WAKE-UP

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Thomalla G, et al. "MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset". New England Journal of Medicine. 2018. 379(7):611-622.
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Clinical Question

In patients with an unknown time of stroke onset and a DWI and FLAIR mismatch, does treatment with intravenous alteplase improve functional outcomes?

Bottom Line

Treatment with intravenous alteplase significantly improves functional outcomes and does not significantly increase the risk of death or major bleeding in patients with an unknown time of stroke onset and a DWI and FLAIR mismatch.

Major Points

In a significant proportion of patients presenting with acute ischemic stroke, the time of onset is unknown, especially if the patient awakens with the neurologic deficit. Currently, guidelines recommend intravenous thrombolysis only if it is known that the onset of symptoms was within 4.5 hours, excluding patients from treatment who may have suffered a stroke soon before awakening. When an ischemic lesion is visible on MRI diffusion weighted imaging (DWI) and not on fluid attenuated inversion recovery (FLAIR), the stroke is likely to have occurred within the prior 4.5 hours. The WAKE-UP trial[1] determined that patients with an unknown time of stroke onset but with DWI and FLAIR mismatch whom are treated with intravenous alteplase have significantly improved functional outcomes without a significantly increased risk of death or major bleeding.

Guidelines

As of October 2018, no guidelines reflect the results of this trial.

Design

  • Randomized, blinded, parallel assignment, multicenter trial
  • N=503
    • Alteplase (0.9 mg/kg, with 10% as a bolus and 90% as a 60-minute infusion) (n=254)
    • Placebo (n=249)
  • Setting: 70 centers in 8 countries in Europe
  • Enrollment: September 2012 to June 2017
  • Follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcomes: Favorable outcome at 90 days (score of 0 or 1 on the modified Rankin scale); Death or dependency at 90 days; Death at 90 days

Population

Inclusion Criteria

  • Presenting with clinical signs of acute stroke
  • Had been able to complete activities of daily living prior to stroke
  • Last known well time greater than 4.5 hours prior to presentation
  • Abnormal signal on MRI DWI imaging
  • No abnormal signal on MRI FLAIR imaging
  • Age 18-80 years

Exclusion Criteria

  • Hemorrhage on MRI
  • Lesions larger then one-third the territory of the middle cerebral artery
  • Planned thrombectomy
  • NIHSS >25
  • Contraindication to treatment with alteplase (with the exception of the time of onset >4.5 hours)

Baseline Characteristics

From the intravenous alteplase group.

  • Mean age: 65.3+/-11.2 years
  • Male sex: 65%
  • Reason for unknown time of symptom onset:
    • Nighttime sleep: 89.4%
    • Daytime sleep: 4.7%
    • Aphasia, confusion, or other: 5.9%
  • Median interval from last known well time and symptom recognition: 7.2 hr
  • Medical history
    • Arterial hypertension: 53.1%
    • Diabetes mellitus: 16.9%
    • Hypercholesterolemia: 36.6%
    • Atrial fibrillation: 11.8%
    • History of ischemic stroke: 14.6%
  • Median NIHSS score (IQR): 6 (4-9)
  • Vessel occlusion on time-of-flight MRA
    • Any: 33.7%
    • Intracranial internal carotid artery: 9.6% (vs 4.5% in the placebo group, P=0.03)
    • Middle cerebral artery main stem: 14.1%
    • Middle cerebral artery branch: 12.9%
    • Other: 4.8%
  • Median lesion volume on DWI (IQR): 2.0 (0.8-7.9) ml
  • Median time from symptom recognition to MRI (IQR): 2.6 (1.9-3.3) hr
  • Median time between MRI and treatment recognition (IQR): 25 (16-35) min
  • Median time from symptom recognition to treatment initiation (IQR): 3.1 (2.5-3.8) hr
  • Interval between last known well time and treatment initiation (IQR): 10.3 (8.1-12.0) hr

Interventions

  • Randomized to intravenous alteplase (0.9 mg/kg, with 10% as a bolus and 90% as a 60-minute infusion) or placebo

Outcomes

Comparisons are alteplase therapy vs. placebo.

Primary Outcomes

Favorable outcome at 90 days (score of 0 or 1 on the modified Rankin scale)
53.3% vs. 41.8% (OR 1.61; 95% CI 1.09 to 2.36; P=0.02)
Death or dependency at 90 days
13.5% vs. 18.3% (Adjusted OR 0.68; 95% CI 0.39 to 1.18; P=0.17)
Death at 90 days
4.1% vs. 1.2% (Adjusted OR 3.38; 95% CI 0.92 to 12.52; P=0.07)

Secondary Outcomes

Median score on modified Rankin scale at 90 days (IQR)
1 (1-3) vs. 1 (1-3) (Common OR 1.62; 95% CI 1.17 to 2.23; P=0.003)
Correlation between treatment response at 90 days and deficit level at baseline
29.3% vs. 18.0% (OR 1.88; 95% CI 1.22 to 2.89; P=0.004)
Global Outcome Score at 90 days
OR 1.47; 95% CI 1.07 to 2.04; P=0.02
Median score on Beck Depression Inventory at 90 days (IQR)
6.0 (2.0-11.0) vs. 7.0 (2.0-14.0) (Mean difference (loge) -0.04; 95% CI -0.22 to 0.15; P=0.69)
Total score on EQ-5D at 90 days
1.9+/-2.1 vs. 2.4+/-2.4 (Mean difference -0.52; 95% CI -0.88 to -0.16); P=0.004)
Score on visual analog scale of EQ-5D at 90 days
72.6+/-19.7 vs. 64.9+/-23.8 (Mean difference 7.64; 95% CI 3.75 to 11.51); P<0.001)
Median infarct volume at 22-36 hr (IQR)
3.0 (0.8-17.7) vs. 3.3 (1.1-16.6) (Mean difference (loge) -0.16; 95% CI -0.47 to 0.15; P=0.32)
Symptomatic intracranial hemorrhage (as defined in SITS-MOST)
2.0% vs. 0.4% (Adjusted OR 4.95; 95% CI 0.57 to 42.87; P=0.15)
Symptomatic intracranial hemorrhage (as defined in ECASS II)
2.8% vs. 1.2% (Adjusted OR 2.40; 95% CI 0.60 to 9.53; P=0.21)
Symptomatic intracranial hemorrhage (as defined in ECASS III)
2.4% vs. 0.4% (Adjusted OR 6.04; 95% CI 0.72 to 50.87; P=0.10)
Symptomatic intracranial hemorrhage (as defined in NINDS)
8.0% vs. 4.9% (Adjusted OR 1.78; 95% CI 0.84 to 3.71; P=0.13)
Parenchymal hemorrhage type 2
4.0% vs. 0.4% (Adjusted OR 10.46; 95% CI 1.32 to 82.77; P=0.03)

Other Outcomes

Space occupying brain infarction or edema with clinical deterioration
2.4% vs. 0.8%
Recurrent ischemic stroke (asymptomatic)
23.1% vs. 22.5%
Recurrent ischemic stroke (symptomatic)
6.8% vs. 3.3%
Major extracranial bleeding
1.2% vs. 0%
Severe anaphylactic reaction
0% vs. 0.4%

Subgroup Analysis

No subgroup analyses were performed.

Adverse Events

No adverse events other than the outcomes listed above were reported.

Criticisms

  • Trial was stopped prematurely due to lack of funding
  • Numerically higher number of deaths in alteplase group may have become statistically significant with a larger sample size
  • Small number of patients with NIHSS >10, limiting generalizability to that group
  • 20% of patients enrolled in the trial could have qualified for thrombectomy in DAWN[2] and DEFUSE 3[3]

Funding

The study was funded by a grant from the European Union Seventh Framework Program. Multiple authors reported support from pharmaceutical companies.

Further Reading

  1. Thomalla G et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N. Engl. J. Med. 2018. 379:611-622.
  2. 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.
  3. 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.