EBM Review Series: To TNK or not to TNK: A discussion of the TenCRAOS trial
VACEP Evidence-Based Medicine for General Emergency Physicians Series
Authors: Arah Emslie, MD, MPH PGY-3 and Ambika Anand, MD | VCU Health
Reviewers: Hunter Williams, DO PGY-2 and Winston Wu, MD | Virginia Tech Carilion
The VACEP Evidence-Based Medicine Review Series allows Virginia emergency medicine residents and attendings to share and analyze a recent peer-reviewed clinical study. You can also read the full article, “A Randomized Trial of Tenecteplase in Acute Central Retinal Artery Occlusion”, in Volume 394, Issue 5 of the New England Journal of Medicine.
THE CASE
A 79-year-old male with a history of hypertension, peripheral arterial disease, hyperlipidemia, coronary artery disease, and diabetes presents to your community emergency department with sudden onset vision loss of the right eye, with onset two hours prior to arrival. He describes the vision loss as a sudden darkening of his vision, and on exam, he is only able to see movement and shadows in the right eye and has 20/30 vision in the left eye. You quickly check tonometry and find a right intraocular pressure of 12 and a left intraocular pressure of 14. On bedside ultrasound, you see no evidence of vitreous hemorrhage or retinal detachment. There is no enlargement of the optic nerve, but you do note a hyperechoic spot overlying the optic nerve, concerning for a “retrobulbar spot sign” on the right eye. You obtain standard stroke imaging for your facility which is negative for acute hemorrhage or large vessel occlusion. The patient is three hours out from the onset of his symptoms at this point. Your hospital has tele-neurology and no in-house ophthalmology but the tele-neurologist agrees with your diagnosis of central retinal artery occlusion (CRAO) and says you can consider administering thrombolytics.
Should you administer tenecteplase to this patient?
STUDY SUMMARY
Central retinal artery occlusion (CRAO) presents with sudden, painless, monocular vision loss, often with an afferent pupillary defect and the classic cherry red macular spot; this condition represents an ophthalmologic emergency associated with permanent blindness. This is the ocular equivalent of a stroke, and the most common cause is ipsilateral carotid artery atherosclerosis. Other risk factors include cardiac embolic disease, pro-thrombotic states including sickle cell disease or leukemia, or, less commonly, autoimmune conditions such as giant cell arteritis and other vasculitides.1 A recent study published in NEJM called the TenCRAOS study examined the role of tenecteplase (TNK) in treatment of acute CRAO. This study was a double-blind, double-dummy, randomized controlled trial to compare intravenous TNK and a placebo oral medication with a placebo intravenous medication and oral aspirin for clinically significant improvement of vision in patients with CRAO at 30 days post-administration.2 While clinical trials in the past have examined the role of alteplase (TPA) or catheter directed thrombolysis, TenCRAOS is the first study to investigate TNK.3,4
METHODS:
This trial was a phase 3, double-blind, double-dummy, parallel-group randomized controlled trial. It compared intravenous TNK with an oral placebo versus 300 mg oral aspirin with an intravenous placebo for treatment of CRAO within a 4.5 hour window from onset of symptoms. It was coordinated by Oslo University Hospital and involved sites across six European countries. Adult patients diagnosed with CRAO within the 4.5 hour treatment window and who had a best corrected visual acuity (BCVA) of 20/200 or worse were included in the study. Patients were assessed initially by ophthalmology, then by an acute stroke team and had neuroimaging in accordance with hospital stroke guidelines. They were admitted to a stroke unit and managed according to institutional stroke guidelines after thrombolytic administration. Following discharge patients had outpatient follow-up with both ophthalmology and neurology. The groups were block randomized with a 1:1 ratio to tenecteplase + placebo vs aspirin + placebo group.
OUTCOMES
The primary outcome was a BCVA of 0.7 logMAR or lower in the affected eye 30 days post-treatment (the equivalent of 20/100 vision). LogMAR stands for Logarithm of the Minimum Angle of Resolution. It is a scoring system which is now the gold standard method for assessing visual acuity and can be converted to the Snellen scoring system most emergency physicians are more familiar with. A logMAR of 0 is equivalent to 20/20 vision while a logMAR of 1 is equivalent to 20/200. Note that lower logMAR scores correspond to better vision. Each line of the Snellen chart has an equivalent logMAR score, and the score also considers individual letters that can be read even if the entire line cannot be read accurately. This threshold was chosen as an improvement from initial visual acuity of at least 0.3 logMAR is regarded as clinically meaningful by ophthalmologic standards.
Secondary outcomes included a BCVA of 0.5 logMAR (the equivalent of 20/63 vision) or less at 30 days, mean change in BCVA from baseline at 30 days, visual field testing at 30 days using the monocular Esterman perimetry score, the National Institute of Health Stroke Scale, and the modified Rankin scale at discharge and 30 days. The study also recorded patient-reported measures of quality of life and vision functioning using the National Eye Institute Visual Function Questionnaire.
About the EBM Review Series
This is a literature review series started by the University of Virginia’s Josh Easter, MD, MSc, a VACEP board member working to connect the academic community in Virginia. We invite each residency in Virginia (and D.C.) to create a faculty/resident team to submit and review articles. Sign up to submit one.
Goals
Provide a brief monthly synopsis of a high yield article germane to the practice of emergency medicine for distribution to all VACEP members
Provide an opportunity for a peer reviewed publication and invited presentation for faculty and trainees
Foster an academic community focused on evidenced based medicine for emergency medicine residency programs in the region
ANALYSIS
A total of 78 patients were enrolled at 16 sites across six European countries. 38 were randomized to the aspirin + placebo group, and 40 were randomized to the TNK + placebo group. Both groups had similar baseline characteristics in terms of baseline visual acuity and other demographic characteristics except for carotid artery disease and diabetes which were more prevalent in the aspirin and TNK group respectively.
The primary outcome of BCVA of 0.7 logMAR or lower in the affected eye showed no clinically or statistically significant difference between the TNK and aspirin groups with a 95% confidence interval (CI) of -22.0 to 14.7 and a p-value of 0.69. Secondary outcomes were similarly non-significant between groups in terms of BCVA of 0.5 logMAR or lower at 30 days, visual field assessment, and patient-reported endpoints. A subgroup analysis of patients who received treatment within 3 hours of symptom onset showed similar results with no clinically or statistically significant difference in primary endpoint.
Adverse events were also reported, with differentiation between serious adverse events and adverse events. The TNK group had 30 adverse events among 19 participants and 10 serious adverse events among 8 patients. One serious adverse event was considered to be directly related to the administration of TNK and resulted in death due to intracerebral hemorrhage related to reperfusion of brain tissue. The aspirin group reported 19 adverse events among 13 patients and 4 serious adverse events among 4 patients, none of which were fatal.
STRENGTHS
The strengths of this study include that it was a double-blind, double-dummy, randomized controlled trial. This study’s results are also supported by previous research including the THEIA (Thrombolysis [Alteplase] in Patients with Acute Central Retinal Artery Occlusion) trial, a multicenter trial in France which utilized alteplase rather than tenecteplase, and the EAGLE (European Assessment Group for Lysis in the Eye) trial which utilized intra-arterial thrombolysis, both of which also found no significant difference in vision regained after thrombolysis administration in CRAO but did have increased adverse events in the thrombolytic group.3,4 Both its design and demonstration of reproducibility lend strength and credibility to its results.
LIMITATIONS
The trial had a relatively small number of patients. Their power calculations were based on estimates from a 2015 meta-analysis by Schrag et al., however this may have resulted in underpowering of this study.8 Studying a rare disease like CRAO which has an incidence of around 1.9 per 100,000 person-years in the US is a limitation by itself as it increases the difficulty of recruiting patients who meet inclusion criteria. While this study’s sample size was representative of demographics of European patients diagnosed with CRAO at large, differences may exist in patient populations from other countries that could affect their risk of adverse events with administration of TNK or underlying etiology for CRAO. For example, there was no mention in the study of patients having to be excluded from the TNK group because they had contraindications to thrombolytic administration. Additionally, there was a higher prevalence of patients with diabetes in the TNK group and a higher prevalence of patients with carotid artery disease in the aspirin/placebo group. Both disease processes are risk factors for CRAO but could modify treatment response to thrombolytics versus antiplatelet agents in differing ways.
In its inclusion criteria, the study targeted patients with a BCVA of 1 logMAR or higher (worse), correlating with a visual acuity of 20/200 or worse. This was also based on the 2015 Schrag et al meta-analysis. By excluding patients with better baseline visual acuity, it’s possible that a clinically significant effect could be missed for patients with less ischemic damage to the retina. The study only notes 3 patients who were ultimately excluded from the initial group, one for TNK administration outside of the 4.5 hour window, one for preserved BCVA score, and one who was ultimately diagnosed with retinal vasospasm rather than true occlusion. The end point and follow up duration of the study also represented a limitation, as patients were only followed for 30 days to the primary endpoint of BCVA logMAR scores, excluding the ability to detect improvements in vision over a longer period of time.
The trial included patients who were within a 4.5 hour window, which is standard for thrombolytic administration for intracranial cerebrovascular accidents, however there is theoretical evidence that earlier reperfusion strategies are more beneficial in CRAO as it is an end artery with limited collaterals, so the lack of effect seen may simply be due to intervention needing to be in an even earlier time window.5
DISCUSSION
This multi-center, double blind, randomized controlled trial did not find a significant improvement across multiple visual testing endpoints for patients who received TNK vs aspirin after being diagnosed with CRAO within a 4.5 hour window from symptom onset time. More concerningly, these patients were found to have a higher number of adverse and serious adverse events including one fatal event related to intracranial hemorrhage.
While CRAO is the stroke equivalent of the eye, current evidence does not support the same treatment modalities as ischemic stroke for functional recovery and decreasing morbidity. Current recommendations for care vary between different academic societies with a stake in treatment of this disease as guidelines evolve with new research. For example, the American Academy of Ophthalmology recommended administration of systemic thrombolytics if a patient is within a 4.5 hour window from symptom onset in 2017, but more recently updated their guidelines to only recommend consideration of thrombolytics.1,5 The American Heart Association recommended consideration of alteplase (tPA) for patients within a 4.5 hour window from symptom onset in their most recent guidelines.6 Within these guidelines published in 2021, they discussed that based on observational data available at the time “more than half of academic neurologists treat selected patients with acute CRAO with intravenous tPA.”6 A study published in Stroke in 2020, cited that around 5.8% of patients presenting with CRAO were receiving tPA at the time.7 These guidelines cited the THEIA study and discussed the TenCRAOS study which was in process at that time. They highlighted the importance of published and upcoming studies to further evaluating treatment of CRAO with thrombolytics in a randomized trial format, rather than the observational studies which had previously indicated some benefit with thrombolysis.8
These changes to data and guidelines within a relatively short span of time emphasize the importance of remaining current with evolving evidence to offer safe and effective treatment options to patients. The TenCRAOS trial adds to a growing body of evidence that does not support the use of thrombolytics in acute CRAO with increased risk to patients and little evidence of benefit in terms of vision regained.2 This study along with other more recent randomized controlled trials can help guide development of new national guidelines as well as discussions surrounding the risks and benefits of treatment options with patients and family presenting with this rare disease.
CASE CONCLUSION
Returning to your patient, you discuss his diagnosis and the risks and benefits of thrombolytic administration in CRAO. Thrombolytic administration is deferred. You call the transfer center and speak with ophthalmology at the nearest comprehensive stroke center, and you ask about potential additional treatments that you could initiate in the ED while awaiting transfer including ocular massage, anterior chamber paracentesis, medications to reduce intraocular pressure such as acetazolamide or timolol drops, or steroids. These interventions have a similar lack of evidence in the literature for improved outcomes with CRAO, and as there is transport ready to take the patient, you agree to hold off on any further interventions before transfer. The patient is transported by advanced life support ground transport for comprehensive neurology and ophthalmology work up.
SOURCES
1. Sim S, Ting D. Diagnosis and management of central retinal artery occlusion. EyeNet Magazine. August 1, 2017. Accessed March 9, 2026. www.aao.org/eyenet/article/diagnosis-and-management-of-crao.
2. 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. doi:10.1056/NEJMoa2508515.
3. Préterre C, Gaultier A, Obadia M, et al. Intravenous alteplase versus oral aspirin for acute central retinal artery occlusion within 4·5 h of severe vision loss (THEIA): a multicentre, double-dummy, patient-blinded and assessor-blinded, randomised, controlled, phase 3 trial. Lancet Neurol. 2025;24(11):909-919. doi:10.1016/S1474-4422(25)00308-4.
4. Feltgen N, Neubauer A, Jurklies B, et al. Multicenter study of the European Assessment Group for Lysis in the Eye (EAGLE) for the treatment of central retinal artery occlusion: design issues and implications. EAGLE Study report no. 1. Graefes Arch Clin Exp Ophthalmol. 2006;244(8):950-956. doi:10.1007/s00417-005-0140-2.
5. Kovach JL, Bailey ST, Kim SJ, et al. Retinal and ophthalmic artery occlusions Preferred Practice Pattern®. Ophthalmology. 2025;132(4):P270-P302. doi:10.1016/j.ophtha.2024.12.024.
6. Mac Grory B, Schrag M, Biousse V, et al. Management of central retinal artery occlusion: a scientific statement from the American Heart Association. Stroke. 2021;52(6). doi:10.1161/STR.0000000000000366.
7. Schorr EM, Rossi KC, Stein LK, Park BL, Tuhrim S, Dhamoon MS. Characteristics and outcomes of retinal artery occlusion: nationally representative data. Stroke. 2020;51(3):800-807. doi:10.1161/STROKEAHA.119.027034.
8. Schrag M, Youn T, Schindler J, Kirshner H, Greer D. Intravenous fibrinolytic therapy in central retinal artery occlusion: a patient-level meta-analysis. JAMA Neurol. 2015;72(10):1148–1154. doi: 10.1001/jamaneurol.2015.1578
