THEIA Trial: IV Alteplase vs Oral Aspirin for Acute Non-Arteritic CRAO within 4.5 Hours
In adults with acute non-arteritic central retinal artery occlusion (Snellen <20/400) within 4.5h of symptom onset, does IV alteplase 0.9 mg/kg improve visual acuity at 1 month compared with 300 mg oral aspirin? First phase 3 RCT of IV thrombolysis for CRAO.
Préterre et al. (Lancet Neurology 2025) · doi:10.1016/S1474-4422(25)00308-4 · 70 patients
Population
Included
- Adults aged 18 years or older
- Sudden severe persistent monocular vision loss (Snellen <20/400; >1.3 LogMAR)
- Suspected non-arteritic acute CRAO confirmed by ophthalmologist (fundoscopy or non-mydriatic retinophotography showing diffuse retinal pallor, macular cherry red spot, vessel attenuation, or visible emboli)
- Relative afferent pupillary defect on the affected side
- Treatment startable within 4.5 hours of symptom onset
- No clinical or laboratory evidence of giant cell arteritis
- No clinical or radiological evidence of stroke within the prior 3 months (except asymptomatic punctate or small DWI lesions)
- Baseline CT or MRI brain imaging available
Core inclusion
- Adults aged 18 years or older
- Sudden, severe, and persistent monocular vision loss due to suspected non-arteritic acute central retinal artery occlusion (CRAO)
- Visual acuity worse than 1.3 LogMAR (Snellen worse than 20/400)
- Diagnosis of acute CRAO confirmed by a trained ophthalmologist on fundoscopic examination or non-mydriatic retinophotography (characteristic signs such as diffuse retinal pallor, a macular cherry red spot, attenuation of retinal vessels, or visible arteriolar emboli) in association with an ipsilateral relative afferent pupillary defect
- Able to start study treatment within 4.5 h of symptom onset
- Clinical examination and brain imaging (CT scan or MRI) required for inclusion
Excluded
- Minor visual acuity deficits or rapid pre-treatment improvement
- Unknown or uncertain symptom onset time
- Isolated branch retinal artery occlusion without clinically significant vision loss
- CRAO with foveal sparing due to cilioretinal artery (no foveal ischaemia)
- Current use of anticoagulant medication
- Standard contraindications to IV alteplase (active bleeding, recent major surgery, BP >185/110)
Key exclusions
- Minor visual acuity deficits or rapid improvement before treatment initiation
- Unknown or uncertain time of symptom onset
- Isolated branch retinal artery occlusion without clinically significant vision loss
- CRAO with foveal sparing due to a cilioretinal artery (CRAO without foveal ischaemia)
- Current use of anticoagulant medication
- Clinical or laboratory evidence of giant cell arteritis
- Clinical or radiological evidence of stroke in the past 3 months, except for asymptomatic punctate or small lesions on diffusion-weighted imaging
Source: Mac Grory et al., Lancet Neurol 2025;24:909-919· Retrieved 2026-06-09
Primary Outcome
Visual acuity improvement ≥0.3 LogMAR (~3 Snellen lines / 15 ETDRS letters) at 1 month
Visual acuity ≥0.3 LogMAR gain at 1 month
Unadjusted risk difference +17.4 pp (95% CI -11.8 to +46.5). Trial was powered for a 30 pp difference; observed aspirin response of 48% (vs assumed 10%) made the trial underpowered for the smaller real difference. p=0.95 reflects no statistical signal — not evidence of no effect.
Study Arms
- Agent
- Alteplase
- Dose
- 0.9 mg/kg of bodyweight, maximum 90 mg
- Route
- Intravenous
- Frequency
- Single dose within 4.5 h of symptom onset
- Duration
- 10% of the dose as a bolus, remainder infused over 1 h
- Co-interventions
- Double-dummy: also received one oral dose of placebo. Standard stroke-unit care and secondary prevention per European Stroke Organisation guidelines. Anticoagulants, additional thrombolytic agents, and antiplatelet drugs were not permitted during the first 24 h.
Patient-blinded and assessor-blinded double-dummy design.
- Agent
- Aspirin
- Dose
- 300 mg
- Route
- Oral
- Frequency
- Single dose within 4.5 h of symptom onset
- Duration
- Single dose
- Co-interventions
- Double-dummy: also received an intravenous saline placebo (10 mL over 1 min, then 50 mL infused over 1 h). Standard stroke-unit care and secondary prevention per European Stroke Organisation guidelines.
Active comparator. The primary outcome (visual acuity improvement of at least 0.3 LogMAR at 1 month) did not differ significantly between groups; the trial was underpowered (N=70).
Safety
Symptomatic intracranial haemorrhage (ECASS II)
0%
0%
Zero symptomatic ICH in either arm. One asymptomatic intracranial haemorrhage (15 mm right parietal haematoma) detected on day 1 CT in the alteplase group. Not present on initial MRI, no neurological consequences. No symptomatic haemorrhages or major bleeding related to study treatment in either arm. This is much lower than the typical ~6% sICH rate with IV alteplase in acute ischaemic stroke, likely reflecting the absence of established ischaemic brain lesion in CRAO.
Major extracranial bleeding related to treatment
0%
0%
Zero major extracranial bleeds related to study treatment in either arm. One after-acute-phase gastrointestinal bleed (colon polyps, requiring transfusion) in the aspirin group attributed to secondary-prevention antithrombotic therapy, not the acute study drug.
Serious adverse events after acute phase (%)
14%
17%
Alteplase 5/35 (14%) vs aspirin 6/35 (17%). Most were extra-ocular ischaemic events (carotid endarterectomy in 6, pyelonephritis in 5, melena on colon polyps, and one manic episode in a known bipolar patient). None related to acute study treatment.
Trial Design
Type
- Phase 3, multicentre randomised controlled trial
- Double-dummy, patient-blinded and assessor-blinded
- 1:1 allocation (alteplase + oral placebo vs aspirin + IV saline placebo)
- Conducted across 16 French stroke units
- Binary-superiority primary; underpowered per investigators
Timeline
Enrolled 8 June 2018 – 2 October 2023; published Lancet Neurology November 2025.
N
70
Enrollment
70 patients (35 alteplase / 35 aspirin) at 16 French stroke units. Enrolled June 2018 to October 2023. Phase 3 double-dummy patient- and assessor-blinded RCT. Primary endpoint: visual acuity ≥0.3 LogMAR gain at 1 month. Underpowered per investigators. Published Lancet Neurology November 2025.
ClinicalTrials.gov
NCT03197194Bedside Pearl
THEIA (Lancet Neurology 2025): first phase 3 RCT of IV alteplase 0.9 mg/kg vs aspirin 300 mg within 4.5h of non-arteritic CRAO. Visual acuity improvement at 1 month 66% vs 48% (adjusted OR 1.10, p=0.95); directionally favouring alteplase but not significant; trial underpowered at N=70. Zero symptomatic ICH in either arm. Result does not prove alteplase ineffective; it underscores the need for the planned IPD meta-analysis (THEIA + TenCRAOS + REVISION). Pre-THEIA guidance (Mac Grory AHA/NANOS 2021): IV alteplase "may be considered" for disabling CRAO meeting criteria. THEIA does not change that.
See also