THAWS Trial: Low-Dose Alteplase for Unknown-Onset Ischemic Stroke
In MRI-selected patients with unknown-onset acute ischemic stroke (DWI-positive, FLAIR-negative), does low-dose IV alteplase 0.6 mg/kg improve excellent 90-day functional outcome (mRS 0-1) compared with standard medical treatment?
Koga et al. (Stroke 2020) · 131 patients
Population
Included
- Acute ischemic stroke with unknown time of onset (including wake-up stroke)
- DWI-positive and FLAIR-negative on MRI (DWI-FLAIR mismatch)
- Met standard thrombolysis criteria except for unknown onset time
- Age 18 or older
- Stroke symptoms on awakening or with unknown time of onset
- Presented more than 4.5 hours since last known well and within 4.5 hours after symptom recognition
- Aged 20 years or older
- Premorbid modified Rankin Scale score consistent with eligibility (per trial criteria)
- Met the standard clinical criteria for intravenous thrombolysis in Japan other than a time last-known-well longer than 4.5 hours
- MRI showed mismatch between an abnormal signal on diffusion-weighted imaging and no marked signal change on fluid-attenuated inversion recovery (negative FLAIR pattern) in the corresponding region of the acute stroke
- Patients with clinically acute ischemic stroke and a negative FLAIR pattern who did not display an abnormal signal on DWI were also enrolled
Excluded
- Known time of onset within the standard treatment window
- FLAIR hyperintensity in the DWI lesion region (established infarct)
- Contraindication to IV thrombolysis
- Severe stroke with NIHSS >25
- Mild stroke with NIHSS below 5 (revised to below 2 in August 2015)
- Severe stroke with NIHSS above 25
- Any contraindication for MRI (for example, cardiac pacemaker)
- Planned or anticipated treatment with surgery or endovascular reperfusion strategies
- Pregnant, lactating, or potentially pregnant
- Life expectancy of 6 months or less according to the judgment of an investigator
- On MRI, intracranial hemorrhage or large infarct with Alberta Stroke Program Early CT Score of 4 or less in the middle cerebral artery territory
- Visual lesion volume over 50% of the anterior or posterior cerebral artery territory, more than half of the brain stem, or more than half of the unilateral cerebellar hemisphere
Source: Koga et al., Stroke 2020· Retrieved 2026-06-09
Primary Outcome
Negligible absolute difference
mRS 0-1 at 90 Days
Study Arms
- Agent
- Alteplase
- Dose
- 0.6 mg/kg (Japanese low-dose)
- Route
- Intravenous
- Frequency
- 10% as a bolus, 90% as a 60-minute infusion
- Co-interventions
- Antithrombotics generally prohibited in the alteplase group within the initial 25 hours. Urokinase, monteplase, and tenecteplase prohibited during the 90-day study period in both groups.
Treatment initiated within 4.5 hours of waking up or discovery.
- Agent
- Standard medical treatment (no thrombolysis)
- Co-interventions
- Standard treatment using 1 to 3 antithrombotic drugs, including oral aspirin (160 to 300 mg/day), oral clopidogrel (75 mg/day), intravenous argatroban, or intravenous unfractionated heparin, but excluding the combination of argatroban and heparin, per attending physician.
No placebo was used, mainly due to financial limitation. Open-label design.
Trial Design
Type
- Multicenter randomized trial
- Open-label with blinded endpoint assessment
- MRI DWI-positive / FLAIR-negative selection
- 1:1 allocation (Alteplase vs. Standard treatment)
Timeline
Stopped early at 131 of planned 300 patients
N
131
Enrollment
131 of 300 planned patients. Stopped pragmatically after WAKE-UP results. Published Stroke 2020.
ClinicalTrials.gov
NCT02002325Bedside Pearl
THAWS tested the Japan-specific 0.6 mg/kg alteplase dose in DWI-FLAIR mismatch wake-up stroke and found no benefit, but the trial was stopped at 44% enrollment, so findings are inconclusive. The correct reference for MRI-guided wake-up stroke treatment is WAKE-UP (alteplase 0.9 mg/kg, mRS 0-1 53.3% vs 41.8%, OR 1.61, P=0.02). Use standard-dose alteplase.
See also