1. The “Code White” Team of Dr. William Ganz: 1979 Goal of IC SK Before PCI: Get the artery open

2. Acute MI Treated with Distal Protection and IC tPA (8 mg) After Percusurge / Angiojet After 8 mg IC tPA Pre PCI Clot

3. Intracoronary Streptokinase after Primary Percutaneous Coronary Intervention Murat Sezer, Hüseyin Oflaz, Taner Gören, Irem Okcular, Berrin Umman, Yılmaz Nişancı, Ahmet Kaya Bilge, Yasemin Şanlı, Mehmet Meriç, Sabahattin Umman Istanbul University, Istanbul Faculty of Medicine, Department of Cardiology

4. Hypothesis Complementary intracoronary streptokinase (ICSK) infusion immediately following primary PCI may further improve tissue level perfusion by dissolving thrombus (either in situ formed or embolized from the proximal origin) at microvascular level. To this end, the effect of low-dose (250 kU) ICSK, administered immediately after primary PCI, on myocardial perfusion was investigated prospectively.

5. Inclusion / Exclusion Criteria Inclusion criteria: –Ongoing chest pain, –ST segment elevation on electrocardiogram, –Occlusion of the infarct-related artery at angiography (Thrombolysis in Myocardial Infarction [TIMI] 0-I flow) Exclusion criteria: –Culprit lesion in a saphenous vein graft, –Additional narrowing >50% distal to the culprit lesion, –Left bundle branch block, –History of prior myocardial infarction, and –Contraindications to streptokinase, tirofiban, aspirin, clopidogrel or heparin.

6. Patients and Randomization Immediately after diagnostic angiography eligible patients (n =41) were randomized to ICSK group (n=21)Control group (n=20) (Primary PCI + 250 kU intracoronary streptokinase) (primary PCI) All patients recieved: - 300 mg of aspirin, - A loading dose of 600 mg of clopidogrel, - Intracoronary unfractioned heparin at a dose of 100 U/kg during the procedure, - Tirofiban as a bolus of 0.1 μg/kg in 3 minutes followed by continuous infusion of 0.15 μg/kg/min for 12 hours, and - Low molecular weight heparin initiated four to five hours after primary PCI and continued for at least 48 hours

7. All patients underwent intracoronary hemodynamic measurement and angiographic analysis two days after primary PCI to evaluate microvascular function ST segment resolution Diastolic deceleration time Echocardiographic assessment of left ventricular volumes and function Coronary flow reserve Index of microvascular resistance Coronary wedge pressure (mean ad systolic) Pressure derived collateral flow index Myocardial blush grades Corrected TIMI frame count Study Design Second angiography and intracoronary hemodynamic measurements 2 days after AMI. Assesing microvascular perfusion and LV volumes in early phase of STEMI Control angiography (TIMI frame count, Myocardial blush grade) Infarct size measurement (SPECT), Echocardiographic assessment of left ventricular volumes and function Long term assesments (at 6 months) Transthoracic echocardiography, 2 days after AMI Pre/post PCI ECG

8. Assessment of Microvascular Perfusion by Invasive Methods Thermodilution-derived Coronary Flow Reserve (CFR)* = Resting mean transit time / hyperemic mean transit time *Pijls NHJ et al.. Circulation 2002;105:2482-2486 Index of Microvascular Resistance (IMR)**: = Distal coronary pressure x hyperemic mean transit time **Fearon WF. et al.. Circulation. 2003;107:3129-3132 Coronary Wedge Pressure (CWP) and Pressure-derived Collateral Flow Index (CFIp): = CWP/Pa Guiding cath. Microvasculature Balloon CWP: mm Hg Pa: mm Hg Pressure wire

10. -00Procedural complications 18 (90%)16 (77%)3 2 (10%)5 (23%)2 0.41 000 - 1 TIMI flow grades 0.593.5 ± 2.84.8 ± 2.1Mean residual stenosis, % 0.711.14 ± 0.351.21 ± 0.41Number of stents 0.2912.4 ± 2.613.4 ± 3.1Max. Inflation pressure, (atm). 12 (10%)3 (14%)Side branch embolization 0.412 (10%)5 (23%)Slow / no-reflow Post-procedural results 0.93218.8 ± 109,8257.7 ± 211.8Pain to balloon time (minute) 1100 Baseline TIMI flow 0/1 (%) 2 (10%)1 (5%)3 4 (20%)4 (19%)2 0.73 14 (70%)16 (76%)1 Number of diseased vessels 1 (5%) Cx 3 (15%)6 (28%)RCA 0.54 16 (80%)14 (67%)LAD Infarct related artery Angiographic characteristics ICSK group Control group p Angiographic Characteristics and Post Procedural Results

11. 0.002 0.17 (0.14)-(0.21) 0.08 (0.05)-(0.11) <0.001 -0.09 (--­­0.13)-(-0.06) 0.17 + 0.070.08 + 0.05 CFIp (mean, unitless) <0.001 29.46 (21.80)-(37.12) 15.17 (8.26)-(22.08) <0.001 -15.56 (-21.27)-(-9.85) 33.80 + 11.018.24 + 6.07 CWP, systolic (mmHg) 0.04 12.54 (6.83)-(18.24) 7.98 (2.84)-(13.12) 0.004 -6.39 (-10.73)-(-2.05) 17.20 + 7.9310.81 + 5.46 CWP, mean (mmHg) 0.002 1.66 (1.25)-(2.07) 2.29 (1.92)-(2.66) <0.001 0.62 (0.35)-(0.93) 1.39 + 0.312.01 + 0.57 CFR <0.001 29.05 (22.17)-(35.92) 11.73 (5.53)-(17.92) <0.001 -16.20 (-21.75)(10.64) 32.49 +11.0416.29 + 5.06 IMR (U) p Control Group, Mean (95% CI) Intracoronary Streptokinase Group, Mean (95% CI) p Mean Difference 95% CI Control Group n:20 Intracoronary Streptokinase Group n:21 MultivariateUnivariate Intracoronary Hemodynamic Indices of Microvascular Perfusion

12. Angiographic (cTFC, MBG), Electrocardiographic (STR) and Echocardiographic (DDT) Indices of Microvascular Perfusion 0.39 71.05 (53.55)-(88.55) 77.26 (61.30)-(93.23) 0.04 16.30 (0.06)-(32.54) 51.25±24.4067.55+22.91 60 minutes after primary PCI 0.45 71.36 (56.66)-(86.07) 66.75 (53.04)-(80.45) 0.42 5.00 (-7.89)-(17.89) 63.21+14.3768.21+20.13 Immediately after primary PCI STR (%) 0.001 257 (-65)-(580) 750 (446)-(1054) <0.001 468 (261)-(676) 360+292828+258 DDT in the LAD artery (milliseconds) # ---7 (53.8)11 (91.7) 2/3 0.13 -- 0.035 -6 (46.2)1 (8.3) 0/1 Six months after primary PCI ---6 (32%)15 (71%) 2/3 0.065 -- 0.012 -13 (68%)6 (29%) 0/1 Two days after primary PCI ---5 (28%)10 (50%) 2/3 0.70 -- 0.16 -13 (72%)10 (50%) 0/1 Immediately after primary PCI MBG 0.023 25.89 (18.76)-(33.02) 18.88 (13.57)-(24.18) 0.014 -6.2 (-11.00)-(-1.39) 27.62 + 6.4621.42 + 4.98 Six months after primary PCI 0.001 27.51 (22.03)-(32.99) 19.10 (14.16)-(24.04) <0.001 -9.27 (-13.50)-(-5.03) 31.79 + 7.5822.52 + 5.58 Two days after primary PCI 0.80 29.36 (21.48)-(37.25) 30.30 (23.14)-(37.46) 0.69 -0.79 (-6.66)-(5.08) 34.44 + 8.2633.6 + 9.45 Immediately after primary PCI cTFC mean UnivariateMultivariate ICSK group Control Mean diff. p ICSK group Control p

13. 0.17 37.28 (21.57-52.99) 27.84 (14.35-41.32) 0.005 37.05 + 13.84 (n: 18) 23 + 13.37 (n: 18) Infarct size %, SPECT 0.82 2.71 (-37.75)- (43.16) 5.97 (-27.32)-(39.26) 0.243.46 + 19.0214.37 + 31.14Change in LVEF, % 0.24 51.56 (36.90-66.23) 57.68 (45.88-69.47) 0.020 46.19 + 12.21 (n: 15) 56.18 + 10.69 (n: 17) Six months after primary PCI 0.078 47.96 (39.86-56.06) 54.25 (46.95-61.55) 0.06 44.51 + 12.40 (n: 20) 51.52 + 10.76 (n: 21) Two days after primary PCI LVEF % 0.036 14.97 (-18.31)- (48.24) -11.19 (-37.95)-(15.58) 0.04 11.90 + 23.50 (n: 15) -4.60 + 22.01 (n: 17) Change in EDV, % 0.089 118.77 (76.98-160.56) 92.72 (59.11-126.33) 0.021 150.13 + 49.28 (n: 15) 115.70 + 29.67 (n: 17) Six months after primary PCI 0.50 118.53 (93.35-143.71) 111.22 (88.52-133.91) 0.07 137.75 + 36.82 (n: 20) 119.88 + 23.36 (n: 21) Two days after primary PCI EDV ml 0.055 15.30 (-28.40)- (59.01) -12.32 (-47.47)-(-22.83) 0.014 12.67 + 30.75 (n: 15) -13.27 + 25.40 (n: 17) Change in ESV % 0.068 58.68 (25.10-92.27) 36.08 (9.07-63.10) 0.004 83.73 + 39.32 (n: 15) 50.64 + 18.23 (n: 17) Six months after primary PCI 0.063 65.03 (47.76-82.30) 50.81 (31.25-66.37) 0.013 78.65 + 30.55 (n: 20) 58.16 + 17.02 (n: 21) Two days after primary PCI ESV ml p (two tailed) Control, mean 95%CI ICSK (+), mean, 95%CI p (two tailed) ControlICSK (+) Univariate Multivariate Left Ventricular End Systolic (ESV) and End Diastolic Volumes (EDV), Ejection Fraction (LVEF) and Infarct Size (%) Comparisons

14. Comments and Conclusions Early phase results: In this pilot trial, low-dose intracoronary streptokinase administration immediately following primary PCI was compared with standard primary PCI without use of intracoronary streptokinase. Almost all indices of microvascular perfusion concordantly pointed out that use of intracoronary streptokinase immediately after primary PCI yields better perfusion at the microvascular level.

15. Comments and Conclusions 2 Late term results At six months, there was no significant difference between the two study groups with regards to left ventricular size or function and infarct size, although there were some trends favoring the streptokinase group. The trial was not originally planned to be large enough to detect differences in long-term outcome, and indeed enrollment was terminated early based on the midterm data on microvascular perfusion. Since trends in favor of the intracoronary streptokinase group were detected, it is possible that the study was underpowered for these analyses.

16. Comments and Conclusions 3 The finding of the current study supports the in situ formed (autochthonous) microvascular thrombus hypothesis and pointed out that this thrombus should be taken into consideration for achieving more efficient reperfusion at microvascular level during primary PCI. The results of the study should be confirmed by a larger randomized study before applying this treatment modality in daily cardiology practice.

17. Following NEJM Publication in 2007 Goal of IC SK After PCI: Get the microvasculature open

18. 0.3 4.6 2.8 9.5 15.6 10.2 20.2 P<0.002 P<0.04 P<0.09 P<0.0008 Urgent Revascularization Urgent Revascularization Recurrent MI Recurrent MI Death MACE IC Compared to IV Abciximab Reduces MACE in ACS Pts Undergoing PCI Wöhrle J et al. Circulation 2003;107:1840. N = 403 pts IC – 294 IV – 109 N = 403 pts IC – 294 IV – 109 UA and MI IV abciximab IC abciximab 49%

19. Clot Disaggregation Following IC Eptifibatide: Pre-PCI Angiogram Pinto et al, Am J Cardiol 2006

20. Retrospective Experience with IC Eptifibatide Pinto et al, Am J Cardiol 2006 59 patients treated with unbuffered IC eptifibatide: TIMI Grade 3 flow in >90% of patients following PCI Normal TIMI myocardial perfusion grade 3 flow (TMPG 3) present in 54.4% of patients following PCI (range 20%-25% in past) There were no in-hospital deaths, reinfarctions, or TIMI major bleeding events No arrhythmias during IC eptifibatide administration

21. Impact of IC Adenosine on Clinical & Electrocardiographic Outcomes in the Setting Primary PTCA % Developing Q Waves % Death, MI, CHF, Recurrent Angina p < 0.02 p < 0.04 p < 0.03 Marzilli et al, Circulation 2000; 101:2154-2159 Placebo Adenosine 4 mg in 2 ml via central lumen of PTCA balloon % of Patients