Highlights
The TenCRAOS trial found no significant difference in vision recovery at 30 days between patients treated with intravenous tenecteplase and those treated with oral aspirin for acute central retinal artery occlusion (CRAO).
Vision recovery, defined as a best corrected visual acuity (BCVA) of 0.7 logMAR or better, occurred in 20% of the tenecteplase group compared to 24% in the aspirin group.
Safety concerns were prominent in the tenecteplase arm, which included one fatal symptomatic intracranial hemorrhage, highlighting the narrow benefit-to-risk ratio of systemic thrombolysis in this population.
The study underscores the continued lack of a gold-standard reperfusion therapy for CRAO and suggests that current stroke-like thrombolysis protocols may not be directly translatable to retinal arterial events.
Background: The Challenge of the Eye Stroke
Central retinal artery occlusion (CRAO) is often referred to as an eye stroke. It represents a medical emergency where the blood supply to the inner layers of the retina is abruptly interrupted, usually by an embolus or thrombus. Without rapid reperfusion, the resulting ischemia leads to irreversible death of retinal ganglion cells and permanent, profound vision loss. For decades, clinicians have grappled with the management of CRAO, often resorting to conservative measures such as ocular massage, anterior chamber paracentesis, or intraocular pressure-lowering medications, none of which have been proven effective in randomized controlled trials.
Given the pathophysiological similarities between CRAO and acute ischemic stroke, the use of thrombolytic agents has long been a subject of intense interest. Previous studies, including the EAGLE trial, investigated intravenous alteplase but failed to show a clear benefit, often due to late presentation or safety issues. Tenecteplase, a genetically engineered variant of alteplase with a longer half-life and greater fibrin specificity, has recently emerged as a preferred agent in ischemic stroke management. The TenCRAOS trial was designed to determine if tenecteplase could provide the breakthrough therapy needed for acute CRAO when administered within a strict 4.5-hour window.
Study Design: The TenCRAOS Methodology
The TenCRAOS trial was a phase 3, multicenter, double-blind, double-dummy, randomized controlled trial. It involved adults presenting with acute, nonarteritic CRAO. To maximize the potential for tissue salvage, the protocol required treatment to be initiated within 4.5 hours of symptom onset—a window mirrored after successful cerebral stroke interventions.
Patient Selection and Intervention
Participants were recruited from 16 sites across six countries. A total of 78 patients were randomized in a 1:1 ratio. The intervention group received intravenous tenecteplase at a dose of 0.25 mg per kilogram of body weight, accompanied by an oral placebo. The control group received an intravenous placebo and a 300 mg loading dose of oral aspirin. This double-dummy design ensured that both patients and investigators remained blinded to the treatment assignment.
Endpoints and Assessment
The primary endpoint was vision recovery at 30 days, defined as a best corrected visual acuity (BCVA) in the affected eye of 0.7 logMAR or better (equivalent to 20/100 or better on the Snellen chart). This threshold was chosen as it represents a level of vision that allows for significant functional independence. Secondary endpoints included a more stringent visual recovery (BCVA ≤ 0.5 logMAR, or 20/63), the mean change in BCVA from baseline, and perimetry scores to assess visual field preservation. Safety endpoints were rigorous, focusing on symptomatic intracranial hemorrhage (sICH), major systemic bleeding, and all-cause mortality.
Key Findings: Efficacy and Safety Data
The results of the TenCRAOS trial were sobering for the ophthalmic and neurological communities. Despite the theoretical advantages of tenecteplase, the clinical data did not support its use over standard antiplatelet therapy in this setting.
Visual Outcomes
At the 30-day mark, 8 out of 40 patients (20%) in the tenecteplase group achieved the primary endpoint of vision recovery. In the aspirin group, 9 out of 38 patients (24%) reached the same threshold. The risk difference was -3.7 percentage points (95% confidence interval [CI], -22.0 to 14.7), with a p-value of 0.69, indicating no statistical significance. Secondary visual outcomes followed a similar trend, with no substantial differences observed in mean BCVA improvement or perimetry scores between the two cohorts.
Safety Profile
The safety data revealed a concerning tilt toward the tenecteplase group. While the overall number of events was small, the severity was significant. One patient in the tenecteplase group suffered a fatal symptomatic intracranial hemorrhage. Other adverse events, including minor bleeding and systemic complications, were also more frequent in the thrombolysis arm. This suggests that the systemic risk of fibrinolysis may outweigh the localized benefit to the retinal vasculature in many patients.
Expert Commentary: Analyzing the Failure of Thrombolysis
Why did tenecteplase fail to outperform aspirin in CRAO, especially when it has shown such promise in cerebral ischemia? Several factors may contribute to this discrepancy. First, the retinal artery is significantly smaller than the middle cerebral artery, and the nature of the occluding embolus may differ. Retinal emboli are frequently composed of cholesterol (Hollenhorst plaques) or calcium, which are not susceptible to fibrinolysis, unlike the fibrin-rich red clots often found in large-vessel cerebral strokes.
Furthermore, the retina is one of the most metabolically active tissues in the body. Its tolerance for total ischemia is remarkably low. While the 4.5-hour window is effective for the brain, the “point of no return” for the human retina may be much earlier. Experimental models have suggested that irreversible damage can occur within 90 to 240 minutes. By the time many patients in the trial received treatment, the window for functional recovery might have already closed, even if reperfusion was technically achieved.
Another consideration is the dosage. The 0.25 mg/kg dose is standard for stroke, but whether this concentration is sufficient to penetrate a distal ophthalmic or retinal artery occlusion remains an open question. However, increasing the dose would likely escalate the already significant risk of intracranial hemorrhage.
Conclusion: Clinical Implications and Future Directions
The TenCRAOS trial provides high-quality evidence that intravenous tenecteplase should not be the routine standard of care for acute CRAO. The lack of efficacy compared to aspirin, combined with the risk of life-threatening hemorrhage, suggests that the search for an effective CRAO treatment must continue in other directions.
For clinicians, the primary takeaway is the importance of cardiovascular risk factor management and the use of antiplatelet therapy, as CRAO is a potent predictor of future stroke and myocardial infarction. While the trial was negative for tenecteplase, it reinforces the need for rapid triage. Patients with sudden vision loss should still be evaluated urgently to rule out giant cell arteritis and to initiate secondary stroke prevention. Future research may need to focus on intra-arterial thrombolysis, neuroprotective agents, or even earlier intervention windows facilitated by tele-ophthalmology.
Funding and Clinical Trial Information
The TenCRAOS trial was funded by Oslo University Hospital, the South-Eastern Norway Regional Health Authority, and other non-profit foundations. ClinicalTrials.gov number: NCT04526951. EU Clinical Trials number: 2024-517606-29-00.
References
1. Ryan SJ, Jørstad ØK, Skjelland M, et al. A Randomized Trial of Tenecteplase in Acute Central Retinal Artery Occlusion. N Engl J Med. 2026;394(5):442-450.
2. Schrag M, Tyagi R, Reznekov O, et al. Intravenous Fibrinolysis for Central Retinal Artery Occlusion: A Pooled Analysis and Systematic Review. JAMA Neurol. 2015;72(10):1148-1154.
3. Schumacher M, Schmidt D, Jurklies B, et al. Central retinal artery occlusion: local intra-arterial fibrinolysis versus conservative treatment, a multicenter randomized trial (EAGLE). Ophthalmology. 2010;117(7):1367-1375.