treated” analyses demonstrated similar results Hochman JS et al. NEJM 2006; 355:2395

71. Death/MI/CHFNYHA IV CHFRe-MI 17.2 15.6 7 5.3 4.4 4.5 % Cumulative 4-year Rates P=NS for all Hochman JS et al. NEJM 2006; 355:2395 PCI Medical

72. LATE REPERFUSION AND EXTRACELLULAR MATRIX REMODELING  Late reperfusion attenuates the activity of a family of enzymes involved in collagen breakdown which leads to aggressive infarct expansion and remodeling  Late reperfusion increases the speed with which the scar is matured  Late reperfusion is associated with a more intense inflammatory reaction that enhances clearence of necrotis debris, improves wound healing and induces an earlier expression of fibroblasts within the infarct zone Experimental evidence Federico II University of Naples

73. In segment restenosis In segment reocclusion 6 months TVR 24 months TVR

74. Federico II University of Naples J Hug et al., AHA 2000