Jueling Mingmu decoction combined with ranibizumab for retinal vein occlusion induced macular edema: A randomized controlled clinical trial

Abstract

Background/aims

To investigate the efficacy of a combined treatment approach using Jueling Mingmu Decoction and ranibizumab in managing macular edema (ME) associated with retinal vein occlusion (RVO).

Methods

This prospective, randomized, controlled, outcome assessor–blinded superiority trial involved 111 patients with treatment-naïve RVO and ME, including 53 patients assigned to the ranibizumab monotherapy group and 58 to the combination therapy group. Participants were randomly assigned to receive either intravitreal injections of 0.5 mg ranibizumab alone (monotherapy group) or combined with daily consumption of Jueling Mingmu Decoction (combination group). Primary outcomes included the number of intravitreal injections administered over 48 weeks. Secondary outcomes included changes in best-corrected visual acuity (BCVA) and central subfield fovea thickness (CST).

Results

99 patients (89.2%) completed the 48-week follow-up, including 46 of 53 patients (86.8%) in the monotherapy group and 53 of 58 patients (91.4%) in the combination group. The monotherapy group received an average of 4.35 ± 1.73 injections, while the combination group received 4.64 ± 1.92 injections (P = 0.471), with no significant difference between the groups. BCVA improved significantly in both groups, with the combination group showing a greater improvement at 48 weeks in patients with branch RVO (BRVO) compared to the monotherapy group (P = 0.031). CST decreased significantly in both groups, with the combination group showing a significantly lower CST at 36 weeks in BRVO patients (P = 0.018). No significant differences were observed between the groups for central retinal vein occlusion (CRVO) patients.

Conclusion

The combination of Jueling Mingmu Decoction and ranibizumab appears to be a potentially effective treatment for improving visual and anatomical outcomes in RVO-related ME, especially in BRVO patients. However, it does not significantly reduce the number of required intravitreal injections compared to monotherapy. Further studies are needed to confirm these findings and explore the long-term efficacy and safety of this treatment approach.

Introduction

RVO, encompassing branch BRVO and central CRVO, is the second most common retinal vascular disorder [1], with a reported global prevalence of 0.50% [2, 3]. Macular edema is a frequent cause of vision loss associated with RVO [4, 5]. Recently, treatment approaches for ME caused by RVO include anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroid therapies, and macular laser procedures [6–8].

Anti-VEGF injections are widely regarded as the first-line treatment for RVO-related ME [9, 10]. However, there is a noticeable gap between the visual and anatomical outcomes achieved in clinical trials and those observed in real-world settings. Many patients undergoing routine anti-VEGF treatment do not experience the same degree of improvement as reported in trials [11, 12]. Furthermore, the requirement for frequent injections places a considerable financial burden on patients [13].

Studies investigating combined therapies, such as intravitreal ranibizumab injections paired with retinal laser treatment, have shown that this approach does not reduce the number of required injections or enhance visual outcomes [14]. On the other hand, dexamethasone implants, known for their strong anti-inflammatory properties, effectively reduce macular edema and suppress neovascularization [8, 15]. However, their use is associated with significant risks, including elevated intraocular pressure, cataract development, and noninfectious endophthalmitis [16, 17].

While VEGF is recognized as a key factor in the development of ME in RVO, targeting VEGF alone may not fully address the condition. The RELATE study demonstrated that increasing ranibizumab anti-VEGF dosing did not lead to better clinical outcomes in RVO patients [14]. This suggests that addressing additional disease pathways beyond VEGF could enhance treatment efficacy and long-term results.

RVO is primarily linked to cardiovascular risk factors, especially in the elderly, which contribute to retinal neuronal damage and optic nerve impairment. According to Traditional Chinese Medicine (TCM), RVO-induced ME is associated with systemic dysfunction, classically described as imbalances in Yin and Yang and stagnation of Qi and blood in the retinal microcirculation. From a biomedical perspective, these descriptions can be interpreted as corresponding to microcirculatory impairment, local inflammatory responses, and fluid accumulation, all of which are implicated in RVO pathophysiology. Herbal formulations such as Jueling Mingmu Decoction have been traditionally used to “clear heat” and “promote diuresis,” which can be viewed as exerting anti-inflammatory effects, improving microcirculation, and reducing retinal vascular congestion. Previous pharmacological studies [18–20] suggest that active components in its ingredients, including salvianolic acid B (from Salvia miltiorrhiza) and triterpenoids (from Poria), can reduce oxidative stress, improve collateral circulation, and enhance retinal microvascular perfusion, thereby potentially supporting edema resolution in RVO.

Previous studies [21, 22] have indicated that Chinese herbal medicines with properties that activate blood circulation and alleviate blood stasis may reduce retinal edema in RVO patients, potentially decreasing the frequency of anti-VEGF injections and improving vision. One such formulation, Jueling Mingmu Decoction, consists of lycopsia, cassia, wormwood, chrysanthemum, red peony, schizonepeta, poria, plantago, salvia miltiorrhiza, rice bud, and licorice. Known for its ability to clear liver heat, promote diuresis, activate blood circulation, and strengthen the stomach and spleen, this decoction offers a targeted approach to managing RVO-induced ME.

This study aims to explore the efficacy of combining Jueling Mingmu Decoction with ranibizumab in treating ME associated with RVO through a randomized, outcome assessor–blinded trial.

Materials and methods

This prospective, randomized, controlled, outcome assessor–blinded trial was designed to evaluate the efficacy of combining Jueling Mingmu Decoction with ranibizumab for the treatment of macular edema associated with retinal vein occlusion. The study received approval from the Institutional Ethical Committee of Dongyang People's Hospital and adhered to the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all participants prior to enrollment. This study was registered at ClinicalTrials.gov (Identifier: NCT06234514) on January 30, 2024.

Patient eligibility and exclusion criteria

Participants eligible for inclusion were aged 18 years or older, diagnosed with treatment-naïve RVO within the past 9 months, presented with a BCVA letter score of 73 to 24 on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart (Snellen equivalent: 20/40 to 20/320), and demonstrated a CST of 250 μm or greater on spectral-domain optical coherence tomography (SD-OCT) using Spectralis HRA + OCT (Heidelberg Engineering). The ≥ 250 μm threshold was selected based on prior similar studies [22, 23] and is consistent with our institutional practice standards. Exclusion criteria included the presence of other macular pathologies, such as age-related macular degeneration (AMD) or diabetic retinopathy (DR), significant systemic illnesses like severe cardiovascular, hepatic, or renal diseases, known hypersensitivity to the study medication, and any personal or medical concerns that could have affected treatment adherence or study participation. Additionally, all CRVO patients underwent baseline fluorescein angiography (FFA) to assess retinal perfusion, and those diagnosed with ischemic CRVO were excluded to ensure comparable baseline characteristics and to avoid confounding effects on outcomes.

Randomization and blinding

This study was conducted as an outcome assessor–blinded trial. Outcome assessors, statisticians, and data analysts were blinded to group allocation, while patients and the healthcare personnel administering the interventions were aware of treatment assignments due to the distinctive taste and preparation of the herbal decoction. In this study, a stratified randomization method was used to allocate participants into two groups in a 1:1 ratio, utilizing SPSS v26.0 (SPSS Inc, Chicago, IL, USA). The randomization process incorporated minimization and accounted for three key variables for stratification: sex (male/female), age (> 50/ ≤ 50 years), and type of retinal vein occlusion (RVO) (CRVO/BRVO). A pre-determined random allocation sequence was generated and sealed in sequentially numbered opaque envelopes to ensure one-time randomization. A researcher, who was not involved in the intervention, monitored the allocation process to maintain impartiality. All personnel involved in the study, including outcome assessors, statisticians, and data analysts, remained blinded to group allocation, while those administering the intervention were informed of the group assignments.

Interventions

All eligible patients were randomly assigned in a 1:1 ratio using a random number table to one of two treatment groups: the monotherapy group, which received intravitreal injections of 0.5 mg of ranibizumab alone, or the combination group, which received both intravitreal injections of 0.5 mg of ranibizumab and daily consumption of Jueling Mingmu Decoction.

The herbal components were sourced from certified suppliers, and all raw materials underwent authentication and quality control testing, including checks for heavy metals, pesticide residues, and microbial contamination. The decoction was prepared and packaged in standardized doses by a GMP-certified pharmaceutical company to ensure consistency and safety.

For the first 3 months, all patients received monthly intravitreal injections of 0.5 mg ranibizumab. From months 4 to 12, patients were evaluated monthly, with additional ranibizumab injections administered if there was a loss of 5 or more letters of BCVA on the ETDRS chart compared to their highest previous score, or if residual macular edema was detected on OCT. Residual macular edema was defined as insufficient CST reduction following three intravitreal anti-VEGF injections, according to the criteria proposed by Sorour [24]: a reduction in CST of < 10% for retinal thickness ≤ 400 μm, < 15% for 401–500 μm, < 20% for 501–600 μm, and < 25% for > 600 μm. Intravitreal injections were administered by ophthalmologists under topical anesthesia in a sterile operating room. Following skin preparation, 0.5 mg (0.05 mL) of ranibizumab (Lucentis®; Novartis, Basel, Switzerland) was injected into the vitreous cavity through the pars plana using a 30-gauge needle. The injection site was gently compressed for one minute after needle withdrawal. Following the injection, patients were instructed to apply 0.3% levofloxacin eye drops four times daily for one week. For patients with intraocular pressure (IOP) ≥ 22 mmHg, topical antiglaucoma medications, either single or in combination, were prescribed.

Patients in the combination group consumed 200 mL of Jueling Mingmu Decoction once daily for the first month of treatment only. The decoction was formulated as a standardized granule extract, packaged in single-dose sachets, and dissolved in 50 mL of hot water prior to ingestion. Each dose consisted of one sachet, administered once daily immediately after a meal. The use of any other TCM or modern Western medicine was strictly prohibited during the treatment period, in addition to the prescribed medications. Adherence was monitored through weekly telephone follow-up during the first month and sachet counts at scheduled visits. To assess safety, liver and renal function tests were performed at baseline and at 1, 3, and 6 months after treatment for patients in the combination group.

Efficacy evaluation

Baseline data were collected on the duration of occlusion, history of prior eye diseases or interventions, and the presence of systemic conditions. Ophthalmic assessments included BCVA, IOP, and detailed anterior and posterior segment evaluations using indirect ophthalmoscopy, including fundus examination findings.

The primary outcome was the mean number of intravitreal ranibizumab injections administered over 48 weeks, compared between the two groups. Secondary outcomes included changes in BCVA and CST from baseline.

Follow-up visits were conducted at weeks 4, 12, 24, 36, and 48. At each visit, BCVA was recorded, and comprehensive evaluations were performed, including slit-lamp examination, IOP measurement, fundus assessment, and OCT imaging.

Statistical analysis

A comprehensive analysis was performed to describe the demographic and clinical characteristics of the patient population. The Shapiro–Wilk test was used to assess the normality of the variables. Continuous data were presented as mean ± standard deviation (SD), while categorical data were expressed as counts (percentages).

Group comparisons were conducted using the independent samples t-test for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables. Categorical variables were analyzed using the chi-square test. Changes in mean BCVA and CST before and after treatment within each group were evaluated using a paired Student’s t-test. All statistical tests were two-tailed, with a significance threshold set at 0.05. Data analysis was carried out using SPSS version 17 (IBM Corporation, Armonk, NY) following standard analytical procedures.

Results

A total of 111 patients were randomized into the study, with 53 allocated to the monotherapy group and 58 to the combination group. Of these, 99 patients (89.2%) completed the trial, including 46 (86.8%) in the monotherapy group and 53 (91.4%) in the combination group (Fig. 1).

Fig. 1.

Flow diagram for the study

The baseline characteristics of the patients are summarized in Table 1. No significant differences were identified between the two groups regarding age, gender, IOP, lens status, presence of diabetes mellitus or hypertension, BMI, symptom duration, baseline BCVA, CST, or the proportion of RVO types.

Table 1.

Comparison of baseline characteristics of the intervention and control groups

Group	Combination therapy group	Intravitreal ranibizumab group	p value
Number of eyes	53	46	NA
Age (years) (Mean ± SD)	62.25 ± 15.14	63.43 ± 13.59	0.68†
Sex (n), male/female	27/26	22/24	0.76‡
IOP (mmHg) (Mean ± SD)	15.13 ± 3.11	14.26 ± 2.20	0.27§
Lens status (n), phakic/IOL	46/7	39/7	0.78‡
Diabetes Mellitus (%)	5(9.4)	5(10.9)	0.81‡
Hypertension (%)	27(50.9)	23(50.0)	0.93‡
BMI (Mean ± SD)	23.72 ± 2.23	23.54 ± 2.24	0.37§
Duration of symptoms (weeks) (Mean ± SD)	15.92 ± 17.90	11.11 ± 13.93	0.22§
BCVA (LogMAR) (Mean ± SD)	1.02 ± 0.33	0.95 ± 0.37	0.32§
CST (um) (Mean ± SD)	706.23 ± 235.53	653.63 ± 216.34	0.19§
Type of RVO (n), CRVO/BRVO	11/42	10/36	0.91‡

SD, standard deviation; n, number; IOP, intraocular pressure; IOL, intraocular lens; BMI, body mass index; BCVA, best-corrected visual acuity; LogMAR, logarithm of minimum angle of resolution; CST, Central subfield fovea thickness; RVO, retinal vein occlusion; CRVO, central retinal vein occlusion; BRVO, branch retinal vein occlusion

^† p values were derived by Independent Samples t-tests

^‡ p values were derived by Pearson’s chi-square tests

^§ p value was derived by Mann–Whitney U test

Primary outcome

At 48 weeks, there was no significant difference in the number of intravitreal injections between the two groups. The monotherapy group received an average of 4.35 ± 1.73 injections, while the combination group received 4.64 ± 1.92 injections (P = 0.471). Similarly, subgroup analysis showed no statistically significant differences (Table 2).

Table 2.

Comparison of the number of intravitreal injections, visual, and anatomic outcomes at 48 weeks between patients treated with intravitreal injection monotherapy and those treated with combination therapy

outcome	Retinal Vein Occlusion			Branch Retinal Vein Occlusion			Central Retinal Vein Occlusion
	Monotherapy	Combination therapy	P value	Monotherapy	Combination therapy	P value	Monotherapy	Combination therapy	P value
Number of intravitreal injections (Mean ± SD)	4.35 ± 1.73	4.64 ± 1.92	0.471	5.50 ± 1.96	5.55 ± 2.25	0.918	4.03 ± 1.54	4.40 ± 1.78	0.284
BCVA (LogMAR) (Mean ± SD)	0.69 ± 0.38	0.57 ± 0.44	0.041	1.12 ± 0.39	0.99 ± 0.47	0.512	0.57 ± 0.28	0.46 ± 0.36	0.031
CST (um) (Mean ± SD)	346.07 ± 196.74	262.87 ± 92.24	0.048	457.10 ± 264.45	294.00 ± 149.16	0.251	315.22 ± 165.18	254.71 ± 70.96	0.102

SD, standard deviation; BCVA, best-corrected visual acuity; LogMAR, logarithm of minimum angle of resolution; CST, Central subfield fovea thickness

p value was derived by Mann–Whitney U test

Secondary outcomes

The mean BCVA improved significantly from baseline in all treatment groups. At the end of the 48-week period, BCVA in the monotherapy group improved from 0.95 ± 0.37 to 0.69 ± 0.38 (P = 0.000), while the combination group showed greater improvement, from 1.02 ± 0.33 to 0.57 ± 0.44 (P = 0.000). During the 48-week follow-up, a statistically significant difference in BCVA between the two groups was observed only at 48 weeks (P = 0.041, Table 2). No significant differences were found at other time points (Fig. 2A). Subgroup analysis showed no significant difference in BCVA between the two groups among patients with CRVO throughout the 48 weeks (Fig. 3A). For patients with BRVO, BCVA was similar between the two groups during the first 36 weeks, but the combination group demonstrated superior improvement at 48 weeks (P = 0.031, Fig. 3C, Table 2).

Fig. 2.

Changes in BCVA and CST in RVO Patients During the 48-Week Follow-Up in the Monotherapy and Combination Therapy Groups. A: Changes in BCVA; B: Changes in CST (RVO = Retinal Vein Occlusion; BCVA = Best-Corrected Visual Acuity; CST = Central Subfield Fovea Thickness; * indicates statistical significance)

Fig. 3.

Subgroup Analysis: Changes in BCVA and CST in BRVO and CRVO Patients During the 48-Week Follow-Up in the Monotherapy and Combination Therapy Groups. A: Changes in BCVA in CRVO Patients; B: Changes in CST in CRVO Patients; C: Changes in BCVA in BRVO Patients; D: Changes in CST in BRVO Patients. (CRVO = Central Retinal Vein Occlusion; BRVO = Branch Retinal Vein Occlusion; BCVA = Best-Corrected Visual Acuity; CST = Central Subfield Fovea Thickness; * indicates statistical significance)

After 48 weeks of treatment, CST decreased significantly in both groups. In the monotherapy group, CST reduced from 653.63 ± 216.34 to 332.48 ± 184.27 (P = 0.000), while in the combination group, it decreased from 706.23 ± 235.53 to 262.87 ± 92.24 (P = 0.000). At all follow-up time points within the 48-week period, there was no statistically significant difference in CST between the two groups (Fig. 2). Subgroup analysis showed that among BRVO patients, the CST in the combination group was significantly lower than that in the monotherapy group at 36 weeks (P = 0.018, Fig. 3D). However, no significant differences in CST were observed between the two groups or among CRVO patients at other time points (Figs. 3B and 3D).

Safety

No treatment-related adverse events were observed in either group during the clinical observation period. Throughout the 12-month follow-up, no major ocular complications, including elevated intraocular pressure, retinal detachment, intraocular inflammation, or vascular events, were reported in either group. In the combination group, liver and renal function tests conducted at baseline and at 1, 3, and 6 months post-treatment revealed no clinically significant abnormalities.

Discussion

This randomized, outcome assessor–blinded trial evaluated the efficacy of combining Jueling Mingmu Decoction with intravitreal ranibizumab injections for treating ME associated with RVO. The findings revealed that while the combination therapy offered certain advantages in improving secondary outcomes—such as better BCVA in BRVO patients at 48 weeks and greater CST reduction at 36 weeks—it did not significantly reduce the number of required intravitreal injections compared to monotherapy.

Current intravitreal therapies for RVO-related ME, when administered consistently and over an adequate duration, effectively sustain initial improvements [25, 26]. However, these interventions primarily address the consequences of venous outflow obstruction without targeting the underlying multifactorial causes. Factors such as elevated central venous pressure, cytokine upregulation, and inflammatory processes are thought to contribute to RVO pathology [27, 28]. Given the complex nature of RVO, a treatment approach that simultaneously targets multiple pathways may more effectively delay disease progression and improve clinical outcomes.

TCM differs from Western medicine in its use of complex formulations composed of multiple herbs, each containing various active ingredients. For example, Poria, a commonly used TCM herb, is known for its ability to reduce swelling and aid in the absorption of retinal hemorrhage, thereby alleviating macular edema. Salvia miltiorrhiza, another key component, has long been used to treat microcirculatory disturbances. Its active compounds, such as salvianolic acid B and protocatechuic aldehyde, can promote collateral circulation, potentially improving visual outcomes and reducing the frequency of injections. These ingredients collectively act on multiple biological pathways, forming a synergistic network of therapeutic effects. Some previous studies have shown that some TCM treatment combined with conventional treatment could have certain advantages [29].

The BCVA and CST improvements observed in both groups underscore the well-established efficacy of anti-VEGF agents as the first-line treatment for RVO-related macular edema. However, BRVO patients in the combination group exhibited greater BCVA improvement at 48 weeks and more pronounced CST reduction at 36 weeks, suggesting that Jueling Mingmu Decoction may provide complementary benefits. By targeting pathways beyond VEGF inhibition—such as enhancing blood circulation, reducing retinal edema, and possibly exhibiting anti-inflammatory and diuretic properties—traditional Chinese medicine could address additional aspects of the disease process. These effects may optimize treatment outcomes by adopting a multi-pathway approach, as proposed in the previous studies [30, 31]. Jueling Mingmu Decoction likely acts as an adjunctive therapy, targeting inflammation, microcirculatory dysfunction, and edema rather than exerting a direct anti-VEGF effect. This multi-pathway action complements ranibizumab and may partly explain the functional and anatomical benefits observed in BRVO patients. The importance of inflammation control in RVO has also been highlighted in recent study [32], which demonstrated the efficacy of long-term dexamethasone implant monotherapy. These findings underscore the potential value of incorporating anti-inflammatory strategies, including TCM formulations, into RVO management. The more pronounced improvements in BRVO patients compared to CRVO patients may be attributed to the relatively less severe retinal obstruction in BRVO, allowing combined treatment to exhibit a more noticeable therapeutic effect. In contrast, CRVO patients, with more severe retinal blockage and poorer baseline vision, may not experience distinguishable benefits from the combination therapy, masking any potential differences in treatment efficacy. As in previous study [33], addition of scatter photocoagulation to ranibizumab might help slow the progression of non-perfusion in patients with BRVO, but not in those with CRVO.

Despite these promising findings, the study did not show a significant reduction in the number of ranibizumab injections required in the combination group. This aligns with previous research, which indicates that adjunct therapies, such as retinal laser treatment or anti-inflammatory treatments [14, 34], often do not lead to a reduction in injection frequency. The financial and logistical burdens associated with frequent anti-VEGF injections remain a significant challenge for patients, highlighting the need for alternative or complementary treatment options.

This study has several strengths, including its robust design, use of stratified randomization, and adherence to established clinical protocols. However, it also has some limitations. First, although the outcome assessor–blinded design reduced the risk of bias by ensuring that assessors and data analysts were blinded, it cannot fully eliminate potential bias. Second, the 48-week follow-up period limits the ability to evaluate long-term outcomes and safety. Third, the study was conducted at a single center with a relatively small sample size, particularly in the CRVO subgroup, where only 10 patients were included in each group, potentially limiting the statistical power and generalizability of the findings. Fourth, the timing of the most recent ranibizumab injection prior to each follow-up visit was not systematically documented; therefore, some of the observed CST reductions—especially at 36 weeks—may partly reflect short-term effects of recent injections rather than sustained anatomical improvement. These limitations should be considered when interpreting the results, and larger multicenter studies with longer follow-up are warranted.

Future studies should explore the long-term efficacy and safety of combining TCM formulations with anti-VEGF therapy in larger, multicenter trials. Investigating the molecular mechanisms underlying the effects of Jueling Mingmu Decoction could provide deeper insights into its therapeutic potential and inform the development of novel treatment strategies for RVO-related ME. Additionally, cost-effectiveness analyses are needed to evaluate the feasibility of incorporating TCM into standard clinical practice.

In conclusion, this study suggests that the combination of Jueling Mingmu Decoction with ranibizumab is a potentially effective treatment for improving visual and anatomical outcomes in patients with RVO-related ME, particularly in BRVO patients. While the results are encouraging, further research is necessary to confirm these findings and refine treatment protocols.

Author Contribution

WHY conceptualized and designed the study. ZHS drafted the main manuscript text. ZY collected the data, and ZHS verified it. ZHS conducted the statistical analyses. All authors critically reviewed and revised the manuscript before submission.

Funding

The research was financially supported by the Jinhua Traditional Chinese Medicine Science and Technology Research Program (2023KY34).

Data availability

The data supporting the study results can be obtained from the corresponding author upon reasonable request.

Declarations

Conflict of interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval

Have been granted by the Institutional Ethical Committee of Dongyang People's Hospital, with reference number Dongrenyi 2023-YX-346. Informed consent will be obtained from all study participants upon their recruitment.