Intracoronary Streptokinase after Primary PCI

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Intracoronary Streptokinase after Primary PCI

• Sezer M et al., NEJM May 3rd 2007

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Context Reperfusion after MI

• Rupture of atherosclerotic plaque -gt sudden
  thrombotic coronary occlusion
• Studies 1960ies nonselective intracoronary
  fibrinolysis can restore perfusion
• After primary PCI 15 inadequate myocardial
  perfusion despite patent epicardial vessels

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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

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Distal Embolization with PCI
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Salvage of viable myocardium in ACS

• IIb/IIIa inhibitors before primary PCI/stenting
• Asa, clopidogrel, heparin
• Mechanical thrombectomy / embolic protection
  devices
• Adjuvant fibrinolytic therapy ?

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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.

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ASSENT-4 PCI Trial profile
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Baseline characteristics
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Table 2 Time Intervals
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Table 3 Medications
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Table 4 TIMI flow grades
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Figure 2 Death, CHF, shock
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Figure 3 Mortality
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Table 5 Clinical endpoints 90 days
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Strokes, bleeding 90 days
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Table 7 Causes of death
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Facilitated angioplasty paradise lost

• The great tragedy of Sciencethe slaying of a
  beautiful hypothesis by an ugly fact
• Thomas Henry Huxley (182595)

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Myocardial salvage and mortality reduction
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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

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Methods

• Inclusion CP, ST-segment elevation, TIMI 0 or 1
  on angio
• Exclusion culprit in SVG, additional gt50 distal
  to culprit, LBBB, prior MI, contraindications to
  meds
• Informed consent, ethics board approved

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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-gt 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

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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

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• 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.
  Excludinggt70 (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

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Statistics

• Estimated number of patients needed to detect a
  30 difference in endpoints 7-39 per group
• Group percentages compared with chi-square or
  Fishers exact tests
• Group means for variables normal vs non-normal
  distributions compared with Students t-test and
  Mann-Whitney U test
• Subgroup ant MI LAD IRA
• Group means adjusted for confounders with
  analysis of covariance

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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

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Microcirculation Data Table 2

• Thermodilution-derived Coronary flow reserve
  2.01 vs 1.39, p0.002
• Microvascular resistance 16.29 vs 32.49 ,
  plt0.001
• Collateral flow index 0.08 vs 0.17 p0.002
• Mean cor wedge 10.81 mmHg vs 17.20, p0.04
• Coronay Diastolic Deceleration time 828 msec vs
  360, p0.001

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Microcirculation cont

• 2 days post PCI TIMI frame count 22 vs 31,
  p0.001
• Myocardial blush grade did not differ
  significantly
• 60 min post PCI resolution of ST-segment
  deviation not significantly higher after
  adjustment

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Long-Term Results

• Table 3 LVF Infarct size Univariate
  analyses improvements, however in multivariate
  only TIMI frame count and EDV retained
  significance

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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

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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 n41, microvascular perfusion
  parameters not uniformely accepted, not
  significant in multivariate model
• Angiographer aware of group assignment, bias
  possible

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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 2004291)
• Thrombolysis before PCI increased risk at full
  dose and no benefit at low dose.

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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

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Review

• Simultaneous pressure and flow-velocity
  measurements likely more accurate than using
  pressure and temperature
• No improvement in LVF, but small n41
• MRI more suitable for LV remodeling measurements,
  instead of SPECT
• 20-30 of small n41 non-anterior infarction
  non-uniform selection might obscure effect on
  hemodynamics

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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