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A Trial Whose Time Has Come

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A Trial Whose Time Has Come

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    1. MAY 2002 A Trial Whose Time Has Come

    2. MAY 2002 LV function was recognized to be the strongest predictor of long term prognosis in the pre-reperfusion era. The recognition of a time dependent wavefront of necrosis from subendocardium to epicardium by Reimer and colleagues and experimental evidence of myocardial salvage led to the classical paradigm of early reperfusion with resultant salvage and preserved LVFX which in turn led to improved survival.LV function was recognized to be the strongest predictor of long term prognosis in the pre-reperfusion era. The recognition of a time dependent wavefront of necrosis from subendocardium to epicardium by Reimer and colleagues and experimental evidence of myocardial salvage led to the classical paradigm of early reperfusion with resultant salvage and preserved LVFX which in turn led to improved survival.

    3. MAY 2002 DeWood and colleagues performed early cardiac catheterization in the setting of ST elevation MI. It became clear from their work that in the early hours post MI, the IRA was totally occluded with thrombus. Total coronary occlusion was observed in 110 of 126 patients (87%) who were evaluated within 4 hours of symptom onset. This proportion decreased significantly to 37/57 (65%) when patients were studied 12-24 hours post symptom onset. DeWood and colleagues performed early cardiac catheterization in the setting of ST elevation MI. It became clear from their work that in the early hours post MI, the IRA was totally occluded with thrombus. Total coronary occlusion was observed in 110 of 126 patients (87%) who were evaluated within 4 hours of symptom onset. This proportion decreased significantly to 37/57 (65%) when patients were studied 12-24 hours post symptom onset.

    4. MAY 2002 Rates of angiographic occlusion are clearly different in the setting of non Q wave or non-ST elevation myocardial infarction. In this cross-sectional study 192, 94, and 55 patients underwent coronary arteriography at the specified time intervals. In patients having a first non-Q MI, the prevalence of total occlusion at 24 hours was on,ly 24%. While this small number appears to contribute to the lack of efficacy of thrombolysis in this setting, the prevalence of total occlusion is not insignificant. These patients are not excluded from the OAT Trial. Rates of angiographic occlusion are clearly different in the setting of non Q wave or non-ST elevation myocardial infarction. In this cross-sectional study 192, 94, and 55 patients underwent coronary arteriography at the specified time intervals. In patients having a first non-Q MI, the prevalence of total occlusion at 24 hours was on,ly 24%. While this small number appears to contribute to the lack of efficacy of thrombolysis in this setting, the prevalence of total occlusion is not insignificant. These patients are not excluded from the OAT Trial.

    5. MAY 2002 A number of randomized trials established the efficacy of early reperfusion with thrombolysis in the early eighties. Early reperfusion became standard of care. However, the true benefit and mechanisms of late reperfusion beyond the period of myocardial salvage remained nebulous. Work from the lab of Hochman et al advanced the clinical paradigm. Using a rat heart model, Hochman and Choo demonstrated that while late reperfusion had no impact on myocardial salvage, infarct expansion was reduced (next slide). A number of randomized trials established the efficacy of early reperfusion with thrombolysis in the early eighties. Early reperfusion became standard of care. However, the true benefit and mechanisms of late reperfusion beyond the period of myocardial salvage remained nebulous. Work from the lab of Hochman et al advanced the clinical paradigm. Using a rat heart model, Hochman and Choo demonstrated that while late reperfusion had no impact on myocardial salvage, infarct expansion was reduced (next slide).

    6. MAY 2002 Late reperfusion had a positive effect on infarct expansion. This benefit, corroborating experiments and ISIS-2, set the stage for the LATE trial which explored the benefit of late thrombolysis in the setting of acute ST elevation myocardial infarction.. Late reperfusion had a positive effect on infarct expansion. This benefit, corroborating experiments and ISIS-2, set the stage for the LATE trial which explored the benefit of late thrombolysis in the setting of acute ST elevation myocardial infarction..

    7. MAY 2002 Preservation of LV Volume Source for collateral flow Recruitment of hibernating myocardium Electrically stable substrate The potential benefits of an open artery on myocardial substrate beyond the time of myocardial salvage is outlined on this slide; although observational data and experimental reperfusion at time equivalent to up to 24 hours support these conclusions, a prospective trial to prove benefit beyond 24 hours has not been performed. The potential benefits of an open artery on myocardial substrate beyond the time of myocardial salvage is outlined on this slide; although observational data and experimental reperfusion at time equivalent to up to 24 hours support these conclusions, a prospective trial to prove benefit beyond 24 hours has not been performed.

    8. MAY 2002 Non-randomized retrospective evidence to support the benefits of a late open artery was recognized early in the reperfusion era. This slide illustrates some of the early randomized thrombolysis trial data. It appears clear from these studies that those with an occluded artery at a given time point post thrombolysis appear to have a better outcome at one year than those with an occluded artery. However, patients who reperfuse and don’t reocclude are different, possibly with less microvascular plugging than those who both reperfuse and stay open. Non-randomized retrospective evidence to support the benefits of a late open artery was recognized early in the reperfusion era. This slide illustrates some of the early randomized thrombolysis trial data. It appears clear from these studies that those with an occluded artery at a given time point post thrombolysis appear to have a better outcome at one year than those with an occluded artery. However, patients who reperfuse and don’t reocclude are different, possibly with less microvascular plugging than those who both reperfuse and stay open.

    9. MAY 2002 Further this benefit cannot be attributed solely to preservation of ejection fraction. This slide shows that despite undisputed benefit for thrombolysis, EF in the placebo and thrombolytic arms of these early trials were only modestly different compared to larger differences in 1 year mortality. Clearly the early paradigm needed to be modified and the late open artery concept was born.Further this benefit cannot be attributed solely to preservation of ejection fraction. This slide shows that despite undisputed benefit for thrombolysis, EF in the placebo and thrombolytic arms of these early trials were only modestly different compared to larger differences in 1 year mortality. Clearly the early paradigm needed to be modified and the late open artery concept was born.

    10. MAY 2002 This slide summarizes the mortality benefit associated with an open artery in various databases which retrospectively sought to prove this hypothesis. Initial therapy mixed with or without early reperfusion therapy. RR Red = Relative Risk Reduction for mortality. This slide summarizes the mortality benefit associated with an open artery in various databases which retrospectively sought to prove this hypothesis. Initial therapy mixed with or without early reperfusion therapy. RR Red = Relative Risk Reduction for mortality.

    11. MAY 2002 This slide outlines an angiographic database study of the SAVE Trial. The SAVE Trial established the role of ACEI inhibition in the setting of post MI LV dysfunction. Patients with EF<40% were randomized to captopril vs. placebo. Other care was clinically determined. Lamas and colleagues compared outcomes in patients who were selected for angiography and had an open or closed IRA artery in the trial. Cardiac cath was performed at a mean of 4.2 days. Follow-up revealed significant mortality benefit in the open artery group. A similar benefit was also seen in the subgroup of patients with occluded arteries who went on to PTCA as compared to those that were not clinically selected for or had failed PTCA. Study limitations: retrospective, nonrandomized, selection bias for less sick patients to undergo successful PTCA. This slide outlines an angiographic database study of the SAVE Trial. The SAVE Trial established the role of ACEI inhibition in the setting of post MI LV dysfunction. Patients with EF<40% were randomized to captopril vs. placebo. Other care was clinically determined. Lamas and colleagues compared outcomes in patients who were selected for angiography and had an open or closed IRA artery in the trial. Cardiac cath was performed at a mean of 4.2 days. Follow-up revealed significant mortality benefit in the open artery group. A similar benefit was also seen in the subgroup of patients with occluded arteries who went on to PTCA as compared to those that were not clinically selected for or had failed PTCA. Study limitations: retrospective, nonrandomized, selection bias for less sick patients to undergo successful PTCA.

    12. MAY 2002 First MI treated with thrombolytic. Cath at mean of 28 days. High risk: defined as LVEF < 50% or high jeopardy score. 39 month follow-up. White and colleagues reported a similar mortality benefit with open artery post lysis vs closed artery post lysis. This study reported a mortality benefit with an open IRA which was strong and independent of ejection fraction only for high risk patients. These high risk criteria are used in OAT. Given these positive data, why do we need a randomized clinical trial. White and colleagues reported a similar mortality benefit with open artery post lysis vs closed artery post lysis. This study reported a mortality benefit with an open IRA which was strong and independent of ejection fraction only for high risk patients. These high risk criteria are used in OAT. Given these positive data, why do we need a randomized clinical trial.

    13. MAY 2002 Pre-Thrombolysis open reflects spontaneous thrombolysis and closed reflects no spontaneous thrombolysis. Post Thrombolysis open reflects successful lysis / no reocclusion or spontaneous lysis and closed reflects unsuccessful lysis or reocclusion. PTCA post MI Open reflects clinical selection for PTCA and successful PTCA Retrospective Non-Randomized Selection Bias PTCA for spontaneous ischemia All the evidence provided this far is clearly retrospective, non randomized and prone to selection and other undocumented biases. In many of these trials, PTCA was performed for spontaneous ischemia. Thus, while the evidence is encouraging, it is by no means proven. All the evidence provided this far is clearly retrospective, non randomized and prone to selection and other undocumented biases. In many of these trials, PTCA was performed for spontaneous ischemia. Thus, while the evidence is encouraging, it is by no means proven.

    16. MAY 2002

    17. This slide demonstrates the microvasculature as a key variable that may explain both failure of reperfusion or sustained patency of the IRA post MI and progressive LV dilation. It highlights why performance of PCI does not guarantee favorable clinical results. This work by Ito et al looked at clinical outcomes in patients with acutely opened IRA < 24 hours with and without tissue level perfusion as outlined by myocardial contrast echo. Despite restoring epicardial flow, 37% of patients continued to have perfusion defects indicating microvascular impairment. These patients (in Black) despite having a patent IRA, did not have improvement in EF at 25 days post MI. This was accompanied by evidence of progressive LV dilatation and increased LVEDV. Patients with late opening 3-28 days post MI as in OAT are likely to have even greater microvascular damage. Consequently there may not be significant benefit to be derived by PCI- and thus the need for this trial. This slide demonstrates the microvasculature as a key variable that may explain both failure of reperfusion or sustained patency of the IRA post MI and progressive LV dilation. It highlights why performance of PCI does not guarantee favorable clinical results. This work by Ito et al looked at clinical outcomes in patients with acutely opened IRA < 24 hours with and without tissue level perfusion as outlined by myocardial contrast echo. Despite restoring epicardial flow, 37% of patients continued to have perfusion defects indicating microvascular impairment. These patients (in Black) despite having a patent IRA, did not have improvement in EF at 25 days post MI. This was accompanied by evidence of progressive LV dilatation and increased LVEDV. Patients with late opening 3-28 days post MI as in OAT are likely to have even greater microvascular damage. Consequently there may not be significant benefit to be derived by PCI- and thus the need for this trial.

    18. MAY 2002 There may be intrinsic biologic differences in the local arterial and systemic factors among patients who have a persistently occluded IRA compared to those who have a patent IRA late after AMI.

    19. MAY 2002 Relation between ACE genetic polymorphism and IRA patency post MI Dakik and co-workers looked at the association of ACEI gene polymorphism and patency of the infarct related artery in patients with acute myocardial infarction. In 113 patients, patients with a DD genotype (increased ACE activity) were found to have a higher likelihood of an occluded IRA.Dakik and co-workers looked at the association of ACEI gene polymorphism and patency of the infarct related artery in patients with acute myocardial infarction. In 113 patients, patients with a DD genotype (increased ACE activity) were found to have a higher likelihood of an occluded IRA.

    20. MAY 2002 Relation between ACE genetic polymorphism and infarct size post MI Similarly the DD genotype was also associated with an increased defect size (Fixed + reversible) on past MI nuclear perfusion scintigrams.Similarly the DD genotype was also associated with an increased defect size (Fixed + reversible) on past MI nuclear perfusion scintigrams.

    21. MAY 2002

    22. MAY 2002 Observational Study 105 non thrombolysis survivors of MI cath > 7 days post MI. Open IRA in 52, occluded IRA in 53. Blood samples 23 ± 13 months post MI. Poorer survival for occluded IRA(Cigarroa)

    24. MAY 2002 Puma and colleagues recently reported the GUSTO-1 experience in the AJC. In this largest database, the independent benefit of an open artery on 30-day mortality was not present at 1 year. Puma and colleagues recently reported the GUSTO-1 experience in the AJC. In this largest database, the independent benefit of an open artery on 30-day mortality was not present at 1 year.

    25. MAY 2002 Meta-analysis of the CABG vs. medical therapy experience is also enlightening. Despite a population having manifest ischemia, CABG was not found to be superior to medical therapy in the setting of single and double vessel disease. Can we then hope for a large benefit in a population with no or minimal ischemia and 1-2 vessel CAD, Meta-analysis of the CABG vs. medical therapy experience is also enlightening. Despite a population having manifest ischemia, CABG was not found to be superior to medical therapy in the setting of single and double vessel disease. Can we then hope for a large benefit in a population with no or minimal ischemia and 1-2 vessel CAD,

    26. MAY 2002

    28. MAY 2002 There are four small trials that have attempted to evaluate the benefit of late opening of an occluded IRA in a randomized trial. There are four small trials that have attempted to evaluate the benefit of late opening of an occluded IRA in a randomized trial.

    29. MAY 2002 The purpose of this prospective, randomized pilot study was to determine the effect of PTCA on left ventricular function in patients with persistent occlusion of the infarct-related artery up to 6 weeks after a first Q-wave myocardial infarction. TOMIIS = Total Occlusion Post-Myocardial Infarction Intervention StudyTOMIIS = Total Occlusion Post-Myocardial Infarction Intervention Study

    30. MAY 2002 Primary Comparison of absolute change in LV ejection fraction between the 2 treatment groups-PTCA = 25 and no PTCA = 19.

    31. MAY 2002 No difference between the groups for primary endpoint. No difference between the groups for primary endpoint.

    32. MAY 2002 All patients received t-PA/ placebo 6-24 hours post-MI. Catheterization <24 hours after randomization. Occluded IRA (TIMI 0/1) randomized to PTCA (n = 34) and no PTCA (n= 37). TAMI-6 explored the benefits of late reperfusion with t-PA in the setting of acute myocardial infarction. Patients 6-24 hours post MI were randomized to t-PA or placebo and had a cardiac cath performed within 24 hours of randomization. Those with an occluded IRA were then randomized to PTCA vs. No PTCA. In these and the following 2 slides the PTCA group is illustrated in blue and no PTCA group is shown in violet. The primary endpoint was LVEF. As depicted in this figure, there was no difference in rates of death, recurrent myocardial infarction and re-hospitalization. TAMI-6 explored the benefits of late reperfusion with t-PA in the setting of acute myocardial infarction. Patients 6-24 hours post MI were randomized to t-PA or placebo and had a cardiac cath performed within 24 hours of randomization. Those with an occluded IRA were then randomized to PTCA vs. No PTCA. In these and the following 2 slides the PTCA group is illustrated in blue and no PTCA group is shown in violet. The primary endpoint was LVEF. As depicted in this figure, there was no difference in rates of death, recurrent myocardial infarction and re-hospitalization.

    33. MAY 2002 The ESV and EDV in both PTCA and no PTCA group were also similar. The ESV and EDV in both PTCA and no PTCA group were also similar.

    34. MAY 2002 There was no difference in EF in the PTCA and no PTCA groups. There was no difference in EF in the PTCA and no PTCA groups.

    35. MAY 2002 83 patients > 24 hours after Q-wave anterior infarction. Randomized to PTCA / No PTCA Endpoints - Cardiac Death - nonfatal MI - development of CHF This recently published study by Horie and colleagues appeared in Circulation. This study was conducted in Japan and enrolled 83 patients with anterior infarction and occluded LAD late post MI. Patients were randomized to PTCA and no PTCA. Mean time to PTCA was 8?9 days. This small trial, unfortunately, has a number of limitations. There was no protocol mandate to exclude patients with spontaneous ischemia or inducible ischemia This recently published study by Horie and colleagues appeared in Circulation. This study was conducted in Japan and enrolled 83 patients with anterior infarction and occluded LAD late post MI. Patients were randomized to PTCA and no PTCA. Mean time to PTCA was 8?9 days. This small trial, unfortunately, has a number of limitations. There was no protocol mandate to exclude patients with spontaneous ischemia or inducible ischemia

    36. MAY 2002 A trend toward a small improvement in LVEF was observed in the PTCA group. A trend toward a small improvement in LVEF was observed in the PTCA group.

    37. MAY 2002 Small study Single center Events including CHF undefined No central adjudication of subjective CHF events in this unblinded trial Clinical events are outlined on this slide. During 1-year follow-up, a significant reduction of events was observed in the PTCA arm. Closer observation reveals that this reduction was driven mainly by differences in the CHF endpoint. This endpoint was not defined and does not appear to have been adjudicated by a blinded committee. This significant potential bias in diagnosis of CHF in this unblinded trial greatly undermines the results of this study. Clinical events are outlined on this slide. During 1-year follow-up, a significant reduction of events was observed in the PTCA arm. Closer observation reveals that this reduction was driven mainly by differences in the CHF endpoint. This endpoint was not defined and does not appear to have been adjudicated by a blinded committee. This significant potential bias in diagnosis of CHF in this unblinded trial greatly undermines the results of this study.

    38. MAY 2002 Entry Criteria Male or Female; aged <75yrs First MI; anterior territory with echo EF<50% or ?3 antero-lateral Q waves Absence of continued ischaemia (symptom-limited exercise test) ? Patient eligible: refer for angiography Coronary angiography (3 days to 4 weeks of MI) TIMI grade 0 or 1 flow in the LAD Non significant disease elsewhere (<50% stenosis in non-infarct artery/ies) ? Patient eligible: randomise Randomisation Computer assisted minimisation of pre-defined baseline variables: (age/sex/systolic BP/b blocker therapy/ACE-I therapy/ESV) OPEN: (PTCA + stent to LAD + optimal medical therapy) [3 days - 6 weeks of MI] CLOSED: (Optimal medical therapy alone) Primary end-point Comparison of echo-derived ESV in OPEN and CLOSED groups 12 months post MI Another randomized trial which recently completed enrollment of 66 patients is the TOAT Trial, in Britain. TOAT- The Open Artery trial Another randomized trial which recently completed enrollment of 66 patients is the TOAT Trial, in Britain. TOAT- The Open Artery trial

    39. MAY 2002 Comprehensive assessment of post-MI LV remodelling: 4 visits: 6 weeks, 3 months, 6 months, 12 months after MI LV geometry and function: (echocardiography) Clinical events: pre-defined events (death, MI, CVA, CCF, revascularisation) Electrical stability: (Resting ECG, SAECG, Holter for HRV) Exercise Tolerance: (Symptom limited Bruce protocol) Quality of Life: (Nottingham Health profile) Biochemical markers: (CRP, BNP, Pro-collagens) Repeat coronary angiography at 12 months Follow-up parameters are outlined here Follow-up parameters are outlined here

    40. MAY 2002 There was no long-term benefit on electrical stability as measured by the SAEKG with a patent IRA. There was no long-term benefit on electrical stability as measured by the SAEKG with a patent IRA.

    41. MAY 2002 Quality of life appeared to be improved in patients assigned to PCI.Quality of life appeared to be improved in patients assigned to PCI.

    42. Surprisingly there was no benefit of PCI on infarct remodeling. In fact EDV and ESV were higher in the PCI group. Surprisingly there was no benefit of PCI on infarct remodeling. In fact EDV and ESV were higher in the PCI group.

    43. MAY 2002 TOAT: First Clinical Event Clinical endpoints for the TOAT study are outlined on this slide. There is no trend favoring the intervention in this study; and there is in fact a suggestion of harm. Clinical endpoints for the TOAT study are outlined on this slide. There is no trend favoring the intervention in this study; and there is in fact a suggestion of harm.

    44. MAY 2002 TOAT- First Event

    45. MAY 2002

    46. MAY 2002 TOAT: All events-combined

    47. MAY 2002 TOAT: All events-combined

    48. MAY 2002 TOAT-Summary No benefit of late PCI on ventricular remodeling over 1 year. LVESV and LVEDV unexpectedly increased more in the PCI group. No benefit of late PCI on electrical stability using SAECG parameters. No clinical benefit of PCI was apparent. A 20% increase in the risk of death/MI/stroke was observed in the PCI group. (These were not procedure related). QOL improved more with PCI.

    49. MAY 2002 COSTA-RICA-AMI The COSTA-RICA AMI was also presented in Anaheim 2001. Patients in this study are similar to OAT in that they are asymptomatic with occluded IRA 3-14 days post MI. This French study randomized subjects to PCI versus conservative therapy. It is different from OAT in that stress testing was done after randomization, and in OAT it is before randomization. Twelve patients in the conservative arm had a positive stress test and underwent PCI. At 5 year follow up the rates of death and MI were equivalent with both strategies. Only betablocker use at discharge was related to MI and death events on follow up. The COSTA-RICA AMI was also presented in Anaheim 2001. Patients in this study are similar to OAT in that they are asymptomatic with occluded IRA 3-14 days post MI. This French study randomized subjects to PCI versus conservative therapy. It is different from OAT in that stress testing was done after randomization, and in OAT it is before randomization. Twelve patients in the conservative arm had a positive stress test and underwent PCI. At 5 year follow up the rates of death and MI were equivalent with both strategies. Only betablocker use at discharge was related to MI and death events on follow up.

    50. MAY 2002 Effect of PCI for total occlusions on collateral circulation A potential explanation for the surprising observations in TOAT was recently elucidated in these observations by Werner et al. Plate shows a RCA occlusion (although this is chronic a similar explanation may be relevant for OAT patients) -in B there is wire passage beyond the occlusion-in C basal collateral flow is measured-D ballon is inflated within stent and recruitable collateral flow measured(F)- E shows vessel post PCI and G shows antegrade flow at the same position. A potential explanation for the surprising observations in TOAT was recently elucidated in these observations by Werner et al. Plate shows a RCA occlusion (although this is chronic a similar explanation may be relevant for OAT patients) -in B there is wire passage beyond the occlusion-in C basal collateral flow is measured-D ballon is inflated within stent and recruitable collateral flow measured(F)- E shows vessel post PCI and G shows antegrade flow at the same position.

    51. MAY 2002 Effect of PCI for total occlusions on collateral circulation 21 patients had occlusions opened in this manner. After recanalization, average peak velocity of recruitable flow fell by >50% . No further change was observed over 24 hours. A considerable fraction of collateral flow is thus lost after recanalization; consequently a chronic occlusion may not be protected from future ischemic events. 21 patients had occlusions opened in this manner. After recanalization, average peak velocity of recruitable flow fell by >50% . No further change was observed over 24 hours. A considerable fraction of collateral flow is thus lost after recanalization; consequently a chronic occlusion may not be protected from future ischemic events.

    52. MAY 2002 Collateral circulation in total coronary occlusions provided 50% antegrade flow. After PCI, the average peak velocity of recruitable collateral flow dropped by > 50%. This reduction in collateral flow reserve was sustained at 24 hours when transient total occlusion was induced. This loss of collateral flow reserve may explain prior reports of angina, MI or death with reocclusion despite pre-PCI clinical stability

    53. To prove the late open artery hypothesis, it is necessary to open and keep open the totally occluded IRA. Chronically occluded vessels pose a challenge to the interventional cardiologist and success and procedural success is closely related to time from MI-intervention. With the advent of stents, dramatic advances in procedural success and reduction of restenosis have been made. These tools now make it possible to truly test the open artery hypothesis. The TOSCA Trial in which Drs. Buller and Dzavik played leading roles, was recently published in Circulation. TOSCA showed that in symptomatic occlusions, stenting was far superior to POBA, thus in the OAT Trial we require that the vessel be stentable as assessed before PTCA. TOSCA= Total Occlusion Study of Canada To prove the late open artery hypothesis, it is necessary to open and keep open the totally occluded IRA. Chronically occluded vessels pose a challenge to the interventional cardiologist and success and procedural success is closely related to time from MI-intervention. With the advent of stents, dramatic advances in procedural success and reduction of restenosis have been made. These tools now make it possible to truly test the open artery hypothesis. The TOSCA Trial in which Drs. Buller and Dzavik played leading roles, was recently published in Circulation. TOSCA showed that in symptomatic occlusions, stenting was far superior to POBA, thus in the OAT Trial we require that the vessel be stentable as assessed before PTCA. TOSCA= Total Occlusion Study of Canada

    54. MAY 2002 This slide outlines the usefulness of stenting for chronic occlusion. Clearly stenting is the superior to PTCA in this clinical setting. This slide outlines the usefulness of stenting for chronic occlusion. Clearly stenting is the superior to PTCA in this clinical setting.

    55. MAY 2002 AHA / ACC PCI guidelines 2001 PCI during subsequent hospital management after acute therapy for AMI including primary PCI Current ACC/AHA guidelines are pertinent with respect to the conduct of the OAT trial. As illustrated above PCI for the asymptomatic occluded IRA is a Class II b indication- this further highlights the equipoise involving management of the late occluded IRA.Current ACC/AHA guidelines are pertinent with respect to the conduct of the OAT trial. As illustrated above PCI for the asymptomatic occluded IRA is a Class II b indication- this further highlights the equipoise involving management of the late occluded IRA.

    56. MAY 2002 AHA / ACC PCI guidelines 2001 This Class III recommendation (not indicated and may be harmful) should dissuade physicians from doing coronary angiography before day 3 (day 1= day of MI) which is the earliest time for cath to establish OAT eligibility. This Class III recommendation (not indicated and may be harmful) should dissuade physicians from doing coronary angiography before day 3 (day 1= day of MI) which is the earliest time for cath to establish OAT eligibility.

    57. AHA/ ACC PCI Guidelines 2001 Primary PCI in Acute MI Class III Have received lytic therapy within 12 hours and have no symptoms of ischemia Are beyond 12 hours after onset of symptoms and have no evidence of ischemia Same as 3Same as 3

    58. AHA/ ACC PCI Guidelines 2001 PCI After Acute Therapy for AMI Same as 3Same as 3

    59. MAY 2002 Although, revascularization clearly reduces the incidence of sudden cardiac death in patients with acute and severe latent ischemia ; the benefit of revascularization in the setting of a scar without provocable ischemia is unknown. There is some evidence to suggest the risk of new onset sustained VT is increased after revascularization in this clinical setting.

    60. MAY 2002 382 patients undergoing non-emergent CABG were studied. 12 (3.1%) developed sustained monomorphic ventricular tachycardia 4.1‡4.8 days post-op. Three patients died in-hospital and 5 survivors undergoing EPS were all inducible. Predictive value of clinical and angiographic findings were analyzed. Clinical Predictors included a decreased EF < 40%, severe CHF and prior MI (p < 0.01)

    61. MAY 2002 The Mid America Study 2007 consecutive patients having PCI for a chronic total occlusion over a 19 year period. Compared early and late outcomes in CTO patients to matched non-CTO cohort. Compared early and late outcomes in patients patients with successful versus failed PCI of the CTO. 37% had Class IV angina Suero et al; JACC 2001;38:409-14 This study reported on the longitudinal mid America Heart Institute experience on PCI for chronic total occlusions over a 19 year period. Thirty-seven percent had Class IV-Rest angina and only 55 % had a history of previous MI again suggesting a significant burden of ischemia in the territory of the IRA.This study reported on the longitudinal mid America Heart Institute experience on PCI for chronic total occlusions over a 19 year period. Thirty-seven percent had Class IV-Rest angina and only 55 % had a history of previous MI again suggesting a significant burden of ischemia in the territory of the IRA.

    62. MAY 2002 Outcomes PTCA success in this population was associated with decreased incidence of death over long term 10 year follow up compared to failed PTCA. The graph on the left is however pertinent to OAT. The in hospital death rate for these patients was not insignificant-1% with PCI success and 2.3% with failure with a MACE rate of 3.2-5.4%. Performance of PCI on the late occluded artery is clearly not without upfront risk.PTCA success in this population was associated with decreased incidence of death over long term 10 year follow up compared to failed PTCA. The graph on the left is however pertinent to OAT. The in hospital death rate for these patients was not insignificant-1% with PCI success and 2.3% with failure with a MACE rate of 3.2-5.4%. Performance of PCI on the late occluded artery is clearly not without upfront risk.

    63. MAY 2002

    64. The landmark DANAMI studied proved the the unequivocal benefit of revascularization in post MI patients with recurrent spontaneous ischemia or significant ischemia on predischarge ETT. Although there were no differences in mortality in conservative vs revascularization arms, there was a dramatic decrease in the rates of recurrent MI on follow up. The landmark DANAMI studied proved the the unequivocal benefit of revascularization in post MI patients with recurrent spontaneous ischemia or significant ischemia on predischarge ETT. Although there were no differences in mortality in conservative vs revascularization arms, there was a dramatic decrease in the rates of recurrent MI on follow up.

    65. DANAMI 5 Year Mortality This slide shows the relative benefit of revascularization versus medical therapy stratified by the nature and degree of ischemia manifested (Symptomatic) or elicited (Silent) and the double product achieved on ETT. Not surprisingly there is a dramatic mortality benefit with revascularization in patients (N=254) with symptomatic ischemia and double product below the median. There was no mortality benefit with revasc in patients with provocable silent ischemia at low double product nor in those achieving > median double product on treadmill with either symptomatic or silent ischemia. In this context OAT patients are clinically asymptomatic with minimal ischemia if any. The mechanism and benefit of revascularization in this population if any is UNPROVEN.This slide shows the relative benefit of revascularization versus medical therapy stratified by the nature and degree of ischemia manifested (Symptomatic) or elicited (Silent) and the double product achieved on ETT. Not surprisingly there is a dramatic mortality benefit with revascularization in patients (N=254) with symptomatic ischemia and double product below the median. There was no mortality benefit with revasc in patients with provocable silent ischemia at low double product nor in those achieving > median double product on treadmill with either symptomatic or silent ischemia. In this context OAT patients are clinically asymptomatic with minimal ischemia if any. The mechanism and benefit of revascularization in this population if any is UNPROVEN.

    66. DANAMI Reinfarction rate at 2.4 years This slide shows reinfarction rates in a similar manner to the prior slide stratified by nature of ischemia and double product above or below the median. No difference in reinfarction rates are evident between the two strategies for patients with symptomatic ischemia and good exercise tolerance as well as patients with silent ischemia either at low or high threshold. There may be a trend toward lower re-MI at low threshold silent ischemia. The rate of reinfarction in patients with silent ischemia and good exercise tolerance is very low and not affected by treatment strategy.This slide shows reinfarction rates in a similar manner to the prior slide stratified by nature of ischemia and double product above or below the median. No difference in reinfarction rates are evident between the two strategies for patients with symptomatic ischemia and good exercise tolerance as well as patients with silent ischemia either at low or high threshold. There may be a trend toward lower re-MI at low threshold silent ischemia. The rate of reinfarction in patients with silent ischemia and good exercise tolerance is very low and not affected by treatment strategy.

    67. MAY 2002 DANAMI Post MI ischemia Patients with severe ischemia are excluded from OAT Those with mild to moderate ischemia, who can be managed with medical therapy alone are eligible. This is consistent with the findings of DANAMI --only those with low threshold ischemia appeared to derive benefit from revascularization.

    68. MAY 2002 See next slideSee next slide

    69. MAY 2002

    70. MAY 2002

    71. MAY 2002 2616 pts undergoing cardiac catheterization after an AMI were logged. 990 (38%) had an occluded IRA. Mean age 62 ? 12 years 72% male 84% Caucasian Mean time to catheterization 4.7 ± 8.6 days To evaluate current clinical practice and the incidence and treatment of occluded IRA, OAT centers screened post MI patients. 990 patients with occluded IRA post MI were identified. The mean time to cath was approximately 5 days post MI. To evaluate current clinical practice and the incidence and treatment of occluded IRA, OAT centers screened post MI patients. 990 patients with occluded IRA post MI were identified. The mean time to cath was approximately 5 days post MI.

    72. MAY 2002 Clinical Indication prospectively defined as rest or low threshold post-MI angina, significant inducible ischemia, left main stenosis › 50% or significant triple vessel disease requiring CABG. A clinical indicating to revascularize as defined on slide was present in 43% of patients. A clinical indicating to revascularize as defined on slide was present in 43% of patients.

    73. MAY 2002 This slide compares patients with (green) and without indication (yellow) for revascularization on clinical grounds. Not surprisingly, based on our definition, patients with a clinical indication had more triple and less single vessel disease. OTA eligible patients are most likely to have single vessel disease, but double vessel disease may also be present. This slide compares patients with (green) and without indication (yellow) for revascularization on clinical grounds. Not surprisingly, based on our definition, patients with a clinical indication had more triple and less single vessel disease. OTA eligible patients are most likely to have single vessel disease, but double vessel disease may also be present.

    74. MAY 2002 Location of the IRA did not help distinguish those with and without a clinical indication for revascularization. Location of the IRA did not help distinguish those with and without a clinical indication for revascularization.

    75. MAY 2002 In both groups, the occlusion was proximal and mean ejection fraction was also similar. In both groups, the occlusion was proximal and mean ejection fraction was also similar.

    76. MAY 2002 PTCA of the IRA was performed in the absence of defined clinical indication 50% of the time. A flip of the coin or as illustrated, like a throw of the die. The OAT study will have a computer flipping the coin. PTCA of the IRA was performed in the absence of defined clinical indication 50% of the time. A flip of the coin or as illustrated, like a throw of the die. The OAT study will have a computer flipping the coin.

    77. MAY 2002 Persistent occlusion of the IRA is present in 38% of patients following initial treatment of AMI. In most cases the site of occlusion is proximal (68%). The EF is often preserved (mean 0.45). Most pts with occluded IRA had no clinical indication for revascularization (57%). Despite the absence of a clinical indication, PTCA is performed in about 50% of pts.

    78. MAY 2002

    79. MAY 2002

    80. MAY 2002 Twenty pilot patients enrolled - feasibility of the trial is established.Twenty pilot patients enrolled - feasibility of the trial is established.

    81. MAY 2002

    82. MAY 2002 Recent MI (3-28 days) MI is defined based on 2/3 criteria.

    83. MAY 2002 TIMI flow 0-1 in the infarct related artery Meets criteria for high risk. EF < 50% or if EF > 50%, the site of occlusion should be proximal in large vessel: Left anterior descending (LAD) proximal third Large right coronary artery (RCA) if supplying posterior descending artery (PDA), part of inferior myocardium, part of the posterolateral wall, and/or apex. Circumflex if supplying large obtuse marginal,l and part of the inferior wall (i.e., a large dominant or co-dominant vessel.) Diagrams of LAD, RCA and Circ are on the next slides. Diagrams of LAD, RCA and Circ are on the next slides.

    84. MAY 2002 Shaded portions indicates the segments where the total occlusion must be present to be OAT eligible - IF EF ? 50%. Shaded portions indicates the segments where the total occlusion must be present to be OAT eligible - IF EF ? 50%.

    85. MAY 2002 Shaded portions indicates the segments where the total occlusion must be present to be OAT eligible - IF EF ? 50%. Shaded portions indicates the segments where the total occlusion must be present to be OAT eligible - IF EF ? 50%.

    86. MAY 2002 Shaded portions indicates the segments where the total occlusion must be present to be OAT eligible - IF EF ? 50%. Shaded portions indicates the segments where the total occlusion must be present to be OAT eligible - IF EF ? 50%.

    87. MAY 2002 Age < 18 years Clinical indication for revascularization Other serious illness that limits 3-year survival such as cancer or severe pulmonary disease Severe renal disease defined as serum creatinine > 2.5 mg/dl that would markedly increase the risk of radiographic contrast

    88. MAY 2002 Prior bypass graft to culprit IRA Severe valvular disease History of anaphylaxis to radiographic contrast unless patient has been treated with a standard dose of corticosteroids Infarct artery too small (reference segment diameter < 2.5 mm)

    89. MAY 2002 NYHA Class III-IV CHF at screening Prior left ventricular aneurysm in the same location as the index infarction Inability to cooperate with the protocol, including long term follow-up Patient refusal or unable to consent

    90. MAY 2002 Refusal of the patient’s physician to allow the patient to participate in the trial Pregnant females (all pre-menopausal females should have a negative serum pregnancy test) Contraindication to anticoagulation during PTCA/stent or antiplatelet therapy following stent implantation

    91. MAY 2002 Chronic occlusion Cardiogenic shock Dilated or hypertrophic cardiomyopathy

    92. MAY 2002 Composite of: Death from any cause Recurrent MI after randomization Class IV CHF requiring hospitalization or admission to short stay unit

    93. MAY 2002 Cost Effectiveness of Intervention Quality of Life Hospitalization for CHF Death Cardiovascular death Recurrent MI Hospitalization for NYHA Class IV CHF

    94. MAY 2002 Sustained ventricular tachycardia / ventricular fibrillation (VT/VF) requiring therapy AICD implantation Revascularization of target vessel Revascularization of non-culprit vessel Stroke

    95. MAY 2002 Endpoints including CHF will be adjudicated by a Morbidity and Mortality Committee. This committee will be independent of Study Investigators. The members of this committee will be blinded to treatment assignment.

    96. MAY 2002 Aspirin Heparin Beta Blocker ACE Inhibitor Anticoagulation if indicated AHCPR guidelines for CHF (if applicable)

    97. MAY 2002 Phone contact with patients every 4 months to ascertain: Vital Status Recurrent hospitalization Canadian Cardiovascular Society angina class NYHA CHF class

    98. MAY 2002 Patients with severe inducible ischemia should undergo revascularization (ACC/AHA guidelines) and will be excluded from the trial.

    99. MAY 2002 Pharmacologic stress testing will be recommended if: Patients are unable to exercise Presence of uninterpretable ECG Physician preference Testing between days 2-4 post MI

    100. MAY 2002

    101. MAY 2002 OAT Timeline (Revised 11/00) The date of the index MI is the calendar day that the symptoms of the MI began. This is Day 1 and angiographic eligibility can be established on Day 3. For example, Mr. G has chest pain beginning at 20:00 hours Monday night. The pain persists all night. He presents to the ER at 12:00 hours the following day. According to the OAT protocol he has presented to the hospital on DAY 2. An angiogram which confirms TIMI 0-1 flow the next morning (DAY 3) will make him angiographically eligible for the trial.

    102. MAY 2002 Finding Eligible Patients

    103. MAY 2002 Suspecting Total Occlusion

    104. MAY 2002 Enrollment at Sites without PTCA

    105. MAY 2002 OAT Registry

    106. MAY 2002 OAT Screening Log

    107. MAY 2002 Study Timeline

    108. MAY 2002 Outpatient Enrollment

    109. MAY 2002 Post-Enrollment Follow-Up

    110. MAY 2002 Enrollment at Sites which do not test for inducible ischemia pre-cath

    111. MAY 2002 Enrollment at Sites which do not test for inducible ischemia pre-cath

    112. MAY 2002 Enrollment at Sites which do not test for inducible ischemia pre-cath

    113. MAY 2002 Is the Patient eligible?

    114. MAY 2002 What do I do?

    115. MAY 2002 Is this an event?

    116. MAY 2002 Phone contact with patients every 4 months to ascertain: Vital Status Recurrent hospitalization Canadian Cardiovascular Society angina class NYHA CHF class

    117. MAY 2002

    118. MAY 2002

    119. MAY 2002

    120. MAY 2002

    121. MAY 2002 Inability to complete Stage 1 Bruce without angina. ST depression > 2mm. ST elevation > 1 mm in leads without Q waves. Failure to achieve 3-4 mets. Exertional hypotension presumed due to ischemia.

    122. MAY 2002 Increased lung uptake (lung/heart > 50%) with any reversible defects Extensive reversible perfusion defect > 20% of the left ventricle. Reversible defects in multiple coronary territories Criteria for Severe Ischemia on Perfusion Scan

    123. MAY 2002 Decreased wall thickening in 2 contiguous segments in the infarcted region- this includes normal segments that become hypokinetic, akinetic or dyskinetic; hypokinetic segments that become akinetic or dyskinetic. Similar criteria apply for pharmacologic stress echo. A biphasic response with dobutamine is evidence for inducible ischemia. Patients with myocardial viability should be included Criteria for Severe Ischemia on Stress Echo

    124. MAY 2002 Increasing Recruitment Sustained screening TARGET LATE PRESENTERS WITHOUT LYSIS Meticulous approach to consent Broaden the net to include referring hospitals/MD’s Engage the cath lab staff Educate and motivate your referring MD’s Increase trial visibility Dinner symposium Slide sets Letters to referring physicians The new guidelines will help Get everyone to THINK OAT

    125. MAY 2002

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