Over recent years, the therapy combining anti-VEGF and Ozurdex® against retinal vein occlusion with macular edema has received increasing attention from ophthalmologists. However, there are still few related studies on combined therapy and a lack of multi-center randomized controlled trials to guide clinical treatment on the interval of reinjection, the number of injections per year, etc. This study aimed to conduct preliminary discussions on these clinical cases.
In 2019, the European Society of Retina Specialists (EURETINA) recommended that the injection interval of Ozurdex® monotherapy should be 3~4 months, with an annual average of 2-3 injections . In this study, the average reinjection interval of the combined therapy (IVR+DEX) was 134 days, which was similar to Singer et al  study. They first used anti-VEGF injection for 2 weeks and then combined DEX to treat 62 RVO-ME patients, who were followed up for 2 years; the reinjection time was 135 days. In a 3-year follow-up study, the average interval between reinjections of DEX was 4.8 months . A 4-5 month interval between reinjections was significantly more beneficial than anti-VEGF monotherapy. These results also provide the basis for clinical re-treatment time (about 4.5 months). Patients may not need monthly monitoring, and they only receive injections before re-edema to ensure that visual and anatomical treatment goals are maintained, which in turn contributes to better compliance.
In this study, we counted the number of injections instead of the times of injections, which was to be convenient for patients to compare the costs of anti-VEGF monotherapy and combination therapy. In order to maintain the best improvement in visual acuity, RVO-ME patients received 8.2-11.8 injections of anti-VEGF per year [11,16], while the average injection of DEX was only 2-3 injections per year . Adopting the combination therapy, patients just received an average of 4.2 injections (range 2 to 6 injections) per year, and 65.8% of the patients only received 4 injections per year to maintain good vision improvement and anatomical reduction. Accordingly, combined therapy reduced the number of injections and hospitalization, thus also reducing the financial burden of patients and medical institutions.
At the end of the follow-up, 52.6% of patients had improved visual acuity by more than 3 lines, which was similar to the results Singer et al . These results were also similar to those of ranibizumab monotherapy (BRVO 60% vs. CRVO 48%~51%) [17-18], which indicated that the combination of anti-VEGF and DEX treatment enhanced the efficacy of anti-VEGF monotherapy but also required a 4-5 month re-treatment interval. These two drugs complemented each other's strengths. Ranibizumab monotherapy resulted in a mean improvement in CFT of 345–452 μm [17-18]. Compared with the baseline, the CFT of RVO-ME in Chinese treated with DEX improved by 407 μm . In this study, the CFT decreased by an average of 400 μm compared with the baseline after combined therapy (IVR+DEX). That might suggested that combined therapy no additive effect compared with monotherapy. However, Singer et al  reported that combined therapy could only decrease by only 200-219 μm from the baseline . It was not clear whether the differences between the two studies were related to race or geography. In conclusion, the BCVA and CFT improvement in this study remained relatively stable during the 12-month follow-up (Figure 1) without a reduction in efficacy caused by repeated treatment.
Ranibizumab had a rapid onset of action, and the BCVA and CFT of patients were significantly improved in the first week after the injection. Visual acuity improvement was best at 1 month after combined therapy. In view of the innovative sustained-release technology of DEX, the effect of a single injection could be maintained for 3-6 months. Therefore, the monthly follow-up was not needed in the present study, and the third follow-up was selected 3 months after injection. Once visual acuity decreased more than 2 lines or macular thickness greater than 300 μm or subretinal fluid, intraretinal fluid, etc., patients needed to immediately receive combined treatment once again. About 10% of patients could be clinically cured based on BCVA and CFT after only one injection without recurrence of macular edema in long-term follow-up.
In terms of safety, it was unavoidable that DEX could raise intraocular pressure and increase the risk of cataracts. Our results showed that the incidence of high IOP was 26.3%. Still, mild to moderate high IOP could be effectively inhibited by medicine without surgery. The safety data of the initial treatment of DEX showed that the incidence of high IOP was 29.5% in Chinese individuals . Intraocular pressure of 25.0% and 37.1% of the patients who received 2 or more injections of DEX were greater than 25 mmHg . The differences in the incidence of high IOP may be related to the different definitions of high IOP, follow-up time, and the number of injections. Cataract surgery rate was similar to other combination therapies and DEX monotherapy [14,20]. The cataract surgery rate was positively correlated with the number of DEX injections .
The present study has certain limitations. First of all, this study was not random, and the choice of therapeutic schedule mainly depended on the patient's wishes and the convenience of follow-up. Second, in most previous studies, patients were about 65 years old, while the average age of the patients in the present study was 53 years old. Lu et al  showed that patients < 40 years of age with dexamethasone intravitreal implants had better long-term outcomes (greater visual acuity and CFT improvement) and fewer total injections. However, more controlled studies are needed to confirm whether younger people respond better to hormonal therapy. Third, this is only a retrospective observational study that did not include strict control groups, as is the case with prospective studies. Consequently, future studies are needed to address these shortcomings and find the optimal regimen.