Efficacy and Safety of Ranibizumab Combined with Dexamethasone Intravitreal Implant Sequential Therapy for Macular Edema Secondary to Non-Ischemic Retinal Vein Occlusion

Abstract

Purpose

To evaluate the efficacy, safety, and treatment burden of intravitreal ranibizumab (RBZ) combined with a dexamethasone (DEX) intravitreal implant compared to ranibizumab monotherapy for macular edema (ME) secondary to non-ischemic retinal vein occlusion (RVO).

Methods

This retrospective controlled study included 138 patients (139 eyes) with treatment-naïve non-ischemic RVO-ME (including both branch and central retinal vein occlusions) diagnosed at Sanmenxia Eye Hospital between 2020 and 2024. Eyes were categorized into two groups: the monotherapy group (RBZ, n=68), receiving standard “3+PRN” ranibizumab; and the combination group (RBZ+DEX, n=71), receiving sequential therapy comprising an initial ranibizumab injection followed by a DEX implant (Ozurdex) within 2–4 weeks, with subsequent PRN retreatment. Primary outcomes included mean change in best-corrected visual acuity (BCVA) and central macular thickness (CMT), as well as the proportion of eyes achieving clinically significant visual gain (>0.3 logMAR) and anatomical resolution (CMT <300 μm). Secondary outcomes quantified treatment burden (injection frequency) and safety profiles. To address potential confounding variables between the two RVO subtypes, all outcomes were further evaluated through a stratified subgroup analysis.

Results

From month 3 to month 9, the RBZ+DEX group showed significantly greater mean BCVA improvement than the RBZ group (P<0.05) and achieved a higher proportion of eyes with clinically significant visual gain (>0.3 logMAR). The combination group demonstrated a significantly greater reduction in CMT at month 2 compared to monotherapy (P=0.006), indicating faster edema resolution, with superior anatomical resolution rates at multiple time points. Regarding treatment burden, the RBZ+DEX group required significantly fewer injections (median counts) and had longer retreatment intervals (P<0.001). Although the incidence of intraocular pressure elevation was higher in the combination group (P=0.013), it was managed with topical medication.

Conclusion

Sequential therapy with ranibizumab and dexamethasone implant offers superior clinical efficacy over ranibizumab monotherapy for RVO-ME. This regimen leverages a synergistic mechanism to provide better mid- to long-term visual gains, faster anatomical restoration, and a reduced treatment burden. The safety profile remains favorable with manageable risks.

Introduction

Retinal vein occlusion (RVO) is a common retinal vascular disorder causing visual impairment, second only to diabetic retinopathy1.2 Based on the site of occlusion, it is classified into central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO).3 These two subtypes exhibit distinct natural histories and baseline visual prognoses, with CRVO generally presenting more severe pathophysiological challenges. Furthermore, based on retinal perfusion status, RVO is broadly divided into ischemic and non-ischemic subtypes. Ischemic RVO involves extensive capillary nonperfusion, inherently carrying a significantly poorer visual prognosis, a higher risk of neovascular complications, and a notoriously poor response to standard treatments compared to the non-ischemic type. Because combining these varied subtypes in clinical evaluations can introduce significant confounding variables, assessing therapeutic outcomes requires rigorous baseline selection and subtype stratification.

Macular edema (ME) secondary to RVO is the primary cause of vision loss in these patients.4 The pathogenesis of RVO-ME is complex; venous occlusion induces hemodynamic stagnation and retinal ischemia/hypoxia.5 This upregulation of HIF-1α promotes the overexpression of vascular endothelial growth factor (VEGF) and triggers a cascade of inflammatory mediators, including interleukin-6 (IL-6) and platelet-derived growth factor (PDGF).6,7 These factors collectively disrupt the blood-retinal barrier and increase vascular permeability, leading to fluid accumulation in the macular region.8

Currently, intravitreal anti-VEGF agents (eg., ranibizumab) are the standard first-line treatment.9,10 Although pivotal trials such as BRAVO and CRUISE confirmed their efficacy in reducing vascular permeability,11,12 the short half-life of anti-VEGF agents often necessitates frequent injections to maintain therapeutic effects, imposing a heavy burden and economic pressure on patients.13 Studies indicate that while anti-VEGF therapy effectively inhibits angiogenesis, its effect on downregulating inflammatory mediators is limited.14 Residual inflammatory factors are considered key drivers of recurrent edema or resistance to anti-VEGF therapy, suggesting that single-target inhibition may be insufficient for long-term disease control.15

Given the critical role of inflammation in RVO-ME pathology, the long-acting intravitreal dexamethasone implant (Ozurdex) has demonstrated potent anti-inflammatory and anti-angiogenic effects.16 It maintains stable intraocular drug concentrations over a prolonged period.17 Combining Ozurdex with anti-VEGF agents can simultaneously target the VEGF pathway and the inflammatory cascade.18 This dual mechanism addresses the limitations of anti-VEGF monotherapy. While combination therapies have been explored, conclusive comparative evidence regarding their ability to reduce injection burden while ensuring mid- to long-term visual and anatomical improvement is lacking. Therefore, this study aims to evaluate the efficacy, safety, and treatment burden of sequential ranibizumab and dexamethasone implant therapy for RVO-ME, providing evidence-based support for clinical decision-making.

Materials and Methods

Study Design

This was a retrospective, controlled clinical study involving patients diagnosed with non-ischemic RVO-ME and treated at Sanmenxia Eye Hospital from 2020 to 2024. The study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Sanmenxia Eye Hospital (Ethics Approval No. 20191213).

Inclusion and Exclusion Criteria

Inclusion criteria were: (1) Age ≥18 years; (2) Diagnosis of non-ischemic RVO-ME (including both BRVO and CRVO subtypes) confirmed by funduscopy, optical coherence tomography (OCT), and fundus fluorescein angiography (FFA); (3) Baseline central macular thickness (CMT) > 290μm; (4) Completion of at least 9 months of follow-up with complete clinical data. Exclusion criteria were: (1) Macular edema caused by other etiologies such as diabetic retinopathy, age-related macular degeneration, or uveitis; (2) Coexisting ocular conditions affecting fundus examination or visual assessment, such as glaucoma or severe cataract; (3) History of vitreoretinal surgery or ocular trauma; (4) Significant data missing. (5) Presence of ischemic RVO (typically defined as >10 disc areas of retinal capillary nonperfusion on FFA).

Treatment Groups

A total of 138 patients (139 eyes) meeting the criteria were included. Based on the treatment received, eyes were divided into two groups: (1) Monotherapy Group (RBZ group, n=68): Received 3 consecutive monthly intravitreal injections of ranibizumab (0.5 mg/0.05 mL), followed by a pro re nata (PRN) regimen. (2) Combination Group (RBZ+DEX group, n=71): Received an initial intravitreal injection of ranibizumab (0.5 mg), followed by the implantation of a dexamethasone sustained-release implant (0.7 mg) within 2–4 weeks, followed by PRN retreatment.

Retreatment Criteria

As a retrospective study, retreatment followed real-world clinical practice principles, determined by the attending physician based on individualized risk-benefit assessment. Our hospital’s retreatment strategy generally follows standard PRN guidelines. (1) a loss of > 0.1 logMAR in BCVA compared with the best value recorded during follow-up; (2) an increase in CMT of ≥ 50μm from the lowest recorded value; or (3) the presence of persistent intraretinal or subretinal fluid on OCT images.

Maintenance Phase Drug Selection

In the monotherapy group, retreatment was limited to ranibizumab. In the combination group, the choice of retreatment drug (ranibizumab or Ozurdex) was based on medical records. Conversion to or repeated use of Ozurdex was generally based on: 1. Lens status (pseudophakic eyes prioritized for Ozurdex); 2. Treatment characteristics (suboptimal response or rapid resistance to prior anti-VEGF); 3. Burden and compliance (excessive injection burden due to frequent recurrence, or poor patient tolerance/compliance).

Data Collection and Outcomes

Data were extracted independently by two researchers from electronic medical records. Discrepancies were resolved through consultation with a senior ophthalmologist. Data collection points included baseline and months 1, 2, 3, 6, and 9 post-treatment. Recorded characteristics included age, sex, RVO type, lens status, laser treatment history, and systemic comorbidities.

Outcome Assessments

Best-corrected visual acuity (BCVA) was measured using a standard Snellen chart at 5 meters and converted to LogMAR. CMT was measured using spectral-domain OCT (Spectralis HRA+OCT, Heidelberg Engineering, Germany). Intraocular pressure (IOP) was measured via non-contact tonometry. Injection counts, medications, and adverse events were recorded.

Endpoints

1. Primary efficacy endpoints: Mean change in BCVA (LogMAR) and CMT, and the proportion of eyes achieving clinically significant visual gain (>0.3 logMAR) and anatomical resolution (CMT <300 μm).

2. Secondary endpoints: Injection frequency and medication usage in the combination group.

3. Safety endpoints: Incidence of adverse events, including IOP elevation (>21 mmHg or >5 mmHg increase from baseline), cataract progression, vitreous hemorrhage, endophthalmitis, and retinal detachment.

In addition to the overall cohort analysis, to eliminate confounding variables arising from the differing natural histories and pathophysiologies of BRVO and CRVO, a pre-planned subgroup analysis was conducted to evaluate efficacy and treatment burden independently within each specific RVO subtype.

Statistical Analysis

Data analysis was performed using SPSS 27.0 (IBM Corp., Armonk, NY, USA). Continuous variables were tested for normality (Shapiro–Wilk test). Normally distributed data are presented as Mean ± SD and compared using independent sample t-tests (inter-group) or paired t-tests (intra-group). Non-normally distributed data are presented as Median (IQR) and compared using the Mann–Whitney U-test. Categorical data are presented as n (%) and compared using the Chi-square test. Repeated measures ANOVA (RM-ANOVA) assessed group, time, and interaction effects for longitudinal data. Sphericity was verified using Mauchly’s test; if violated, Greenhouse-Geisser correction was applied. All tests were two-sided with P<0.05 considered statistically significant.

Results

Baseline Characteristics

The baseline demographic and clinical characteristics of the 139 eyes (RBZ: n=68; RBZ+DEX: n=71) are summarized in Table 1. All included eyes across both BRVO and CRVO subgroups were confirmed as non-ischemic. There were no significant differences between groups regarding age, sex, RVO type (BRVO/CRVO), duration of disease, lens status, laser history, or systemic diseases (P>0.05), indicating comparable baseline profiles.

Table 1.

Baseline Demographic and Clinical Characteristics of the Study Population

Characteristic	RBZ (n=68)	DEX+RBZ (n=71)	t/Z/χ2	P
Age	61.22±14.80	57.24±11.31	1.776	0.078
Time of Onset (days)	30 (10,60)	30 (10,60)	−0.308	0.758
Sex			0.002	0.963
Male	39	41
Female	29	30
Eye Laterality
Left	31	32	0.004	0.951
Right	37	39
Lens status			0.000	1.000
Phakic eyes	66	68
Pseudophakic eye	2	3
Type of RVO			0.438	0.508
BRVO	43	41
CRVO	25	30
Laser History			5.041	0.169
None	39	37
Treat	29	34
Underlying Diseases			2.708	0.100
None	25	17
Present	43	54

Note: Data are mean ± SD, median (IQR), or n. Stats: Independent t-tests, Mann–Whitney U-test, or χ² test.

Abbreviations: RBZ, Ranibizumab; DEX, Dexamethasone Implant.

Best-Corrected Visual Acuity (BCVA)

Both groups showed significant BCVA improvement from baseline at all follow-up points (P<0.05). No significant difference in mean BCVA improvement was observed at months 1 and 2 (P=0.326 and P=0.084, respectively). However, at month 3, the RBZ+DEX group showed a significantly greater mean improvement (−0.44±0.27 logMAR) compared to the monotherapy group (−0.33±0.31 logMAR, P=0.042). This advantage persisted at month 6 (P=0.014) and was most pronounced at month 9 (RBZ+DEX: −0.53±0.28 vs. RBZ: −0.37±0.32 logMAR, P=0.004). RM-ANOVA confirmed significant time (F=19.694, P<0.001) and group effects (F=4.399, P=0.038), demonstrating superior mid- to long-term visual outcomes in the combination group (Table 2).

Table 2.

Comparison of Mean Change in Best-Corrected Visual Acuity (BCVA) from Baseline

Group	n	1month	2 Months	3 Months	6 Months	9 Months
RBZ	68	−0.21±0.25	−0.29±0.28	−0.33±0.31	−0.35±0.33	−0.37±0.32
DEX+RBZ	71	−0.25±0.26	−0.38±0.27	−0.44±0.27	−0.48±0.27	−0.53±0.28
t		0.986	1.738	2.053	2.499	2.960
P		0.326	0.084	0.042*	0.014*	0.004*

Note: Data are mean ± SD (logMAR). *P < 0.05. Stats: independent t-tests. RM-ANOVA: Group (F=4.40, P=0.038), Time (P<0.001), Interaction (P=0.531).

Abbreviations: RBZ, Ranibizumab; DEX, Dexamethasone Implant.

The proportion of patients achieving clinically significant visual gain (≥0.3 logMAR) is shown in Figure 1. While rates were similar at months 1 and 2, the combination group showed significantly higher proportions from month 3 onwards (Month 3: 74% vs 49%, P=0.002; Month 6: 79% vs 48%, P<0.001; Month 9: 81% vs 51%, P<0.001).

Figure 1.

Proportion of patients with BCVA gain ≥ 0.3 logMAR. *P < 0.05.

Abbreviations: BCVA, Best-Corrected Visual Acuity; RBZ, Ranibizumab; DEX, Dexamethasone implant.

Central Macular Thickness (CMT)

Baseline CMT was comparable between groups (P=0.110). Both groups achieved significant CMT reduction at all time points. At month 2, the RBZ+DEX group showed a significantly greater reduction in CMT compared to the RBZ group (290.83±56.66 vs 321.26±71.59 μm, P=0.006). Although differences at months 3, 6, and 9 were not statistically significant, the combination group consistently maintained lower CMT levels. RM-ANOVA indicated significant time (F=75.416, P<0.001) and group effects (F=6.215, P=0.014), confirming better anatomical outcomes with combination therapy (Table 3).

Table 3.

Comparison of Mean Central Macular Thickness (CMT)

Group	n	Baseline	1 Month	2 Months	3 Months	6 Months	9 Months
RBZ	68	656.21±216.01	351.24±79.93	321.26±71.59	291.49±48.49	307.03±54.77	287.27±46.20
DEX+RBZ	71	601.89±181.52	348.06±68.44	290.83±56.66	276.02±43.23	290.83±53.98	270.69±53.58
t		1.608	0.252	2.785	1.904	1.659	1.758
P		0.110	0.801	0.006*	0.059	0.100	0.082

Note: Data are mean ± SD (μm). *P < 0.05. Stats: Independent t-tests. RM-ANOVA: Group (F=6.22, P=0.014), Time (P<0.001), Interaction (P=0.217).

Abbreviations: RBZ, Ranibizumab; DEX, Dexamethasone Implant.

Regarding anatomical resolution (CMT ≤300 μm), the combination group showed a significantly higher rate at month 2 (75% vs 54%, P=0.013) and month 6 (73% vs 55%, P=0.032) compared to the monotherapy group (Figure 2).

Figure 2.

Percentage of patients with CMT ≤300μm. *P < 0.05.

Abbreviations: CMT, Central Macular Thickness; RBZ, Ranibizumab; DEX, Dexamethasone Implant.

Subgroup Analysis (BRVO vs. CRVO)

Baseline characteristics were balanced within both BRVO and CRVO subgroups (Table 4).

• Visual Acuity: In the BRVO subgroup, the RBZ+DEX group showed significantly greater BCVA improvement from month 2 through month 9 (P<0.05). In the CRVO subgroup, while the combination group showed numerically higher improvement, the difference was not statistically significant (Table 5).

• CMT: In the BRVO subgroup, RM-ANOVA showed significant group and interaction effects, with the combination group demonstrating significantly better edema resolution at months 2 and 9. In the CRVO subgroup, no significant difference in CMT was observed between groups (Table 6).

Table 4.

Baseline Demographic and Clinical Characteristics Stratified by RVO Subtype

	Group	Sex		Age	Time of Onset (days)	Laser Treatment
		Male	Female			None	Treat
BRVO	RBZ (n=43)	21	22	59.21±11.78	30 (15,60)	22	21
	RBZ+DEX (n=41)	25	16	56.78±9.45	20 (7.5,40)	21	20
	t/Z/χ2	χ2=1.248		t=1.039	Z=−1.435	χ2=0.000
	P	0.264		0.302	0.151	0.996
CRVO	RBZ (n=25)	18	7	62.28±12.14	20 (10,60)	17	8
	RBZ+DEX (n=30)	16	14	56.63±9.00	30 (30,90)	16	14
	t/Z/χ2	χ2=2.013		t=1.979	Z=−1.819	χ2=1.222
	P	0.156		0.053	0.069	0.269

Note: Data are mean ± SD, median (IQR), or n. Stats: Independent t-test, Mann–Whitney U-test, or χ² test.

Abbreviations: RBZ, Ranibizumab; DEX, Dexamethasone Implant.

Table 5.

Comparison of Mean Change in BCVA Stratified by RVO Subtype

	Group	n	1 Month	2 Months	3 Months	6 Months	9 Months
BRVO	RBZ	43	−0.17±0.21	−0.25±0.25	−0.32±0.27	−0.32±0.28	−0.34±0.25
	RBZ+DEX	41	−0.22±0.27	−0.40±0.29	−0.45±0.30	−0.49±0.30	−0.52±0.31
	t		0.994	2.437	2.054	2.42	2.575
	P		0.323	0.017*	0.043*	0.018*	0.012*
CRVO	RBZ	25	−0.28±0.31	−0.37±0.31	−0.36±0.37	−0.38±0.40	−0.41±0.40
	RBZ+DEX	30	−0.30±0.25	−0.35±0.25	−0.42±0.22	−0.47±0.22	−0.55±0.24
	t		0.229	−0.312	0.722	1.019	1.559
	P		0.819	0.757	0.473	0.313	0.126

Note: Data are mean ± SD (logMAR). *P < 0.05. RM-ANOVA: BRVO: Group (F=5.03, P=0.029), Time (P<0.001), Interaction (P=0.267); CRVO: Group (P=0.515), Time (P<0.001), Interaction (P=0.691).

Abbreviations: RBZ: Ranibizumab; DEX, Dexamethasone Implant.

Table 6.

Comparison of Mean CMT Stratified by RVO Subtype

	Group	n	Baseline	1 Month	2 Months	3 Months	6 Months	9 Months
BRVO	RBZ	43	616.81±212.07	345.07±79.64	315.30±61.10	292.09±52.50	309.33±53.09	288.50±50.87
	DEX+RBZ	41	566.95±157.44	334.02±57.04	268.76±45.68	274.83±48.21	289.20±56.16	245.61±35.11
	t		1.219	0.728	3.939	1.510	1.553	3.882
	P		0.226	0.469	<0.001*	0.135	0.125	<0.001*
CRVO	RBZ	25	723.96±209.76	361.84±80.94	331.52±87.18	290.44±41.69	303.58±58.18	285.57±39.83
	DEX+RBZ	30	649.63±203.11	367.23±78.49	321.00±56.93	277.72±35.74	292.79±52.15	299.48±57.10
	t		1.331	−0.250	0.538	1.158	0.712	−0.982
	P		0.189	0.803	0.593	0.253	0.480	0.331

Notes: Data are mean ± SD (μm). *P < 0.05. RM-ANOVA: BRVO: Group (F=4.42, P=0.040), Time (P<0.001), Interaction (F=3.28, P=0.012); CRVO: Group (F=2.38, P=0.130), Time (P<0.001), Interaction (F=2.33, P=0.060).

Abbreviations: RBZ, Ranibizumab; DEX, Dexamethasone Implant.

Treatment Burden

Over the 9-month follow-up, the RBZ+DEX group had a significantly lower treatment burden. The median number of injections was 4 [IQR: 3–4] in the combination group versus 6 [IQR: 5–6] in the monotherapy group (P<0.001). The mean retreatment interval was significantly prolonged in the combination group (96.79±15.41 days vs. 56.28±7.42 days; P<0.001). This trend was consistent across both BRVO and CRVO subgroups (Table 7).

Table 7.

Comparison of Injection Frequency and Reinjection Intervals

	Group	n	Injection Frequency (count)	Z	P	Injection Interval (days)	t	P
RVO	RBZ	68	6(5,6)	−7.324	<0.001*	56.28±7.42	−19.606	<0.001*
	RBZ+DEX	71	4(3,4)			96.79±15.41
BRVO	RBZ	43	5(4,6)	−5.771	<0.001*	55.66±7.52	−4.581	<0.001*
	RBZ+DEX	41	4(3,4)			71.78±21.74
CRVO	RBZ	25	6(5,7)	−5.605	<0.001*	55.37±6.16	−17.180	<0.001*
	RBZ+DEX	30	4(3,4)			97.78±11.71

Notes: Data are median (IQR) for frequency and mean ± SD for interval. *P < 0.05. Stats: Mann–Whitney U-test (frequency) and t-test (interval).

Abbreviations: RBZ, Ranibizumab; DEX, Dexamethasone implant.

Safety and Adverse Events

The overall incidence of adverse events was higher in the RBZ+DEX group (P=0.023), primarily driven by a higher rate of IOP elevation (26.8% vs 10.3%, P=0.013). IOP elevation in the combination group was significantly noted at months 2 and 3. Among the 19 affected eyes, 17 (89.5%) were controlled with 1–2 topical anti-glaucoma medications, and 2 (10.5%) required 3 medications. All IOP levels returned to normal by the end of follow-up without surgical intervention or optic nerve damage. There were no significant differences in cataract progression or vitreous hemorrhage, and no cases of endophthalmitis or retinal detachment occurred (Table 8 and Figure 3).

Table 8.

Comparison of Ocular Adverse Events

Complications	RBZ (n=68)	RBZ+DEX (n=71)	χ2	P
Cataract progression	1	2	<0.001	>0.99
Vitreous Hemorrhage	2	1	0.001	0.980
Ocular Hypertension pressure	7	19	6.193	0.013*
Total	10	22	5.195	0.023*

Notes: Data are n (%).*P < 0.05. Stats: Fisher’s exact test used due to low counts.

Abbreviations: RBZ, Ranibizumab; DEX, Dexamethasone implant.

Figure 3.

Changes in intraocular pressure (IOP). *P < 0.05.

Note: Data are n (%).*P < 0.05. Stats: Fisher’s exact test used due to low counts.

Abbreviations: RBZ, Ranibizumab; DEX, deXamethasone Implant.

Discussion

The definition of success in treating RVO-ME is evolving from short-term anatomical improvement to sustainable, clinically meaningful visual gain with minimal treatment burden. This study evaluated a sequential regimen of ranibizumab and dexamethasone implant.

While initial visual and anatomical improvements were comparable, the combination therapy demonstrated superior visual gains starting from month 3, maintaining significance through month 9. This divergence at month 3 highlights distinct pharmacokinetics.17,19 Anti-VEGF agents rapidly reduce permeability but have short half-lives, necessitating frequent injections. The sustained efficacy in the combination group is likely due to the prolonged, consistent release of dexamethasone and the dual targeting of VEGF-mediated permeability and corticosteroid-sensitive inflammatory pathways.20,21 We observed a significantly higher proportion of patients achieving >0.3 logMAR gain in the combination group, consistent with findings that persistent edema in monotherapy can lead to irreversible photoreceptor damage.22,23 Dexamethasone’s broad anti-inflammatory properties, including ICAM-1 downregulation and leukostasis inhibition, help preserve the blood-retinal barrier and long-term visual function.24

Anatomically, the combination group achieved significantly faster edema resolution (Month 2), laying a stable foundation for the maintenance phase. This aligns with Maturi et al,25 suggesting that the peak pharmacokinetic effect of early dexamethasone implantation facilitates structural recovery.

Subgroup analysis revealed that combined therapy yielded significant visual and anatomical improvements in patients with BRVO. In the CRVO subgroup, which involves more complex pathological mechanisms, no statistically significant intergroup differences were observed; however, the combined group still exhibited a trend toward superior improvement compared with monotherapy, alongside a significant reduction in injection frequency. These findings suggest that even for refractory CRVO, sequential therapy offers unique clinical value by maintaining therapeutic efficacy while effectively alleviating the injection burden and economic pressure on patients.

Crucially, it must be emphasized that our study strictly ruled out the ischemic capillary drop-out variety of RVO. Because ischemic RVO is driven by severe hypoxia and extensive nonperfusion, it exhibits a vastly different clinical trajectory and a notoriously poor response to standard treatments. By meticulously excluding these ischemic cases, we eliminated a major confounding variable, ensuring that our BRVO and CRVO subgroup analyses accurately reflect the true efficacy of the treatments in non-ischemic populations. Consequently, our conclusions regarding the benefits of sequential therapy apply specifically to non-ischemic RVO, and the efficacy of this combined regimen in patients with significant ischemic capillary drop-out remains to be evaluated in future dedicated studies.

Crucially, this study confirmed that sequential therapy significantly reduces injection frequency and extends retreatment intervals. In real-world practice, maintaining the rigorous injection schedules of clinical trials is challenging. Extending the interval addresses this burden and may improve compliance, corroborating findings by Singer et al26 Unlike Fan et al27 who used triamcinolone, our use of Ozurdex offers a more consistent release profile and better safety.

Regarding safety, while IOP elevation was more common in the combination group (26.76%), it was transient and manageable with topical medication, consistent with studies in Chinese populations.28 No surgical intervention was required.

However, several limitations of this study must be acknowledged. First, due to the retrospective, real-world nature of the study, a formal a priori statistical power calculation was not performed, and there is a potential for inherent selection bias. Second, while the 9-month follow-up timeframe is reasonable for assessing mid-term visual and anatomical outcomes, it is fundamentally insufficient for comprehensively evaluating long-term steroid-related safety profiles. Extended longitudinal observation is necessary to accurately capture the true incidence of late-onset complications, such as cataract progression.

Conclusion

This study demonstrates that sequential therapy with ranibizumab and a dexamethasone implant offers significant synergistic efficacy in the treatment of RVO-ME. Compared with anti-VEGF monotherapy, this combined regimen not only achieves superior long-term visual outcomes and faster resolution of macular edema but also significantly reduces injection frequency and the associated treatment burden. Although the therapy carries a risk of transient intraocular pressure elevation, it exhibits a favorable safety profile under standardized monitoring and medical management. Consequently, this sequential protocol represents a highly efficient therapeutic strategy that warrants priority consideration for RVO-ME management.

Funding Statement

This study was supported by the Henan Province Medical Science and Technology Joint Co-construction Project (Grant No. LHGJ20210967).

AI Disclosure Statement

1. Name of Tool(s): Grammarly and Google AI.

2. Purpose of Use: These tools were used strictly for English language editing, grammar refinement, and technical term translation to ensure the manuscript met the linguistic standards required for international publication.

Data Sharing Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Sanmenxia Eye Hospital (No. 20191213).

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent to Publish

The images included in this manuscript contain no personal details that could lead to patient identification. All data were anonymized prior to analysis.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no competing interests in this work.