PROTECT: What Have We Learned Lesson 2: TMPG is associated with clinical and biomarker outcomes following PCI

Association of Post PCI TMPG 3 with Adverse Outcomes % p=0.005 p=0.084 p=0.011 TMPG 0,1,2n=327 TMPG 3n=411

Association of CFR and Post-PCI TMPG with Clinical, Biomarker and Holter Outcomes D/MI/Ischemia 1.38 (-) vs 1.29 (+); P= % vs 11.4%; p=0.005 D/MI 1.38 (-) vs 1.25 (+); P= % vs 5.6%; p=0.084 Holter 1.36 (-) vs 1.36 (+); P= % vs 7.0%; p=0.011 Duration of Holter (Min) Rho = ; P= vs ; p=0.034 Baseline tn 1.36 (tn-) vs 1.39 (tn+); P= vs 0.12; p=0.017 Rise in tn Rho = ; p= vs 0.15; p=0.89 Peak tn Rho = ; P= vs 0.65; p=0.033 Post PCI tn (-) vs 1.45 (+); P= vs 72.2%; p=0.08 Baseline CK-MB Rho = ; p= vs 1.0; p=0.048 Rise in CK-MB Rho = ; p= vs 0.5; 2 way p=0.31; 4 way of all TMPGs p=0.044 Peak CK-MB Rho = ; P= vs 2.3; p=0.017 Post PCI CK-MB (CKMB-) vs 1.40 (CKMB+); p= % vs 30.5%; p=0.018 Coronary Flow Reserve (CFR) TMPG 0,1,2 vs TMPG 3

Multivariate Model Of Death / MI / Ischemia on Holter Through 48 Hours Odds ratio of death / MI / Ischemia on Holter 1.7 (95% CI , p=0.017) for closed muscle (TMPG 0,1,2) when adjusting for post PCI CFR (p=0.27, NS)

Lesson 3: What is the most powerful predictor of the baseline troponin before PCI?

Impaired Myocardial Perfusion on the Diagnostic Cath Circulation 2002;106:

Association of Baseline Troponin I with the Pre-PCI TMPG Troponin I p< Median: 0.36 Mean Median: 0.07 Mean N=289 N=362N=362 Odds of leaving cath lab with an open muscle were 6.2 times higher if you arrive to lab with an open muscle (p<0.001)

PROTECT: What Have We Learned Lesson 4: The peak and the rise in markers of myonecrosis is related not only to myocardial perfusion after PCI, but also to the myocardial perfusion before the PCI

Myocardial Perfusion Before and After PCI & Its Relationship to Rise in Markers of Myonecrosis Post PCI by Treatment Group Open Myocardium TMPG 3 Closed Myocardium TMPG 0/1/2 Open Myocardium Closed Myocardium p=NS Rise in Tn I Post PCI p=0.04 p=NS p=NS p=NS p=0.009 p=NS p=NS Rise in CKMB Post PCI

Univariate Correlates of Post-PCI TMPG 3 Variable Univariate p – value Pre-PCI TMPG 3 p< TMPG 3 = 75.1% vs TMPG 0,1,2 = 31.9% Culprit artery location p< LAD=59.1%; LCx=66.7%;RCA=41.6% Prior Statin Use p= hx 50.3% vs – hx 59.5% History of Smoking p= hx 50.5% vs – hx 58.5% History of Dyslipidemia req. Tx p= hx 52.3% vs – hx 59.9% Systolic BP on Admission p=0.04 TMPG 3 = 141 vs TMPG 0,1,2 =139 Eptifibatide vs Bivalirudin p=0.074 Epti = 57.9% vs Bival = 50.9% Clopidogrel Tx > 6 hours p=NS Non-significant covariates: age (p=0.49); gender (p=0.42); race (p=0.51); prior CHF (p=0.67); prior MI (p=0.69); history of angina (p=0.46); prior stenosis > 50% (p=0.98); prior PCI (p=0.26); history of CABG (p=0.35); known EF 1.0 mm (p=0.75); systolic BP at randomization (p=0.64); diastolic BP (p=0.27); heart rate (p=0.92); weight (p=0.83); prior ASA use (p=0.95); prior beta blocker use (p=0.70); prior ACE use (p=0.93); prior Ca channel blocker use (p=0.37); prior ARB (p=0.91); prior nitrates (p=0.50); pre-PCI TIMI Flow Grade (p=0.84).

Multivariate Correlates of Post-PCI TMPG 3 Variable Multivariate p – value Pre-PCI TMPG 3 p<0.001 OR = 6.18 Eptifibatide vs Bivalirudin p=0.042 OR =0.67 times as likely to have TMPG3 with Bivalirudin Prior Statin Use p=0.016 OR= 0.55 History of Smoking p=0.024 OR = 0.64 Systolic BP on Admission p=0.081 OR = per 1 unit mm Hg rise Troponin I ≥0.1 ng/ml at baseline p=0.099 OR = 0.73 Clopidogrel tx > 6 hours p=0.14 History of Dyslipidemia p=0.56 Culprit artery location Compared to LAD OR for LCx = 1.74 (p=0.025); OR for RCA = 0.99 (p=0.98); OR for diagonal / ramus = 2.93 (p=0.023)

Gray per sec P=0.05 N=27 N=18 Rate of Increase in DSA Brightness (Gray /sec) Rate of Increase in DSA Brightness (Gray /sec) ESPRITESPRIT Heparin Heparin + Eptifibatide Gibson CM et al, AJC 2001;87(11): p = Index of Absolute Number of 2b3a Receptors Unoccupied 51.2  24.8K Median 54.0K 51.2  24.8K Median 54.0K Post PCI TMPG 2/3 Post PCI TMPG 0/ K Median 67.8K K Median 67.8K n=26 n=21 Count (in thousands) INTEGRITIINTEGRITI Gibson CM et al, Circulation. 2004;110: N = 253 % TMPG 3 p = “Upstream” Duration (> median) “Upstream” Duration (> median) Gibson. Am J Cardiol. 2004; 94:492-4 Prior Studies Linking GP IIbIIIa Inhibition and Improved Myocardial Perfusion Longer / Earlier Upstream GPIIbIIIa Inhibition Improves Rate of TMPG3 TACTICSTACTICS

GP IIbIIIa Inhibition was Associated with a More Rapid Rate of Rise in Myocardial Contrast ECHO (MCE) Intensity Following Reperfusion in Animal Model Kunichika, … Demaria A et al, J Am Coll Cardiol 2004;43:276–83 Prior Studies Linking GP IIbIIIa Inhibition and Improved Myocardial Perfusion

PROTECT: What Have We Learned Lesson 5: Abnormal myocardial perfusion post-PCI is related to ischemia post-PCI, and Eptifibatide significantly reduces the duration of ischemia compared to Bivalirudin when it does occur

Association of Post PCI TMPG 3 with Holter Findings % Ischemia TMPG 0,1,2n=327 TMPG 3n=411 Duration (min) p=0.034 p=0.011 TMPG 0,1,2 TMPG 3

CAPTURE & PROTECT Trials Holter Substudies Klootwijk, Circulation 1998;98: Total Duration ST Depression Per Patient (min) p=0.10 HeparinAbciximabBivalirudin Integrilin + UFH or Enox P=0.013 CAPTURE PROTECT