Narrative review of the management of macular edema due to retinal vein occlusion

Introduction

Background

The macula is the central part of the retina at the back of the eye that senses light, playing a crucial role in vision. Abnormalities in this region are directly related to vision loss. Recently, macular edema (ME), a notable macular disease, has gained prominence in ophthalmology. The advent of optical coherence tomography, which provides a tomographic image of the macula, has enabled a more detailed understanding of ME morphology (1-6). Vascular endothelial growth factor (VEGF) causes ME (7-9). Therefore, the mainstream treatment for ME involves intravitreal injection of anti-VEGF drugs to suppress VEGF (10,11). Despite numerous reported anti-VEGF treatments, injections have a temporary effect, typically requiring multiple administrations. Injection regimens comprise loading and maintenance periods, with the number of loading injections and maintenance dosing regimens varying in clinical practice across different reports. In large studies, a high number of loading injections is associated with favorable therapeutic effects; however, the overall number of injections remains substantial (12-15). Given the expense associated with intravitreal anti-VEGF injections and associated complications, including traumatic cataracts, endophthalmitis, and rhegmatogenous retinal detachment (16), achieving efficacy with as few injections as possible is desirable. In the pro re nata (PRN) regimen, patients are examined monthly during the maintenance period. Patients are re-injected if ME recurs beyond the re-injection criteria. The treat and extend (TAE) regimen is a proactive therapy in which the frequency of visits is adjusted depending on the presence or absence of ME recurrence, with additional injections necessitated at each visit.

Retinal vein occlusion (RVO) is the second most common retinal vascular disease after diabetic retinopathy (17,18). Approximately 0.5% of individuals over 30 years old have this condition, establishing it as a prevalent retinal disease (19). Clinically, ME arises from plasma leakage into the macula, resulting in visual impairment. If the obstruction occurs in the optic papillary segment, it is termed central RVO (CRVO), whereas obstruction at an arteriovenous crossing of the retina is termed branch RVO (BRVO) (Figure 1). Risk factors for RVO include hypertension, advanced age, and a high hematocrit level (20). Hypertension and age are associated with arterial stiffness, and RVO develops when the hardening of retinal arteries compresses adjacent retinal veins, causing turbulence. Hematocrit levels are related to dehydration; specifically, high hematocrit levels indicate dehydration, potentially increasing blood viscosity and leading to RVO. Studies on the relationship between RVO and seasonal variation suggest a higher incidence in winter and during periods of high humidity (21-23), providing convincing evidence regarding this risk factor.

Figure 1 Fundus photography and optical coherence tomography of retinal vein occlusion. (A) Fundus photograph of branch retinal vein occlusion. (B) Optical coherence tomography of macular edema due to branch retinal vein occlusion. (C) Fundus photograph of central retinal vein occlusion. (D) Optical coherence tomography of macular edema due to central retinal vein occlusion.

Rationale and knowledge gap

To date, no comprehensive narrative review exists on the treatment regimens for RVO-ME and factors influencing visual outcomes. This review will shed light on the administration regimens for RVO-ME and factors influencing visual outcomes, aiding clinicians in the treatment of RVO-ME.

Objective

This article aimed to provide more knowledge on the administration regimens for RVO-ME and the factors influencing visual outcomes. We present this article in accordance with the Narrative Review reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-23-237/rc).

Methods

This article provides a review of RVO, which can be categorized into two conditions (BRVO and CRVO), which will be reviewed separately. This review aimed to discuss the relevant literature that has investigated the optimal anti-VEGF treatment regimen for each disease (Table 1). A literature search was conducted in PubMed and Scopus using the search words “RVO anti-VEGF”, “BRVO anti-VEGF”, and “CRVO anti-VEGF”, yielding 1,305 [243+291 (RVO) + 163+196 (BRVO) + 193+219 (CRVO)] results. After considering the inclusion criteria, a total of 219 full texts were obtained. Following the title review, 138 studies were included. Subsequently, 100 studies were included after reviewing the abstracts. Finally, after a full-text review, 65 articles were included based on study quality. This review aimed to answer the following question: what is the optimal dosing regimen for BRVO and CRVO?

Number of induction injections

In the first comprehensive study of anti-VEGF therapy for RVO, patients with BRVO and CRVO received six induction injections (12-15). The BRAVO study investigated the efficacy and safety of intravitreal ranibizumab (Lucentis^Ò, Genentech, United States) injections in patients with ME associated with BRVO (12,13). Enrolled patients were assigned to three groups: those receiving ranibizumab (Lucentis^Ò, Genentech) 0.3, 0.5 mg, or sham injections, with a 12-month observation period. The mean change in the highest corrected visual acuity score from baseline was an increase of 18.3 and 7.3 letters in the ranibizumab (Lucentis^Ò, Genentech) 0.5 mg and sham injection groups, respectively. The least squares mean (95% confidence interval) for the difference between the ranibizumab (Lucentis^Ò, Genentech) 0.5 mg and sham injection groups was 10.6 letters (range, 7.6–13.6 letters), verifying the superiority of the ranibizumab (Lucentis^Ò, Genentech) 0.5 mg group over the sham injection group, with a significant increase in the best-corrected visual acuity score (P=1×10⁻⁴).

The Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion Study (CRUISE) trial examined the efficacy and safety of intravitreal ranibizumab injection in patients with ME associated with CRVO (14,15). Enrolled patients were randomized to receive 0.3, 0.5 mg, or a sham injection. The primary endpoints included the mean change in visual acuity from baseline, the percentage of patients with a 15-letter increase in visual acuity tests, and the percentage of patients with a decrease of 15 or more letters in visual acuity tests. Decreases in central fossa thickness and changes from the baseline were also measured. After 6 months, the 0.3 and 0.5 mg ranibizumab groups exhibited an average increase of 12.7 and 14.9 letters, respectively, compared with 0.8 letters in the sham group. In the 0.3 and 0.5 mg ranibizumab groups, 46.2% and 47.7% of patients had an increase of 15 letters, respectively. Moreover, compared with 16.9% of patients in the sham group, 47.7% in the 0.3 mg ranibizumab group achieved at least a 15-letter increase in best corrected visual acuity from baseline.

However, these findings are specific to early, large-scale studies. As described below, the number of injections during the induction phase in clinical studies has been reported to be fewer than that in large-scale studies.

Initially, studies on BRVO reported varying induction injection regimens, including one, three, and six injections (24-32). Sakanishi et al. and Shiono et al. reported one induction period (24-26), whereas others reported three induction injections (27-30). In Canada, the consensus is to administer three injections during the induction period (33), a practice commonly employed in clinical studies globally. However, a one-year prospective comparative study in Japan comparing one induction period with three induction periods revealed that the number of injections was 3.8±1.8 times and 4.6±1.4 times, respectively. Moreover, using logarithm of the minimum angle of resolution (logMAR), the visual acuity improvement was 20.245±0.227 and 20.287±0.222 for one and three induction periods, respectively. No significant differences were observed in the number of injections or improvement in visual acuity between the two induction periods (P=0.73, P=0.06) (34). Additionally, both counties reported significant visual acuity improvement in cases with good and poor vision. This report suggests that the treatment effect is similar whether the induction period involves one or three injections. Moreover, some physicians in Japan even report treating patients only once during the loading period (35).

In CRVO, the reported number of induction periods varies from one to five, with three being the most frequently reported (25,36-41). A study directly comparing one and three induction periods (42) observed no significant difference in the 12-month improvement in visual acuity (−0.172±0.372 for one induction period and −0.142±0.317 for three induction periods; P=0.77). However, the number of injections for one induction period (4.1±2.8) was significantly lower than that for three induction periods (5.9±2.1) (P=0.02). Furthermore, the study revealed that in CRVO, the number of injections during a one-injection induction period is equivalent to that during a three-injection induction period. This report further suggested that more frequent injections are associated with better visual acuity, indicating that patients with more frequent recurrences may have poorer retinal health and function. Based on these results, a single injection during the induction period should be sufficient; however, the prognosis for CRVO considerably differs between its ischemic and non-ischemic forms. Specifically, the ischemic type has a poor prognosis for visual acuity, especially in cases of macular ischemia (43). However, no significant differences were observed in visual acuity improvement between the ischemic and non-ischemic types (44), suggesting that treatment adjustments based on type may be unnecessary.

Regimens during maintenance periods and re-administration criteria

Maintenance regimens for RVO-ME include PRN, administered as needed, and the TAE regimen with an adjustable injection interval. TAE, originally found effective for anti-VEGF treatment in exudative age-related macular degeneration (45-47), has also demonstrated efficacy in BRVO (48), with a reported therapeutic effect equivalent to that of fixed administration after 12 months of treatment. Studies directly comparing PRN and TAE are limited; however, a meta-analysis comparing the two has been reported (49). The results revealed a higher number of injections over 12 months for TAE (7.48) compared to PRN (5.13) (P=2×10⁻⁴). However, the improvement in visual acuity over 12 months did not significantly differ, with ETDRS +14.74 letters for TAE and ETDRS +15.90 letters for PRN (P=0.5). Therefore, these results suggest that PRN, requiring fewer injections while maintaining an equivalent therapeutic effect to TAE, is preferable for RVO-ME.

In PRN, re-dosing criteria are important, focusing on two main criteria: visual acuity and central foveal retinal thickness. Several reports have used central foveal retinal thickness (specifically 250 or 300 µm) as a criterion for re-dosing (12-15,50). No report has compared the use of different central foveal retinal thickness thresholds as criteria for re-dosing. However, considering that the normal macula is 250 µm or less, and even a slight amount of ME is poorly tolerated and requires strict treatment, 250 µm should be considered as the criterion for re-dosing. However, 300 µm may be a better standard to employ, with some tolerance, since positive outcomes have been reported even at this threshold (26,51,52). Furthermore, nearly no studies have used a central foveal retinal thickness greater than 300 µm as a re-dosing criterion; nevertheless, 300 µm is generally considered the consensus. Regarding central fossa retinal thickness, some consider a 20% or greater increase in retinal thickness as the criterion rather than a specific absolute value. However, the complexity of this criterion reduces its practicality in clinical practice. Therefore, using absolute values as the criterion is preferred.

Conversely, some studies have suggested using decreased visual acuity in addition to central retinal thickness as a re-dosing criterion (29,50), a practice deemed unnecessary. This is because visual acuity loss can result from various causes, whereas visual acuity loss caused by ME is always accompanied by structural changes in the central fossa. In contrast, visual acuity loss alone, without edema, may be due to causes other than edema. Therefore, using only central foveal retinal thickness, excluding visual acuity loss, is preferable as the re-dosing criterion.

In summary, for BRVO and CRVO, a central foveal retinal thickness greater than 300 µm is recommended as the criterion for re-administration after a single PRN administration during the induction phase (Table 2).

Which patients have good visual prognoses?

In BRVO, Miwa et al. identified younger age, good visual acuity at baseline, and a thin central foveal retinal thickness at baseline as preoperative factors associated with a good visual prognosis (34). Sakanishi et al. similarly highlighted good visual acuity at baseline as a preoperative factor (25), suggesting that milder retinal damage at baseline may lead to a good prognosis. Additionally, since increased central retinal thickness correlates with intraocular VEGF concentration, a thin central retinal thickness suggests a low intraocular VEGF concentration, making the disease more responsive to anti-VEGF therapy and yielding a favorable treatment prognosis (53). Muraoka et al. also identified subcentral foveal hemorrhage at baseline as a poor prognostic factor for visual acuity (54), suggesting that subcentral foveal hemorrhage may damage the retinal pigment epithelium and photoreceptor cells, leading to a poor visual outcome. Thus, it is possible to predict visual prognosis to some extent at baseline.

In addition to these prognostic factors, Chatziralli et al. reported that the presence of intraretinal fluid and a lapse of more than three months after disease onset are poor prognostic factors for visual outcome (38). Intraretinal fluid, requiring passage through the outer limiting membrane for metabolism, can cause outer limiting membrane damage (55). Its presence may affect visual prognosis by causing disruption. Moreover, a prolonged period of over 3 months since disease onset suggests prolonged ME, which likely causes outer retinal damage. Data suggest a better prognosis when the time from onset to injection is shorter, as highlighted by several similar reports (56-58). The BVO study, one of the larger studies conducted in the 1980s, focused on BRVO cases between 3 and 18 months after onset. Previously, the only treatment for BRVO was retinal photocoagulation. As exemplified by this study, BRVO, which could be treated spontaneously, involved a three-month follow-up period, with treatment initiated only if there was no improvement after that period (59). However, with the advent of anti-VEGF therapy, as mentioned earlier, initiating treatment soon after disease onset leads to better treatment outcomes, rendering it unnecessary to delay treatment after onset. Sakanishi et al. previously reported that cases with a shorter time from onset to treatment required fewer injections in the second year of treatment than those with delayed treatment (26). Specifically, patients who required injections in the second year of treatment had a significantly longer time from disease onset to injection (3.9±2.1 months) than patients who did not (2.2±1.5 months; P=0.03). In other words, patients who received injections within approximately 3 months of onset were less likely to require injections in the second year. One possible reason is that retinal arteriolar aneurysms develop in BRVO 3 months after onset (60). Animal studies have demonstrated that retinal arteriolar aneurysms form when the concentration of intraocular VEGF increases (61). Therefore, the intraocular VEGF concentration remains elevated throughout the natural course of the disease, causing intractable ME due to retinal microaneurysms. The usefulness of early injections is underscored, as early initiation of anti-VEGF therapy from disease onset leads to a better visual prognosis and minimizes the need for long-term injections.

In CRVO, macular ischemia has been identified as a poor prognostic factor for visual outcomes (43). Similarly, Hasegawa et al. reported that macular ischemia is associated with visual outcomes and the number of injections (62). Essentially, this means that a decrease in vascular density corresponds with a decrease in macular vascular density. In other words, decreased vascular density indicates a decrease in the number of vessels causing ME, which potentially reduces the recurrence of ME and the number of injections. In light of these facts, whether macular ischemia is detrimental or not is uncertain; although it may negatively affect vision, the number of injections required may also be reduced.

Strengths and limitations

The strength of this review lies in that it provides an overview of all anti-VEGF treatment regimens for RVO that have been reported to date. Although direct comparisons between regimens might be impossible owing to varied reporting, the review provides a comparison of the number of induction injections (one vs. three injections) that can be used as a reference. This section synthesizes information from several reports and includes the author’s perspective.

One limitation of the review is the evolving landscape of anti-VEGF drugs. Although bevacizumab was previously used off-label for RVO (63), ranibizumab (Lucentis^Ò, Genentech) and aflibercept (Eylea^Ò, Bayer, Germany) are the only anti-VEGF drugs currently covered by insurance. Other drugs will be covered by insurance for RVO treatment in the future, necessitating careful consideration of injection regimens tailored to each specific drug type. Additionally, the availability of these drugs differs across countries. Many reports indicate equivalent efficacy between ranibizumab (Lucentis^Ò, Genentech) and aflibercept (Eylea^Ò, Bayer) for RVO (50,64,65), and either drug may represent a good treatment option.

Conclusions

Previous studies have re-evaluated the treatment regimen for RVO-ME using intravitreal injections of anti-VEGF drugs and recommended a single PRN dose during the induction phase for BRVO and CRVO, with a central foveal retinal thickness greater than 300 µm as the re-dosing criterion. Furthermore, a shorter time interval between onset, and the initial injection is associated with better outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-23-237/rc

Peer Review File: Available at https://amj.amegroups.com/article/view/10.21037/amj-23-237/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-23-237/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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