Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke - WAKE-UP

Contribution To Literature:

Among patients with unclear time of stroke onset but with evidence of DWI-FLAIR mismatch on MRI, functional outcome at 90 days was better, but death and symptomatic ICH were numerically higher among patients who received alteplase compared with placebo.


The goal of the trial was to compare the safety and efficacy of using magnetic resonance imaging (MRI) to identify eligible patients for reperfusion among those who presented with an ischemic stroke, but without a clear time of onset.

Study Design

Patients were randomized in a 1:1 ratio to either alteplase 0.9 mg/kg (n = 254) or placebo (n = 249). All patients were technically outside the 4.5-hour window clinically (last time well known >4.5 hours). Patients underwent MRI with diffusion-weighted imaging (DWI), fluid-attenuated inversion recovery (FLAIR), and time-of-flight imaging. Patients were only included if they had a mismatch on MRI DWI (indicative of ischemic stroke) and no visible signal change on FLAIR in the region of stroke (indicative of stroke >4.5 hours).

  • Total screened: 1,362
  • Total number of enrollees: 503
  • Duration of follow-up: 90 days
  • Mean patient age: 65.3 years
  • Percentage female: 35%
  • Percentage with diabetes: 16%

Inclusion criteria:

  • Clinical signs of acute stroke
  • Age 18-80 years
  • Able to carry out usual activities in their daily life without support prior to stroke
  • Patient reported stroke on awakening or could not report timing of onset of symptoms due to aphasia or confusion
  • Last well known >4.5 hours without upper limit
  • Met MRI criteria for inclusion
  • Sites enrolling had to be experienced stroke research centers, had to have experience with routine use of alteplase in standard stroke care, and had to be able to perform MRI for emergent stroke imaging

Exclusion criteria:

  • Intracranial hemorrhage (ICH) on MRI
  • Lesions larger than one-third territory of middle cerebral artery
  • Planned thrombectomy
  • Severe stroke (National Institutes of Health Stroke Scale [NIHSS] score >25)
  • Other contraindications to alteplase

Other salient features/characteristics:

  • Prior ischemic stroke: 14%
  • Atrial fibrillation: 12%
  • Median NIHSS score: 6
  • Median time between last time patient was known to be well and symptom recognition clinically: 7.1 hours
  • Median time from symptom recognition to treatment initiation: 3.2 hours
  • Any vessel occlusion on time-of-flight MR angiography: 34%

Principal Findings:

The trial was terminated early due to cessation of funding from the sponsor. Of 1,362 screened patients, only 503 were enrolled; nearly one-half of excluded patients were excluded due to lack of MRI DWI-FLAIR mismatch. The primary efficacy outcome, favorable outcome at 90 days, for alteplase vs. placebo, was 53.3% vs. 41.8%, p = 0.02.

  • Primary safety outcome: death or dependency at 90 days: 13.5% for alteplase vs. 18.3% for placebo, p = 0.17
  • Death at 90 days: 4.1% for alteplase vs. 1.2% for placebo, p = 0.07

Secondary outcomes (for alteplase vs. placebo):

  • Median score on modified Rankin Scale at 90 days: 1 vs. 2, p = 0.003
  • Median infarct volume: 3.0 vs. 3.3 ml, p = 0.32
  • Symptomatic ICH per National Institute of Neurological Disorders and Stroke (NINDS): 8.0% vs. 4.9%, p = 0.13
  • Recurrent ischemic stroke: 29.9% vs. 25.8%


The results of this trial indicate that among patients with unclear time of stroke onset but with evidence of DWI-FLAIR mismatch on MRI, functional outcome at 90 days was better among patients who received alteplase compared with placebo. However, both death and symptomatic ICH were numerically higher with this strategy. Both findings have to be considered in the light of a prematurely halted trial.

This trial sought to study an interesting hypothesis. The presence of DWI-FLAIR mismatch on MRI has modest sensitivity (62%), but a relatively high positive predictive value (82%) for identifying acute ischemic stroke within 4.5 hours of symptom onset. This trial only included patients who had unclear onset of stroke and who would thus be otherwise excluded from clinical use of thrombolytics (outside the 4.5-hour window). Out of all patients screened, approximately 40% met the MRI criteria. The role of thrombectomy for large vessel occlusion in this patient population is unclear.


Thomalla G, Simonsen CZ, Boutitie F, et al., on behalf of the WAKE-UP Investigators. MRI-Guided Thrombolysis for Stroke With Unknown Time of Onset. N Engl J Med 2018;May 16:[Epub ahead of print].

Editorial: Jovin TG. MRI-Guided Intravenous Alteplase for Stroke — Still Stuck in Time. N Engl J Med 2018;May 16:[Epub ahead of print].

Clinical Topics: Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Cardiac Surgery and Arrhythmias, Lipid Metabolism, Interventions and Imaging, Angiography, Magnetic Resonance Imaging, Nuclear Imaging

Keywords: Aphasia, Brain Ischemia, Coronary Angiography, Diagnostic Imaging, Fibrinolytic Agents, Intracranial Hemorrhages, Magnetic Resonance Imaging, Primary Prevention, Reperfusion, Stroke, Thrombectomy, Tissue Plasminogen Activator, Vascular Diseases

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