Pro: t-PA Should Be Given to the Patient With Acute Central Retinal Artery Occlusion: Robert A. Egan, MD
The management of central retinal artery occlusion (CRAO) is controversial due to lack of large-scale clinical trial data. Currently, patients are treated with conservative measures or with fibrinolysis given intra-arterially or intravenously. This report deals with local intra-arterial fibrinolysis (LIF) only. The goal LIF is to restore vision at a rate greater than conservative therapy currently provides. Because of poor prognosis for visual recovery, I would treat the patient with LIF because I believe that there is a better chance for visual recovery with LIF than without this therapy.
CRAO is the ophthalmic equivalent of a hemispheric stroke and is a medical emergency. The incidence is approximately 1.9/100,000 in the United States (1). Patients typically present with devastating vision loss with little chance for visual recovery. The natural history suggests that 80% of eyes affected by CRAO suffer a final visual acuity of counting fingers or worse (2, 3). Patients who suffer a CRAO also are at increased risk for hemispheric stroke. Anterior chamber paracentesis and carbon dioxide and oxygen (Carbogen) inhalation therapy have been used to help improve the natural course of this disabling ocular condition but are no better than no intervention (4).
Because the pathophysiology of CRAO is akin to that of hemispheric stroke, an assumption can be made that beneficial therapies in 1 disorder may be effective in the other. t-PA, when given intravenously to patients suffering from ischemic cerebral stroke, was found to be efficacious at improving clinical outcomes up to 4.5 hours from onset of symptoms (5, 6). A meta-analysis of 54 studies including 5019 ischemic stroke subjects showed that t-PA given intra-arterially is efficacious and more effective than placebo but seems to offer really no benefit over t-PA when administered intravenously (7).
Both the clinical characteristics and most meta-analyses support the notion that CRAO may respond to LIF. Unfortunately, well-controlled trials regarding the usage of LIF in patients with CRAO are limited. The largest is the European Assessment Group for Lysis in the Eye (EAGLE) study where 84 subjects were recruited from Austria and Germany; 44 received LIF (8). No subject had a symptom duration of longer than 20 hours. Despite the LIF group time interval to therapy being almost 2 hours longer than the conservative treatment group, both arms experienced an improvement in the best-corrected visual acuity. Clinically significant visual improvement was equal between study arms. Adverse reactions occurred in 4.3% of the conservative treatment group and 37.1% in the LIF group. The study was stopped early by the safety monitoring committee. At the time of publication of the results, the authors of the EAGLE study recommended against the routine use of LIF in CRAO.
What most treating physicians agree on is that time is of the essence when treating CRAO. This presents a significant challenge because the percentage of patients with CRAO that do not reach the angiography suite by 8 hours approaches 50% (9). Even in the EAGLE study, the mean treatment time in the LIF group was close to 13 hours after onset of symptoms, an interval, that is, far longer than the time when it is believed that treatment would be effective. Although the exact duration of retinal ganglion cell survival with ischemia is not known, it has been proposed that the limit is between 6 and 6.5 hours (10, 11). Even the EAGLE investigators suggest that the best treatment window lies closer to symptom onset rather than their arbitrary 20-hour treatment window (8). In 1 study, final visual acuity only improved significantly when LIF was administered in less than 6.5 hours after CRAO (11).
Given the lack of efficacy proven in clinical trials, LIF for CRAO should not be routinely administered. The reasoning for this is that interventional centers capable of offering this treatment must be able to demonstrate their ability to catheterize the ophthalmic artery with a low complication rate. Also, centers offering this treatment must also have a program in place that can deliver patients to the angiography suite in a very timely fashion.
The main argument for continuing to explore the potential benefits of using LIF in CRAO is that the only “large” randomized trial to date included only 44 patients in the treatment group, a number far too low to draw definite conclusions about benefits and risks (8). My recommendation is for a large multicenter clinical trial to be designed and implemented to study the safety and efficacy of this treatment. A trial of this scope should include a number of treatment centers in North America and Europe that have shown a good track record for the treatment of ischemic cerebral stroke with a low complication rate. Until this time, all patients undergoing LIF for CRAO should be enrolled in a registry to help provide data for planning of this potential treatment trial.
Con: Patients With Acute Central Retinal Artery Occlusion Should Not Be Treated With Intra-arterial tPA: Renee Van Stavern, MD
The acute management of CRAO is controversial, largely because of the published natural history of a poor visual outcome juxtaposed against the ready availability of intravenous (IV) and endovascular therapies for other vascular disorders affecting the brain. Although thrombolytic and interventional treatments have been studied and are available for acute stroke, there are no large randomized trials in CRAO to help inform practice standards and the evidence available is weak. Current evidence does not support the routine use of intra-arterial tPA for patients with CRAO.
Defense of Position
The treatment window for intravenous thrombolysis in acute stroke is less than 4.5 hours from the time last known well, and IV tPA trials have consistently demonstrated that time to treatment has an impact on clinical outcome. When intra-arterial therapies are considered, there is an additional delay required to initiate treatment in an angiography suite. Data from the Interventional Management of Stroke pilot trials suggested that patients who achieved angiographic reperfusion less than 7 hours from the time last known well achieved the best clinical outcomes (12). In the EAGLE trial, the only randomized controlled trial examining the use of intra-arterial thrombolysis vs conservative treatment for CRAO, patients were enrolled up to 20 hours from the time last known well, with a mean time from last known well to treatment of 12.78 hours, range 4.75–23.43 hours (13). In addition, patients with CRAO may have additional delays before receiving treatment, as they often present to another health care provider before seeking treatment in an emergency department. In 1 recent retrospective review, fewer than half of the patients with CRAO received an in-hospital evaluation in fewer than 20 hours, with the meantime to emergency department evaluation of 13.1 hours (14). Only 3 of 31 patients presented directly to the emergency department, and there was a mean treatment delay of 5.2 hours when the patient was referred to an in-hospital ophthalmologist from another health care provider.
EAGLE Results and Risk of Harm
The EAGLE study was the first randomized clinical trial to compare the benefit of intra-arterial tPA with conservative treatments in patients with CRAO (8). The treatment groups did not differ in the final analysis of the primary end point of the best-corrected visual acuity. Both treatment groups demonstrated a benefit in the best-corrected visual acuity at 1 month compared with baseline. About 60% of patients in each group had a clinically significant visual improvement, defined as a decrease in logMAR of ≤0.3 at 1 month. Two intracerebral hemorrhages occurred in the intraarterial (IA) treatment group, along with 34.3% experiencing at least 1 minor adverse reaction including 1 ischemic stroke, and 2.1% had minor adverse reactions in the conservatively treated group.
Failure of Interventional Therapies in Acute Ischemic Stroke
More recent interventional treatment trials comparing intra-arterial tPA, clot retrievers, and/or stent retrievers to IV tPA alone have also failed to demonstrate a benefit. The IMS-3, SYNTHESIS, and MR-RESCUE randomized trials each failed to demonstrate superiority of endovascular therapy compared with IV tPA, with a combined total of more than 1000 patients (15–17). IMS-3 and SYNTHESIS included intra-arterial tPA as one of the treatment options in the endovascular arm. Data are not available regarding the number of patients receiving intra-arterial tPA in IMS-3; however, in SYNTHESIS, 109 patients of the 165 randomized to endovascular treatment received intra-arterial tPA alone without the use of other devices. Each of these studies excluded patients with isolated visual loss, as they required NIH stroke scale scores of at least 8.
The benefit of intra-arterial tPA over IV tPA in acute ischemic stroke is suspect, given the available data. However, its use reflects trends supported by other interventional trials in acute stroke using different interventional devices (18, 19). The SWIFT-PRIME, EXTEND-IA, and REVASCAT trials are currently underway and will compare interventional devices directly with IV tPA. Unfortunately, patients with isolated visual loss will not be included in these trials, as enrollment is limited to patients with moderate-to-severe ischemic strokes and large-vessel intracranial vascular occlusions.
Unknown Benefit of IV tPA in CRAO and Risk of Harm
Given that the basis for using IA tPA is to extend the short treatment window for IV tPA, we would expect to see some demonstrated benefit of IV tPA in patients with CRAO as we have with acute stroke. Part of the purported rationale for using IA tPA in acute stroke is the benefit of IV therapy but with a smaller dose locally delivered to the clot. A phase II, placebo-controlled, randomized trial of IV tPA in CRAO was conducted at multiple hospitals in Australia from 2008 to 2010, enrolling 16 patients (20). The trial found no difference in visual outcomes between the treated and placebo groups at 1 week, 1 month, 3 months, or 6 months. In addition, there was 1 serious adverse event, an intracranial hemorrhage in the tPA-treated group. The average time to treatment delivery was greater than 7 hours in both the groups. Data compiled by Biousse et al (21) in a systematic review of 35 case reports or case series in 2007 revealed a 13% complication rate, including 10 systemic or cerebral hemorrhages, in patients treated with IV tPA. Among those treated with intra-arterial tPA, the overall complication rate was similar, although the adverse outcomes included more ischemic events and fewer hemorrhages. The benefit of both IV and IA tPA in this review seemed to be better than previous natural history studies; however, the outcomes seem to be similar to those reported in the conservative arm of the EAGLE trial.
Rebuttal: Robert A. Egan, MD
I appreciate the cogent arguments put forth by my colleague Dr. Van Stavern. As both of us have stated there is a paucity of data regarding the usage of tPA in CRAO whether it is given intra-arterially or intravenously. I completely agree with her that the benefit of treatment of CRAO is time dependent and that complication rates will likely increase the longer the treatment window.
Another question is whether or not thrombolytics should be given to patients intravenously or intra-arterially. Intravenous therapy can be delivered quickly and safely. Intra-arterial therapy adds time to the treatment window, which is not in favor of clot lysis and beneficial treatment outcomes. Intra-arterial therapy also adds the complication rate associated with catheter manipulation of the extracranial and intracranial arteries.
The restrictions determining patient eligibility for treatment with thrombolytics are also too strict. These include head injury or stroke within 3 months, major surgery within the last 14 days, a history of intracranial hemorrhage, systolic blood pressure over 185 or diastolic blood pressure over 110, rapidly improving symptoms, seizure at onset of stroke, current usage of anticoagulants or prothrombin times greater than 15 seconds, platelet counts less than 100,000 per cubic millimeter, or abnormally high or low blood glucose (6). We must remember that the original criteria establishing the ideal patient to be treated in the NINDS stroke trial published in 1995 were established a priori without any clinical evidence. These likely outdated restrictions may lead to a great reduction in the number of potential patients who could be treated with this drug. This is actually known widely by stroke experts but has not been communicated to treating physicians at large. The most common criterion that is ignored is that of age and many patients are treated safely over the age of 80 now.
The most feared complication of thrombolytic treatment is symptomatic intracerebral hemorrhage (SICH). The criteria of the NINDS trial were established to attempt to reduce this complication. However, as more data are compiled regarding treating these patients, it has been found that patients with NIHSS scores of 7 or less, the equivalent of smaller strokes and smaller areas of potentially affected brain tissue, have a much lower SICH rate than in patients with higher NIHSS scores. In the patient with CRAO, it is presumed that these patients have an NIHSS of 0, which should indicate that they have a very low risk of SICH. Tong et al found that in his series of patients treated with NIHSS scores of ≤7, the rate of SICH was 0% and this has been observed before (Tong D, Barazangi N, Rose J, McDermott D, Grosvenor D, Bedenk A, Barakos J. Increasing rt-PA Use using Simplified criteria: the SMART study, personal communication, September 2014) (22–24).
Currently, I would dissuade against common usage of local IA therapy at this time, but believe that it should continue under stringent conditions. This is corroborated by Biousse et al (21). Given the devastating vision loss that occurs, especially in a monocular patient, we have the possibility of restoring vision. My recommendation is that IA therapy in CRAO should only be undertaken in a clinical trial setting or in centers using registries. These centers must have an interventional program that has demonstrated proven expertise with this form of treatment in stroke to help guarantee the lowest complication rates as well as develop a system to attract patients in a very expedited fashion to support intra-arterial therapy within a short time window. All patients should have a stat computed tomography of the head to rule out possible stroke as well as intracerebral hemorrhage. The patients should have a very low NIHSS preferably 0. I believe that dismissing further study of this therapy at this juncture given the poverty of cases reported in the literature would be shortsighted. It is hoped that continued study can determine whether this is a treatment that can benefit patients in the future and that we can also understand why some patients had SICH during treatment, which seems unexpected given data referenced above.
Rebuttal: Renee Van Stavern, MD
Dr. Egan and I agree that intra-arterial tPA should not be used routinely for CRAO, and I also agree with many of his points regarding circumstances when intra-arterial approaches might be considered. My continued concern is patient safety and the risk of intracranial hemorrhage in the trials I originally referenced, which I will emphasize here. Depending on the skill of the examiner, these patients should have National Institutes of Health Stroke Scale (NIHSS) scores of 0-1, 1 perhaps if an inexperienced examiner misinterpreted monocular vision loss to be a hemifield defect. If given IV tPA, patients in this category should have the lowest risk of symptomatic intracranial hemorrhages, about 2% based on a recent pooled analysis that included multiple subgroup studies of those with minor stroke (NIHSS score, 0–5) (22). The symptomatic intracranial hemorrhage rate was 4% in the EAGLE trial and 12.5% in the Australian randomized controlled trial of IV tPA. Although the complication rate in the EAGLE trial is encouraging, a symptomatic hemorrhage rate twice that of patients who have had a completed minor stroke is still troubling, especially considering that there was no difference in the visual outcomes in either trial.
Actively enrolling clinical trials of clot retriever devices may provide an opportunity to investigate this approach in the acute treatment of CRAO in the future. In addition, treating patients with CRAO earlier, less than 6 hours from the time they were last visually and neurologically normal for IA procedures or fewer than 4.5 hours for IV tPA, may demonstrate improved outcomes and minimize harm, as has been seen with IV tPA in acute stroke (23). If intra-arterial thrombolytic or interventional therapies are to be used for CRAO at this point, enrollment in clinical trials, participation in clinical registries, or monitoring outcomes through patient safety and quality improvement initiatives should be encouraged given the weakness of the evidence.
There is a natural bias toward wanting to treat any patient presenting with acute profound vision loss. There is ample evidence supporting the use of IV tPA for acute cerebral stroke, and it is tempting to try and extrapolate these data and apply them to acute CRAO. Our experts have done an excellent job reviewing the arguments for and against the use of IA tPA in acute CRAO. At this time, the use of IA (as well as possibly IV) tPA for acute CRAO should be considered only on a case-by-case basis (e.g., in a patient presenting with severe visual loss in the fellow eye), or as part of a randomized clinical trial. Including any treated patients in a registry, with assessment of clinical outcomes, might provide further evidence for or against treatment.
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