Neurology Clinical Trial Database
WAKE-UP
Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial
Year of Publication: 2018
Authors: G. Thomalla, C.Z. Simonsen, F. Boutitie, ..., and C. Gerloff
Journal: The New England Journal of Medicine
Citation: N Engl J Med 2018;379:611-22.
PDF: Clinical Question
Do patients with acute stroke with an unknown time of onset and features suggesting recent cerebral infarction on MRI (diffusion-weighted imaging lesion without parenchymal hyperintensity on FLAIR) benefit from intravenous thrombolysis with alteplase?
Bottom Line
In patients with acute stroke with an unknown time of onset selected by diffusion-weighted imaging (DWI)-FLAIR mismatch on MRI, intravenous alteplase resulted in a significantly better functional outcome at 90 days compared to placebo. However, it was also associated with a numerically higher incidence of intracranial hemorrhages.
Major Points
- WAKE-UP was the first trial to use MRI-based tissue signatures (DWI-FLAIR mismatch) to select stroke patients with UNKNOWN onset time for thrombolysis — pioneering imaging-guided rather than clock-based treatment decisions.
- DWI-FLAIR mismatch concept: a visible DWI lesion (acute ischemia) WITHOUT corresponding FLAIR hyperintensity suggests stroke onset within ~4.5 hours — because FLAIR signal changes take several hours to develop. This imaging 'tissue clock' replaced the traditional 'time clock.'
- Primary outcome: favorable outcome (mRS 0–1) at 90 days in 53.3% alteplase vs 41.8% placebo (adjusted OR 1.61, 95% CI 1.09–2.36, p=0.02) — an 11.5% absolute benefit, one of the largest treatment effects in any thrombolysis trial.
- Ordinal mRS analysis also highly significant: common OR 1.62 (95% CI 1.17–2.23, p=0.003). Median mRS was 1 (alteplase) vs 2 (placebo) — a clinically meaningful difference between independence with no significant disability vs slight disability.
- Trial stopped early due to cessation of funding (503 of planned 800 patients enrolled) — this reduced statistical power and may have overestimated the treatment effect. Despite early stopping, the primary endpoint was significant.
- Mortality signal: 10 deaths (4.1%) alteplase vs 3 (1.2%) placebo (OR 3.38, p=0.07) — numerically higher but not significant. This imbalance is concerning and may reflect the risks of treating patients with potentially older strokes.
- sICH (SITS-MOST definition): 2.0% alteplase vs 0.4% placebo (OR 4.95, p=0.15). PH-2 hemorrhage: 4.0% vs 0.4% (p=0.03) — the hemorrhage signal was present but consistent with known tPA risks. sICH by ECASS-III definition was 2.8% vs 1.2%.
- 89% of patients presented after waking from nighttime sleep — the classic 'wake-up stroke' scenario where onset is truly unknown. Median time from last-seen-well to treatment was ~10 hours — far beyond any traditional time window.
- Double-blind, placebo-controlled design — the gold standard for thrombolysis trials. This contrasted with the open-label design of IST-3 and ENCHANTED, providing higher-quality evidence.
- Together with EXTEND (perfusion-guided CT), WAKE-UP established the paradigm of IMAGING-BASED patient selection for thrombolysis beyond the traditional time window — fundamentally changing acute stroke treatment from 'time is brain' to 'tissue is brain.'
Design
Study Type: Investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial
Randomization: 1
Blinding: Double-blind (patients, investigators, central image-reading committee, central safety-adjudication committee).
Enrollment Period: September 24, 2012, to June 30, 2017 (stopped early)
Follow-up Duration: 90 days
Centers: 70
Countries: 8 European countries
Sample Size: 503
Analysis: Intention-to-treat (ITT) population for primary and secondary efficacy outcomes. Unconditional logistic-regression model for primary efficacy (odds ratio, 95% CI). Proportional-odds logistic-regression model for ordinal mRS (common odds ratio). Safety end points analyzed in safety population. Multiple imputation for missing primary outcome data. Two-sided alpha level of 0.05.
Inclusion Criteria
- Patients presented with clinical signs of acute stroke.
- 18 to 80 years of age.
- Able to carry out usual activities in daily life without support before the stroke.
- Patient either recognized stroke symptoms on awakening or could not report the timing of onset (e.g., aphasia or confusion).
- Time elapsed since last known to be well >4.5 hours (no upper limit).
- MRI examination showed a mismatch between the presence of an abnormal signal on MRI diffusion-weighted imaging and no visible signal change on FLAIR in the region of the acute stroke.
Exclusion Criteria
- MRI showed intracranial hemorrhage or lesions larger than one third of the territory of the middle cerebral artery.
- Thrombectomy was planned.
- Severe stroke (NIHSS score >25).
- Generally recognized contraindications to alteplase (except for unknown time of symptom onset).
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Mean age ±SD - yr | 5.2±11.9 | 65.3±11.2 |
| Male sex no. (%) | 160 (64.3) | 165 (65.0) |
| Reason for unknown time of symptom onset - Nighttime sleep no. (%) | 222 (89.2) | 227 (89.4) |
| Reason for unknown time of symptom onset - Daytime sleep no. (%) | 11 (4.4) | 12 (4.7) |
| Reason for unknown time of symptom onset - Aphasia, confusion, or other no. (%) | 16 (6.4) | 15 (5.9) |
| Median interval between last time the patient was known to be well and symptom recognition (IQR) -hr | 7.0 (5.0-9.0) | 7.2 (4.7-8.7) |
| Medical history - Arterial hypertension no. (%) | 131 (52.6) | 135 (53.1) |
| Medical history - Diabetes mellitus no. (%) | 39 (15.7) | 43 (16.9) |
| Medical history - Hypercholesterolemia no. (%) | 85 (34.1) | 93 (36.6) |
| Medical history - Atrial fibrillation no. (%) | 29 (11.6) | 30 (11.8) |
| Medical history - History of ischemic stroke no. (%) | 31 (12.4) | 37 (14.6) |
| Median NIHSS score (IQR) | 6 (4-9) | 6 (4-9) |
| Vessel occlusion on time-of-flight MRA - Any no./total no. (%) | 84/246 (34.1) | 84/249 (33.7) |
| Vessel occlusion on time-of-flight MRA - Intracranial internal carotid artery no. (%) | 11/246 (4.5) | 24/249 (9.6) |
| Vessel occlusion on time-of-flight MRA - Middle cerebral artery main stem no. (%) | 37/246 (15.0) | 35/249 (14.1) |
| Vessel occlusion on time-of-flight MRA - Middle cerebral artery branch no. (%) | 36/246 (14.6) | 32/249 (12.9) |
| Vessel occlusion on time-of-flight MRA - Other no. (%) | 12/246 (4.9) | 12/249 (4.8) |
| Median lesion volume on diffusion-weighted imaging (IQR) - ml. | 2.5 (0.7-8.8) | 2.0 (0.8-7.9) |
| Median time from symptom recognition to MRI (IQR) -hr | 2.6 (2.1-3.3) | 2.6 (1.9-3.3) |
| Median time between end of MRI and treatment initiation (IQR) min | 26 (18-37) | 25 (16-35) |
| Median time from symptom recognition to treatment initiation (IQR)-hr | 3.2 (2.6-3.9) | 3.1 (2.5-3.8) |
| Interval between last time that the patient was last known to be well and treatment initiation (IQR) -hr | 10.4 (8.1-12.1) | 10.3 (8.1-12.0) |
Arms
| Field | Alteplase Group | Control |
|---|---|---|
| Intervention | Intravenous alteplase (0.9 mg per kilogram of body weight, with 10% as bolus and remainder infused over 60 minutes). | Matching placebo. |
| Duration | 60 minutes infusion (followed by 90-day follow-up) | 60 minutes infusion (followed by 90-day follow-up) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Favorable clinical outcome, defined as a score of 0 or 1 on the modified Rankin scale of neurologic disability at 90 days. | Primary | 102/244 (41.8%) | 131/246 (53.3%) | 1.61 | 0.02 |
| Median score on modified Rankin scale at 90 days (ordinal distribution) | Secondary | 2 (IQR 1-3) | 1 (IQR 1-3) | 1.62 | 0.003 |
| Correlation between treatment response at 90 days and deficit level at baseline (proportion of patients) | Secondary | 44/244 (18.0%) | 72/246 (29.3%) | 1.88 | 0.004 |
| Global Outcome Score at 90 days (multidimensional favorable outcome) | Secondary | 1.47 | 0.02 | ||
| Median score on Beck Depression Inventory at 90 days | Secondary | 7.0 (IQR 2.0-14.0) | 6.0 (IQR 2.0-11.0) | -0.04 | 0.699 |
| Total score on EQ-5D at 90 days | Secondary | 2.4±2.4 | 1.9±2.1 | -0.52 | 0.004 |
| Score on visual analog scale on EQ-5D at 90 days | Secondary | 64.9±23.8 | 72.6±19.7 | 7.64 | <0.001 |
| Median infarct volume on diffusion-weighted imaging at 22-36 hr (ml) | Secondary | 3.3 (IQR 1.1-16.6) | 3.0 (IQR 0.8-17.7) | -0.16 | 0.32 |
| Death or dependency at 90 days (mRS 4-6) | Adverse | 44 (18.3%) | 33 (13.5%) | 0.68 | 0.17 |
| Death at 90 days | Adverse | 3 (1.2%) | 10 (4.1%) | 3.38 | 0.07 |
| Symptomatic intracranial hemorrhage (SITS-MOST definition) | Adverse | 1 (0.4%) | 5 (2.0%) | 4.95 | 0.15 |
| Symptomatic intracranial hemorrhage (ECASS II definition) | Adverse | 3 (1.2%) | 7 (2.8%) | 2.4 | 0.21 |
| Symptomatic intracranial hemorrhage (ECASS III definition) | Adverse | 1 (0.4%) | 6 (2.4%) | 6.04 | 0.10 |
| Symptomatic intracranial hemorrhage (NINDS definition) | Adverse | 12 (4.9%) | 20 (8.0%) | 1.78 | 0.13 |
| Parenchymal hemorrhage type 2 | Adverse | 1 (0.4%) | 10 (4.0%) | 10.46 | 0.03 |
| Space-occupying brain infarction or edema with clinical deterioration | Adverse | 2 (0.8%) | 6 (2.4%) | ||
| Recurrent ischemic stroke - Asymptomatic | Adverse | 55 (22.5%) | 58 (23.1%) | ||
| Recurrent ischemic stroke - Symptomatic | Adverse | 8 (3.3%) | 17 (6.8%) | ||
| Major extracranial bleeding | Adverse | 0 | 3 (1.2%) | ||
| Severe anaphylactic reaction | Adverse | 1 (0.4%) | 0 | ||
| Any serious adverse event | Adverse | 52 (21.3%) | 56 (22.3%) | 0.83 | |
| Nervous system disorders (including sICH and recurrent stroke) | Adverse | 8.6% | 13.5% |
Criticisms
- Stopped early due to anticipated funding cessation — only 503 of planned 800 patients enrolled, leaving trial underpowered for secondary endpoints and safety signals including the numerically higher death rate in the alteplase group (4.1% vs 1.2%).
- Excluded patients planned for thrombectomy, limiting generalizability to the modern endovascular era where many unknown-onset patients are thrombectomy candidates.
- Two-thirds of screened patients excluded — primarily for lacking DWI-FLAIR mismatch — limiting applicability to the broader unknown-onset stroke population and raising questions about external validity.
- sICH type 2 parenchymal hemorrhage significantly higher with alteplase (4.0% vs 0.4%, p=0.03) — consistent with other tPA trials but concerning given the population's inherently uncertain symptom onset.
- Infarct volume at 22-36 hours not significantly different between groups despite clinical benefit — unexpected finding that challenges the assumed mechanism of penumbral salvage.
- No CT-based alternative pathway — trial mandated MRI with DWI-FLAIR, excluding hospitals without 24/7 MRI access and limiting real-world implementation, especially in resource-limited settings.
- EU-only enrollment (61 centers in 8 European countries) — ethnic and geographic homogeneity may limit generalizability to non-European populations with different stroke demographics.
- Relatively mild strokes (median NIHSS 6) — treatment effect in severe strokes with unknown onset remains uncertain given very few patients with NIHSS >10.
- No long-term follow-up beyond 90 days — durability of functional benefit and delayed safety outcomes (including post-stroke dementia risk) were not assessed.
Subgroup Analysis
Array
Funding
European Union Seventh Framework Program
Based on: WAKE-UP (The New England Journal of Medicine, 2018)
Authors: G. Thomalla, C.Z. Simonsen, F. Boutitie, ..., and C. Gerloff
Citation: N Engl J Med 2018;379:611-22.
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