1. Intracoronary Streptokinase after Primary PCI Sezer M et al., NEJM May 3 rd 2007

2. Context: Reperfusion after MI Rupture of atherosclerotic plaque -> sudden thrombotic coronary occlusion Studies 1960ies: nonselective intracoronary fibrinolysis can restore perfusion After primary PCI 15% inadequate myocardial perfusion despite patent epicardial vessels

3. Inadequate Reperfusion “no-reflow” due to microvascular damage after ischemia, cell necrosis / regional inflammatory response due to reperfusion Microvascular obstruction due to embolization Clinically: Larger MI, worse LVF, worse outcomes

4. Distal Embolization with PCI

5. Salvage of viable myocardium in ACS IIb/IIIa inhibitors before primary PCI/stenting Asa, clopidogrel, heparin Mechanical thrombectomy / embolic protection devices Adjuvant fibrinolytic therapy ?

6. ASSENT-4 PCI (2006) Assessment of the Safety and Efficacy of a New Treatment Strategy with PCI Tenecteplase before primary PCI Higher incidence cardiac complications and stroke, stopped prematurely.

7. ASSENT-4 PCI: Trial profile

8. Baseline characteristics

9. Table 2: Time Intervals

10. Table 3: Medications

11. Table 4: TIMI flow grades

12. Figure 2: Death, CHF, shock

13. Figure 3: Mortality

14. Table 5: Clinical endpoints 90 days

17. Strokes, bleeding 90 days

18. Table 7: Causes of death

19. “Facilitated angioplasty: paradise lost” “The great tragedy of Science—the slaying of a beautiful hypothesis by an ugly fact” Thomas Henry Huxley (1825–95)

20. Myocardial salvage and mortality reduction

21. Intracoronary Streptokinase after Primary PCI Hypothesis: (Local) intracoronary infusion of low-dose streptokinase (250 kU) immediately after primary PCI might improve tissue level perfusion by dissolving thrombi. Prospective pilot trial

22. Methods Inclusion: CP, ST-segment elevation, TIMI 0 or 1 on angio Exclusion: culprit in SVG, additional >50% distal to culprit, LBBB, prior MI, contraindications to meds Informed consent, ethics board approved

23. Study Protocol Primary PCI/stent, asa 300, clopidogrel 600, intracoronary heparin 100U/kg, tirofiban 12 hrs, LMWH after procedure 48 hrs, TIMI frame count: number of cine frames for dye to travel: ostium-> distal landmark Myocardial blush grade (angiographic measure of capillary perfusion) 250 kU streptokinase in 20mL NS infused guiding cath 3 min Asa 100, clopidogrel 75x1y, BB, ACE

24. Intracoronary Hemodynamics 2 days after: Cor angio for TIMI frame count and myocardial blush grade Guidewire with pressure/temp tip distal to stent: at rest vs papaverine induced hyperemia Transit time NS, coronary flow reserve, microvascular resistance Coronary wedge pressures after stent occlusion with ballon, collateral flow index

25. If LAD IRA echo for deceleration time of coronary diastolic flow, coronary flow velocity pattern 6 months f/o echo, angio, SPECT for infarct size. Excluding>70% (in-stent restenosis) Primary endpoints: coronary flow reserve, index microvascular resistance, coronary wedge, collateral-flow index, coronary deceleration time Secondary: TIMI frame count, myocardial blush grade, infarct size, LV volume, reinfarction, revascularization, death

26. Statistics Estimated number of patients needed to detect a 30% difference in endpoints: 7-39 per group Group percentages compared with chi- square or Fisher’s exact tests Group means for variables normal vs non- normal distributions compared with Student’s t-test and Mann-Whitney U test Subgroup ant MI LAD IRA Group means adjusted for confounders with analysis of covariance

27. Study Patients and Angiographic Outcomes Mean age 52 y, mostly male (see Figure 1) IRA opened in all patients, at least one stent each, one femoral pseudoaneurysm in streptokinase group

30. Microcirculation Data: Table 2 Thermodilution-derived Coronary flow reserve: 2.01 vs 1.39, p=0.002 Microvascular resistance: 16.29 vs 32.49, p<0.001 Collateral flow index: 0.08 vs 0.17 p=0.002 Mean cor wedge: 10.81 mmHg vs 17.20, p=0.04 Coronay Diastolic Deceleration time: 828 msec vs 360, p=0.001

31. Microcirculation cont’ 2 days post PCI TIMI frame count 22 vs 31, p=0.001 Myocardial blush grade did not differ significantly 60 min post PCI: % resolution of ST- segment deviation not significantly higher after adjustment

33. Long-Term Results: Table 3: LVF & Infarct size: Univariate analyses improvements, however in multivariate only TIMI frame count and % EDV retained significance

35. Discussion Better perfusion on microvascular level based on multiple endpoints Only limited statistical evidence of benefit, possibly chance associations Trends favoring streptokinase group detected, but likely underpowered Streptokinase may improve perfusion through mechanisms beyond distal protection devices: inhibition red-cell + platelet aggregation, reduced congestion

36. Discussion Intracoronary 250-kU streptokinase after IRA opening vs systemic lysis iv 1.5 MU: Quicker arrival at target, x50 higher concentration at target x6 less systemic concentration Limitations: n=41, microvascular perfusion parameters not uniformely accepted, not significant in multivariate model Angiographer aware of group assignment, bias possible

37. Discussion Intracranial hemorrhage increased in ASSENT-4 PCI (full dose tenecteplase) Early half dose reteplase in PCI with abciximab: No significant reduction in ischemic events (Kastrati et al. JAMA 2004;291) Thrombolysis before PCI increased risk at full dose and no benefit at low dose.

38. Review Microvascular parameters: Study patients should serve as their own controls; intrapatient longitudinal assessment vs random interpatient comparison. No measurements immediately after PCI, nor at 6 months. (Only once at 2 days) Streptokinase associated reduction in microvascular resistance based on randomly assigned patients rather than intrapatient analysis

39. Review Simultaneous pressure and flow-velocity measurements likely more accurate than using pressure and temperature No improvement in LVF, but small n=41 MRI more suitable for LV remodeling measurements, instead of SPECT 20-30% of small n=41 non-anterior infarction: non-uniform selection might obscure effect on hemodynamics

40. Review No suggestion that intracoronary low dose streptokinase has harmful effects, e.g. hemorrhagic expansion of an infarct Larger-scale clinical study to evaluate this new approach as an adjunct to current therapy