PDF: THEIA
(2025)Objective
To compare the safety and efficacy of IV alteplase versus aspirin in patients with acute non-arteritic central retinal artery occlusion (CRAO) treated within 4.5 hours of onset of severe vision loss
Study Summary
• No significant difference in visual outcomes; one asymptomatic intracranial hemorrhage in alteplase group; no symptomatic bleeding
Intervention
Intravenous alteplase 0.9 mg/kg (max 90 mg: 10% bolus, 90% over 1 hour) + oral placebo vs oral aspirin 300 mg + IV saline placebo, administered within 4.5 hours of symptom onset
Inclusion Criteria
Age ≥18 years, sudden severe persistent monocular vision loss (Snellen <20/400, LogMAR >1.3) due to suspected non-arteritic acute CRAO confirmed by ophthalmologist, treatment within 4.5h of onset, able to verbalize pain score
Study Design
Arms: Alteplase group (n=35): IV alteplase 0.9 mg/kg + oral placebo; Aspirin group (n=35): oral aspirin 300 mg + IV saline placebo
Patients per Arm: 35 alteplase, 35 aspirin (70 total randomized); 34 alteplase, 31 aspirin received treatment; 34 alteplase, 30 aspirin in full analysis set
Outcome
• Visual acuity ≤1.3 LogMAR at 1 month: 24% alteplase vs 26% aspirin (p=0.91)
• Functional visual recovery (≤0.5 LogMAR): 14% alteplase vs 7% aspirin (p=0.67)
• mRS 0-1 at 3 months: 71% alteplase vs 57% aspirin (p=0.46)
• One asymptomatic intracranial hemorrhage in alteplase group; no symptomatic hemorrhages or major bleeding
Bottom Line
Intravenous alteplase administered within 4.5 hours of CRAO onset was not associated with a significant improvement in visual acuity compared with aspirin, despite a numerically higher rate of improvement in the alteplase group (66% vs 48%). The study was likely underpowered to detect a statistical difference. No safety concerns related to alteplase were identified, but overall modest recovery rates underscore the need for individual patient-level data meta-analyses to clarify the potential benefit.
Major Points
- First published phase 3 RCT directly comparing IV alteplase with oral aspirin in acute CRAO within 4.5h
- Multicenter (16 French hospitals), double-dummy, patient-blinded, assessor-blinded design
- Mean time from symptom onset to treatment: 232.4 minutes (SD 43.6)
- Primary outcome: 66% alteplase vs 48% aspirin achieved ≥0.3 LogMAR improvement at 1 month (p=0.95)
- No significant difference in any secondary outcomes including functional visual recovery
- Baseline visual acuity very poor: mean 2.4 LogMAR (most patients off-chart, unable to read ETDRS)
- 94% of patients had off-chart visual acuity at presentation (>1.7 LogMAR)
- Only one asymptomatic intracranial hemorrhage (15 mm parietal hematoma) in alteplase group
- No symptomatic hemorrhages or major bleeding related to study treatment
- Mean improvement at 3 months: 6.7 lines (alteplase) vs 4.0 lines (aspirin), not significant
- Study underpowered due to higher than expected improvement in aspirin group (48% vs anticipated 10%)
- Unexpectedly high dropout rate (20% vs anticipated 10%)
- Independent DSMB oversight throughout trial
Study Design
- Study Type
- Multicenter, double-dummy, patient-blinded, assessor-blinded, randomized, controlled, phase 3 trial
- Randomization
- Yes
- Blinding
- Patient-blinded and assessor-blinded (double-dummy design). Patients, outcome assessors (neurologists, ophthalmologists, orthoptists), and sponsor were masked. Treating nurses and neurologists were unmasked due to differences in alteplase preparation. Randomization 1:1 stratified by center using Ennov software with pre-established randomization list.
- Sample Size
- 70
- Follow-up
- 3 months (90 days)
- Centers
- 16
- Countries
- France
Primary Outcome
Definition: Improvement in visual acuity from baseline to 1 month, defined as gain of ≥0.3 LogMAR (≥3 Snellen lines/15 letters on ETDRS chart). For off-chart patients (counting fingers, hand motion, light perception, no light perception), change between categories considered ≥0.3 LogMAR improvement. Analyzed in full analysis set.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 13/27 (48%) | 19/29 (66%) | - (Unadjusted RD 17.4 (95% CI -11.8 to 46.5); Adjusted OR 1.10 (95% CI 0.07 to 18.39)) | 0.95 |
Limitations & Criticisms
- Study likely underpowered to detect significant difference - smaller than expected sample size
- Unexpectedly high improvement rate in aspirin group (48% vs anticipated 10%)
- Higher than anticipated dropout rate (20% vs expected 10%)
- Recruitment challenges: COVID-19 pandemic, low CRAO incidence, narrow therapeutic window
- Double-dummy design prevented masking of treating neurologists and nurses (potential behavioral bias)
- Three patients in aspirin group mistakenly received alteplase
- Primary outcome measure (≥0.3 LogMAR improvement) may be less clinically relevant than functional recovery measures
- No clear relationship between onset-to-treatment time and visual improvement in alteplase group
- Only 8 patients treated within 3 hours - limited early treatment window data
- Imbalance in baseline characteristics: more females in alteplase group (49% vs 23%), more hypercholesterolemia in aspirin group (66% vs 26%)
- Overall modest recovery rates in both groups suggest retinal ischemic tolerance may be much lower than previously thought
- No assessment of retinal viability imaging (e.g., OCT) to optimize patient selection
- Limited generalizability due to restrictive inclusion criteria
- No long-term follow-up beyond 3 months for late neovascular complications
- Question about benefit of aspirin within 4.5h window - no placebo arm to assess this
Citation
Lancet Neurol 2025; 24: 909–19