Intracoronary Streptokinase after Primary PCI

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