Intra-arterial Thrombolysis for Acute Retinal Ischemia: A Retrospective, Observational, Cohort Study

To determine whether intra-arterial thrombolysis (IAT) within 16 hours after the onset of symptoms is feasible and associated with better visual outcomes in patients with acute retinal ischemia (ARI).

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Intra-arterial Thrombolysis for Acute Retinal Ischemia: A Retrospective, Observational, Cohort Study Yuan Gao, MD, Wenbo Zhao, MD, Di Wu, PhD, Wayne Feng, MD, Brian Mac Grory, MD, Wenting Guo, MD, Dawei Zhang, MD, Xinjie Su, MD, Xunming Ji, MD, PhD, Xuxiang Zhang, MD, PhD Background: To determine whether intra-arterial thrombolysis (IAT) within 16 hours after the onset of symptoms is feasible and associated with better visual outcomes in patients with acute retinal ischemia (ARI). Methods: The retrospective cohort study was performed from January 2014 to December 2021 in the Xuanwu Hospital of Capital Medical University. Patients with ARI who initially presented visual acuity of 20/100 or worse were screened in the study. Visual end points were evaluated at one week and at final visit after treatment. Serious adverse events were recorded during operation and within 1 week after IAT treatment. Results: The amount of clinically significant visual improvement ($0.3 logarithm of the minimum angle of resolution) in the IAT group was significantly higher than that in the conservative treatment group at one week after the treatment (47.8% vs 16.7%; P = 0.014) and at final visit (52.2% vs 20%; P = 0.014). After controlling confounding factors, ARI treatment was the only factor significantly associated with the amount of clinically significant visual improvement (OR, 4.364; 95 CI, 1.298–14.667; P = 0.017). A patient (4.3%) experienced retinal hemorrhage without symptom Department of Biomedical Engineering, School of Biological Science and Medical Engineering (YG, XJ), Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing, China; Department of Neurology (WF, BG), Duke University Medical Center, Durham, North Carolina; Departments of Ophthalmology (YG, XZ), Neurology (WZ, WG, XJ), Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine (WZ), ChinaAmerica Institute of Neuroscience (DW), Xuanwu Hospital, Capital Medical University, Beijing, China; Beijing Institute for Brain Disorders (WZ, XJ), Capital Medical University, Beijing, China; and Department of Ophthalmology (DZ, XS), Beijing Luhe Hospital, Capital Medical University, Beijing, China. The authors report no conflicts of interest. Supported by the General Project of National Natural Science Foundation of China (No. 82071312), Beijing Municipal Science and Technology Commission, Capital Clinical Characteristics Application Research Special General Topic (No. Z171100001017029), Beijing Nova Program (No. Z201100006820143), National Natural Science Foundation of China (No. 82001257 and 82027802). Address correspondence to Xuxiang Zhang, MD, PhD, Department of Ophthalmology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; E-mail: [e-mail] 202 within 1 week after IAT treatment. No patients experienced new symptomatic cerebral infarction, intracranial hemorrhage, TIA, artery dissection, vascular perforation, and distal embolization during operation and within 1 week after IAT treatment. Conclusions: IAT may be associated with better visual improvement within 16 hours after the onset of symptoms. Besides, IAT is feasible and associated with a low risk of periprocedural complications for ARI. This study will aid in feasibility testing and sample size calculations in advance of future, fully-powered efficacy studies for ARI. Journal of Neuro-Ophthalmology 2023;43:202–208 doi: 10.1097/WNO.0000000000001710 © 2022 by North American Neuro-Ophthalmology Society A cute retinal ischemia (ARI) is an ophthalmologic emergency caused by the occlusion of the central retinal artery (CRAO), branch retinal arterioles, or ophthalmic artery occlusion and is associated with a devastating visual outcome (1). There is no level 1 evidence to inform any emergency treatments for ARI (2,3). Currently, intravenous and intra-arterial thrombolysis (IAT) are considered as the most promising therapies for the treatment of ARI. However, intravenous thrombolysis (IV-tPA) is associated with a risk of intracranial and systemic hemorrhage and a low rate of arterial recanalization (4). Infusion of a thrombolytic agent into the ophthalmic and retinal circulations (“intraarterial thrombolysis”), may avoid the adverse effects of systemic administration. However, it had mostly been tested at later time points, and thus, its efficacy is questioned. Therefore, further studies evaluating the effects of IAT for ARI are needed. Recently, endovascular thrombectomy has been currently recommended for eligible patients with stroke who are treated within 16 hours after the onset of symptoms (5,6). The American Stroke Association and American Heart Association regard ARI as the equivalent of acute cerebral ischemia because they share the same risk factors Gao et al: J Neuro-Ophthalmol 2023; 43: 202-208 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution and etiologies (7). By consulting the experience in endovascular treatment of stroke in this study of patients with ARI, we aimed to describe our institutional experience with IATurokinase within 16 hours after the onset of symptoms, assess the feasibility of this condition, and obtain pilot data on efficacy end points. METHODS Study Design and Participants The retrospective cohort study was performed from January 2014 to December 2021, which was based on a prospective registry study in the Xuanwu Stroke Center. Consecutive patients who presented with acute, painless, monocular vision loss (20/100 or less) and diagnosed with ARI were eligibly screened in this study. Patients were excluded if their symptoms were caused by iatrogenic procedure, loss data of initial visual acuity, transient monocular vision loss with spontaneous improvement in vision, time from symptoms onset to IAT .16 hours, treated with hyperbaric oxygen, branch retinal arterioles, and combined with RVO. Patients with ARI enrolled in the study were divided into 2 groups according to whether they had received IAT. Conservative treatment including ocular massage (repeated manual compression for 10–15 seconds followed by sudden release), IOP-lowering agents, microcirculation improvement, or antiplatelet aggregation (8,9).We conducted the study in accordance with the Declaration of Helsinki and performed after the approval of the Ethics Committee of the Xuanwu Hospital, Capital Medical University (Approval Number 2017030). Preinterventional Workup and Endovascular Procedures The ophthalmic emergency department in the Xuanwu Hospital was responsible for screening of potential patients with ARI. An ophthalmologist obtained a medical history in detail, determined the time of symptom onset, and assessed the best-corrected visual acuity (BCVA), intraocular pressure, slit-lamp biomicroscopy, fundus camera, and fundus fluorescein angiography examination for patients. For patients who were suspected of acute ARI and consent to IAT therapy, head CT and serological laboratory tests were performed to evaluate whether the patient was eligible for thrombolytic treatment. According to the local catheter laboratory regulations, interventionists, who has been practicing interventional neuroradiology for more than 5 years and able to perform extracranial and intracranial stents proficiently, were qualified to perform endovascular treatment for patients with ARI. Local anesthesia was used, and all procedures were performed using a transfemoral approach. During IAT procedures, a superselective microcatheter was placed in the proximal segment of the ophthalmic artery, and then, urokinase was infused at a Gao et al: J Neuro-Ophthalmol 2023; 43: 202-208 rate of 10,000 IU/min. The total dose of urokinase ranged from 250,000 to 750,000 IU (median dose, 407,000 IU) depending on visual acuity improvement and the recanalization status of the occluded artery evaluated by digital subtraction angiography (10). During the IAT procedures, the type and size of microcatheter and other necessary devices were left to the discretion of the interventionists. After surgery, head CT were performed again to assess cerebral infarction or hemorrhage within 1 week. Antiplatelet aggregation medication (aspirin 300 mg/day for 2 weeks, then aspirin 100 mg/day for longer) began the second day after the procedure. Data Collection The following demographic and clinical variables of patients from the electronic medical record were used for this study: age, gender, the affected eye, concurrent diseases including hypertension, diabetes mellitus, hyperlipidemia, coronary heart diseases, ischemic or hemorrhagic stroke, transient ischemic attack, peripheral vascular disease, atrial fibrillation, valvular heart disease, smoking, alcohol use, time from symptom onset to IAT, dosage of urokinase, BCVA, and adverse events. Follow-ups were conducted by telephone interviews with patients or their relatives. End points The primary end point was the percentages of clinically significant visual improvement of the BCVA at 1 week and final visit after IAT treatment. Clinically significant visual improvement was defined as an improvement of 0.3 on the logarithm of the minimum angle of resolution (logMAR) scale (8). The secondary end points included serious adverse events associated with the procedures defined as one of those events (new symptomatic cerebral infarction, intracranial hemorrhage, artery dissection, vascular perforation, distal embolization, and retinal hemorrhage). Statistical Analysis Data were described as mean ± SD, median and interquartile range, or frequency counts and percent. Best-corrected visual acuity (BCVA) was measured using a Snellen chart at 6 m and converted into the logMAR for statistical analysis. No light perception, light perception, hand motion, and count fingers vision were approximated by logMAR values of 3.0, 2.7, 2.28, and 1.85, respectively (11). The Mann– Whitney U test or Student t-test was used to compare means of continuous variables, which conform to normality (determined by the Shapiro–Wilk test). Dichotomous data were analyzed using the x 2 test or Fisher exact text. The Wilcoxon test was used for the analysis of different periods. Binary logistic regression analysis was performed with the forward LR (forward stepwise regression based on maximum likelihood estimation). The amount of clinically significant visual improvement at final visit was selected as the 203 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. The study flow chart. ARI, acute retinal ischemia; BRAO, branch retinal artery occlusion; CRVO, central retinal vein occlusion; IAT, intra-arterial thrombolysis. TABLE 1. Baseline characteristics At baseline Age, mean (SD), years Male, n (%) Right eyes, n (%) Concurrent diseases Hypertension, n (%) Diabetes mellitus, n (%) Hyperlipidemia, n (%) Coronary heart disease, n (%) Ischemic or hemorrhagic stroke, n (%) Peripheral vascular disease, n (%) TIA, n (%) Atrial fibrillation, AF, n (%) Valvular heart disease, n (%) Smoking, n (%) Alcohol use, n (%) Time from symptoms onset to admission, mean (SD), h Time from symptoms onset to IAT, mean (SD), h Urokinase dose, median (IQR) Follow-up time Lost to follow-up, n (%) All (N = 53) IAT Group (N = 23) Conservative Treatment group (N = 30) P 60.5 (13.6) 42 (79.2) 22 (41.5) 54.7 (14.4) 15 (65.2) 11 (47.8) 64.1 (8.8) 27 (90) 11 (36.7) 0.001* 0.062 0.414 30 (56.6) 11 (20.8) 10 (18.9) 11 (20.8) 15 (28.3) 7 (13.2) 3 (5.7) 2 (3.8) 1 (1.9) 15 (28.3) 14 (26.4) — 13 (56.5) 1 (4.3) 3 (13) 2 (8.7) 3 (13) 0 0 0 0 1 (4.3) 1 (4.3) 7.5 (4) 17 (56.7) 10 (33.3) 7 (23.3) 9 (30) 12 (40) 7 (23.3) 3 (10) 2 (6.7) 1 (3.3) 14 (46.7) 13 (43.3) — 0.992 0.025* 0.552 0.120 0.064 0.015* 0.249 0.499 1 0.002* 0.004* — — 9.2 (4.1) — — — 26.6 (18.1) 2 (3.8) 40.7 (25–50)† 22.5 (13.8) 1 (4.3) NA 29.5 (20.4) 1 (3.3) — 0.162 0.147 * These variables with statistically significant differences (p,0.05). There were 2 patients who loss the data of the dose of urokinase. NA, not applicable, IQR, interquartile range; IAT, intra-arterial thrombolysis; TIA, transient ischemic attacks. † 204 Gao et al: J Neuro-Ophthalmol 2023; 43: 202-208 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution dependent variable, and variables with statistically significant differences (P , 0.05) at baseline or possible visual prognosis associated factors between the 2 groups were selected as covariables. The missing value of baseline characteristics was filled by mean value in our study. The missing value of final visit BCVA was imputed from the one-week BCVA values by the last-observation-carriedforward principle. A sensitivity analysis will be performed by comparing results from analysis data sets without and with missing data imputation. Significance level was set to a = 0.05. All tests were 2 sided. Statistical analyses were conducted using SPSS, version 25.0 (IBM Corporation). Data Availability Data related to the current article are available from the corresponding author on reasonable request. RESULTS Demographic Characteristics During the study period, 53 patients with ARI (age 60.5 ± 13.6 years) were included in the final analysis including 23 patients treated with IAT within 16 hours after the onset of symptoms and 30 patients treated with conservative treatment (Fig. 1). The baseline demographic characteristics are summarized in Table 1. The significant differences in the majority of demographic data between IAT (n = 23) and conservative treatment group (n = 30) were not found, except for age, diabetes mellitus, peripheral vascular disease, smoking, and alcohol use (P , 0.05, each). Patients in the IAT group were younger than the conservative treatment group (P = 0.001). The median dose of urokinase used during the IAT procedures was 407,000 IU (interquartile range: 25.0–50.0). The mean time from symptoms onset to IAT was 9.2 hours. The mean follow-up time was 22.5 months in the IAT group and 29.5 months in the conservative treatment group, respectively. At last, 1 of 23 patients lost to follow-up in the IAT group, and 1 of 30 patients lost to follow-up in the conservative treatment group. Two patients in IAT group had loss data of the dose of urokinase. In the sensitivity analysis, the results were consistent after excluding or including missing data imputation. Typical clinical cases with ARI are shown in Figure 2A. Visual End points At the initial visit, the percentage of eyes with equal to light perception or less were not significantly different between the IAT and conservative treatment groups (52.2% vs 40%; P = 0.378). The mean BCVA values at the initial visit, 1 week after the treatment, and final visit were not significantly different between the IAT and conservative treatment groups (P . 0.05, each). At 1 week after the treatment, compared with the baseline BCVA, visual improvement was observed in the IAT group (P = 0.027), whereas there was Gao et al: J Neuro-Ophthalmol 2023; 43: 202-208 FIG. 2. Typical clinical cases with fundus photographs and fluorescein angiographs at the time of pre-IAT and post-IAT within 1 week. A. Compared with pre-IAT, retinal edema in macular region was significantly reduced (black arrowheads); the arm–retinal circulation time (ARCT) at post-IAT (12.18 s) was shorter than that at post-IAT (38.43 s). In the 30 s of fluorescein angiographs, retinal blood perfusion was significantly improved at post-IAT. B. Fundus photograph of post-IAT showed that there was retinal hemorrhagic foci near the optic disc (black arrow); the visual acuity was NLP at pre-IAT treatment and improved to HM at post-IAT. IAT, intra-arterial thrombolysis; NLP, no light perception; HM, hand movement. no improvement in the conservative treatment group (P = 0.089). At the final visit, visual improvement was observed in both the groups (P , 0.05, each). The amount of 205 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Visual end points BCVA of LP or less (at first evaluation), n (%) BCVA, median (IQR) Baseline logMAR One week after treatment, logMAR P The final visual acuity, logMAR P Clinically significant visual improvement at 1 week, n (%) Clinically significant visual improvement at final visit, n (%) IAT Group (N = 23) Conservative Treatment Group (N = 30) P 12 (52.2) 12 (40) 0.378 2.7(2.3–3) 2.3 (1.9–2.7) 0.027* 2.3 (1.9–2.7) 0.025* 11 (47.8) 12 (52.2) 2.3(1.9–2.7) 2.3 (1.9–2.7) 0.089 2.3 (1.9–2.7) 0.041* 5 (16.7) 6 (20) 0.206 0.775 — 0.805 — 0.014* 0.014* IQR, interquartile range; LP, light perception; BCVA, best-corrected visual acuity. clinically significant visual improvement ($0.3 logMAR) in the IAT group was significantly higher than that in the conservative treatment group at one week after the treatment (47.8% vs 16.7%; P = 0.014) and final visit (52.2% vs 20%; P = 0.014) (Table 2). In the sensitivity analysis, the results were consistent after excluding or including 2 participants who lost follow-up. acuity was no light perception at pre-IAT treatment and improved to hand movement at post-IAT, which suggest that the small hemorrhagic foci near the optic did not aggravate visual impairment (Fig. 2B). No patients experienced new symptomatic cerebral infarction, intracranial hemorrhage, artery dissection, vascular perforation, or distal embolization. Factors Associated With Visual End points DISCUSSION The binary logistic regression analysis was performed to assess the relationship between the visual end points at the final visit and its possible associated factors or statistically significant differences (P , 0.05) between the 2 groups at baseline (e.g., age, sex, the affected eyes, treatment, initial BCVA, the number of LP or less at first evaluation, diabetes mellitus, peripheral vascular disease, smoking, alcohol use). Treatment were the only factor significantly associated with the amount of clinically significant visual improvement (OR, 4.364; 95 CI, 1.298–14.667; P = 0.017) after multivariate adjustment. Serious Adverse Events The serious adverse events during operation and within 1 week in the IAT group are summarized in Table 3. There is a patient (4.3%) who experienced retinal hemorrhage without symptom within 1 week after IAT treatment. The visual In this study, we found that the percentage of clinically significant visual improvement in the IAT group was higher than that in the conservative treatment group within 16 hours after the onset of symptoms, which indicated that ARI patients treated with IAT urokinase may have better visual improvement than those treated with conservative therapy. After controlling confounding factors, treatment was the only factor significantly associated with the amount of clinically significant visual improvement. In addition, in this study, no patients experienced serious adverse events, including new symptomatic cerebral infarction, intracranial hemorrhage, artery dissection, vascular perforation, and distal embolization except for 1 patient who experienced retinal hemorrhage without symptom within 1 week after IAT treatment. Thus, we believed that IAT seems to be feasible and associated with a low risk of periprocedural complications for ARI. TABLE 3. Serious adverse events in IAT group (N = 23) New symptomatic cerebral infarction, n (%) Asymptomatic intracranial hemorrhage, n (%) Symptomatic intracranial hemorrhage, n (%) TIA n (%) Artery dissection, n (%) Vascular perforation, n (%) Distal embolization, n (%) Retinal hemorrhage, n (%) During Operation Within One week 0 0 0 0 0 0 0 — 0 0 0 0 — — — 1 (4.3) IAT, intra-arterial thrombolysis; TIA, transient ischemic attacks, 206 Gao et al: J Neuro-Ophthalmol 2023; 43: 202-208 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Hayreh believed that “treatment instituted more than 4 hours, or even days, after the onset of CRAO cannot claim any scientific rationale for improvement of vision, unless retinal circulation has returned to normal within 4 hours” (12). However, the conclusion was based on nonhuman primate experiments rather than clinical trials in humans. Besides, retinal artery occlusion may be incomplete, and return of vision may be achieved even after delays of 8 to 24 hours in the clinical setting (13). Hence, there is no consistent conclusion on the tolerance time of retinal ischemia in humans, which need further study. In our previous study and other respective case series and cohort studies, it was concluded that IAT could improve visual function in patients with acute CRAO within 6 hours of symptom onset (9,14–16). This study further confirmed that IAT may partially improve visual acuity within 16 h of symptom onset, which may be associated with incomplete ARI having a certain percentage. Certainly, our conclusions need a multicenter, randomized, controlled clinical trial for further verification. In addition, there are large evidences that neuroprotectant may be protective when the reperfusion is achieved, for example, NA1 study (17). For better visual improvement, we may attempt to implement a multicenter, randomized, controlled clinical trial to further observe the efficacy of IAT combine with neuroprotection for ARI at early time points in future. The results of major adverse events were similar with the study of S.J. Ahn, which showed that no symptomatic intracranial hemorrhage happened after IAT treatment (10). However, the results of this study were inconsistent with the randomized prospective cohort study (EAGLE trial), in which 2 patients had serious adverse reactions in the local intra-arterial fibrinolysis group, including cerebral (n = 1) and cerebellar (n = 1) hemorrhage with paresis within the first 24 hours after treatment (8). These discrepancies may be attributable to several reasons. First, different inclusion criteria (the patients’ age was 54.7 ± 14.4 in the IAT group of our study, whereas it was 63 ± 10 in the local intra-arterial fibrinolysis of EAGLE trial). Second, different exclusion criteria (patients with intracranial hemorrhage history were excluded in our study, whereas patients with intracerebral bleeding or surgery within the past 4 weeks were excluded in the EAGLE trial). In addition, the different fibrinolytic drugs (recombinant tissue plasminogen activator was used in the EAGLE trial and urokinase was used this study) might influence the risk of hemorrhage. Although IAT has risks of arterial dissection and distal embolization, none of these severe adverse events occur in this study subjects. In general, our study demonstrated that IAT appears to be safe in patients with ARI without increasing the risk of symptomatic or asymptomatic intracranial hemorrhage. Intravenous recombinant tissue plasminogen activator thrombolysis is the gold standard treatment for acute cerebral stroke within 4.5 hours of onset, which also been considered Gao et al: J Neuro-Ophthalmol 2023; 43: 202-208 for nonarteritis CRAO treatment (2). However, it is a common occurrence about taking so long time from the symptoms of onset to hospital visit and treatment that few patients can be treated with intravenous rt-PA thrombolysis within 4.5 hours. Thus, its application is limited. Conversely, IAT may prolong the treatment window and has the ability to directly offer a smaller dose fibrinolytic drug locally to the occluding clot (18). Thus, IAT may have lower risk of systemic hemorrhage than IVT due to the advantages mentioned above. Therefore, we recommend that patients with ARI should be treated with IAT within 16 hours of onset of symptoms if no contraindications to IAT. A limitation of our study was a small size sample, single center, nonrandomized, respective cohort study. Thus, our conclusion needs multicenter, randomized, controlled clinical trial for verification in future. In conclusion, IAT may be associated with better vision improvement as compared with conservative management within 16 hours of symptom onset, and it appears to be safe for the treatment of ARI; however, due to the nature of observational study, a formal assessment regarding the efficacy and safety of IAT as compared with conservative treatment through a randomized clinical trial should still be considered. 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