Association Between Anti-vascular Endothelial Growth Factor Therapy Exposure and Visual Outcomes in Diabetic Macular Edema and Retinal Vein Occlusion

Summary

In this retrospective cohort, greater injection frequency, longer treatment duration, and earlier treatment initiation were each independently associated with better visual outcomes. Although non-standard treatment patterns were common and associated with poorer unadjusted outcomes, composite standard-treatment classification did not retain independent prognostic value after accounting for these specific treatment-exposure metrics.

Abstract

Anti-vascular endothelial growth factor (anti-VEGF) therapy is first-line treatment for diabetic macular edema (DME) and retinal vein occlusion (RVO), but real-world practice often differs from clinical trial findings. This single-center retrospective cohort study used hospital electronic medical records to evaluate anti-VEGF treatment patterns and associations with visual outcomes. We included 332 adults who received at least one intravitreal injection of ranibizumab, aflibercept, or conbercept between January 2022 and January 2024 and had at least one post-baseline best-corrected visual acuity (BCVA) measurement. The cohort included 180 patients with DME, 138 with RVO, and 14 with other retinal vascular diagnoses. Standard treatment required three monthly loading doses, a treat-and-extend regimen with intervals of 4–16 weeks, no interval >16 weeks, and treatment duration ≥12 months; all other patterns were classified as non-standard. The primary outcome was change in LogMAR BCVA at the last available follow-up. The standard and non-standard groups included 132 and 200 patients, respectively. Treatment interruption for ≥6 months was common in the non-standard group (68.50%). Unadjusted visual outcomes favored the standard group (median ΔBCVA, −0.23 vs. −0.07 LogMAR; improvement rate, 68.18% vs. 35.00%; P<0.001). In adjusted analyses, baseline BCVA, total number of injections, and treatment duration were positive predictors of improvement, whereas longer time to first injection was a negative predictor; standard/non-standard grouping was not significant (P=0.853). Safety events were infrequent, limiting comparison of rare events. Non-standard treatment patterns were common and associated with poorer unadjusted visual outcomes; optimizing injection exposure and treatment timing may improve real-world outcomes.

Introduction

Retinal vascular diseases, particularly diabetic macular edema (DME) and retinal vein occlusion (RVO), are leading causes of global visual impairment^1,2,3. Their incidence is rising due to increasing diabetes prevalence and population aging⁴, placing a heavy burden on public health systems⁵. The IDF reports ~500 million adults with diabetes, one-third of whom have diabetic retinopathy⁶. As its leading cause of vision loss, DME affects up to 5% of patients⁷. RVO, the second most common retinal vascular disease after diabetic retinopathy, has an annual incidence of ~0.5%, rising significantly with age^8,9. A recent comprehensive systematic review and meta-analysis further confirms the substantial global burden of RVO, highlighting the urgent need for optimized management strategies to mitigate its visual impact¹⁰. Therefore, exploring effective treatment strategies is of both clinical and social significance.

Anti-VEGF drugs specifically bind to the VEGF-A isoform, blocking VEGF binding to its receptors, thereby inhibiting neovascularization, reducing vascular permeability, and alleviating macular edema, ultimately improving and stabilizing vision^11,12. Commonly used anti-VEGF drugs in clinical practice include ranibizumab, aflibercept, conbercept, and the recently approved faricimab. Contemporary meta-analyses and network comparisons have provided a comprehensive comparative landscape of these agents, confirming the overall efficacy of anti-VEGF therapy while also highlighting nuanced differences in treatment burden and dosing regimens that are particularly relevant to real-world practice¹³. Numerous RCTs have shown that anti-VEGF therapy is significantly superior to conventional laser photocoagulation and corticosteroids in improving visual acuity in DME and RVO, making it the recommended first-line treatment per major international guidelines^14,15. However, a significant gap exists between the ideal treatment outcomes reported in RCTs and those observed in real-world clinical practice. RCTs typically have strict inclusion and exclusion criteria, and the study populations are often highly selected, excluding patients with severe systemic diseases, poor adherence, or limited life expectancy¹⁶. At the same time, RCTs employ standardized treatment protocols and rigorous follow-up monitoring to ensure that patients receive standardized care. In contrast, the real-world setting is more complex and variable, with greater patient heterogeneity, more flexible treatment choices, variable adherence to follow-up, and more frequent treatment interruptions and discontinuations. This highlights the need for in-depth analysis of real-world treatment patterns and the factors that influence them to optimize clinical practice and improve patient outcomes.

Treatment pattern is a key factor in anti-VEGF efficacy, with three main regimens: fixed, pro re nata (PRN), and treat-and-extend (T&E)¹⁷. The fixed regimen requires patients to receive regular injections at predetermined intervals. While this ensures continuity of treatment, it may lead to overtreatment, increasing healthcare costs and injection-related risks¹⁸. The PRN regimen uses disease activity indicators, such as changes in central macular thickness on optical coherence tomography, to determine whether to inject. Although theoretically enabling individualized treatment, in practice, it often results in undertreatment and greater fluctuations in vision¹⁹. The T&E regimen combines the advantages of the previous two approaches. After completing the initial loading dose, it dynamically adjusts the follow-up interval based on the patient's treatment response, ensuring both individualized therapy and continuity of care. In recent years, it has gradually become the mainstream treatment model²⁰. However, how the T&E regimen is implemented in the real world and whether it achieves the expected therapeutic outcomes currently lacks sufficient local data support. Anti-VEGF therapy requires long-term, repeated intravitreal injections, and the treatment process is burdensome with substantial financial costs, often leading to suboptimal patient adherence. Poor treatment adherence not only directly affects the control of macular edema and maintenance of vision but may also lead to disease recurrence and irreversible visual impairment. Nevertheless, there is currently no unified definition of treatment adherence, and the evaluation criteria vary considerably across different studies, limiting the comparability of research findings.

In recent years, with the widespread adoption of electronic medical record systems, real-world studies have received increasing attention and have been applied in ophthalmology. Based on data generated in routine clinical practice, real-world studies can reflect treatment conditions and outcomes in broader patient populations, address the limitations of RCTs in generalizability, and provide more practice-relevant evidence to support clinical decision-making. However, real-world studies on anti-VEGF therapy for retinal vascular diseases in China remain relatively limited, with a particular lack of systematic analyses of treatment pattern regularity, adherence, and their relationship to visual outcomes. Most existing studies have small sample sizes, short follow-up periods, and predominantly employ univariate analyses, failing to adequately control for confounding factors.

Against this background, the present study aims to use single-center electronic medical record data to retrospectively analyze real-world anti-VEGF treatment patterns in a cohort of Chinese patients with retinal vascular diseases, focusing on associations among treatment regularity, drug selection, baseline characteristics, and visual outcomes. The primary novelty of this study lies in its systematic and quantitative evaluation of treatment regularity using a locally defined set of criteria and the identification of specific modifiable treatment behaviors—beyond simple group classification—that are independently associated with visual prognosis in a Chinese clinical setting. Through this study, we hope to identify existing problems and deficiencies in current local clinical practice, determine key factors influencing vision improvement, and provide evidence-based support to optimize anti-VEGF treatment strategies, improve treatment regularity, and enhance long-term visual prognosis in patients. Additionally, the findings may serve as a reference for establishing a quality evaluation system for anti-VEGF therapy tailored to the Chinese context, thereby contributing to the standardization of fundus disease diagnosis and treatment.

Protocol

This study was approved by the Tianjin Medical University Ethics Committee (Approval number: 2024-025). This study adhered to the principles of the Declaration of Helsinki and the Measures for Ethical Review of Biomedical Research Involving Humans. As this was a retrospective analysis using previously de-identified clinical data, the study protocol was reviewed and approved by the hospital ethics committee, and the requirement for informed consent was waived.

Study design
This single-center, retrospective cohort study used real-world data from our hospital’s electronic medical records and ophthalmic picture archiving system to analyze anti-VEGF treatment patterns and visual outcomes in patients with retinal vascular diseases. The study period spanned from January 2022 to January 2024. All clinical data were extracted through the hospital information system and the specialized ophthalmic database, including patient demographic characteristics, diagnostic information, treatment regimens, follow-up records, and visual acuity examination results. The detailed study workflow is shown in Figure 1.

Cohort definition and follow-up rules
Index date: The date of the first intravitreal anti-VEGF injection.

Minimum follow-up: To be eligible for the primary outcome analysis, patients were required to have at least one post-baseline BCVA measurement after the index date.

Primary outcome assessment time point: To balance the inherent variability in real-world follow-up, the primary outcome (change in BCVA from baseline) was assessed at the last available follow-up visit within the study window (up to January 2024). This approach reflects real-world practice but introduces variability in observation time.

Censoring rules: Patients were censored at the time of their last recorded clinic visit, death, or the end of the study period (January 2024), whichever occurred first. Patients who switched to a non-anti-VEGF therapy (e.g., a corticosteroid implant) or underwent vitrectomy during follow-up were censored at the time of the switch or surgery and were not included in the primary outcome analysis.

Standard Treatment Group classification rule: Classification into the Standard Treatment Group required that the patient met all criteria (completion of 3 loading doses, T&E regimen, no interval >16 weeks, duration ≥ 12 months) during the entire observable follow-up period. Patients who had not yet reached 12 months of follow-up by the data cut-off were classified based on their observed pattern; if they met all other criteria but had <12 months of follow-up, they were not classified as Standard.

Justification for the standard treatment definition: The selected cutoffs were based on a combination of clinical trial protocols and real-world practice standards. The 16-week (4-month) maximum interval corresponds to the upper limit of the approved dosing schedule for aflibercept and the treat-and-extend (T&E) extension phase recommended in major guidelines²¹. The 12-month treatment duration was chosen because it represents the minimum period required to complete the initial loading phase (3 monthly injections) and achieve stable disease control under a T&E regimen, as supported by previous real-world studies^22,23,24. These thresholds were predefined in the study protocol and were not derived from outcome-driven data exploration.

Critical methodological note on group definition: The definition of the Standard Treatment Group inherently requires that patients remain under active treatment and observation for at least 12 months and maintain regular injection intervals throughout that period. Consequently, this grouping is partly conditional upon treatment opportunity and follow-up duration. Patients with shorter follow-up, those who discontinued early, or those who experienced interval prolongation prior to completing 12 months were automatically assigned to the non-standard group. This temporal conditioning may introduce a form of immortal-time or conditioning bias in comparisons between groups, as the exposure (standard vs. non-standard) is not purely baseline-defined but is ascertained over the follow-up period. Therefore, group comparisons should be interpreted primarily as descriptive associations, and the independent contribution of the grouping variable beyond its constituent components (e.g., injection number, treatment duration) should be evaluated with caution in the multivariable model.

Inclusion criteria
Patients were eligible for inclusion if they met the diagnostic criteria for a retinal vascular disease, which was confirmed by fluorescein fundus angiography (FFA), optical coherence tomography (OCT), and clinical examination, including diabetic macular edema (DME), retinal vein occlusion (RVO) (either central or branch), or other ischemic retinopathies (e.g., ocular ischemic syndrome) as diagnosed by a treating retinal specialist. All included patients were required to have received at least one intravitreal injection of an anti-VEGF agent, including ranibizumab, aflibercept, or conbercept. The study was limited to patients aged 18 years or older. Furthermore, complete records of best-corrected visual acuity (BCVA) at baseline and at least one follow-up visit were mandatory for study participation.

Exclusion criteria
Patients were excluded from the study if they presented with other ocular diseases that could severely affect vision, such as age-related macular degeneration (AMD), severe cataract, advanced glaucoma, or optic atrophy. Those who had previously undergone panretinal photocoagulation (PRP) or focal macular laser treatment, where the treatment period overlapped with the follow-up period of this study, were also excluded. A history of intraocular surgery, including cataract extraction, vitrectomy, or ocular trauma that could affect the accuracy of visual acuity assessment, was another reason for exclusion. Patients with active ocular infection or inflammation, such as infectious endophthalmitis or active uveitis, were not included. Pregnant or lactating individuals were excluded, as were those with severe systemic diseases and a life expectancy of less than one year, or those who were unable to cooperate with visual acuity examinations. Finally, patients with severely missing medical record data were excluded from the analysis.

Sample size calculation
Based on the difference in vision improvement rates between the standard treatment group (defined as completion of three loading doses, adherence to a treat-and-extend regimen with intervals ≤16 weeks, and treatment duration ≥12 months) and the non-standard treatment group (defined as any deviation from these criteria) in previous real-world studies (expected improvement rates of 65% and 35%, respectively)²⁵. With α=0.05 and β=0.20 (80% statistical power), the sample size calculation formula for comparing two proportions was used. It was estimated that at least 52 patients were required in each group. Given a 20% data-missing rate, a final planned enrollment of at least 130 patients was set. A total of 332 patients were actually included in this study, meeting the statistical requirements.

Treatment regimens and group definitions

Types of anti-VEGF agents and drug-group assignment
The anti-VEGF agents involved in this study included: Ranibizumab: 0.5 mg/0.05 mL, administered by intravitreal injection; Aflibercept: 2 mg/0.05 mL, administered by intravitreal injection; Conbercept: 0.5 mg/0.05 mL, administered by intravitreal injection. In this cohort, no patient switched anti-VEGF agents during the follow-up period; each patient received a single agent exclusively. Therefore, drug-group assignment for subgroup analysis was based on the agent received throughout the entire treatment course.

Grouping criteria for treatment patterns
Based on treatment adherence and follow-up regularity, patients were divided into two groups. Patients were classified in the Standard Treatment Group only if all of the following criteria were met: completion of the initial three consecutive monthly loading-dose injections; adoption of a T&E regimen with intervals dynamically adjusted based on macular edema/retinal ischemia activity (4–16 weeks); no injection interval > 16 weeks (4 months); and treatment duration ≥ 12 months. Patients were classified in the Non-standard Treatment Group if any of the following criteria were met: treatment interruption (no injection for ≥6 consecutive months, with main reasons including financial difficulties, transportation inconvenience, or subjective perception of disease improvement); incomplete loading dose; insufficient injection frequency (mean injection interval >16 weeks); excessively long follow-up interval (two consecutive follow-up intervals >4 months under the T&E regimen); or patient-initiated self-termination without physician assessment.

Clinical outcome measures

Primary outcome measure
Change in best-corrected visual acuity (ΔBCVA): The change in BCVA (after LogMAR transformation) from baseline at the last available follow-up visit. For the 96 patients with bilateral disease (28.92%), the average LogMAR change across both eyes was used as the patient's visual outcome.

Secondary outcome measures
Vision improvement rate: Proportion of patients with a LogMAR improvement of ≥0.2 (equivalent to a gain of ≥2 lines on the Snellen chart). Vision stability rate: Proportion of patients with an absolute change in LogMAR of <0.1 (visual fluctuation within ±1 line). Vision worsening rate: Proportion of patients with a LogMAR increase of ≥0.1 (vision loss of ≥1 line). Anatomical improvement: Reduction in central subfield thickness (CST) from baseline (applicable only to DME patients). Treatment burden: Total number of injections, mean injection interval. Safety indicators: Incidence of endophthalmitis, incidence of retinal detachment, incidence of elevated intraocular pressure (>21 mmHg or an increase of >5 mmHg from baseline), and incidence of other serious adverse events (SAEs).

Statistical analysis
Continuous variables are presented as mean ± SD; categorical variables are presented as frequencies (%). Group comparisons used the t-test or Mann-Whitney U test for continuous variables and the chi-square test or Fisher's exact test for categorical variables. Multivariate logistic regression identified factors associated with vision improvement (LogMAR improvement ≥0.2). Exploratory stratified analyses by disease type and anti-VEGF agent summarized subgroup outcomes; no formal interaction testing was performed. Two-tailed P<0.05 was considered significant. We acknowledge that several clinically important confounders—including but not limited to ischemic vs. non-ischemic RVO, diabetic retinopathy severity, glycemic control (HbA1c), renal function, OCT biomarkers (e.g., presence of intraretinal fluid, subretinal fluid, hyperreflective foci), lens status/cataract progression, insurance/payment status, travel distance, and physician-directed reasons for extending injection intervals—were not consistently available in this retrospective dataset and could not be included in the model. Given the observational, retrospective design and the potential for residual confounding, all findings are reported as associations rather than causal effects.

Results

Baseline characteristics of patients
A total of 332 patients were included. Among them, 180 (54.22%) had diabetic macular edema (DME), 138 (41.57%) had retinal vein occlusion (RVO; comprising 72 with central RVO and 66 with branch RVO), and 14 (4.22%) carried other diagnoses, including retinal vasculitis and ischemic retinopathy. Measured baseline characteristics were not statistically different between the standard and non-standard treatment groups, including age, sex, affected side, disease type di...

Discussion

In this single-center, real-world cohort, we systematically characterized anti-VEGF treatment patterns in patients with retinal vascular diseases and explored their associations with visual outcomes. The main findings are threefold. First, non-standard therapy was common, affecting 60.24% of the cohort, with treatment interruption for ≥6 months being the most frequent manifestation. Second, patients in the standard-treatment group had significantly better unadjusted visual outcomes than those in the non-standard gr...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Aflibercept (Eylea)	Bayer	61755-005-02	Anti-VEGF agent administered by intravitreal injection.
Alternative SD-OCT System	Carl Zeiss Meditec AG	Cirrus HD-OCT 5000	Alternative spectral-domain OCT system used for retinal thickness analysis and retinal imaging.
Best-Corrected Visual Acuity (BCVA) Assessment	Precision Vision, La Salle, IL, USA	Revised 2000 ETDRS Charts	ETDRS charts used for standardized BCVA assessment.
Conbercept (Langmu)	Chengdu Kanghong Biotech	S20130002	Anti-VEGF agent administered by intravitreal injection.
Fundus Fluorescein Angiography (FFA) System	Heidelberg Engineering GmbH	222611 / FDA 510(k): K101223	System used for fluorescein angiography and retinal imaging.
Ranibizumab (Lucentis)	Novartis	50242-080-03	Anti-VEGF agent administered by intravitreal injection.
Slit-Lamp Biomicroscope	Haag-Streit AG, Bern, Switzerland	BQ 900	Slit-lamp biomicroscope used for anterior and posterior segment examination.
Spectral-Domain Optical Coherence Tomography (SD-OCT) System	Heidelberg Engineering, Germany	222611	Used to measure central subfield thickness (CST) and assess macular edema morphology.
SPSS Statistics Software	IBM Corp.	Version 26.0	Used for statistical analyses, including t-tests, Mann-Whitney U tests, chi-square tests, Fisher's exact tests, and logistic regression.