WAKE-UP Trial: MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset
In patients with acute ischemic stroke of unknown onset or on awakening, does IV alteplase improve outcome when DWI-FLAIR mismatch on MRI suggests the stroke is within a treatable time window?
Thomalla et al. (NEJM 2018) · doi:10.1056/NEJMoa1804355 · 503 patients
Population
Included
- Age 18 to 80 years
- Acute ischemic stroke with wake-up presentation or unknown time of onset
- MRI showing positive DWI lesion with negative FLAIR in the same territory (tissue-based mismatch)
- NIHSS score 1 to 25
- Treatment able to start within 4.5 hours of first recognition of deficit
- No plan for mechanical thrombectomy
Clinical
- Clinical signs of acute stroke
- Aged 18 to 80 years
- Able to carry out usual activities in daily life without support before the stroke
- Either recognized stroke symptoms on awakening or could not report the timing of the onset of symptoms (for example, as a result of aphasia or confusion)
- The time that had elapsed since the patient was last known to be well had to be more than 4.5 hours (with no upper limit) in order to exclude patients who would otherwise have fulfilled the standard eligibility criteria for the use of alteplase
- Otherwise met the clinical criteria for intravenous thrombolysis
Imaging (DWI-FLAIR mismatch)
- MRI examination including diffusion-weighted imaging, FLAIR (a sequence sensitive to hemorrhage), and time-of-flight magnetic resonance angiography of the circle of Willis
- An acute ischemic lesion visible on diffusion-weighted imaging
- No marked parenchymal hyperintensity on FLAIR in the region of the acute ischemic lesion (a mismatch between the abnormal signal on diffusion-weighted imaging and the absence of a clearly visible hyperintense signal on FLAIR)
Excluded
- FLAIR lesion clearly positive in the same territory as DWI (suggesting onset over 4.5 hours)
- DWI lesion exceeding one third of the MCA territory
- Standard contraindication to IV alteplase (active hemorrhage, recent surgery, anticoagulation)
- NIHSS below 1 or above 25
- Planned or already performed mechanical thrombectomy
Imaging
- Intracranial hemorrhage on MRI
- An ischemic lesion larger than one third of the territory of the middle cerebral artery
- A visible signal change on FLAIR in the region of the acute ischemic stroke
Clinical / treatment
- Planned thrombectomy
- Severe stroke, defined as a score of more than 25 on the NIHSS (range 0 to 42)
- Generally recognized contraindications to treatment with alteplase (except for the unknown time of symptom onset)
Source: Thomalla et al., N Engl J Med 2018;379(7):611-622· Retrieved 2026-06-09
Primary Outcome
mRS 0-1 at 90 Days
Study Arms
- Agent
- Alteplase (recombinant tissue plasminogen activator)
- Dose
- 0.9 mg/kg of body weight
- Route
- IV
- Frequency
- 10% of the dose administered as a bolus, then the remainder as an infusion
- Duration
- 60-minute infusion (remainder after bolus)
- Co-interventions
- Concomitant treatment and procedures performed according to the standard of care at each center in compliance with European or national guidelines for acute stroke. Patients with planned thrombectomy were excluded.
Dose and administration verbatim from Thomalla NEJM 2018 p.613 (Randomization and Treatment). Randomization 1:1 by a Web-based permuted-block design stratified by trial center, age (60 years or younger vs older than 60), and NIHSS (10 or lower vs higher than 10). NCT01525290; EudraCT 2011-005906-32. Enrollment stopped early after 503 of a planned 800 patients owing to cessation of funding (not a prespecified efficacy stopping rule).
- Agent
- Matching placebo
- Dose
- Volume-matched to alteplase
- Route
- IV
- Frequency
- Identical bolus-then-infusion schedule
- Duration
- 60-minute infusion
- Co-interventions
- Same standard-of-care concomitant treatment as the alteplase group per European or national acute-stroke guidelines.
Double-blind, placebo-controlled, 1:1 allocation. Source: Thomalla NEJM 2018 p.612-613.
Safety
Symptomatic ICH at 7 days (ECASS III definition)
2%
0.4%
Parenchymal hematoma type 2 with NIHSS worsening of 4 or more points within 7 days. 2.0% alteplase vs 0.4% placebo; P=0.15 (not statistically significant in this sample of 503 patients). Source: Thomalla et al., NEJM 2018, Table 2.
Mortality at 90 days
4.1%
1.2%
All-cause mortality at 90 days was 4.1% (alteplase) vs 1.2% (placebo). This numerical difference should be interpreted cautiously: the trial enrolled 503 of 800 planned patients and was not powered to detect mortality differences reliably. Source: Thomalla et al., NEJM 2018, Table 2.
Trial Design
Type
- Multi-center randomized controlled trial
- Double-blind, placebo-controlled
- 1:1 allocation (Alteplase vs. Placebo)
Timeline
Enrolled Sep 2012 – Jun 2017
N
503
Enrollment
503 of 800 planned patients (251 alteplase / 252 placebo). Stopped early when funding lapsed. Enrolled Sep 2012 to Jun 2017.
ClinicalTrials.gov
NCT01525290Bedside Pearl
WAKE-UP showed an NNT of roughly 9 for excellent recovery, better than EXTEND (NNT 17). The tradeoff is real: sICH was 2.0% vs 0.4% and mortality was numerically higher (4.1% vs 1.2%) in the alteplase arm, though neither reached significance in 503 patients. The DWI-FLAIR mismatch criterion is the gatekeeping rule; without it, you do not have WAKE-UP evidence.