Improving outcome in central retinal artery occlusion (CRAO) - is thrombolysis the answer?

This piece was written by my research team and approved by Dr Leo Sheck.

Patients diagnosed with central retinal artery occlusion (CRAO) typically present with sudden, painless monocular vision loss. CRAO is considered an ophthalmologic emergency, with less than 20% of patients recovering functional vision in the affected eye. Conservative treatments, such as anterior chamber paracentesis and ocular massage, have shown poor efficacy and variability in achieving favourable outcomes. Moreover, these treatments have been associated with significantly worse visual acuity outcomes when compared to untreated CRAO patients. This leaves the field with no universal standard of care to guide management for CRAO patients.

The use of intravenous (IV) thrombolytic therapy, namely tissue plasminogen activator (tPA), is the current mainstay treatment for cerebral ischemic stroke. Given the similarity in pathogenesis and comorbidity of ischemic stroke and CRAO, the use of thrombolytic therapy appears rational. However the evidence for tPA use in CRAO patients is limited, with no adequate randomised clinical trials to prove its benefit.

The Eagle Study

The EAGLE study was the first large multi-centre trial to investigate the benefits of thrombolytic therapy vs conservative treatment in CRAO patients. Patients were randomised to receive intra-arterial tPA or a conservative treatment regime, and change in vision acuity was recorded at 1 month. The study ended prematurely due to the failure of the thrombolytic therapy to outperform the conservative regime, as well as being associated with a higher rate of adverse events. However, mean time between symptom onset and treatment was found to be 13 hours, with no patient being treated within 4.5 hours. This time period is critical when considering treatment options. As seen with ischemic cerebral stroke, rapid administration of thrombolytic therapy within 4.5 hours of symptom onset is an effective treatment; outside of this window the benefit is outweighed by associated risks such as intracranial haemorrhage. 

Meta-analysis and new studies 

A 2015 meta-analysis of observational cohorts highlighted the importance of this therapeutic window, where they reported a significant treatment benefit of IV thrombolysis for CRAO patients when it was administered within a 4.5 hour timeframe. Vision recovery was reported in 50% of patients receiving IV thrombolysis, compared to 17.7% of patients who were untreated and 7.4% of patients who received a conservative treatment. A sub-analysis showed that the benefits of IV tPA reduced as the treatment window increased to 12 hours.

Since this publication, tPA has since been re-evaluated in several studies, and an updated meta-analysis has reconfirmed the beneficial treatment effect seen within 4.5 hours. These results have formed the basis for new clinical trials that are currently underway in Europe.  THEIA (NCT03197194), REVISON (NCT04965038), and TenCRAOS (NCT04526951) all aim to evaluate the efficacy of IV thrombolysis therapy vs placebo in CRAO patients within 4.5 hours of symptom onset.  

Until the evidence from these trials is released, there remains no level 1 evidence to support best practice treatment for CRAO patients. The American Heart Association released a statement in 2021 assessing the available literature in the field in order to give expert opinion for acute management. They concluded that there was clinical equipoise in the utility of early administration of IV tPA, and that the decision rests on a thorough discussion of the evidence available and treatment risks between the specialist and patient.  

The problems with thrombolytic treatment

Utility of thrombolytic treatment is the same concept for CRAO as it is for cerebral stroke, namely that it can break down clots and restore tissue perfusion. However, a major complication associated with its use is intracranial haemorrhage, with a reported rate of 1.7 - 8.8% in an acute stroke population. A survey of adults with normal vision found that over one third would accept some risk of stroke or even death if it would triple the chances of 20/100 vision acuity following a CRAO diagnosis. This highlights the impact that vision loss has on a person’s quality of life. The risk of intracranial haemorrhage appears low when tPA is used for CRAO, with no recorded cases when administered within a 4.5-hour window of symptom onset, and without concomitant anticoagulation use.  

A study published this year highlighted the issue that CRAO patients often have delayed hospital presentation, and those that did present early did not receive ophthalmologic evaluation in a manner timely enough to allow for IV thrombolytic treatment. A focus on educational campaigns for both patients and medical providers to recognise CRAO symptoms so treatment can be administered within the recommended time frame is needed.

The way forward

As there is clinical equipoise in the utility of early administration of IV tPA in CRAO, the possibility of this treatment modality should be discussed with all patients presenting with CRAO within a 4.5 hour window. However, the major problem is getting patients seen in such a short time frame, especially given most eye clinics in New Zealand work on a referral basis causing further delays. Furthermore, if a patient can be assessed in the Emergency Department, there is often limited equipment (e.g. optical coherence tomography [OCT] imaging) and expertise available to obtain a concrete diagnosis prior to treatment.

IV tPA is given by the neurology service, and the above results have not been universally accepted by neurologists in New Zealand. Further discussion will be required between ophthalmology and neurology to assess the utility of IV tPA in CRAO. As CRAO is devastating for the patient and there is unlikely to be any visual recovery, if I see a patient with CRAO within 4.5 hours of symptom onset, I will immediately contact the neurologist on call to explore if tPA thrombolysis can be considered. 

About Dr Leo Sheck

Dr Sheck is a RANZCO-qualified, internationally trained ophthalmologist. He combined his initial training in New Zealand with a two-year advanced fellowship in Moorfield Eye Hospital, London. He also holds a Doctorate in Ocular Genetics from the University of Auckland and a Master of Business Administration from the University of Cambridge. He specialises in medical retina diseases (injection therapy), cataract surgery, ocular genetics, uveitis and electrodiagnostics.