Intracoronary Streptokinase after Primary PCI

Sezer M et al., NEJM May 3rd 2007

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

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

Distal Embolization with PCI

Salvage of viable myocardium in ACS

• IIb/IIIa inhibitors before primary PCI/stenting

• Asa, clopidogrel, heparin

• Mechanical thrombectomy / embolic protection devices

• Adjuvant fibrinolytic therapy ?

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.

ASSENT-4 PCI: Trial profile

Baseline characteristics

Table 2: Time Intervals

Table 3: Medications

Table 4: TIMI flow grades

Figure 2: Death, CHF, shock

Figure 3: Mortality

Table 5: Clinical endpoints 90 days

Strokes, bleeding 90 days

Table 7: Causes of death

“Facilitated angioplasty: paradise lost”

• “The great tragedy of Science—the slaying of a beautiful hypothesis by an ugly fact”

Thomas Henry Huxley (1825–95)

Myocardial salvage and mortality reduction

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

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

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

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

• 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

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

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

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

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

Long-Term Results:• Table 3: LVF & Infarct size: Univariate

analyses improvements, however in multivariate only TIMI frame count and % EDV retained significance

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

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

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.

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

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

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