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Nogueira RG, et al. "Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct". The New England Journal of Medicine. 2018. 378(1):11-21.
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Clinical Question

Do ischemic stroke patients with a clinical deficit disproportionately severe compared to imaging studies benefit from endovascular thrombectomy more than 6 hours after the onset?

Bottom Line

Patients with acute ischemic stroke who were last well 6 to 24 hours ago and who had a greater clinical deficit than expected based on infarct size on imaging benefited from thrombectomy plus standard care in terms of disability at 90 days compared to those who received standard care alone.

Major Points

Recent randomized trials (MR CLEAN[1], ESCAPE[2], REVASCAT[3], SWIFT PRIME[4], and EXTEND IA[5]) showed that endovascular thrombectomy for acute ischemic stroke was beneficial when performed within 6 hours [6] and that benefits diminished as the time since onset increased.[7] However, there is a subset of acute stroke patients with brain tissue that is ischemic but not yet infarcted. This group of patients present with a clinical deficit that is disproportionately severe when compared to the amount of tissue demonstrating evidence of infarction on radiographic imaging. Among these patients, there is currently limited evidence as to whether the ischemic tissue may be salvaged with reperfusion via thrombectomy. Therefore, the purpose of this trial was to recruit patients with a mismatch between their clinical deficit and the volume of infarct on imaging studies.

This trial enrolled patients who had evidence an occluded intracranial internal carotid artery (ICA) or proximal middle cerebral artery (MCA). In addition, patients had to have presented within 6 to 24 hours of the time they were last seen well, and had to have a disproportionately severe clinical deficit relative to infarct volume. After 31 months of enrolment, the trial was stopped after a prespecified interim analysis. In the end, 206 patients had been randomized - 107 patients to the thrombectomy plus standard care group and 99 to the standard care alone group. The thrombectomy group had a higher utility-weighted modified Rankin scale score at 90 days (5.5 compared to 3.4 in the control group) and a higher functional independence rate at 90 days (49% compared to 13%). There was no statistically significant difference in symptomatic intracranial hemorrhage or 90-day mortality. In summary, this trial found that endovascular thrombectomy reduces disability and improves functional recovery when performed 6 to 24 hours after onset of symptoms among patients with a clinical deficit that is disproportionate to infarct volume.

This trial provides evidence for offering endovascular thrombectomy up to 24 hours after onset. IT involved many multi-national treatment centers and featured an extensive subgroup analysis. However, the results of this trial aren't generalizable to patients with large volume infarcts as they were excluded from this trial.

Guidelines

AHA/ASA 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke[8]
  • Two recent trials (DAWN[9] and DEFUSE 3[10]) demonstrated that mechanical thrombectomy can be beneficial for certain patients with large vessel ischemic stroke even up to 24 hours after onset of symptoms.
    • Perfusion imaging (CT-P or MR-P) or MRI with diffusion-weighted imaging (DWI) is recommended for patients who present within 6-24 hours of acute large vessel anterior circulation stroke and meet other DAWN or DEFUSE 3 eligibility criteria to determine whether the patient would benefit from mechanical thrombectomy.
    • Mechanical thrombectomy is recommended for patients who present with 6-16 hours of a large vessel occlusion in the anterior circulation and meet other DAWN or DFUSE 3 eligibility criteria.
    • Mechanical thrombectomy is reasonable for patients who present within 6-24 hours of a large vessel occlusion in the anterior circulation and meet other DAWN eligibility criteria.

Design

  • Multi-center, prospective, randomized trial with blinded assessment of end points
  • N=206
    • Thrombectomy (n=107)
    • Control (n=99)
  • Setting: 26 centers in the United States, Canada, Europe, and Australia
  • Enrollment: September 2014 through February 2017
  • Primary outcome: mean score for disability on the utility-weighted modified Rankin scale and the rate of functional independence (a score of 0 - 2 on the modified Rankin scale) at 90 days.

Full protocol was published in 2017 [11]

Population

Inclusion Criteria

General Inclusion Criteria:

  • Clinical diagnosis of an acute ischemic stroke and failed IV tPA therapy or contraindication to IV tPA
  • Age ≥18
  • Baseline NIHSS ≥10
  • Randomization occurs between with 6 to 24 hours after time last known well
  • Pre-stroke mRS <2
  • Anticipated life expectancy ≥6 months

Imaging Inclusion Criteria:

  • < 1/3 MCA territory involved via CT or MRI
  • Occlusion of either intracranial ICA and/or M1 via MRA or CTA
  • Clinical Imaging Mismatch (CIM) via MR-DWI or CTP-rCBF:
    • 0 - 20 core infarct, NIHSS ≥ 10, age ≥ 80 years
    • 0 - 30 cc core infarct, NIHSS ≥ 10, age < 80 years
    • 31 - 50 cc core infarct, NIHSS ≥ 20, age < 80 years

Exclusion Criteria

General Exclusion Criteria:

  • Severe head injury within 90 days
  • Rapid improvement to NIHSS <10 or vessel recanalization prior to randomization
  • Pre-existing neurological or psychiatric disease
  • Seizures at stroke onset
  • Blood glucose <50mg/dL or >400mg/dL
  • Hemoglobin <7 mmol/L
  • Platelets <50,000/uL
  • Sodium <130 mmol/L, potassium <3 mEq/L or >6 mEq/L
  • Renal failure
  • Hemorrhagic diathesis or INR >3.0 or PTT >3 times normal
  • Active or recent hemorrhage within 30 days
  • Severe allergy to contrast medium
  • Systolic Blood Pressure >185 mmHg or Diastolic Blood Pressure >110 mmHg
  • Pregnancy or lactation
  • Participation in another study
  • Presumed septic embolus or suspicion of bacterial endocarditis
  • Prior treatment with thrombectomy intra-arterial therapies

Imaging Exclusion Criteria:

  • Intracranial hemorrhage
  • Flow limiting carotid dissection, high-grade stenosis, or complete cervical carotid occlusion
  • Excessive cervical vessel tortuosity
  • Suspected cerebral vasculitis
  • Suspected aortic dissection
  • Existing stent in the same vascular territory
  • Occlusions in different vascular territories
  • Significant mass effect/midline shift
  • Intracranial tumor

Baseline Characteristics

Comparisons are thrombectomy vs. control

  • Mean age: 69.4 vs. 70.7
  • ≥80 years old: 23% vs. 29%
  • Male: 39% vs. 52%
  • Atrial fibrillation: 40% vs. 24%
  • Diabetes mellitus: 24% vs. 31%
  • Hypertension: 78% vs. 76%
  • Previous ischemic stroke or transient ischemic attack: 11% vs. 11%
  • NIHSS score:
    • Median: 17 vs. 17
    • Interquartile range: 13-21 vs. 14-21
    • 10 to 20: 73% vs. 73%
  • Treatment with intravenous alteplase: 5% vs. 13%
  • Infarct volume (ml):
    • Median: 7.6 vs. 8.9
    • Interquartile range: 2.0-18.0 vs. 3.0-18.1
  • Type of stroke onset:
    • On awakening: 63% vs. 47%
    • Unwitnessed stroke: 27% vs. 38%
    • Witnessed stroke: 10% vs. 14%
  • Occlusion site:
    • Intracranial internal carotid artery: 21% vs. 19%
    • First segment of middle cerebral artery: 78% vs. 78%
    • Second segment of middle cerebral artery: 2% vs. 3%
  • Interval between time that patient was last known to be well and randomization (hr):
    • Median: 12.2 vs. 13.3
    • Interquartile range: 10.2-16.3 vs. 9.4-15.8
    • Range: 6.1-23.5 vs. 6.5-23.9
  • Time from first observation of symptoms to randomization (hr):
    • Median: 4.8 vs. 5.6
    • Interquartile range: 3.6-6.2 vs. 3.6-7.8

Interventions

  • All patients were admitted to dedicated stroke units or intensive care units.
  • Patients were randomized 1:1 to receive either endovascular thrombectomy with the Trevo device (Stryker Neurovascular), a retrievable self-expanding stent, in addition to standard medical care or to standard medical care alone.

Outcomes

Comparisons are thrombectomy vs control.

Primary Outcomes

Utility-weighted modified Ranking scale at 90 days
5.5±3.8 vs. 3.4±3.1 (AD 2.0; 95% CI 1.1 to 3.0; posterior probability of superiority>0.999)
Functional independence at 90 days
52 (49%) vs. 13 (13%) (AD 33%; 95% CI 24 to 44; posterior probability of superiority>0.999).

Secondary Outcomes

Early response
51 (48%) vs. 19 (19%) (RR 3; 95% CI 2-4; P<0.001).
Recanalization at 24 hours
82 (77%) vs. 39 (39%) (RR 2; 95% CI 2-4; P<0.001).
Change in infarct volume at 24 hour (median)
1ml vs. 13ml
Infarct volume at 24 hour (median)
8ml vs. 22ml
Gade of 2b or 3 on mTICI scale
90 (84%) vs. NA

Subgroup Analysis

Prespecified subgroups included age, stroke severity, occlusion site, time to treatment, and type of stroke onset. No heterogeneity in treatment effect was found, but the benefit of thrombectomy was found across all subgroups. The power of the study was limited by the relatively small sample size.

Adverse Events

There was no difference found in safety end points or serious adverse events (death at 90 days and symptomatic intracerebral hemorrhage).

Criticisms

  • The study has a relatively small sample size, and was funded by Stryker Neurovascular.
  • There were some significant differences between the two groups in baseline variables.
  • The results of this trial also aren't generalizable to patients with large volume infarcts.

Funding

Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283 [12]

Further Reading

  1. Berkhemer OA et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N. Engl. J. Med. 2015. 372:11-20.
  2. Sajobi TT et al. Early Trajectory of Stroke Severity Predicts Long-Term Functional Outcomes in Ischemic Stroke Subjects: Results From the ESCAPE Trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times). Stroke 2017. 48:105-110.
  3. Jovin TG et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N. Engl. J. Med. 2015. 372:2296-306.
  4. Saver JL et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N. Engl. J. Med. 2015. 372:2285-95.
  5. Campbell BC et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N. Engl. J. Med. 2015. 372:1009-18.
  6. Goyal M et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016. 387:1723-31.
  7. Saver JL et al. Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis. JAMA 2016. 316:1279-88.
  8. Powers WJ et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2018. :.
  9. Nogueira RG et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N. Engl. J. Med. 2018. 378:11-21.
  10. Albers GW et al. A multicenter randomized controlled trial of endovascular therapy following imaging evaluation for ischemic stroke (DEFUSE 3). Int J Stroke 2017. 12:896-905.
  11. Jovin TG et al. Diffusion-weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake up and late presenting strokes undergoing neurointervention with Trevo (DAWN) trial methods. Int J Stroke 2017. 12:641-652.
  12. https://clinicaltrials.gov/show/NCT02142283