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Intracoronary Streptokinase a fter Primary Percutaneous Coronary Intervention *

Intracoronary Streptokinase a fter 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

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Intracoronary Streptokinase a fter Primary Percutaneous Coronary Intervention *

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  1. 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 *N Engl J Med 2007;356:1823-34.

  2. Rational of the studyFrom Epicardial Coronaries… • Primary percutaneous coronary intervention (PCI) is the most effective reperfusion method in the treatment of STEMI. • Nevertheless, processes causing myocardial damage are not immediately terminated despite elimination of epicardial occlusion with successful primary PCI. • It has been presumed that mechanisms of reperfusion injury including embolization of epicardial thrombus and plaque content to microvasculature are responsible for this ongoing damage. • Unfortunately, almost all of the previous studies based on these hypothesis and aiming to stop reperfusion injury have not been succeeded.

  3. … to the Microvasculature • There is a growing evidence pointing concordance between myocardial and microvascular damage in STEMI patients. • Microvascular damage might not be only an accompanying process to the myocardial damage. Also there might be a causal relationship in between. • If one focused to microvasculature during peri-PCI procedure, it can be easily realized that another and important contributor might have a role in this process. insitu microvascular thrombus!

  4. Virchow’s Triad and Autochthonous Thrombus • All three components of Virchow’s triad (blood constituent, endothelial damage and stasis) exist at extreme levels in the microvasculature of infarcted myocardium. • Therefore, in situ (de-novo) formed fraction may constitute the main part of the thrombus located in infarct site’s microvasculature. Virchow RR. Cellular Pathology. London, Churchill, 1860.

  5. Coronary Vascular Resistance • If epicardial and microvascular vessels are considered as serially connected resistances, elimination of the proximal epicardial occlusion and retrieval of whole epicardial thrombus would not be enough to normalize total coronary resistance and perfusion at affected segments.

  6. 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.

  7. 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.

  8. 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 0.15μg/kg/min for 12 hours, and - Low molecular weight heparin initiated four to five hours after primary PCI and continuedfor at least 48 hours

  9. Study Design • 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 Pre/post PCI ECG Transthoracic echocardiography, 2 days after AMI Assesing microvascular perfusion and LV volumes in early phase of STEMI Second angiography and intracoronary hemodynamic measurements 2 days after AMI. Long term assesments (at 6 months) Control angiography (TIMI frame count, Myocardial blush grade) Infarct size measurement (SPECT), Echocardiographic assessment of left ventricular volumes and function

  10. Pressure wire Microvasculature Guiding cath. Balloon CWP: mm Hg Pa: mm Hg 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

  11. Study Endpoints • Primary endpoints: • Coronary flow reserve, • Index of microvascular resistance, • Coronary wedge pressure, • Collateral flow index, and • Coronary diastolic deceleration time were primary endpoints. • Secondary endpoints: • Corrected TIMI frame count, • Myocardial blush grade, • Infarct size, • Changes in left ventricular volumes and • Major adverse cardiac events (reinfarction, revascularization and death) • were secondary endpoints.

  12. Statistical Analysis • Calculations were then made of the necessary sample size to detect a 30% difference between the intracoronary streptokinase and control groups for each end point (α=0.05, β=0.20, power=0.80). • Group proportions were compared by means of the chi-square test or Fisher exact test, as appropriate. Group means were compared by Student’s t test for independent groups or the Mann-Whitney U test, for variables with normal or non-normal distribution, respectively • Group means were also adjusted for possible confounding factors (age, pain-to-balloon time, diabetes, hypertension, hyperlipidemia, pre-myocardial infarction angina, slow flow, side branch embolization, smoking and infarct location) using analysis of covariance (ANCOVA).

  13. Results

  14. Study GroupBaseline and Demographic Characteristics. Intracoronary Streptokinase Group n: 21 Control Group n: 20 p (two tailed) Age (mean, yrs) 51.4± 5.7 52.2±10.9 0.79 Sex (male) 21 19 0,98 Smoking 17 (81%) 14 (70%) 0.65 Diabetes Mellitus 2 (10%) 3 (16%) 0.65 Hypertension 4 (19%) 7 (37%) 0.20 Dyslipidemia 12 (57%) 14 (74%) 0.27 History of preinfarction angina 5 (24%) 5 (26%) 0.85 Infarct localization Anterior 14 (67%) 16 (80%) 0.54 Non-anterior 7 (33%) 4 (20%) Peak troponin T 9.1 ± 6.5 10.4 ± 7.6 0,61 Initial ST elevation (mean, mm) 15.6 ± 10.5 19 ± 9.7 0.18

  15. Post-procedural Results Slow / no-reflow 5 (23%) 2 (10%) 0.41 Side branch embolization 3 (14%) 2 (10%) 1 Max. Inflation pressure, (atm). 13.4 ± 3.1 12.4 ± 2.6 0.29 Number of stents 1.21 ± 0.41 1.14 ± 0.35 0.71 Mean residual stenosis, % 4.8 ± 2.1 3.5 ± 2.8 0.59 TIMI flowgrades 0 - 1 0 0 0.41 2 5 (23%) 2 (10%) 3 16 (77%) 18 (90%) Procedural complications 0 0 -

  16. Invasive Microvascular Parameters Two Days after PCIIndex of Microvascular Resistance p<0.001 Units n : 21 n : 20

  17. Invasive Microvascular Parameters Two Days after PCICoronary Flow Reserve p : 0.002 (unitless) n : 21 n : 20

  18. Invasive Microvascular Parameters Two Days after PCICoronary Wedge Pressures (Mean and Systolic) p : 0.04 p < 0.001 mm Hg n : 21 n : 20

  19. Invasive Microvascular Parameters Two Days after PCIPressure Derived Coronary Flow Index p : 0.002 (unitless) n : 21 n : 20

  20. Relatively Less Invasive Microvascular Parameters Immediately,Two Days, and Six Months after PCICorrected TIMI Frame Count p : 0,80p : 0,001p : 0,023 Frame/second n : 21 n : 20 n : 21 n : 20 n : 19 n : 18

  21. Non-invasive Microvascular Parameters Two Days after PCIDiastolic Desceleration Time (in LAD pts) p : 0,001 milliseconds n : 21 n : 20

  22. ST Segment ResolutionImmediately and 60 Minutes after PCI p : 0,45 p : 0,39 % n : 21 n : 20 n : 21 n : 20

  23. Angiographic(cTFC, MBG), Electrocardiographic (STR) and Echocardiographic (DDT) Indices of Microvascular Perfusion Univariate MultivariateICSK group Control Mean diff. pICSK group Control p mean+SD mean+SD mean and 95%CI mean and 95%CI cTFC mean Immediately after primary PCI 33.6 + 9.45 34.44 + 8.26 -0.79 (-6.66)-(5.08) 0.69 30.30 (23.14)-(37.46) 29.36 (21.48)-(37.25) 0.80 Two days after primary PCI 22.52 + 5.58 31.79 + 7.58 -9.27 (-13.50)-(-5.03) <0.001 19.10 (14.16)-(24.04) 27.51 (22.03)-(32.99) 0.001 Six months after primary PCI 21.42 + 4.98 27.62 + 6.46 -6.2 (-11.00)-(-1.39) 0.014 18.88 (13.57)-(24.18) 25.89 (18.76)-(33.02) 0.023 MBG Immediately after primary PCI 0/1 10 (50%) 13 (72%) - 0.16 - - 0.70 2/3 10 (50%) 5 (28%) - - - Two days after primary PCI 0/1 6 (29%) 13 (68%) - 0.012 - - 0.065 2/3 15 (71%) 6 (32%) - - - Six months after primary PCI 0/1 1 (8.3) 6 (46.2) - 0.035 - - 0.13 2/3 11 (91.7) 7 (53.8) - - - DDT in the LAD artery (milliseconds)# 828+258 360+292 468 (261)-(676) <0.001 750 (446)-(1054) 257 (-65)-(580) 0.001 STR (%) Immediately after primary PCI 68.21+20.13 63.21+14.37 5.00 (-7.89)-(17.89) 0.42 66.75 (53.04)-(80.45) 71.36 (56.66)-(86.07) 0.45 60 minutes after primary PCI 67.55+22.91 51.25±24.40 16.30 (0.06)-(32.54) 0.04 77.26 (61.30)-(93.23) 71.05 (53.55)-(88.55) 0.39

  24. Echocardiographic Volumesat Two Days and Six Months after PCIEnd-Systolic Volumes p : 0,063 p : 0,068 ml n : 21 n : 20 n : 19 n : 18

  25. Echocardiographic Volumesat Two Days and Six Months after PCIEnd-Diastolic Volumes p : 0,50 p : 0,089 ml

  26. Echocardiographic Volumesat Two Days and Six Months after PCILV Ejection Fraction p : 0,078 p : 0,24 %

  27. Infarct Size Six Monts after PCI p : 0,17 % n : 18 n : 18

  28. ICSK (+) Control p (two tailed) ICSK (+), mean, 95%CI Control, mean 95%CI p (two tailed) ESV ml Two days after primary PCI 58.16 + 17.02 (n: 21) 78.65 + 30.55 (n: 20) 0.013 50.81 (31.25-66.37) 65.03 (47.76-82.30) 0.063 Six months after primary PCI 50.64 + 18.23 (n: 17) 83.73 + 39.32 (n: 15) 0.004 36.08 (9.07-63.10) 58.68 (25.10-92.27) 0.068 Change in ESV % -13.27 + 25.40 (n: 17) 12.67 + 30.75 (n: 15) 0.014 -12.32 (-47.47)-(-22.83) 15.30 (-28.40)-(59.01) 0.055 EDV ml Two days after primary PCI 119.88 + 23.36 (n: 21) 137.75 + 36.82 (n: 20) 0.07 111.22 (88.52-133.91) 118.53 (93.35-143.71) 0.50 Six months after primary PCI 115.70 + 29.67 (n: 17) 150.13 + 49.28 (n: 15) 0.021 92.72 (59.11-126.33) 118.77 (76.98-160.56) 0.089 Change in EDV, % -4.60 + 22.01 (n: 17) 11.90 + 23.50 (n: 15) 0.04 -11.19 (-37.95)-(15.58) 14.97 (-18.31)-(48.24) 0.036 LVEF % Two days after primary PCI 51.52 + 10.76 (n: 21) 44.51 + 12.40 (n: 20) 0.06 54.25 (46.95-61.55) 47.96 (39.86-56.06) 0.078 Six months after primary PCI 56.18 + 10.69 (n: 17) 46.19 + 12.21 (n: 15) 0.020 57.68 (45.88-69.47) 51.56 (36.90-66.23) 0.24 Change in LVEF, % 14.37 + 31.14 3.46 + 19.02 0.24 5.97 (-27.32)-(39.26) 2.71 (-37.75)-(43.16) 0.82 Infarct size %, SPECT 23 + 13.37 (n: 18) 37.05 + 13.84 (n: 18) 0.005 27.84 (14.35-41.32) 37.28 (21.57-52.99) 0.17 Left Ventricular End Systolic(ESV) and End Diastolic Volumes (EDV), Ejection Fraction (LVEF) and Infarct Size (%) Comparisons Un i var i ateMult i var i ate

  29. 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.

  30. 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.

  31. 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.

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