IMS III

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Broderick J, et al. "Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke". The New England Journal of Medicine. 2013. 368:893-903.
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Clinical Question

Does IV t-PA followed by endovascular therapy compared to IV t-PA alone improve outcomes after acute ischemic stroke?

Bottom Line

There was no significant difference between combined therapy (endovascular therapy and IV t-PA) compared to IV t-PA alone in this trial that had low recruitment rates, older endovascular devices, and longer treatment times.

Major Points

IV t-PA is currently the only proven reperfusion therapy for acute ischemic stroke. It was uncertain whether combining IV t-PA and endovascular therapy (including endovascular thrombolysis, mechanical thrombectomy, aspiration thrombectomy, and stent-retriever technology) would lead to higher rates of recanalization and better functional outcomes.

IMS III was stopped early because of futility, according to the prespecified rules. The trial failed to show a benefit in functional outcome with the use of additional endovascular therapy compared with standard therapy of IV t-PA alone.

Design

  • International, multicenter, phase 3, open-label, randomized, controlled trial with a blinded outcome
  • N=656
    • IV t-PA plus endovascular therapy (n=434)
    • IV t-PA alone (n=222)
  • Setting: 58 centers in US, Canada, Australia, and Europe
  • Enrollment: 2006-2012
  • Mean follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome: modified Rankin score of 2 or less at 90 days

Population

Inclusion Criteria

  • Age 18-80
  • Receipt of IV t-PA within 3 hours after symptom onset
  • Moderate to severe neurologic deficit defined as NIHSS score greater than or equal to 10, or after amendment 3 a score of 8 or 9 with CT angiographic evidence of an occlusion in the M1, ICA, or basilar artery

Exclusion Criteria

  • History of stroke in the past 3 months
  • Previous ICH, neoplasm, SAH, or AVM
  • SBP >185 or DBP >110, or aggressive measures needed to lower BP
  • Presumed septic embolus
  • Presumed pericarditis
  • Recent surgery or biopsy of parenchymal organ within 30 days
  • Recent severe head trauma or head trauma with loss of consciousness within 90 days
  • Any active or recent hemorrhage within 30 days
  • Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR > 1.5
  • Females known to be pregnant or lactating
  • Glucose < 50 or > 400, platelets < 100,000, Hct < 25
  • Patients who received heparin with 48 hours (unless PTT is normal)
  • Arterial puncture at a non-compressible site or a lumbar puncture in the previous 7 days
  • Patients with seizure at onset of stroke
  • Other serious or advanced terminal illness

Baseline Characteristics

  • Median age: 69 years
  • Male: 52%
  • Median NIHSS score: 17
  • ASPECTS of 8, 9, or 10: 58
  • Time from stroke onset to initiation of IV t-PA: 122 +/- 34 mins

Interventions

  • Randomized in a 2:1 ratio to IV t-PA plus endovascular therapy or IV t-PA alone
  • Randomization was required within 40 mins after initiation of IV t-PA
  • IV t-PA group received standard IV t-PA dose (0.9 mg/kg of body weight, max dose 90 mg)
  • Endovascular therapy group received either two thirds dose of stndard IV t-PA dose, or after amendment 5, the full standard dose of IV t-PA
    • Participants underwent angiography ASAP. (Initially, CT angiography was used infrequently to assess the presence of vascular occlusions. Amendment 3 made to protocol after 284 participants had been randomized, CT angiography was allowed to determine presence of vascular occlusions.)
    • Participants with a treatable vascular occlusion received thrombectomy with the Merci retriever, Penumbra system, Solitaire device, or endovascular delivery of t-PA. (Initially, only a single thrombectomy device had been cleared for use by the FDA. Additional devices were allowed as they became cleared by regulatory authorities of participating countries.)

Outcomes

Comparisons are IV t-PA plus endovascular therapy vs. IV t-PA alone.

Primary Outcome

Modified Rankin score of 2 or less
40.8% vs. 38.7% (NS)

Secondary Outcomes

Rate of symptomatic ICH or parenchymal hematoma

Subgroup Analysis

  • Subgroup analyses suggest benefit for patients treated with endovascular therapy in shorter time windows.

Adverse Events

  • No significant differences in mortality at 7 days or 90 days, in rate of symptomatic ICH, or in rate of parenchymal hematoma.
  • Rate of asymptomatic ICH was higher in endovascular therapy group than in IV t-PA group (P=0.01)

Criticisms

  • The use of older recanalization devices in this trial was associated with lower recanalization rates than those found with new devices in other trials.
  • The median interval between onset of stroke and intervention was long: 4 hours 9 min.
  • Low recruitment rates (or lack of equipoise) suggested that many suitable patients had been treated outside of the trial.
  • Significant number of participants with no demonstrated vascular occlusion was randomized to the endovascular therapy group (89 out of 423).

Funding

Supported by grants from the National Institutes of Health and the National Institute of Neurological Disorders and Stroke (UC U01NS052220, MUSC U01NS054630, and U01NS077304) and by Genentech, EKOS, Concentric Medical, Cordis Neurovascular, and Boehringer Ingelheim.

Further Reading