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MR CLEAN Trial: A Randomized Trial of Intra-arterial Treatment for Acute Ischemic Stroke

Summary:

  • MR CLEAN was a well designed prospective, multicenter, clinical trial involving 500 patients presenting with acute ischemic stroke with a proximal intracranial arterial occlusion who were randomized to either receive usual care or intra-arterial treatment (delivery of a thrombolytic, mechanical thrombectomy, or both) plus usual care. 
  • The primary endpoint was the Modified Rankin score at 90 days.
  • More patients receiving the intervention compared to usual care had more independence with a NNT of 7.
  • Intra-arterial therapy in conjunction with IV tPA is safe and effective in patients presenting with an acute ischemic stroke secondary to a large, proximal occlusion of the anterior circulation.

MR CLEAN Trial Summary

  • Reference: Berkhemer et al (MR CLEAN investigators). A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. N Engl J Med. 2015 Jan 1;372(1):11-20. PubMed
    Level of Evidence 1b
    Study Design Prospective, Randomized, Open-label, Blinded end-point, Multi-center
    Sample Size n = 500
    Population Patients with acute ischemic stroke and a proximal intracranial occlusion of the anterior circulation confirmed on imaging (CTA, MRA, or DSA)
    Inclusion Criteria
    • Age ≥ 18 years
    • NIHSS ≥6
    • Occlusion of the distal intracranial carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery (A1 or A2), established by imaging
    • Treatment initiation within 6 hours of stroke onset
    Exclusion Criteria
    • General exclusion criteria for intra-arterial treatment (arterial blood pressure exceeding 185/110 mmHg, blood glucose less than 2.7 or over 22.2 mmol/L (48 to 400 mg/dL), treatment with IV thrombolysis in a dose exceeding 0.9 mg/kg or 90 mg, cerebral infarction in the distribution of the relevant occluded artery in the previous 6 weeks)
    • Coagulation abnormalities
    • Specific exclusion criteria for intra-arterial thrombolysis (history of cerebral hemorrhage, severe head injury in < 4, treatment with oral thrombin or factor X antagonists)
    Interventions
    • N = 267 (53.4%):  Control Group = Usual care alone vs.
    • N = 233 (46.6%):  Intervention Group = Intra-arterial treatment (delivery of thrombolytic, mechanical thrombectomy, or both) plus usual care
    • Thrombolytic therapy included 1 of 2 options: 1) maximum of 90 mg alteplase loading dose if no prior alteplase was given or restricted to 30 mg if a prior dose was used. 2) max dose of 1,200,000 IU of urokinase if no prior alteplase was given or 400,000 IU if alteplase was already given.
    Follow Up 90 days
    Primary Endpoint
    • Modified Rankin score at 90 days 
    • Score ranges from 0 (no symptoms) to 6 (death) with a score of less than or equal to 2 being functional independence.
    Secondary Endpoint
    • Imaging parameter vessel recanalization at 24 hours (Clot Burden score and collateral score)
    • Infarct size at 5 days assessed with ASPECTS
    • Final infarct volume calculation
    • NIHSS and NIH supplemental motor scale at 24 hours and at 1 week or discharge
    Results
    • 233 were assigned to intra-arterial treatment group and 267 to usual care alone.
    • The median age was mid 60s, 58% being males, and having a median NIH stroke scale of 17.
    • The median time to groin puncture was 4 hours and 20 minutes.
    • 445 patients (89.0%) were treated with IV tPA before randomization. There were too few that were not treated with IV tPA prior to endovascular intervention to draw any statistically significant conclusions.
    • Retrievable stents were used in 190 of the 233 patients (81.5%).
    • Patients with a modified Rankin score of 0-2 at 90 days in the intervention group was 32.6% vs. 19.1% in the usual care group - absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2). The adjusted common odds ratio (OR) was 1.67 (95% CI, 1.21 to 2.30).
    • There were no significant difference in mortality
    • Complication rate was 6% with no significant differences in symptomatic intracerebral hemorrhage.  However, the intervention group experienced more new ischemic strokes involving a different vascular territory (5.6% vs 0.4%, p < 0.001).
    NNT/NNH Number Needed to Treat = 7
    Conclusions Intra-arterial therapy in conjunction with IV tPA is safe and effective in patients presenting with an acute ischemic stroke secondary to a large, proximal occlusion of the anterior circulation.
    Location 16 medical centers in the Netherlands
    Funding Dutch Heart Foundation and others
    Comments
    • While MR CLEAN did conduct imaging to identify a proximal occlusion in the anterior circulation, it did not require evidence of an ischemic penumbra with an infarcted core for enrollment.
    • Urokinase is also not a treatment option in the United States like alteplase (Activase).
    • Patients were not enrolled until after the administration of IV tPA suggesting that non-responsive patients may have been preferentially selected.
    • 90 day modified Rankin Score was calculated by a telephone interview and subjective report by the patient and/or representative.

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MESH Terms & Keywords

  • tPA Alteplase, Acute Ischemic Stroke, MR CLEAN Trial