EXTEND-IA

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Campbell BC, et al. "Endovascular therapy for ischemic stroke with perfusion-imaging selection". The New England Journal of Medicine. 2015. 372(11):1009-1018.
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Clinical Question

Do patients with acute ischemic stroke in the anterior circulation benefit from early endovascular thrombectomy with the Solitaire FR device (Flow Restoration) when performed within 4.5 hours?

Bottom Line

For patients with acute ischemic stroke who are found to have a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever (within 4.5 hours) shows benefit in terms of reperfusion, early neurologic recovery, and functional outcome.

Major Points

Previous trials of endovascular thrombectomy for ischemic stroke (MR RESCUE[1], IMS III[2], SYNTHESIS[3]) had neutral findings. However, many experts thought these studies had inappropriate patient selection, inadequate radiographic evidence of reperfusion after thrombectomy, and inefficiencies resulting in delayed reperfusion. Newer device technology has improved the speed and efficacy of recanalization, and used modern imaging techniques to confirm the presence of vessel occlusion and salvageable, non-infarcted brain tissue [4][5][6]. After the results of the MR CLEAN trial recently demonstrated a clinical benefit from endovascular thrombectomy for patients with ischemic stroke[7], the EXTEND-IA study sought to test whether advanced imaging, more appropriate patient selection, newer devices, and an emphasis on earlier intervention could show a benefit.

This study randomly assigned patients to receive endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever with alteplase or alteplase alone. The trial was stopped after 70 patients due to efficacy. Of those randomized to endovascular therapy, treatment was initiated at a median of 210 minutes since onset of symptoms. Reperfusion at 24 hours, early neurologic improvement at 3 days, functional outcome at 90 days, and functional independence were higher in the thrombectomy group. There were no significant differences in rates of death or symptomatic intracerebral hemorrhage. In summary, acute ischemic stroke patients with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging benefit from endovascular thrombectomy within 4.5 hours with the Solitaire FR stent retriever.

Limitations of this study include its small sample size and patient inclusion criteria, which makes it non-generalizeable to all acute ischemic stroke patients. In addition, most patients were treated in urban tertiary care centers in Australia, with expertise and efficiency (median time to treatment initiation 210 minutes) that isn't generalizeable to all centers.

Guidelines

2015 AHA/ASA Focused Update of the 2013 Guidelines [8]
  • Endovascular thrombectomy with stent retrievers is recommended if all of the following are met: (Level of Evidence A):
    • acute ischemic stroke
    • prestroke mRS ≤1;
    • IV r-tPA within 4.5 hours;
    • causative occlusion of the internal carotid artery or proximal MCA (M1);
    • age ≥18 years;
    • NIHSS score ≥6;
    • ASPECTS ≥6;
    • treatment can be initiated (groin puncture) within 6 hours of symptom onset.
  • Benefits of treatment are uncertain beyond 6 hours
  • Endovascular thrombectomy with stent retrievers within 6 hours of stroke onset is reasonable (Class IIa; Level of Evidence C)
  • Endovascular thrombectomy with stent retrievers may be reasonable within 6 hours for patients with occlusion of the M2 or M3, anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries (Class IIb; Level of Evidence C).

Design

  • Multicenter, prospective, randomized, open-label, blinded-end-point
  • N=70
    • Endovascular (n=35)
    • Control (n=35)
  • Setting: 14 centers in Australia and New Zealand
  • Enrollment: August 2012 through October 2014
  • Primary outcomes:
    • Reperfusion at 24 hours
    • Early neurologic improvement (reduction ≥8 on the NIHSS or a NIHSS ≤1 at 3 days).
  • Secondary outcomes:
    • Modified Rankin Scale score at 90 days
    • Death
    • Symptomatic intracranial hemorrhage

Full protocol published in 2012 [9]

Population

Inclusion Criteria

  • Anterior circulation acute ischaemic stroke receiving IV tPA within 4.5 hours
  • Age is ≥18 years
  • Groin puncture within 6 hours

Imaging inclusion criteria

  • Dual target:
    • Arterial occlusion of the ICA, M1 or M2 on CTA or MRA
    • CT or MRI: mismatch ratio >1.2, absolute mismatch >10 ml, and infarct core volume <70mL

Exclusion Criteria

  • Intracranial haemorrhage (ICH)
  • Rapidly improving symptoms
  • Pre-stroke mRS score ≥ 2
  • Inaccessible cerebral vasculature
  • Contraindication to contrast agents
  • Terminal illness with prognosis <1 year
  • Pregnancy
  • Stroke within last 3 months
  • History of ICH, SAH, AVM, aneurysm, or cerebral neoplasm
  • Current use of oral anticoagulants and INR > 1.6
  • Use of heparin in the previous 48 hours and elevated aPTT
  • Use of glycoprotein IIb - IIIa inhibitors within 72 hours
  • Clinically significant hypoglycaemia
  • sBP >185 mmHg or dBP >110 mmHg
  • Haemorrhagic diathesis
  • Gastrointestinal or urinary bleeding within 21 days
  • Major surgery within 14 days
  • Exposure to a thrombolytic agent within 72 hrs

Baseline Characteristics

Comparisons are control vs. endovascular

  • Age (yr): 70.2 vs. 68.6
  • Male: 17 (49%) vs. 17 (49%)
  • Median NIHSS score (IQR): 13 (9–19) vs. 17 (13–20)
  • Clinical history:
    • Atrial fibrillation: 11 (31%) vs. 12 (34%)
    • Hypertension: 23 (66%) vs. 21 (60%)
    • Diabetes: 8 (23%) vs. 2 (6%)
    • Smoking: 15 (43%) vs. 12 (34%)
  • Serum glucose (mmol/liter): 7.6±3.6 vs. 7.1±2.5
  • Cause of stroke:
    • Cardioembolic occlusion: 14 (40%) vs. 23 (66%)
    • Large-artery occlusion: 13 (37%) vs. 7 (20%)
    • Undetermined or other: 8 (23%) vs. 5 (14%)
  • Median time from stroke onset to hospital arrival (min): 80 vs. 78
  • Median time from stroke onset to initiation of alteplase (min): 145 vs. 127
  • Site of vessel occlusion:
    • Internal carotid artery: 11 (31%) vs. 11 (31%)
    • Middle cerebral artery:
      • First segment: 18 (51%) vs. 20 (57%)
      • Second segment: 6 (17%) vs. 4 (11%)
  • Ischemic core volume at initial imaging (ml):
    • Mean: 19.6±17.4 vs. 18.9±18.5
    • Median: (IQR) 18 (4–29) vs. 12 (4–32)
  • Perfusion-lesion volume at initial imaging (ml):
    • Mean: 116±48 vs. 105±39
    • Median (IQR): 115 (72–158) vs. 106 (76–137)

Interventions

  • All patients received alteplase at a dose of 0.9 mg per kilogram
  • Patients were randomly assigned 1:1 to receive either endovascular thrombectomy or no thrombectomy

Outcomes

Comparisons are control vs. endovascular

Primary Outcomes

Median reperfusion at 24 hr
37 vs. 100 (Effect Size 4.7; 95% CI 2.9-9.0; P<0.001)
Early neurologic improvement
13 (37%) vs. 28 (80%) (Effect Size 6.0; 95% CI 2.0-18.0; P=0.002)

Secondary Outcomes

Modified Rankin Scale score at 90 days
  • Median score (IQR) on ordinal analysis:
3 (1 to 5) vs. 1 (0 to 3) (Effect Size 2.0; P=0.02)
  • Independent outcome:
14 (40%) vs. 25 (71%) (Effect Size 4.2; 95% CI 1.4-12; P=0.01)
  • Excellent outcome:
10 (29%) vs. 18 (51%) (Effect Size 2.4; 95% CI 0.87-6.6; P=0.09)

Tertiary Outcomes

Reperfusion of >90% at 24 hr without symptomatic intracerebral hemorrhage
12 (34%) vs. 31 (89%) (Effect Size 27.0; 95% CI 5.5-135.0; P<0.001)
Recanalization at 24 hr
15 (43%) vs. 33 (94%) (Effect Size 29.0; 95% CI 5.4-155.0; P<0.001)
Median infarct growth at 24 hr (ml)
35.3 vs. 19.9 (Effect Size -0.44; 95% CI -0.76 to -0.13; P=0.007)
Median home time (days)
15 vs. 73 (Effect Size 64; 95% CI 28-90; P=0.001)

Adverse Events

Death
7 (20%) vs. 3 (9%) (Effect Size 0.45; 95% CI 0.1-2.1, P=0.31)
Symptomatic intracerebral hemorrhage
2 (6%) vs. 0
Parenchymal hematoma
3 (9%) vs. 4 (11%)

Criticisms

  • Small sample size and inability to perform subgroup analyses
  • Rigorous patient inclusion criteria
  • Primarily conducted at urban tertiary care centers in Australia, with expertise and efficiency that isn't generalizeable
  • Early termination of trial

Funding

Supported by grants from the Australian National Health and Medical Research Council of Australia (1043242 and 1035688), Royal Australasian College of Physicians, Royal Melbourne Hospital Foundation, the National Heart Foundation of Australia, and the National Stroke Foundation of Australia; and by infrastructure funding from the state government of Victoria. The Solitaire FR device and trial infrastructure were provided under an unrestricted grant from Covidien. EXTEND-IA ClinicalTrials.gov number, NCT01492725[10], and Australian New Zealand Clinical Trials Registry number, ACTR N12611000969965[11].

Further Reading

  1. Kidwell CS et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N. Engl. J. Med. 2013. 368:914-23.
  2. Broderick JP et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N. Engl. J. Med. 2013. 368:893-903.
  3. Ciccone A et al. Endovascular treatment for acute ischemic stroke. N. Engl. J. Med. 2013. 368:904-13.
  4. Pereira VM et al. Prospective, multicenter, single-arm study of mechanical thrombectomy using Solitaire Flow Restoration in acute ischemic stroke. Stroke 2013. 44:2802-7.
  5. Saver JL et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet 2012. 380:1241-9.
  6. Nogueira RG et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet 2012. 380:1231-40.
  7. Berkhemer OA et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N. Engl. J. Med. 2015. 372:11-20.
  8. Powers WJ et al. 2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015. 46:3020-35.
  9. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1414792/suppl_file/nejmoa1414792_protocol.pdf
  10. https://clinicaltrials.gov/show/NCT01492725
  11. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12611000969965