DAWN

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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

Among patients with acute stroke between 6-24 hours of symptom onset, does thrombectomy improve 90-day outcomes compared to standard care alone?

Bottom Line

Among patients with acute stroke with symptom onset 6-24 hours prior to presentation, and with clinical deficits out of proportion to infarct size, thrombectomy improved 90-day outcomes compared to standard care alone.

Major Points

Several studies including MR CLEAN demonstrated the superiority of endovascular thrombectomy versus standard care alone among patients with acute stroke when performed within 6 hours of symptom onset. The benefits of the intervention declined as the time since onset increased.[1] However, a subset of acute stroke patients have brain tissue that is ischemic but not yet infarcted; these patients have a clinical deficit that is disproportionately severe when compared to the amount of infarcted tissue on 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.

Published in 2018, DAWN enrolled patients with acute stroke who had evidence of 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 on imaging. Patients were randomized to thrombectomy plus standard care, or to standard care alone. Standard care consisted of specialty stroke unit care, systemic thrombolysis for eligible patients, hemicraniectomy for young patients with malignant MCA ischemia, antiplatelet therapy, antihypertensive management, VTE prophylaxis, and stroke rehabilitation. After 31 months of enrollment, the trial was stopped after a prespecified interim analysis. In the end, 206 patients had been randomized; 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 stroke 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 international 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 Guidelines for the Early Management of Patients With Acute Ischemic Stroke (2018, adapted)[2]

  • Two recent trials (DAWN[3] and DEFUSE 3[4]) 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 DEFUSE 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

  • Multicenter, prospective, randomized trial with blinded assessment of end points
  • N=206 patients with acute stroke and clinical deficits out of proportion to infarct volume
    • Thrombectomy (n=107)
    • Standard care (n=99)
  • Setting: 26 centers in the United States, Canada, Europe, and Australia
  • Enrollment: 2014-2017
  • 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.

Population

Inclusion Criteria

  • Acute stroke and persistent occlusion after IV thrombolysis or contraindication to thrombolysis
  • Age ≥18
  • Baseline NIHSS ≥10
  • Randomization occurs between with 6 to 24 hours after time last known well
  • Pre-stroke modified Rankin score <2
  • Anticipated life expectancy ≥6 months
  • <1/3 MCA territory involved as assessed by 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

  • 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
  • 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 years
  • ≥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

  • Full protocol published in 2017.[5]
  • 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.
  • Other endovascular reperfusion methods were prohibited (stents, aspiration, thrombolysis)

Outcomes

Comparisons are presented as thrombectomy vs. control.

Primary Outcomes

Coprimary endpoints:

90-day modified Rankin score
5.5 vs. 3.4 (adjusted difference 2.0; 95% CI 1.1-3.0; posterior probability of superiority >0.999)
90-day functional independence
49% vs. 13% (adjusted difference 33%; 95% CI 24-44%; 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

90-day stroke-related death
16% vs. 18%
90-day all-cause mortality
19% vs. 18%
Symptomatic intracranial hemorrhage at 24h
6% vs. 3%
Neurologic deterioration at 24 h
14% vs. 26%
Procedural complications
7% vs. not applicable

Criticisms

  • Funding and data analysis was provided by Stryker Neurovascular
  • The study has a relatively small sample size
  • 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 as these patients were excluded from the study.

Funding

Funded by Stryker Neurovascular

Further Reading

  1. Saver JL et al. Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis. JAMA 2016. 316:1279-88.
  2. 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. :.
  3. 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.
  4. 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.
  5. 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.