Examining Therapeutic Timing in RVO-Related Macular Edema

Managing macular edema secondary to retinal vein occlusion (RVO-ME) remains a balance between anatomical control, visual recovery, and treatment burden. Anti-vascular endothelial growth factor (anti-VEGF) therapy is well established as first-line care, while intravitreal corticosteroids are often reserved for later lines. This prospective multicenter study published in the International Journal of Ophthalmology explores whether that sequence matters—specifically, whether initiating simultaneous anti-VEGF and steroid therapy offers measurable advantages over delaying combination treatment until patients become refractory.

The investigators evaluated concurrent intravitreal ranibizumab (IVR), a monoclonal antibody targeting VEGF, and an extended-release dexamethasone implant (Dex-I), which suppresses inflammatory mediators and stabilizes the blood–retinal barrier. By addressing both vascular permeability and inflammation at once, the strategy aims to interrupt multiple drivers of edema early in the disease course.

Study Design
The trial enrolled 66 patients, of whom 63 completed 12 months of follow-up. 31 eyes were classified as naïve and 32 as refractory. All participants received simultaneous intravitreal ranibizumab (0.5 mg) and a 0.7 mg dexamethasone implant administered during the same procedure. Follow-up visits occurred monthly, with retreatment based on predefined criteria that included visual acuity decline, OCT-based evidence of recurrent or persistent edema, or new cystic changes.

Primary outcome was best-corrected visual acuity (BCVA) defined by the ETDRS protocol at 12 months and central macular thickness, injection frequency, retreatment interval, and safety outcomes were secondary.

Visual Acuity Outcomes
At 1 year, both groups demonstrated statistically significant improvement in BCVA relative to baseline. The magnitude of improvement, however, differed between cohorts. Treatment-naïve patients gained an average of 19.67 ETDRS letters, compared with 11.74 letters in refractory patients (p=0.014). A gain of more than 15 letters, a clinically meaningful threshold, was achieved by 71% of naïve patients versus 34.4% of refractory patients (p=0.005).

Regression analyses performed by the authors did not identify age, sex, RVO subtype, ischemic status, cataract progression, or intraocular pressure changes as significant contributors to BCVA change.

Anatomical Response
Central macular thickness decreased substantially in both cohorts over 12 months. Mean CMT reduction did not differ significantly between groups (364 µm vs 410 µm; p=0.43), reinforcing a clinical observation: structural improvement does not always translate directly into functional recovery. The authors propose that in refractory eyes, prolonged macular edema may result in irreversible photoreceptor and retinal pigment epithelium damage, thereby constraining visual gains despite comparable reductions in retinal thickness.

Injection Burden
Over the 12-month follow-up, patients required relatively few combined injections. The mean number of co-injections was 2.52 in the naïve group and 2.33 in the refractory group, with no significant difference between them. Retreatment intervals averaged approximately four months in both cohorts.

Safety Findings
Adverse events observed during the study were consistent with known risks of intravitreal dexamethasone. Elevated intraocular pressure occurred in roughly 13% of eyes in each group and was managed with topical therapy in all cases. No patient required anti-glaucoma surgery. Cataract progression was observed in a small number of eyes, more frequently in the refractory cohort, though the difference was not statistically significant.

No cases of endophthalmitis, retinal detachment, vitreous hemorrhage, or systemic complications were reported.

Interpreting the Findings
The authors situate their findings within existing literature that documents incomplete response to anti-VEGF monotherapy and variable outcomes with delayed steroid use. They hypothesize that chronic edema may lead to irreversible photoreceptor and retinal pigment epithelium damage, potentially constraining visual recovery even when edema is later controlled. This hypothesis is presented as a possible explanation rather than a demonstrated mechanism.

Several limitations are acknowledged explicitly. The sample size was modest, the study was open-label, and there was no monotherapy control arm. The follow-up period, while clinically relevant, does not address longer-term durability or late adverse effects. These constraints limit generalizability and preclude changes to guideline-level recommendations.

What the Data Support
Taken on its own terms, the study demonstrates that simultaneous intravitreal ranibizumab and dexamethasone improves visual acuity and reduces macular thickness in both treatment-naïve and refractory RVO-ME over 12 months. It also shows that treatment-naïve eyes achieved greater visual gains under the same regimen.

The data do not establish that early combination therapy is superior to anti-VEGF monotherapy, nor do they define which patients should receive upfront combination treatment. What they add is a controlled comparison of outcomes by disease status under identical treatment conditions, contributing evidence to an ongoing discussion about timing rather than redefining standards of care.

Reference:

Sun YY, Meng J, Li SS, et al. Effect of simultaneous intravitreal ranibizumab and extended-release dexamethasone injection on patients with naïve versus refractory retinal vein occlusion macular edema: a prospective, multicenter, and interventional open-label study. Int J Ophthalmol. 2025;18(5):860-867. Published 2025 May 18. doi:10.18240/ijo.2025.05.11