Evaluating the One-Year Efficacy of Combined Anti-VEGF and Dexamethasone Implant Treatment for Macular Edema in Retinal Vein Occlusions

Background

Retinal vein occlusion (RVO), including central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO), is an obstruction of the retinal venous system, and macular edema (ME) secondary to RVO (RVO-ME) can lead to visual dysfunction [1,2]. Various cytokines such as inflammatory factors play a key role in the development of RVO-ME [3]. Therefore, inflammation has become an important target in RVO-ME therapy [4]. Since 2009, the US Food and Drug Administration (FDA) has approved intravitreal sustained-release dexamethasone implant (DEX I, OZURDEX®) as treatment for RVO-ME. In 2017, the Chinese State Food and Drug Administration (SFDA) approved OZURDEX® for the treatment of ME caused by RVO. It has been observed in domestic phase III clinical trials and clinical practices that intravitreal DEX I can improve vision acuity and reduce macular thickness in patients with RVO-ME, and has good safety [5].

In addition, a previous ex vivo study using autologous aqueous or vitreous humor indicated that inflammatory cytokine levels and vascular endothelial growth factor (VEGF) concentration are elevated and correlated with the severity of ME in eyes with RVO [6]. Therefore, we speculated that the combined use of glucocorticoids and anti-VEGF drugs can improve clinical outcomes in patients with RVO-ME. Previous case series studies in which patients receiving DEX I 2 weeks after anti-VEGF injections in eyes with ME due to RVO showed longer duration of effect, and better improvements in vision and central foveal thickness [7,8]. However, there are few reports on the effects of combination therapy using anti-VEGF drugs and steroids on RVO-ME. In this study, we summarized the real-world visual and anatomical outcomes in CRVO and BRVO patients treated with a combined treatment regimen (anti-VEGF plus DEX I).

Material and Methods

STATISTICAL ANALYSIS:

All data are presented as mean±standard division (SD) or percentages, as appropriate. Normal distribution was tested by the Kolmogorov-Smirnov test. Normally distributed data were analyzed with the t test or one-way analysis of variance (ANOVA) followed by the post hoc LSD test, while non-normally distributed variables were analyzed by Mann-Whitney U test. Binary data were analyzed by Fisher’s exact test. IBM SPSS Statistics software (vision 20.0) was used in the data analysis. Statistical significance was set at a 2-sided P value of less than 0.05. Figures were generated using GraphPad Prism version 9.0 for Windows (La Jolla, CA, www.graphpad.com).

Results

Overall, 40 patients were initially enrolled, and 6 patients were excluded because they were lost to follow-up. Finally, 34 eyes from 34 participants (15 males, mean age 55.12±6.28 years) identified with RVO-ME were included, and all participants underwent a mean of 3.15 ± 1.02 injections. Table 1 shows the characteristics of included participants with RVO-ME.

According to the fundus examinations, 17 eyes from 17 patients had CRVO, and 17 eyes from 17 patients had BRVO. There were no significant differences in demographics, medical history, and ophthalmic examinations between eyes with CRVO and those with BRVO (Table 2).

As shown in Table 3, BCVA, IOP, central retinal thickness (CRT), retinal vessel density (VD) of the SCP, and DCP levels were significantly different before and after combination therapy (all P<0.05). After stratification by type of RVO, eyes with BRVO-ME had better BCVA improvement at 2 months, 3 months, 4 months, and 6 months after treatment and CRT reduction at 1 month, 2 months, 4 months, and 6 months after treatment compared with eyes with CRVO-ME (all P<0.05), respectively (Figures 1A–1D, 2A–2C).

Overall, at 12-month follow-up, adverse events (AEs) were observed in 10 eyes, of which most cases (n=5, 50%) were IOP elevation and 3 of them received IOP-lowering medications to manage IOP levels. Furthermore, 2 cases with subconjunctival hemorrhage were reported during the study period. No serious AEs were reported.

Discussion

We comprehensively investigated functional anatomic indicators such as structural and vascular retinal changes in eyes affected by RVO before and after anti-VEGF plus DEX I combination intravitreal injections therapy.

During the development of RVO-ME, VEGF plays a key role in vascular permeability, resulting in the appearance of ME [11–13]. Therefore, anti-VEGF drugs have become the first-line treatment for ME, and have been found to be effective in improving vision [14]. However, in some cases, the inflammatory factors might also play crucial roles in the pathogenesis of RVO occurrence [15]. Anti-inflammatory drugs may be another treatment for RVO-ME, and DEX I was approved for treatment of ME associated with RVO. The platelet-to-lymphocyte ratio (PLR), which is an inexpensive marker calculated from routine complete blood count test, is a new biomarker that shows the existence of thrombosis and inflammation. PLR are elevated in RVO, suggesting that PLR may be a useful marker for RVO [16]. We performed this retrospective study to evaluate the effects of combination therapy using anti-VEGF drugs and steroids for ME in eyes with RVO.

In this real-world retrospective study, we found that anti-VEGF plus DEX I treatment improved BCVA, CRT, and retinal vessel density in patients with BRVO-ME and CRVO-ME, after an average of 3 injections. Previous studies have shown that intravitreal injection of anti-VEGF drugs (5.5 injections in 1 year) or DEX I can relieve RVO-ME [17,18]. Additionally, our findings indicated that after combination therapy RVO-ME patients had functional effects, and the curative effect peaked at 2 months after injection. Anatomically, the curative effect can occur at 1 month and last up to 12 months after treatment. Small increases in IOP that occur after combination therapy should be noted but can usually be managed with topical medication. Similarly, IOP increases were also found in another real-world study with DEX I treatments [17]. No glaucoma incisional surgeries were required during combination therapy treatment.

Patients with BRVO-ME had larger gains in BCVA and reduction in CRT over 12 months of follow-up, confirming the benefit of combination therapy. Recently, a prospective, observational, post-marketing surveillance study revealed that RVO-ME eyes administered a first DEX I acquired stable/improved BCVA tended to decrease after 2 months through 6 months of follow-up, but the decline was greater in the CRVO subgroup [17].

Notably, we also found that our combined therapy could improve the retinal VD including SCP, and DCP. To date, few reports have been published on the effects of this combination therapy on vessel density in eyes with RVO. Previously, both anti-VEGF and steroid monotherapy had statistically significant effects on the improvement of visual acuity and increased VD of the SCP as well as the DCP [19].

There were some limitations in our study. First, our study was a retrospective observational and auditing report on relatively small numbers without a comparator. Second, although we had acquired high-quality OCTA images, it was difficult to divide VD of parafoveal into different quadrants. Finally, our study provided “real-world” results and the evaluations were at the discretion of the treating physician and according to normal practice; thus, there was no standardization of assessments.

Conclusions

Taken together, the findings of the current study illustrate the multicenter real-world effects of combined therapy of anti-VEGF drugs and DEX I in eyes with RVO-ME, which is associated with good long-term BCVA, anatomical outcomes, and VD changes, and favorable safety profile with fewer intravitreal re-treatments.