PDF: Efficacy of tPA in CRAO
(2011)Objective
To determine whether IV tPA administered within 24 hours of symptom onset would improve visual acuity in patients with acute central retinal artery occlusion (CRAO)
Study Summary
• Both responders received tPA within 6 hours of onset
Intervention
IV alteplase 0.9 mg/kg (max 90 mg): 10% bolus over 1 minute, remainder over 1 hour, within 24 hours of CRAO onset vs IV saline placebo (10 mL bolus over 1 min, 50 mL over 1 hour). Antiplatelet therapy started 24 hours after infusion in both groups after CT to exclude hemorrhage.
Inclusion Criteria
Age ≥18 years, acute CRAO within 24 hours of symptom onset, presumed thromboembolic cause, no temporal arteritis by clinical/lab assessment, baseline non-contrast CT showing no ICH/infarction/mass, CT angiogram showing no ipsilateral carotid occlusion
Study Design
Arms: IV tPA group (n=8) vs Placebo/saline group (n=8); randomized 1:1 block design via website
Patients per Arm: 8 per arm (16 total randomized and analyzed)
Outcome
• At 1 week: 25% (2/8) tPA vs 0% placebo had ≥3 line improvement
• Mean change at 1 week: -0.275 (SD 0.53) logMAR tPA vs -0.05 (SD 0.14) placebo, p=0.144
• VA improvement not sustained at 6 months in either patient
• Both responders treated within 6 hours; reocclusion suspected
• ICH: 1/8 (12.5%) tPA vs 0/8 placebo
• Retinal neovascularization: 1/8 each group
• Mean time to treatment: 14.4h (tPA) vs 7.3h (placebo), p=0.01
Bottom Line
Although essentially a negative study (primary endpoint not met), it provides important evidence that the time window for intervention in CRAO is likely ≤6 hours rather than 24 hours. Two patients receiving tPA within 6 hours showed early visual improvement at 1 week, but neither sustained improvement at 6 months, suggesting reocclusion may be a problem requiring adjuvant anticoagulation. One patient (12.5%) suffered intracranial hemorrhage, leading to early study termination.
Major Points
- First RCT of IV tPA vs placebo in acute CRAO
- Phase 2 trial conducted at 2 Australian centers (2008-2010)
- Primary outcome (≥3 line VA improvement at 6 months) not achieved in either group
- At 1 week: 2/8 (25%) tPA patients had ≥3 line improvement vs 0/8 placebo
- Both responders received tPA within 6 hours of symptom onset
- Visual improvement not sustained at 6 months in either responder
- Reocclusion suspected in both cases (FFA showed delayed arterial filling)
- One serious adverse event: ICH in 64-year-old patient (12.5% of tPA group)
- ICH required hemicraniectomy and evacuation; patient recovered with mRS 2
- Study halted early by DSMB due to lack of sustained benefit and ICH
- Suggests therapeutic window for CRAO is ≤6 hours, not 24 hours
- Adjuvant anticoagulation may be needed to prevent reocclusion
- No 'standard therapies' (paracentesis, carbogen, massage) used in any patient
- Trial registration: ACTRN12608000441314
Study Design
- Study Type
- Phase 2, placebo-controlled, randomized controlled trial
- Randomization
- Yes
- Blinding
- Treating stroke team blinded to allocation. Concealed printout passed to trial nurse who prepared tPA or placebo. Ophthalmologists performing follow-up blinded to treatment allocation.
- Sample Size
- 16
- Follow-up
- 6 months
- Centers
- 2
- Countries
- Australia
Primary Outcome
Definition: Improvement in Snellen visual acuity by ≥3 lines between baseline and 6 months, equating to ≥0.3 change in logMAR vision score. Assessed by ophthalmologist blinded to treatment allocation.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0/8 (0%) achieved ≥3 line improvement at 6 months | 0/8 (0%) achieved ≥3 line improvement at 6 months | - | Not achieved in either group |
Limitations & Criticisms
- Study terminated early - only 16 of planned 50 patients enrolled
- Severely underpowered: 16 patients vs 50 planned (32% of target enrollment)
- Imbalance in time to treatment: 14.4h (tPA) vs 7.3h (placebo), p=0.01
- Imbalance in time to presentation: 9.1h (tPA) vs 3.9h (placebo), p=0.04
- Inclusion window too wide (24 hours) based on results showing only <6h beneficial
- No heparin anticoagulation used post-tPA, which may have contributed to reocclusion
- Small sample size limits generalizability and statistical power
- One serious ICH (12.5%) - higher than anticipated 0.3% based on MI literature
- Primary outcome not achieved - essentially negative trial
- Visual improvement not sustained at 6 months in the 2 responders
- Reocclusion suspected but not definitively proven in responders
- No standardized adjuvant therapies protocol post-thrombolysis
- Treating team not blinded (though outcome assessors were)
- DSMB stopped trial due to lack of benefit and ICH - appropriate but limits evidence
- No assessment of retinal perfusion by objective measures beyond FFA
- Limited follow-up neuroimaging to assess for asymptomatic cerebral infarcts
- Study conducted at only 2 centers - limited geographic diversity
Citation
Stroke. 2011;42:2229-2234