PDF: WAKE-UP
(2018)Objective
To determine whether IV alteplase improves outcomes in patients with unknown stroke onset time, selected via MRI mismatch between DWI and FLAIR.
Study Summary
• IV alteplase improved functional outcomes at 90 days in patients with unknown-onset stroke selected by DWI-FLAIR mismatch on MRI; • Alteplase was associated with a higher risk of symptomatic intracranial hemorrhage and mortality.
Intervention
IV alteplase 0.9 mg/kg vs. placebo, administered to patients with MRI-confirmed mismatch pattern.
Inclusion Criteria
Adults 18–80 with unknown-onset ischemic stroke and DWI-FLAIR mismatch, without planned thrombectomy.
Study Design
Arms: Alteplase vs. Placebo
Patients per Arm: Alteplase: 254, Placebo: 249
Outcome
• mRS 0–1 at 90 days: 53.3% vs. 41.8% (OR 1.61, 95% CI 1.09–2.36, p=0.02). <br>• sICH: 2.0% vs. 0.4%; mortality: 4.1% vs. 1.2%..
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.'
Study Design
- Study Type
- Investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial
- Randomization
- Yes
- Blinding
- Double-blind (patients, investigators, central image-reading committee, central safety-adjudication committee).
- Sample Size
- 503
- Follow-up
- 90 days
- Centers
- 70
- Countries
- 8 European countries
Primary Outcome
Definition: Favorable clinical outcome, defined as a score of 0 or 1 on the modified Rankin scale of neurologic disability at 90 days.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 102/244 (41.8%) | 131/246 (53.3%) | 1.61 (1.09 to 2.36) | 0.02 |
Limitations & 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.
Citation
N Engl J Med 2018;379:611-22.