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Intracoronary Streptokinase after Primary PCI


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Intracoronary Streptokinase after Primary PCI

  1. 1. Intracoronary Streptokinase after Primary PCI Sezer M et al., NEJM May 3 rd 2007
  2. 2. Context: Reperfusion after MI <ul><li>Rupture of atherosclerotic plaque -> sudden thrombotic coronary occlusion </li></ul><ul><li>Studies 1960ies: nonselective intracoronary fibrinolysis can restore perfusion </li></ul><ul><li>After primary PCI 15% inadequate myocardial perfusion despite patent epicardial vessels </li></ul>
  3. 3. Inadequate Reperfusion <ul><li>“ no-reflow” due to microvascular damage after ischemia, cell necrosis / regional inflammatory response due to reperfusion </li></ul><ul><li>Microvascular obstruction due to embolization </li></ul><ul><li>Clinically: Larger MI, worse LVF, worse outcomes </li></ul>
  4. 4. Distal Embolization with PCI
  5. 5. Salvage of viable myocardium in ACS <ul><li>IIb/IIIa inhibitors before primary PCI/stenting </li></ul><ul><li>Asa, clopidogrel, heparin </li></ul><ul><li>Mechanical thrombectomy / embolic protection devices </li></ul><ul><li>Adjuvant fibrinolytic therapy ? </li></ul>
  6. 6. ASSENT-4 PCI (2006) <ul><li>Assessment of the Safety and Efficacy of a New Treatment Strategy with PCI </li></ul><ul><li>Tenecteplase before primary PCI </li></ul><ul><li>Higher incidence cardiac complications and stroke, stopped prematurely. </li></ul>
  7. 7. ASSENT-4 PCI: Trial profile
  8. 8. Baseline characteristics
  9. 9. Table 2: Time Intervals
  10. 10. Table 3: Medications
  11. 11. Table 4: TIMI flow grades
  12. 12. Figure 2: Death, CHF, shock
  13. 13. Figure 3: Mortality
  14. 14. Table 5: Clinical endpoints 90 days
  15. 17. Strokes, bleeding 90 days
  16. 18. Table 7: Causes of death
  17. 19. “ Facilitated angioplasty: paradise lost” <ul><li>“The great tragedy of Science—the slaying of a beautiful hypothesis by an ugly fact” </li></ul><ul><li>Thomas Henry Huxley (1825–95) </li></ul>
  18. 20. Myocardial salvage and mortality reduction
  19. 21. Intracoronary Streptokinase after Primary PCI <ul><li>Hypothesis: (Local) intracoronary infusion of low-dose streptokinase (250 kU) immediately after primary PCI might improve tissue level perfusion by dissolving thrombi. </li></ul><ul><li>Prospective pilot trial </li></ul>
  20. 22. Methods <ul><li>Inclusion: CP, ST-segment elevation, TIMI 0 or 1 on angio </li></ul><ul><li>Exclusion: culprit in SVG, additional >50% distal to culprit, LBBB, prior MI, contraindications to meds </li></ul><ul><li>Informed consent, ethics board approved </li></ul>
  21. 23. Study Protocol <ul><li>Primary PCI/stent, asa 300, clopidogrel 600, intracoronary heparin 100U/kg, tirofiban 12 hrs, LMWH after procedure 48 hrs, </li></ul><ul><li>TIMI frame count: number of cine frames for dye to travel: ostium-> distal landmark </li></ul><ul><li>Myocardial blush grade (angiographic measure of capillary perfusion) </li></ul><ul><li>250 kU streptokinase in 20mL NS infused guiding cath 3 min </li></ul><ul><li>Asa 100, clopidogrel 75x1y, BB, ACE </li></ul>
  22. 24. Intracoronary Hemodynamics <ul><li>2 days after: Cor angio for TIMI frame count and myocardial blush grade </li></ul><ul><li>Guidewire with pressure/temp tip distal to stent: at rest vs papaverine induced hyperemia </li></ul><ul><li>Transit time NS, coronary flow reserve, microvascular resistance </li></ul><ul><li>Coronary wedge pressures after stent occlusion with ballon, collateral flow index </li></ul>
  23. 25. <ul><li>If LAD IRA echo for deceleration time of coronary diastolic flow, coronary flow velocity pattern </li></ul><ul><li>6 months f/o echo, angio, SPECT for infarct size. Excluding>70% (in-stent restenosis) </li></ul><ul><li>Primary endpoints: coronary flow reserve, index microvascular resistance, coronary wedge, collateral-flow index, coronary deceleration time </li></ul><ul><li>Secondary: TIMI frame count, myocardial blush grade, infarct size, LV volume, reinfarction, revascularization, death </li></ul>
  24. 26. Statistics <ul><li>Estimated number of patients needed to detect a 30% difference in endpoints: 7-39 per group </li></ul><ul><li>Group percentages compared with chi-square or Fisher’s exact tests </li></ul><ul><li>Group means for variables normal vs non-normal distributions compared with Student’s t-test and Mann-Whitney U test </li></ul><ul><li>Subgroup ant MI LAD IRA </li></ul><ul><li>Group means adjusted for confounders with analysis of covariance </li></ul>
  25. 27. Study Patients and Angiographic Outcomes <ul><li>Mean age 52 y, mostly male (see Figure 1) </li></ul><ul><li>IRA opened in all patients, at least one stent each, one femoral pseudoaneurysm in streptokinase group </li></ul>
  26. 30. Microcirculation Data: Table 2 <ul><li>Thermodilution-derived Coronary flow reserve: 2.01 vs 1.39, p=0.002 </li></ul><ul><li>Microvascular resistance: 16.29 vs 32.49 , p<0.001 </li></ul><ul><li>Collateral flow index: 0.08 vs 0.17 p=0.002 </li></ul><ul><li>Mean cor wedge: 10.81 mmHg vs 17.20, p=0.04 </li></ul><ul><li>Coronay Diastolic Deceleration time: 828 msec vs 360, p=0.001 </li></ul>
  27. 31. Microcirculation cont’ <ul><li>2 days post PCI TIMI frame count 22 vs 31, p=0.001 </li></ul><ul><li>Myocardial blush grade did not differ significantly </li></ul><ul><li>60 min post PCI: % resolution of ST-segment deviation not significantly higher after adjustment </li></ul>
  28. 33. Long-Term Results: <ul><li>Table 3: LVF & Infarct size: Univariate analyses improvements, however in multivariate only TIMI frame count and % EDV retained significance </li></ul>
  29. 35. Discussion <ul><li>Better perfusion on microvascular level based on multiple endpoints </li></ul><ul><li>Only limited statistical evidence of benefit, possibly chance associations </li></ul><ul><li>Trends favoring streptokinase group detected, but likely underpowered </li></ul><ul><li>Streptokinase may improve perfusion through mechanisms beyond distal protection devices: inhibition red-cell + platelet aggregation, reduced congestion </li></ul>
  30. 36. Discussion <ul><li>Intracoronary 250-kU streptokinase after IRA opening vs systemic lysis iv 1.5 MU: </li></ul><ul><li>Quicker arrival at target, x50 higher concentration at target </li></ul><ul><li>x6 less systemic concentration </li></ul><ul><li>Limitations: n=41, microvascular perfusion parameters not uniformely accepted, not significant in multivariate model </li></ul><ul><li>Angiographer aware of group assignment, bias possible </li></ul>
  31. 37. Discussion <ul><li>Intracranial hemorrhage increased in ASSENT-4 PCI (full dose tenecteplase) </li></ul><ul><li>Early half dose reteplase in PCI with abciximab: No significant reduction in ischemic events (Kastrati et al. JAMA 2004;291) </li></ul><ul><li>Thrombolysis before PCI increased risk at full dose and no benefit at low dose. </li></ul>
  32. 38. Review <ul><li>Microvascular parameters: Study patients should serve as their own controls; intrapatient longitudinal assessment vs random interpatient comparison. </li></ul><ul><li>No measurements immediately after PCI, nor at 6 months. (Only once at 2 days) </li></ul><ul><li>Streptokinase associated reduction in microvascular resistance based on randomly assigned patients rather than intrapatient analysis </li></ul>
  33. 39. Review <ul><li>Simultaneous pressure and flow-velocity measurements likely more accurate than using pressure and temperature </li></ul><ul><li>No improvement in LVF, but small n=41 </li></ul><ul><li>MRI more suitable for LV remodeling measurements, instead of SPECT </li></ul><ul><li>20-30% of small n=41 non-anterior infarction: non-uniform selection might obscure effect on hemodynamics </li></ul>
  34. 40. Review <ul><li>No suggestion that intracoronary low dose streptokinase has harmful effects, e.g. hemorrhagic expansion of an infarct </li></ul><ul><li>Larger-scale clinical study to evaluate this new approach as an adjunct to current therapy </li></ul>