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EXTEND-IA Trial: Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Studies

Summary:

  • EXTEND-IA was a well designed prospective, multicenter, clinical trial involving 70 patients presenting within 4.5 hours of an acute ischemic stroke due to a proximal intracranial arterial occlusion who all received IV tPA were randomized to either receive usual care or endovascular therapy (intra-arterial treatment with a stent retriever) plus usual care. 
  • The primary endpoints include the median percentage reperfusion at 24 hours and early neurologic improvement (≥8 point reduction in NIHSS or reaching 0-1 at 3 days).
  • This trial was terminated early after the release of the MR CLEAN results and an unplanned interim efficacy analysis was conducted based on the Haybittle-Peto stopping rule.
  • Patients who received IV tPA for acute ischemic stroke with identified salvageable tissue on CT perfusion imaging and went on to get adjunctive endovascular therapy with a retrievable stent had more improvement in reperfusion, neurologic recovery and functional outcome.

EXTEND-IA Trial Summary

  • Reference: Campbell et al (EXTEND-IA Investigators). Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection. N Engl J Med 2015 Mar 12;372(11):1009-18. PubMed
    Level of Evidence 1b
    Study Design Prospective, Randomized, Open-label, Blinded end-point, Multicenter Trial
    Sample Size N = 70 (study was terminated early)
    Population Patients with ischemic stroke who were receiving IV tPA within 4.5 hours after onset of anterior circulation ischemic stroke due to large, proximal occlusion with evidence of an ischemic penumbra
    Inclusion Criteria
    • Patients presenting with anterior circulation acute ischemic stroke eligible using standard criteria to receive IV tPA within 4.5 hours of stroke onset
    • Patient, family member or legally responsible person depending on local ethics requirements has given informed consent
    • Patient's age is ≥18 years (no restriction on age)
    • Intra-arterial clot retrieval treatment can commence (groin puncture) within 6 hours of stroke onset
    • Arterial occlusion on CTA or MRA of the internal carotid artery, proximal middle cerebral artery, distal middle cerebral artery
    • Mismatch - Using CT or MRI with a Tmax >6 second delay perfusion volume and either CT-rCBF or DWI infarct core volume. A) Mismatch ratio of greater than 1.2, and B) Absolute mismatch volume of greater than 10 ml, and C) Infarct core lesion volume of less than 70mL
    Exclusion Criteria
    • Intracranial hemorrhage, rapidly improving symptoms, pre-stroke modified Rankin score of ≥ 2 inability to access the cerebral vasculature, stenosis proximal to the thrombus site, carotid dissection, terminal illness with less than 1 year life expectancy, pregnant women, previous stroke within last three months, recent past history or clinical presentation of intracranial hemorrhage, subarachnoid hemorrhage, arterio-venous malformation, aneurysm, or cerebral neoplasm, current use of anticoagulants with coagulation prolongation, use of glycoprotein IIb - IIIa inhibitors within the past 72 hours, hypoglycaemia, blood pressure > 185/110, hemorrhagic diathesis, gastrointestinal or urinary bleeding within the preceding 21 days, major surgery within the preceding 14 days, exposure to a thrombolytic agent within the previous 72 hours.
    Interventions

    All patients received alteplase IV at a dose of 0.9 mg/kg per standard of care and then randomized into one of two groups:

    • Control Group = Usual care only vs.
    • Intervention Group = Intra-arterial treatment with a stent retriever (Solitaire FR retrievable stent by Covidien) plus usual care
    Follow Up 90 days
    Primary Endpoint

    Co-primary end points:

    • Median percentage reperfusion at 24 hours
    • Early neurologic improvement (≥8 point reduction in NIHSS or reaching 0-1 at 3 days)
    Secondary Endpoint
    • Reperfusion at 24 hrs post stroke without symptomatic intracerebral hemorrhage.
    • Recanalization at 24 hrs post stroke
    • Infarct growth within 24 hrs
    • Stroke severity (NIHSS) at 24hrs
    • Symptomatic intra-cranial hemorrhage
    • Death due to any cause
    • Modified Rankin Scale (mRS) 0-1 at 3 months
    • Modified Rankin Scale (mRS) 0-2 at 3 months
    • Categorical shift in mRS at 3 months
    • NIHSS reduction ≥8 points or reaching 0-1 at 3 months
    Results
    • The median age was 69 years. The median NIH stroke scale was 15. The median stroke to puncture time was 210 minutes.
    • Reperfusion at 24 hours for the endovascular intervention group was 89% as compared with the alteplase-only group at 34% (P<0.001).
    • Early neurologic improvement at 3 days was 80% for endovascular intervention group vs the 37% for the alteplase-only group (adjusted P < 0.001)
    • 71% of patients in the endovascular treatment group had functional independence (modified Rankin score of 0-2) as compared to 40% in the alteplase-only group - absolute difference of 33% (P = 0.01)
    • Although not statistically significant, at the time of early termination of the study more deaths occurred in the alteplase only group compared to the endovascular plus alteplase group (20% vs 9%).
    • The median infarct growth at 24 hr was also less with the intervention group (35.3 mL vs 10.9 mL; P = 0.007)
    • The rate of symptomatic intracerebral hemorrhage was 6% the alteplase only group vs 0% for the intervention group.
    NNT/NNH Number Needed to Treat = 3
    Conclusions In patients receiving IV tPA for acute ischemic stroke with identified salvageable tissue on CT perfusion imaging, adjunctive endovascular therapy with a retrievable stent improves reperfusion, neurologic recovery and functional outcome.
    Location 14 centers in Australia and New Zealand
    Funding Funded by the Australian National Health and Medical Research Council and others;
    Comments
    • This study had no upper limit age restrictions
    • This study had no restrictions based on NIHSS score.
    • The investigators had originally planned to enroll 100 patients. 
    • The EXTEND-IA trial was terminated early after the release of the MR CLEAN results and an unplanned interim efficacy analysis was conducted based on the Haybittle-Peto stopping rule.
    • This was a poorly powered study

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MESH Terms & Keywords

  • tPA Alteplase, Endovascular Treatment of Acute Ischemic Stroke, EXTEND-IA Trial