In this study, we compared the therapeutic effects and safety of anti-VEGF monotherapy (RBZ) and combination therapy (RBZ + intravitreal DEX implant) in the treatment of RVO-ME. The pathogenesis of RVO-ME is highly complex and is believed to involve VEGF and inflammatory mechanisms [19–21]. Currently, most patients with RVO-ME are treated with monotherapy in clinical practice. Both intravitreal anti-VEGF injections and intravitreal corticosteroid injections have demonstrated effectiveness and limitations in the treatment of RVO-ME [22, 23]. Therefore, we devised a combination therapy approach based on pharmacological mechanisms, with the aim of reducing the VEGF concentration in the vitreous while inhibiting the production of various pro-inflammatory cytokines. This approach enables more comprehensive targeting of factors leading to the development of ME. Our results revealed that compared with anti-VEGF monotherapy (RBZ), combination therapy resulted in a sustained and rapid improvement in BCVA, which significantly prolonged the time to re-injection to 4–7 months.
Maturi et al. [24] compared the effects of bevacizumab (BEV) + DEX combination therapy with those of BEV alone in patients with early stage RVO-ME. Patients receiving combination therapy underwent implantation of DEX 1 week after intravitreal anti-VEGF injection. In that study, combination therapy did not lead to greater improvement in VA compared with that with anti-VEGF monotherapy. However, BEV + DEX resulted in greater improvement in macular thickness, which is contrary to our findings. This is likely attributed to differences in study design and the relatively short follow-up period of 6 months in the aforementioned study. Our study had a follow-up duration of 12 months, and participants regularly underwent FFA based on the results of fundus examinations. During the study period, supplementary treatment with retinal laser photocoagulation was additionally performed on non-perfused retinal areas indicated by FFA, in accordance with the 2019 Guidelines for the Management of RVO by the European Society of Retina Specialists (EURETINA). The supplementary treatment aimed to reduce hypoxia in the retinal lesion area and retinal vascular leakage, to maintain the anatomical structure of the macular region as far as possible. In the long term, timely supplementation of laser photocoagulation in the retinal lesion area can reduce the incidence of major complications such as vitreous hemorrhage and neovascular glaucoma. Singer et al. [25] reported that BEV and DEX exerted a synergistic effect, leading to VA improvement and prolongation of the interval between injections. Another study by the same author [26] demonstrated that combined anti-VEGF and DEX therapy provided significant VA/anatomical benefits that lasted up to 2 years. Unlike the two aforementioned studies, we established a RBZ monotherapy group as the control group to enhance the study design. Although BCVA improved in both groups at the study endpoint, the rate of VA improvement in the RBZ + DEX group was significantly higher than that in the RBZ group. Furthermore, VA variability over time was lesser in the RBZ + DEX group, suggesting that combination therapy resulted in rapid restoration and better stability of VA during the middle to late stages of treatment. Therefore, the VA-improving effect was more pronounced with combination therapy than with RBZ alone. This was mainly attributed to the reduction or disappearance of intraocular VEGF after anti-VEGF treatment. Moreover, DEX exerted a sustained, slow-release anti-inflammatory effect. The dual action of anti-VEGF and DEX led to normalization of the intraocular microenvironment, which resulted in better and sustained maintenance of BCVA and ultimately improved the visual quality.
In this study, combination therapy significantly improved CMT. This is consistent with the findings of Singer et al. and Nagpal et al. that the initiation of combination therapy reduced the number of injections and burden of treatment while providing visual and anatomical benefits to patients [26, 27]. However, comparison with anti-VEGF monotherapy was not performed in the aforementioned studies, which limited the comparability of research results. In contrast, an anti-VEGF monotherapy group was established as control in the present study. Our results indicated that RBZ + DEX did not provide a significant advantage over RBZ for the improvement of macular anatomical structure. This may be related to the immediate and multiple re-injections administered to the RBZ group upon ME recurrence and rapid onset of therapeutic action, which led to a lack of differences between the two groups at different timepoints. Although the two groups did not exhibit significant differences in CMT, therapeutic effects were sustained for a shorter duration in the RBZ group, as indicated by the recurrence of ME at 3 months after treatment. In contrast, combination therapy with RBZ + DEX was effective with sustained slow drug release, and CMT continued to decrease 3 months after treatment with a reduction of 307.48 ± 19.42 µm compared to that at baseline. At the study endpoint, the RBZ + DEX group exhibited lower variability in CMT and consistently lower CMT values compared with the RBZ group. This result suggests that RBZ + DEX attenuated the repeated development and resolution of ME and reduced visual cell damage compared to that with RBZ alone. In the long term, it can assist in maintaining CMT within a certain range and reduce visual damage caused by excessive and recurrent edema. Studies comparing combination therapy with anti-VEGF monotherapy are limited. A study that compared combination therapy with DEX monotherapy [28] reported that combination therapy provided a synergistic effect and was superior to DEX implant monotherapy for the improvement of VA and CMT. Results of a meta-analysis [29] revealed that combined anti-VEGF and steroid therapy improved BCVA and CMT, reduced the risk of IOP elevation, enhanced patient prognosis, prolonged the average time to anti-VEGF re-injection, and reduced the number of injections during the follow-up period compared with anti-VEGF or steroid monotherapy. In contrast, another study that adopted the ranibizumab and Ozurdex with laser photocoagulation (RandOL) protocol for RVO-ME treatment [30] reported that similar favorable anatomical and visual outcomes were obtained with the combination therapy regimen and monotherapy after one year of treatment. The frequency of intravitreal re-treatment during the first year was also lower.
In the present study, RBZ + DEX significantly prolonged the average time to re-injection (151 days). This is similar to the interval reported by Singer et al. [26] (135.5 days), who also demonstrated that anti-VEGF combined with Ozurdex reduced the burden of injection and enabled the maintenance of a stable interval between injections (4–5 months) during a 2-year treatment period. Iu et al. [28] reported that sequential therapy with RBZ and intravitreal DEX implant was superior to DEX monotherapy for the treatment of RVO-ME. Combination therapy enabled rapid disease control, and the effect of two injections could be sustained for 4–7 months (i.e., 1 month after RBZ injection and 3–6 months after intravitreal DEX implant injection). Our results also showed that compared with patients administered anti-VEGF monotherapy, those receiving combination therapy required fewer injections and experienced fewer ME recurrences. Fewer intravitreal injections lead to a reduction in patient expenses, which in turn reduces the economic burden on patients. Moreover, the overall health-insurance spending for these patients is reduced, leading to considerable savings in healthcare funds. The DEX implant used in the RBZ + DEX group is a long-acting, sustained-release formulation that provides the advantages of uniform and controlled release, long duration of action, and long interval between injections. These characteristics are favorable for maintaining macular stability and avoiding repeated fluctuations that may damage anatomical structures. Compared with the RBZ group, the RBZ + DEX group had more patients with stable disease. During the follow-up period, 4 participants in the RBZ + DEX group had stable disease and did not require re-treatment. In contrast, only one participant in the RBZ group had stable disease.
Complications during treatment occurred in both groups, with IOP elevation and cataract being the most common complications. The higher incidence of cataract in the RBZ group may be related to frequent intravitreal injections. Cataract surgery was performed in 1 of the 4 patients in the RBZ group who developed cataract. The incidence of ocular hypertension was higher in the RBZ + DEX group, which was likely caused by corticosteroid use. IOP elevation was especially pronounced at 2–3 months of medication use, but the degree of IOP elevation generally ranged from mild to moderate. All patients achieved effective IOP control with one or two types of ocular hypotensive agents and did not require surgical intervention for glaucoma. During subsequent re-treatment, the incidence of IOP elevation in the RBZ + DEX group was lower compared with that in the earlier treatment stage, which is consistent with the results reported by Singer et al. [26]. Patients in both groups did not experience severe ocular adverse reactions such as vitreous hemorrhage, retinal detachment, and intraocular inflammation, or cardiovascular accidents during the treatment process. This indicates that both anti-VEGF monotherapy and combined anti-VEGF and sustained-release anti-inflammatory DEX therapy had good safety profiles in the treatment of RVO-ME.
In this study, we adhered to the principles of randomization and control to the best of our ability. However, certain limitations and inadequacies exist in the study due to the limited sample size, short follow-up duration, and relatively high loss to follow-up rate. Therefore, future large-scale, multicenter randomized controlled studies are required for validation of our findings.