Choroidal neovascularisation (CNV) is a leading cause of irreversible central vision loss globally, primarily resulting from age-related macular degeneration (AMD), pathological myopia, and other retinal disorders. Globally, CNV due to neovascular AMD affects millions of individuals, with prevalence increasing with age; it is estimated that by 2040, over 288 million people worldwide will be affected by AMD, with a significant proportion developing CNV.¹ The disease is characterized by the growth of abnormal choroidal vessels beneath the retina, leading to leakage, haemorrhage, and subretinal fibrosis, ultimately causing severe visual impairment if untreated. CNV also occurs in other retinal disorders such as myopic CNV, angioid streaks, and inflammatory retinal diseases, contributing further to the global burden of vision loss.²

In India, the prevalence of AMD-related CNV is rising due to an aging population and increased life expectancy. Epidemiological studies suggest that approximately 2–3% of individuals over 50 years of age in India have neovascular AMD, with CNV accounting for the majority of severe visual loss in this group. Other causes of CNV, such as pathological myopia and post-inflammatory CNV, are also encountered frequently in the Indian population, making it a significant public health concern. Delayed diagnosis and limited access to advanced retinal imaging or anti-VEGF therapy in rural and semi-urban regions often result in late presentation and poorer visual outcomes.³ Vascular endothelial growth factor (VEGF) plays a pivotal role in CNV pathogenesis by stimulating angiogenesis and increasing vascular permeability. The introduction of intravitreal anti-VEGF therapy, including bevacizumab, ranibizumab, and aflibercept, has revolutionized CNV management, improving both visual acuity and anatomical outcomes. Bevacizumab, a full-length monoclonal antibody targeting VEGF-A, is widely used off-label worldwide and particularly in India due to its proven efficacy, favourable safety profile, and cost-effectiveness compared to other anti-VEGF agents.⁴ This is crucial in countries with limited healthcare resources, where treatment affordability significantly affects patient adherence and long-term outcomes. Different treatment regimens for intravitreal anti-VEGF therapy exist, including fixed monthly dosing and variable regimens such as pro re nata (PRN) or treat-and-extend approaches. Clinical trials globally including the CATT, IVAN and HORIZON studies have demonstrated comparable visual outcomes between fixed and variable regimens for anti-VEGF therapy, but the data specifically for bevacizumab remains limited.^5,6

In India, limited studies have explored fixed versus variable dosing of intravitreal bevacizumab for CNV. With the growing prevalence of AMD and other causes of CNV, optimizing dosing regimens is critical to balance efficacy, safety and treatment burden in both urban and rural populations.⁷ Therefore, this study was undertaken to evaluate and compare the visual and anatomical outcomes of intravitreal bevacizumab administered using fixed and variable dosing regimens in Indian patients with CNV, providing evidence relevant for clinical practice in resource-limited settings.

AIM

To evaluate and compare the visual and anatomical outcomes of intravitreal bevacizumab in patients with choroidal neovascularisation using fixed and variable dosing regimens.

OBJECTIVES

1. To assess the improvement in best-corrected visual acuity (BCVA) in patients receiving fixed versus variable dosing of intravitreal bevacizumab.
2. To compare changes in central foveal thickness (CFT) measured by OCT between the two dosing regimens.

tudy Design and Setting

This was an open-labelled, prospective interventional study conducted at the Regional Institute of Ophthalmology and Government Ophthalmic Hospital (RIO GOH), Egmore, Chennai, after obtaining approval from the Institutional Ethics Committee. The study was carried out over one year (October 2020 – September 2021).

Study Population

All treatment-naïve patients diagnosed with choroidal neovascularisation (CNV) of any cause attending the vitreoretinal services at RIO GOH were considered for inclusion. Written informed consent was obtained from all participants.

Sample Size

Based on reference studies, with P1 = 2.5%, P2 = 14.3%, level of significance 5%, and power 80%, the required sample size was 83 eyes per group, resulting in a total of 166 eyes.

Inclusion Criteria

• Newly diagnosed CNV involving the central macula or within 500 microns of the macula
• Age ≥40 years
• Treatment-naïve eyes

Exclusion Criteria

• Previously treated CNV
• Visually significant cataract
• Pregnancy
• Recent cerebrovascular accident or myocardial infarction (within 3 months)
• Chronic kidney disease or diabetic nephropathy
• Patients with only one functional eye

Baseline Evaluation

A detailed clinical history and systemic examination were performed to confirm eligibility. Patients were counselled regarding treatment, follow-up, and possible complications.

Ocular Examination included:

• Best Corrected Visual Acuity (BCVA) using Log MAR chart
• Anterior segment examination with slit-lamp bio microscopy
• Posterior segment examination with 90D slit-lamp lens and 20D indirect ophthalmoscopy
• Intraocular pressure measurement with Goldmann applanation tonometry
• Fundus photography
• Optical Coherence Tomography (OCT)
• Fundus Fluorescein Angiography (FFA)
• Amsler grid charting

Systemic Investigations included:

• Blood pressure
• Fasting and postprandial blood sugar
• Lipid profile
• HbA1c
• Cardiologist evaluation if indicated

Treatment Protocol

Patients were alternatively assigned into two groups:

Group 1 (Fixed Dosing)

• 83 eyes received intravitreal bevacizumab 1.25 mg/0.05 mL monthly for 3 consecutive months, with follow-up at 6th and 9th month.

Group 2 (Variable Dosing / Pro Re Nata – PRN)

• 83 eyes received intravitreal bevacizumab as needed, based on disease activity, with follow-up every 4 weeks up to 9 months.

PRN Criteria for Retreatment (Group 2):

• Increase in central foveal thickness (CFT) ≥50 μm on OCT
• No significant reduction in CFT
• Decrease in BCVA from previous visit
• Persistent or new subretinal/intraretinal fluid on OCT

Intravitreal Injection Procedure

• Topical anaesthesia with 0.5% proparacaine
• Eyes cleaned with 5% povidone-iodine and draped
• Lid speculum applied
• Injection site:
• Phakic eyes: 4 mm from limbus
• Pseudophakic eyes: 3.5 mm
• Aphakic eyes: 3 mm
• Intravitreal bevacizumab 1.25 mg/0.05 mL injected inferotemporal or supertemporal
• Post-injection medications:
• Topical antibiotics 1 drop 4 times/day
• NSAID eye drops 1 drop 4 times/day
• Oral acetazolamide 250 mg twice daily for 3 days
• Patients examined on Day 0 and Day 3 post-injection for safety

Statistical Analysis

Data analyzed using SPSS. Continuous variables expressed as mean ± SD, categorical variables as frequencies and percentages. Comparison between groups: Independent t-test or Mann–Whitney U test for continuous variables. Chi-square test or Fisher’s exact test for categorical variables. p-value <0.05 considered statistically significant.

Table 1: Age and gender distribution of patients considered for study

The sample set considered for study consists of totally 136 eyes. The main notion behind this analysis is to check if the age and gender factor has dominance in cause of CNV. In the data considered, around 75% of population are found to be between the ages of 51 to 70. The age below 40 accounts up to 2% and age above 81 accounts around 5%. This study is concentrated towards the patients of age 51 to 80.

Table 2: Age wise and gender wise level of significance

We can infer the male female ratio and age distribution among patients of age above 50 and below 50 are quite significant from the Table 2 which showing the p value of gender distribution as 0.002 and p value of age distribution as 0.003 which is statistically significant.

1. Bilaterality

Out of 136 eyes considered for the study, 18 eyes i.e., 9 patients are observed with wet AMD on both their eyes. Within the subset of unilateral condition of population 118 eyes, 27 eyes are affected by dry AMD on the other eye and rest of 91 eyes are seen to be normal. This figure helps us in understanding the dynamics of patients with respect to the CNV.

Fig1: Bilaterality in CNV

1. Incidence of CNV in dry AMD

Among the 27 eyes with dry AMD in the other eye, one eye reported with incidence of CNV during the course of study which is statistically significant with p value of 0.004. The incidence is found using home amsler grid chart monitoring for the other eye weekly.

Fig 2: Incidence of Wet AMD

Table 3: Significance of incidence of wet AMD

Table 4: Progression of Dry AMD to Neovascular AMD During Follow-up

Interpretation
During the study period, one eye (3.7%) with dry AMD progressed to neovascular AMD.

C. SYSTEMATIC ILLNESS

Before classifying population in two groups, it is important to understand the systemic illness of the patients as the treatment and follow-up can differ based on the history and severity of the same. Out of 136 eyes, 108 are found to be not associated with any comorbidities, whereas rest of 28 are found to be with hypertension or diabetes or both. Around 4% (4 eyes) are found to be with the history of both diabetes and hypertension. The patients with history of either hypertension or diabetes only are found to be 40% and 46% respectively.

Figure 3: Comorbidities associated with CNV

Table 5:   Significance of bilaterality and systemic illness

It is evident that people of CNVM with other eye involvement are significant with p value of 0.0001 and the people without systemic illness are significant with p value of 0.0001.

D. ETIOLOGY OF CNVM

Around 92% of population are observed to have AMD as a cause of CNVM. 8% of other population are presented with high myopic and inflammatory CNVM. Out of 125 eyes, 82 eyes and 43 eyes observed with AMD are male and female respectively. This ratio is seen to prevail with high myope and inflammatory type of CNVM.

Figure 4: Types of CNVM

Table 6: Significance of type of CNVM and patients with smoking habits

AMD-related CNVM formed the majority of cases, followed by myopic and inflammatory CNVM, with this distribution being statistically significant (p = 0.008). Smoking was also found to have a statistically significant association with CNVM (p = 0.023), suggesting smoking as an important risk factor in the development of CNV.

Table 7: Age and gender wise distribution of patients in group 1 & 2

Table 8 depicts the age and gender distribution of patients in both fixed dosing (Group 1) and variable dosing (Group 2) regimens. The majority of patients in both groups belonged to the 51–70-year age group. The distribution pattern across age groups appears comparable between the two groups, indicating adequate matching and minimizing selection bias.

Table 8: Significance of age in group 1 & 2

This uniformity in distribution of patients among the group is statistically proved  using the chi square test of mean of age in both the groups. We can see that p value is following the null hypothesis and converging at a fact that patients are equally distributed among the group.

Table 9: Pre-treatment analysis of BCVA, IOP and CFT in group 1 & 2

Table 10 compares baseline BCVA, IOP and CFT between Group 1 and Group 2 prior to treatment initiation. No statistically significant differences were observed for any parameter (p > 0.05), confirming that both groups were comparable at baseline and suitable for outcome comparison.

Table 10: Comparison of Number of Clinical Visits and Injections Between Group 1 and Group 2

* Statistically significant (p < 0.05)

Results interpretation:
Patients in the fixed dosing group required significantly fewer clinic visits and injections compared to the PRN group.

Table 11: Age-wise Distribution of Mean Number of Injections in Group 1 and Group 2

Results interpretation:
Across all age groups, patients in Group 2 required a higher mean number of injections, with the greatest injection burden observed in patients aged above 60 years.

Table 12: Safety Profile of Intravitreal Bevacizumab Injections

Results interpretation:
Intravitreal bevacizumab was well tolerated in both groups, with no serious ocular or systemic complications observed during the study period.

Table 13: Comparative analysis of BCVA, IOP and CFT in group 1 & 2 at 12 weeks

The mean values of BCVA and IOP are close to each other proving that the changes are statistically insignificant whereas the mean value of CFT of group 1 and group 2 are observed to be 296 microns and 375 microns making it statistically significant with p value of 0.002

Table 14: post-treatment analysis of BCVA, IOP and CFT in group 1 & 2

The significance of BCVA, IOP and CFT findings of patients of group 1 and group 2 at the end of 9 months of treatment are presented. BCVA and IOP values on comparison proves to be insignificant as the mean value in both the groups are close to each other. The mean value of CFT of group 1 and group 2 are witnessed to be 292 microns and 325 microns ascertaining it statistically significant with p value of 0.002.

Fig 5: Comparison of Visual and Anatomical Outcomes Between Group A and Group B

In Group A, mean BCVA showed a progressive improvement from baseline to the 9-month follow-up, with a statistically significant improvement observed over time (p = 0.020). Similarly, Group B demonstrated a significant improvement in mean BCVA from baseline to the final follow-up visit (p = 0.015), confirming the effectiveness of intravitreal bevacizumab in improving visual acuity in both treatment protocols.

With respect to intraocular pressure, Group A showed no statistically significant change in mean IOP from baseline to the final follow-up (p = 0.618). Likewise, Group B demonstrated stable IOP values throughout the follow-up period, with no statistically significant difference between baseline and the final visit (p = 0.915). These findings indicate that repeated intravitreal bevacizumab injections were safe in both groups with respect to intraocular pressure.

Regarding anatomical outcomes, Group A exhibited a significant reduction in mean central foveal thickness (CFT) from baseline to the 9th month (p = 0.001), indicating substantial anatomical improvement on OCT. A similar significant reduction in mean CFT was observed in Group B from baseline to the final follow-up (p = 0.00012), reflecting effective resolution of retinal edema and subretinal fluid.

Choroidal neovascularisation (CNV) primarily results from increased expression of vascular endothelial growth factor (VEGF) by choroidal vessels, leading to pathological angiogenesis and vascular leakage. Based on available literature, intravitreal bevacizumab has been shown to play a significant role in the management of CNV. Numerous clinical trials have independently evaluated the efficacy of intravitreal anti-VEGF therapy in CNV secondary to age-related macular degeneration (AMD), pathological myopia, and inflammatory causes^.8,9

In the present study, a comprehensive approach was adopted by including patients with CNV of diverse etiologies and comparing the efficacy of fixed (periodic) dosing with variable (PRN) dosing of bevacizumab. The objective was to determine an optimal dosing strategy and to identify factors influencing treatment response. The sample size was calculated using two proportions derived from a reference study to ensure adequate statistical power.

Analysis of demographic characteristics revealed that CNV was most commonly observed in patients aged between 51 and 70 years, with a mean age of presentation of 61.3 ± 10.3 years. This finding differs from the study conducted by Rotsos et al., where the mean age was 74 years, ranging from 64 to 95 years.10 In the present study, AMD accounted for 92% of CNV cases, while myopic and inflammatory CNV constituted 4% each. In contrast, Rotsos et al. reported CNV distribution as 82% AMD, 9% pathological myopia, and 9% angioid streaks.¹⁰

Among the 136 eyes evaluated, 86 (63%) belonged to male patients and 50 (37%) to female patients. Studies on age-related eye disease and gender, such as those by Zetterberg et al., have shown no definitive gender predilection.¹¹ However, Khan et al. demonstrated a strong association between smoking and AMD, with individuals smoking more than 40 pack-years exhibiting an odds ratio of 2.93 for CNV development.¹² In the present study, 48% of male patients had a history of smoking, further supporting the role of smoking as a significant risk factor. Bilaterality of CNV was observed in 13.3% of eyes, with all bilateral cases attributed to age-related macular degeneration. Among patients with unilateral CNV, evaluation of the fellow eye revealed dry AMD in 45% of cases. Similar observations were reported by Wang et al., who documented bilateral involvement in 57% of AMD patients, particularly in those with geographic atrophy. ¹³ These findings underscore the importance of vigilant surveillance of the fellow eye in patients with AMD. Accordingly, all patients with dry AMD were advised regular home monitoring using the Amsler grid. During the follow-up period, 3.7% of eyes with dry AMD progressed to neovascular AMD, which is comparable to the five-year conversion rate of 2.87% reported by Sudhalkar et al.¹⁴ An interesting observation in this study was that only 21% of patients had systemic comorbidities such as diabetes or hypertension, while 79% presented without systemic illness, a statistically significant finding. This contrasts with the observations by Uchiki et al., who reported a strong association between high glycemic index diets and AMD development.¹⁵

Patients in Group 1 (fixed dosing) attended a mean of five clinic visits during the study period, whereas patients in Group 2 (PRN dosing) required a significantly higher number of visits (mean 8 visits; p < 0.001) (Table 12). The mean number of intravitreal injections was significantly lower in Group 1 (3.2 ± 0.6) compared to Group 2 (4.3 ± 1.1) (p < 0.001). Age-wise analysis revealed an increasing injection burden with advancing age in both groups, particularly in the PRN group (Table 13). Safety analysis demonstrated that intravitreal bevacizumab was well tolerated, with only minor transient ocular adverse events and no serious complications such as endophthalmitis or retinal detachment (Table 14). In Group 1, mean LogMAR BCVA improved significantly from 1.71 ± 0.7 at baseline to 1.44 ± 0.5 at nine months, corresponding to a gain of approximately 15 ETDRS letters (three Snellen lines) (p = 0.020). Mean intraocular pressure remained stable (p = 0.618), while mean central foveal thickness (CFT) showed a significant reduction from 471.33 ± 170.41 µm to 292.82 ± 57.54 µm (p = 0.001). The mean number of injections required was 3.2, with a few patients requiring additional doses. These findings are comparable to those reported by Schauwvlieghe et al., who observed significant visual and anatomical improvement following bevacizumab therapy.¹⁶

In Group 2, outcomes were comparable to studies on variable dosing regimens. Lalwani et al. reported significant improvement in visual acuity and CFT with PRN dosing using ranibizumab.¹⁷ Similarly, in the present study, Group 2 showed significant improvement in BCVA and CFT with a mean of 4.3 injections. Intraocular pressure changes were not statistically significant, confirming the safety of repeated intravitreal injections.

Patients in Group 2 received between one and seven injections, with individuals aged 50–70 years commonly requiring four to five doses. Inflammatory CNV showed favorable response with fewer injections, consistent with findings by Roy et al., who reported resolution of inflammatory CNVM with a mean of 2.6 ± 1.2 injections.¹⁸

Comparative analysis between the two groups at baseline, 12 weeks, and nine months demonstrated no significant difference in BCVA and IOP. However, the reduction in CFT was statistically significant and more pronounced in the fixed-dosing group, indicating superior anatomical response. Group 1 required fewer injections and fewer visits, improving patient compliance and reducing treatment burden, whereas Group 2 involved more frequent visits and injections, increasing cost and the likelihood of loss to follow-up.

Intravitreal bevacizumab is an effective treatment modality for choroidal neovascularisation, resulting in significant anatomical and functional improvement. Fixed monthly dosing demonstrated superior reduction in central foveal thickness compared to variable dosing, with comparable visual outcomes and stable intraocular pressure. The fixed regimen required fewer injections and clinic visits, improving patient compliance and cost effectiveness. Overall, fixed dosing of intravitreal bevacizumab offers a more practical and efficient treatment strategy for CNV.

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