Time to Recurrence and Early Risk Indicators in BRVO-Related Macular Edema

Macular edema (ME) remains the main driver of vision loss in branch retinal vein occlusion (BRVO), and anti-VEGF therapy has become the established first-line foundation of care. But beyond achieving initial resolution, two practical questions remain: how long the treatment effect persists before ME recurs, and whether OCT features at presentation are associated with earlier recurrence.  

A prospective randomized trial from Stockholm now addresses both, comparing aflibercept and ranibizumab head-to-head while also examining subfoveal choroidal thickness (SFCT) as a potential OCT biomarker linked to time to recurrence.

Study Design
Published in Ophthalmology Retina, the double-masked study enrolled 110 treatment-naïve patients with center-involving ME due to BRVO between 2018 and 2021. Participants were randomized to intravitreal aflibercept 2 mg or ranibizumab 0.5 mg, administered monthly until complete ME resolution, with a protocol-mandated minimum of three injections. Patients then entered a structured observation phase, allowing precise measurement of time to recurrence, defined anatomically by OCT. Total follow-up was nine months.

Aflibercept Demonstrates Longer Time to Recurrence of ME
The primary finding was a modest but statistically robust difference in time to recurrence. Mean time to recurrence was 10.7 weeks with aflibercept versus 8.9 weeks with ranibizumab, a difference of 1.7 weeks (P < 0.001). At the first recurrence assessment point, eight weeks after the last injection, nearly twice as many ranibizumab-treated eyes experienced recurrence compared with those who received aflibercept, corresponding to a relative risk of 1.8 (P < 0.001).

Comparable Anatomic and Visual Outcomes Between Agents
Both agents achieved high rates of ME resolution, 92% with aflibercept and 96% with ranibizumab, and required the same mean number of injections to achieve anatomic resolution (2.1 in both groups). Visual outcomes converged by the end of follow-up, with final best-corrected visual acuity averaging approximately 76 ETDRS letters in both arms, consistent with results from pivotal BRVO trials. Central subfield thickness (CST) also improved similarly over time, despite a thicker baseline CST in the aflibercept group.

Differences between treatment arms were therefore observed after recurrence. Among patients who adhered to protocol following recurrence, those initially assigned to ranibizumab required nearly one additional injection over follow-up compared with aflibercept (7.4 vs 6.5 injections, P = 0.003).

Choroidal Thickness as a Potential Predictor of ME Recurrence
Beyond drug comparison, one of the study’s novel contributions is its large-scale, prospective assessment of the relationship between choroidal thickness and time to recurrence of ME. At baseline, SFCT was significantly greater in affected eyes than in healthy fellow eyes, reinforcing prior observations that BRVO involves not only retinal but also choroidal vascular changes. Both absolute SFCT and the inter-eye difference, diffSFCT, showed a negative correlation with time to recurrence.

Patients in the highest quartile of diffSFCT experienced recurrence roughly two weeks earlier, on average, than those in the lowest quartile. Although the predictive strength of these correlations was modest, the association remained significant after adjustment for age and treatment arm.

Dynamic Choroidal Changes Mirror Disease Activity
Longitudinal OCT data added biological plausibility. SFCT decreased after the loading phase, then thickened again at recurrence, consistent with changes in disease activity. This pattern supports the hypothesis that choroidal thickening may reflect VEGF-driven vascular hyperpermeability rather than a purely static anatomic characteristic. The authors argue that comparing the diseased eye with the fellow eye may be more clinically useful than relying on absolute SFCT values, which vary widely with age, axial length, and diurnal factors.

Limitations and Considerations for Real-World Practice
Several limitations temper interpretation. The first recurrence assessment occurred eight weeks after the last injection, so earlier recurrences may have been missed, potentially underestimating differences between agents. Follow-up was limited to nine months, and the cohort excluded nonresponders who required treatment switching, which may limit generalizability to routine clinical practice. Still, the randomized, masked design and standardized recurrence assessment strengthen confidence in the time-to-recurrence findings.

Implications for Individualized BRVO Care
For clinicians managing BRVO, these findings reinforce two practical points:

1. Aflibercept may allow slightly longer treatment intervals than ranibizumab without sacrificing visual outcomes, a difference that accumulates over time in injection burden.
2. Baseline choroidal metrics, particularly diffSFCT, may help identify patients at higher risk of early recurrence, although their predictive value remains modest and exploratory and is not yet sufficient for standalone clinical decision-making.

As retina clinics contend with rising anti-VEGF demand and increasing availability of biosimilars, integrating recurrence data and OCT-based risk stratification alongside agent selection may support more individualized treatment strategies.

Reference

Cullhed Farrell A, Casselholm de Salles M, Lindberg C, Epstein D. Recurrence of macular edema in branch retinal vein occlusion: a comparison of aflibercept and ranibizumab in a randomized trial. Ophthalmology Retina. 2025;9:1098-1105. doi:10.1016/j.oret.2025.05.012.