Comparative evaluation between ranibizumab combined with laser and bevacizumab combined with laser versus laser alone for macular oedema secondary to branch retinal vein occlusion.

PURPOSE: To evaluate the anatomical and functional efficacy of combination therapy of intravitreal ranibizumab with laser or intravitreal bevacizumab with laser treatment compared to only laser treatment for macular edema due to branch retinal vein occlusion (BRVO).
MATERIALS AND METHODS: Thirty eyes of 30 patients with BRVO of at least 6 weeks duration were randomized into three groups: Group 1 received a single dose of intravitreal Ranibizumab followed by grid laser treatment, Group 2 received a single dose of intravitreal Bevacizumab followed by grid laser treatment, and Group 3 received grid laser alone. Outcomes at 6 months follow-up were reported. Data were collected on best corrected visual acuity (BCVA), central foveal thickness (CFT), and gain in lines of Snellen acuity.
RESULTS: At 6 month follow-up, the difference in the mean BCVA and CFT between the three treatment groups was not statistically significant (P > 0.05, all comparisons). Six eyes (60%) in Group 1, four eyes (40%) in Group 2 and two eyes (20%) in Group 3 had a statistically significant gain of ≥3 lines of Snellen acuity (P < 0.05).
CONCLUSION: Both ranibizumab and bevacizumab combined with laser photocoagulation, resulted in better outcomes than grid laser treatment.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Retinal vein occlusion (RVO) is the second most common cause of retinal vascular disease after diabetic retinopathy.12 In the population-based studies, the prevalence of retinal vein occlusion was 0.6% to 2%.345 Branch retinal vein occlusion (BRVO) is the more common of the two presentations, accounting for approximately 80% of RVO.5

Macular edema is one of the leading causes of vision loss in patients with either central retinal vein occlusions (CRVO) or BRVO.6 This edema is found to be due to hypoxia-induced upregulation of vascular endothelial growth factor (VEGF) that loosens endothelial tight junctions leading to increase in vascular permeability and deposition of exudative material.78 Although, laser photocoagulation is considered the current standard of care, there have been attempts to reduce macular edema with other treatments such as intravitreal injections of triamcinolone acetonide, bevacizumab and ranibizumab, laser chorioretinal anastomosis, vitrectomy, and arterio-venous sheathotomy.9101112131415161718 Currently, however there is no universal approach.9101112131415161718

To the best of our knowledge there are no peer review studies of combined therapy of anti-VEGF agents (specifically, ranibizumab and bevacizumab) and laser therapy in patients with macular edema due to BRVO. This study evaluates the anatomical and functional efficacy of intravitreal ranibizumab and intravitreal bevacizumab with standard laser treatment in patients with macular edema due to BRVO.

MATERIALS AND METHODS

This prospective, comparative study was performed at a tertiary eye care facility in India over a period of 12 months. This study adhered with the tenets of the Declaration of Helsinki. Inclusion criteria were, diagnosis of macular edema due to BRVO (non-ischemic), with baseline Snellen best corrected visual acuity (BCVA) in the study eye less than 6/12, central foveal thickness (CFT) on optical coherence tomography (OCT) greater than 250 microns, age greater than 40 years. All subjects consented to participating in the study. Patients were excluded if they had additional eye disease that could compromise visual acuity, ocular inflammation, intraocular surgery less than a month before presentation, uncontrolled glaucoma, prior treatments with laser photocoagulation or other intervention for macular edema due to BRVO. Patients who excluded if they were pregnant or did not consent to participate in the study.

Thirty eyes (30 patients) were included in the study. These patients underwent a thorough ophthalmologic examination, including measurement of BCVA with a Snellen chart, applanation tonometry, indirect ophthalmoscopy, slit lamp examination with + 90 D, fluorescein angiography (FFA), and OCT, (Model 3000; Carl Zeiss Meditec Inc., Dublin, CA, USA). The patients were randomized into one of three groups: Group 1 received a single intravitreal injection of ranibizumab (Lucentis; Genentech, San Francisco, CA, USA) (0.5 mg/0.05 ml) on Day 0 followed by standard laser treatment on Day 7; Group 2 received a single dose of intravitreal bevacizumab on Day 0 followed by standard laser treatment on Day 7 and; Group 3 received laser treatment only.

Patients who underwent intravitreal injections received a drop of proparacaine followed by cleansing of the periocular area with 5% povidone-iodine solution. Subsequently, a sterile drape placed over the eyes. Another drop of proparacaine was instilled, followed by infiltration of conjuctival cul-de-sac by 5% povidone-iodine solution. After 2 minutes the povidone-iodine solution was washed and intravitreal injection (0.05 ml) was delivered through a pars plana route. The distance for injection was measured with Castrovejo calipers, using 3 mm for aphakic patients, 3.5 mm for pseudophakic patients and 4 mm for phakic patients. Pressure was applied with a sterile cotton swab at the injection site. Intraocular pressure (IOP) was measured with applanation tonometry. One drop of antibiotic was instilled and the eye was patched with a sterile pad. Patients were prescribed systemic antibiotics (ciprofloxacin) and topical antibiotic for a period of 5 days.

In all the groups, laser photocoagulation was performed with a spot size of 50 microns, exposure time of 0.1 seconds. The power was adjusted and started at 50 mw and increased in steps of 10 mw to produce mild intensity covering areas of capillary leakage as seen on FFA, 1 burn width apart. In Groups 1 and 2, patients were monitored for potential injection-related complications such as cataract, glaucoma, vitreous hemorrhage, retinal detachment, endophthalmitis on day 1 and day 7 follow-up visits.

Patients were followed at 1 month, 3 months, and 6 months. At each follow up visit, BCVA, slit lamp biomicroscopy, direct and indirect ophthalmoscopy, IOP, clinical fundus photography, and OCT were performed. Patients with loss of more than 2 lines of Snellen acuity or an increase in CFT more than 100 microns from previous visit were retreated as per the primary protocol of the Group. These patients underwent repeat FFA to reveal persistent areas of capillary leakage and then treatment was performed as per the noted protocol.

Primary measures of efficacy demonstrated during the study period were, improvement in mean BCVA, reduction in mean CFT and incidence of significant visual gain defined as gain of ≥3 lines on Snellen acuity at 6 months from baseline.

Statistical analysis was performed using SPSS for Windows, version 16.0 (IBM Corp., New York, NY, USA). One way analysis of variance (ANOVA) was performed for intergroup comparisons of quantitative variables that did not follow a normal distribution between the three treatment Groups. Differences in the gender distribution in the different study Groups, differences between proportions of patients exhibiting and visual gain of ≥3 lines were assessed for statistically significant changes with the Chi-square test with Yates correction. A probability P ≤ 0.05 was considered statistically significant.

RESULTS

Demographics

Thirty patients (30 eyes), comprising 12 males and 18 females, who presented with macular edema due to BRVO during the study period were included. The mean age of the patients in Group 1, Group 2 and Group 3 was 58.8 ± 9.47 years (range 42-74 years), 58.4 ± 8.55 years (range 38-68 years) and 57.0 ± 8.97 years (range 38 to 69 years), respectively. Patient demographics (age, gender, associated systemic diseases) and baseline ocular characteristics did not differ statistically significantly across all three Groups (P > 0.05 all comparisons).

Visual outcomes

The mean BCVA in the three interventional groups was assessed at baseline (presentation), and 1 month, 3 months, and 6 months after intervention [Figure 1]. At baseline, there were no statistically significant differences in the mean BCVA (decimal notation) between Group 1, Group 2 and Group 3 (0.177 ± 0.085, 0.1663 ± 0.103 and 0.21 ± 0.12, respectively) (P > 0.05 all comparisons). The same trend was observed at each of the subsequent follow-up visits. At one month follow-up, the mean BCVA (decimal notation) in Group 1, Group 2, and Group 3 was 0.397 ± 0.17, 0.365 ± 0.23 and 0.38 ± 0.28, respectively (P > 0.05, all comparisons). At the third months follow-up, the mean BCVA (decimal notation) in Group 1, Group 2, and Group 3 treatment groups was 0.423 + 0.13, 0.337 ± 0.23 and 0.399 ± 0.28, respectively (P > 0.05, all comparisons). At the sixth months follow-up, the mean BCVA (decimal notation) in Group 1, Group 2, and Group 3 was 0.44 ± 0.12, 0.38 ± 0.21 and 0.399 ± 0.28, respectively (P > 0.05, all comparisons).

Figure 1

Comparison of visual outcomes between Group 1 (ranibizumab + laser), Group 2 (bevacizumab + laser) and Group 3 (laser) over a period of 6 months

Visual gain in Snellen acuity in terms of additional lines (compared to baseline) was evaluated compared to baseline out to six months [Table 1]. At 1 month after intervention, 6 of 10 (60%) eyes in Group 1, 3 of 10 (30%) eyes in Group 2 and 2 of 10 (20%) eyes in Group 3 showed a visual gain of ≥3 lines on Snellen acuity (compared to baseline). These intergroup differences were statistically significant (P < 0.05, all comparisons). At 3 months after intervention, 6 of 10 (60%) eyes in Group 1, 2 of 10 (20%) eyes in Group 2 and 2 of 10 (20%) eyes in Group 3 showed a visual gain of ≥3 lines of Snellen acuity (compared to baseline). These intergroup differences approached statistical significance (P > 0.05, all comparisons). At 6 months after intervention, 6 of 10 (60%) eyes in Group 1, 4 of 10 (40%) eyes in Group 2 and 2 of 10 (20%) eyes in Group 3 showed a visual gain of ≥ 3 lines on Snellen acuity (compared to baseline). The intergroup differences approached statistical significance (P > 0.05, all comparisons). This can be explained as all of these modalities are well established for the treatment of macular edema secondary to BRVO, as presented by results in our study. However, a higher percentage of patients (60%) in Group 1 attained more than 3 lines of visual improvement as compared to Group 3 (20%). Although Group 1 had the worst visual acuity at presentation (0.177), final visual acuity was highest (0.44) in group 1 as compared to other Groups.

Table 1

Gain in Snellen acuity in different group of patients at different time periods

Anatomical outcome

The mean CFT was also assessed in the three interventional groups at baseline (presentation), and 1 month, 3 month, and 6 month follow-up visits [Figure 2]. At baseline, the mean CFT in Group 1, Group 2, and Group 3 (623.2 ± 328.04 microns, 561.2 ± 187 microns and 511 ± 135.52 microns, respectively) did not differ significantly (P > 0.05, all comparisons). The same trend was observed at each of the subsequent follow-up visits. At the 1 month follow-up visit, the mean CFT in Group 1, Group 2, and Group 3 was 236.6 ± 126.37 microns, 254.3 ± 106.9 microns and 274.1 ± 83.41 microns respectively (P > 0.05, all comparisons). At the 3 months follow-up visit, the mean CFT in Group 1, Group 2 and Group 3 was 216.0 ± 69.12 microns, 284.7 ± 130.4 microns and 207.2 ± 39.52 microns, respectively (P > 0.05, all comparisons). At 6 months following intervention, the mean CFT in Group 1, Group 2 and Group 3 was 216.2 ± 63.85 microns, 241.0 ± 88.9 microns and 204.1 ± 38.34 microns respectively (P > 0.05, all comparisons) [Figures 3–5].

Figure 2

Changes in the mean retinal thickness measured with optical coherence tomography in the three groups over 6 months following treatment

Figure 3

Changes in the fundus, fluorescein angiography and optical coherence tomography in Group 1 at 1, 3, and 6 months follow up

Figure 5

Changes in the fundus, fluorescein angiography and optical coherence tomography in Group 3 at 1, 3, and 6 months follow up

Changes in the fundus, fluorescein angiography and optical coherence tomography in Group 2 at 1, 3, and 6 months follow up

DISCUSSION

BRVO is the one of the most common cause of retinal pathology after diabetic retinopathy. In most patients, macular edema is the predominant cause of visual loss although severe non-perfusion of perifoveal capillaries is an additional cause of reduced vision. Elevated intraocular levels of VEGF have been demonstrated in eyes with BRVO and this has been linked to vascular leakage.19 Thus, there is a strong rationale for using VEGF antagonists such as ranibizumab and bevacizumab in eyes with macular edema following BRVO.

The natural history of macular edema secondary to BRVO was delineated in the Branch Vein Occlusion Study (BVOS).9 BVOS also demonstrated a benefit with grid photocoagulation in eyes with BRVO of 3-18 months duration and visual acuity 20/40-20/200.9 Treated eyes were more likely to gain 2 lines of visual acuity (65%) compared to untreated eyes (37%).9 Furthermore, treated eyes were more likely to have 20/40 or better vision at 3 years follow-up (60% vs 34% untreated), with a mean visual acuity improvement of 1.3 lines ETDRS versus 0.2 lines in the untreated group.9

Although the effect of anti-VEGF agents is very rapid and dramatic, the effect is short-lived and repeated injections are required which increases the cost of treatment. If the prolonged effects of laser (i.e. sustained stoppage of vascular leakage as compared to the temporary effects of intravitral injections) can be combined with the rapid effect of intravitreal injections of anti-VEGF agents, then it not only reduces the number of intravitreal injections but also reduces the financial burden of treatment, which is very important in developing countries such as India.

The largest study to date involving ranibizumab for macular edema following BRVO (BRAVO study) found that an intraocular injection of 0.3 or 0.5 mg of ranibizumab provided a rapid, effective treatment for macular edema due to BRVO.14 The BRAVO study utilized a monthly injection of ranibizumab for 6 months, with an option of rescue laser beginning from three months, if eligible.14 Rescue laser eligibility was defined as clearing of hemorrhage with visual acuity of <6/12 or CFT >250 microns.14 In the present study however, a different protocol was used. All patients received anti-VEGF agents at the first visit, followed by laser after 7-10 days as soon maximal effect of anti-VEGF agent was expected. This was performed on the following two premises; first, to reduce the number of intravitreal injections required, thereby reducing the cost of treatment and circumventing potential adverse effects of intravitreal injections; secondly, to provide a reduction in vascular leakage by photocoagulating the areas of leakage to create a prolonged and sustained effect.

The degree of improvement in visual acuity and reduction in CFT in the present study, where intravitreal ranibizumab was used was comparable to the BRAVO study14 despite different treatment protocols between studies.

Although several studies have found intravitreal bevacizumab to be effective in reducing macular edema secondary to BRVO, to our knowledge no study has compared the efficacy of intravitreal ranibizumab and bevacizumab. Intravitreal ranibizumab appeared more effective than bevacizumab in terms of ≥3 line visual gain of Snellen acuity at the 1 month, 3 months, and 6 months follow-up visits [Table 1]. However reduction in CFT in patients treated with ranibizumab, compared to patients treated with bevacizumab and laser did not produce a statistically significant outcome. The reason for the slightly better results with ranibizumab could be related to the smaller molecular size, allowing rapid penetration through the retinal layers as well as greater affinity for VEGF established by ranibizumab. However the small sample size in our study precludes a definitive conclusion about superiority of ranibizumab.

Although laser is the current gold standard for treatment of macular edema due to BRVO, the BVOS9 study found a modest improvement in patients treated with laser photocoagulation. Laser treatment cannot be performed on patients with fresh venous occlusions owing to retinal hemorrhages and it takes several months for the haemorrhages to clear. During this time, severe retinal edema could compromise retinal cells leading to permanent structural damage.

Both improvement in visual acuity and reduction in CFT appeared to be better in eyes that had received intravitreal ranibizumab therapy as compared to eyes treated with laser alone during the entire study.

In conclusion, both ranibizumab and bevacizumab for macular edema due to BRVO resulted in a gain in visual acuity and a rapid reduction in intraretinal thickness. These anti-VEGF agents could be combined with a more permanent treatment such as laser photocoagulation, which would yield much better results than any single mode of treatment alone. However, a larger sample size and longer follow up to evaluate the observations of this study.