GUSTO 1 Trial 41,000 patients enrolled, landmark study tPA improved rate of TIMI grade 3 flow by 20% over SK tPA lowered mortality by 1% compared to SK (7% vs 6%) tPA becomes most widely prescribed lytic, SK rarely if ever used FDA uses 1% change in mortality as “benchmark” for equivalency studies because this magnitude of mortality reduction changed clinical practice Subsequent trials required to demonstrate that 2 lytic agents within 1% of each other to demonstrate equivalency

Mortality Among 23,230 Patients 6 Mo. Mortality (%)

Recent Association of Myonecrosis with Mortality Among 23,230 Patients P< 0.001 vs Normal P< 0.001 vs Normal 6% of Pts 19% of Pts Relative Risk of Death Estimated 6 Mo. Mortality (%) Based on 3.7% in Normals Normal 1-3X 3-5X >5X Normal 1-3X 3-5X >5X J Am Coll Cardiol 2003;42:1406 –11

Multivariable Modeling of 30-day Mortality Normal Peak CK-MB 1–2 x ULN 2–3 x ULN 3–5 x ULN 5–10 x ULN > 10 x ULN Other Variables: age, gender, region, weight, diabetes, hypertension, smoking status, worst CCS-class prior 6 weeks, prior CHF, prior MI, prior CVA, prior PVD, prior PTCA, prior CABG, heart rate, systolic BP, ST-depression, eptifibatide Finally, inorder to assess the independent prognostic value of peak C-MB we included it in a multivariable model with other predictors of 30-day mortality. We found a strong, linear positive association between peak CK-MB and mortality. After adjustment, the increased risk of 30-day death associated with CK-MB elevations 1 to 2 times the upper limit of normal was no longer statistically significant. 1 2 3 4 5 6 7 Alexander JH et al. Circulation. 1999; Suppl 1:1-629. 17

Among Patients with a Stent and TIMI Grade 3 Flow Why Is The CK Elevated? Abnormal TMPG & 10 Fold Rise in CK Elevation p = 0.002 41.2% Even with a stent and TIMI 3 Flow, if you leave the cath lab with abnormal myocardial perfusion, risk of CK elevation goes up 10 fold Slow 10 fold rise in risk of MI Maximum CK-MB >2x ULN (%) Stain Lecture Notes All patients had a stent placed with minimal residual stenosis. The Corrected TIMI Frame Count was not related to CK-MB levels. 100% of patients achieved TIMI Grade 3 Flow post PCI and this was not related to the peak CK MB. Thus, epicardial blood flow does not appear to be related to CK release in these patients with patent arteries following PCI. Obviously, if a patient had a closed artery following PCI, this would likely account for the CK release in this patient. However, the vast majority of patients undergoing intervention do have normal flow following stent placement, and this does not appear to account for the release of CK. While these measures of epicardial blood flow were not related to CK MB, the TIMI myocardial perfusion grade, a measure of tissue level perfusion was associated with the magnitude of CK-MB leak. Those patients with a closed myocardium or TIMI myocardial perfusion grades 0 or 1, had a significantly higher peak CK-MB with levels that were more than twice the upper limit of normal at their institution. References: 1. Gibson CM, Murphy SA, Hynes C, Marble SJ, Cohen DJ, Cohen E, Lui HK, Kitt MM, Lorenz TJ, and Tcheng JE for the ESPRIT study group. Relationship of CK-MB Release to TIMI Myocardial Perfusion Grade Following Intracoronary Stent Placement: An ESPRIT Substudy. Am Heart J. 2002 Jan;143(1):106-110. 4.2% Normal Pale 1/24 14/34 Gibson CM et al, Am Heart J. 2002 Jan;143(1):106-110.

TMPG and Maximum CK-MB 24 Hours Post-Stent All Patients Have TIMI 3 Flow at Completion of Stenting TIMI Grade 3 Flow: 100% CTFC 13 TIMI Grade 3 Flow: 100% CTFC 17.5 p=0.02 2.23 + 2.70 p = 0.01 Maximum CK-MB / Upper Limit of Normal 0.78 + 0.60 Lecture Notes 100% of patients achieved TIMI Grade 3 Flow post PCI and this was obviously not related to the peak CK MB. The Corrected TIMI Frame Count was not directly related to CK-MB levels. While these measures of epicardial blood flow were not related to CK MB, the TIMI myocardial perfusion grade, a measure of tissue level perfusion was associated with the magnitude of CK-MB release. Those patients with a closed myocardium or TIMI myocardial perfusion grades 0, 1 or 2, had a significantly higher peak CK-MB with levels that were more than twice the upper limit of normal at their institution. While there was no direct relationship of the CK-MB to the CTFC, it is notable that those patients with impaired microvascular perfusion had slower frame counts. In a multivariate model of CK-MB release, TIMI myocardial perfusion grade 3 flow was related to a reduced risk of CK-MB release even after correcting for epicardial flow. References 1. Gibson CM, Murphy SA, Hynes C, Marble SJ, Cohen DJ, Cohen E, Lui HK, Kitt MM, Lorenz TJ, and Tcheng JE for the ESPRIT study group. Relationship of CK-MB Release to TIMI Myocardial Perfusion Grade Following Intracoronary Stent Placement: An ESPRIT Substudy. Am Heart J. 2002 Jan;143(1):106-110. n = 24 n = 34 TMPG 3 TMPG 0, 1 , 2 Gibson, Am Heart J 2002

1 Year Death, MI, Urgent TVR Among Patients with a Stent and TIMI Grade 3 Flow What Is The Association of Abnormal TMPG & Clinical Outcomes? 1 Year Death, MI, Urgent TVR 32.4% p = 0.01 Slow Composite Event (%) Stain Lecture Notes Again, all patients had TIMI grade 3 flow at the completion of stenting, and therefore post PCI TIMI grade 3 flow was not related to early or late clinical outcomes. While there were no events among patients with normal tissue level perfusion following PCI, the risk of death, MI, urgent TVR and thrombotic bailout was 17.7% among those patients with TMPG 0/1/2. Even more importantly, preserved tissue level perfusion was associated with improved outcomes at one year. While the risk of death, recurrent MI and urgent TVR was only 4.2% among those patients with an open myocardium at one year, this rose 7 fold to a risk of 32.4% among those patients with TMPG 0/1/2 at one year. References 1. Gibson CM, Murphy SA, Hynes C, Marble SJ, Cohen DJ, Cohen E, Lui HK, Kitt MM, Lorenz TJ, and Tcheng JE for the ESPRIT study group. Relationship of CK-MB Release to TIMI Myocardial Perfusion Grade Following Intracoronary Stent Placement: An ESPRIT Substudy. Am Heart J. 2002 Jan;143(1):106-110. 4.2% Normal 1/24 11/34 Pale Gibson CM et al, Am Heart J. 2002 Jan;143(1):106-110.

TMPG and Maximum Troponin Post-stent All Patients Have TIMI 3 Flow at Completion of Stenting p = 0.001 5.3 Slow Maximum Troponin Stain 1.5 Lecture Notes All patients had a stent placed with minimal residual stenosis. The Corrected TIMI Frame Count was not related to CK-MB levels. 100% of patients achieved TIMI Grade 3 Flow post PCI and this was not related to the peak CK MB. Thus, epicardial blood flow does not appear to be related to CK release in these patients with patent arteries following PCI. Obviously, if a patient had a closed artery following PCI, this would likely account for the CK release in this patient. However, the vast majority of patients undergoing intervention do have normal flow following stent placement, and this does not appear to account for the release of CK. While these measures of epicardial blood flow were not related to CK MB, the TIMI myocardial perfusion grade, a measure of tissue level perfusion was associated with the magnitude of CK-MB leak. Those patients with a closed myocardium or TIMI myocardial perfusion grades 0 or 1, had a significantly higher peak CK-MB with levels that were more than twice the upper limit of normal at their institution. References: 1. Gibson CM, Murphy SA, Hynes C, Marble SJ, Cohen DJ, Cohen E, Lui HK, Kitt MM, Lorenz TJ, and Tcheng JE for the ESPRIT study group. Relationship of CK-MB Release to TIMI Myocardial Perfusion Grade Following Intracoronary Stent Placement: An ESPRIT Substudy. Am Heart J. 2002 Jan;143(1):106-110. Normal Pale Bolognese L et al, Circulation. 2004;110:1592-1597.