|Year : 2018 | Volume
| Issue : 2 | Page : 140-146
Aflibercept for macular edema after branch retinal vein occlusion
Department of Ophthalmology, Alexandria University, Alexandria, Egypt
|Date of Submission||19-Dec-2017|
|Date of Acceptance||16-Mar-2018|
|Date of Web Publication||7-Jun-2018|
8 Hassan Allam Street Smouha, Alexandria 1103
Source of Support: None, Conflict of Interest: None
Purpose The aim was to evaluate the real-world results of aflibercept in the treatment of macular edema due to branch retinal vein occlusion (BRVO) without prior treatment.
Patients and methods The study included patients with treatment-naive symptomatic BRVO causing macular edema with a best corrected visual acuity (VA) of 0.1 or better, central macular thickness (CMT) of more than 300 μm, and a duration less of than 6 months. Patients received intravitreal 2.0 mg of aflibercept. Follow-up examinations were performed monthly after the first injection for at least 6 months. At each visit, complete examination and optical coherence tomography scans were performed with recording of the best corrected VA and CMT on optical coherence tomography. At the monthly follow-up visits, additional Aflibercept injections were given as needed (pro-re-nata) when intraretinal/subretinal fluid was still present.
Results A total of 25 patients were included in the study. Their age ranged from 42 to 75 years with a mean of 61.12±8.34 years. There were 16 men and nine women. Duration of vein occlusion ranged from 10 to 50 days with a mean of 21.8±12.29 days. Baseline logarithm of the minimal angle of resolution VA mean was 0.790±0.16. It improved at the 6-month follow-up visit to 0.244±0.22, which was statistically significant (P=0.001). Baseline CMT mean was 538.84±186.96 µm. It improved at the end of follow-up to 284.680±68.22 µm, which was statistically significant (P=0.001).
Conclusion Aflibercept given with pro-re-nata regimen was safe and effective in the treatment of macular edema after BRVO.
Keywords: aflibercept, branch retinal vein occlusion, macular edema
|How to cite this article:|
Abouhussein M. Aflibercept for macular edema after branch retinal vein occlusion. Delta J Ophthalmol 2018;19:140-6
| Introduction|| |
Branch retinal vein occlusion (BRVO) is a relatively common disorder affecting the retinal circulation. This condition can lead to severe loss of vision. The prevalence of BRVO is about 4 per 1000 persons compared with central retinal vein occlusion (CRVO) which has a prevalence of about 0.8 per 1000 persons .
The possible complications of BRVO include retinal neovascularization, epiretinal membrane, vitreous hemorrhage, and macular ischemia, but the most common cause of diminution of vision is macular edema ,.
In contrast to central vein occlusion, macular edema following BRVO has treatment with proven benefit, which was macular grid laser photocoagulation. The landmark branch vein occlusion study proved that macular grid laser treatment was beneficial in treating macular edema after BRVO .
The first pharmacological treatment used for macular edema after BRVO was corticosteroids in the form of intravitreal triamcinolone. Corticosteroids stabilize vascular permeability and antagonize inflammatory mediators including the vascular endothelial growth factor (VEGF) .
The SCORE study (Standard Care vs. Corticosteroid for Retinal Vein Occlusion) compared intravitreal triamcinolone acetonide with the standard of care (grid laser photocoagulation) for macular edema after BRVO. This was the first major trial for BRVO to use optical coherence tomography (OCT) in the evaluation of macular edema. The final results of this study showed that intravitreal Triamcinolone and macular grid laser photocoagulation were equally effective, but there was a high rate of cataract progression and ocular hypertension in the triamcinolone group .
Recently, a new method of corticosteroid delivery was introduced; the intravitreal dexamethasone sustained-release implant (OZURDEX; Allergan) was Food and Drug Administration (FDA) approved for treating macular edema after BRVO . The GENEVA trial (Global Evaluation of Implantable Dexamethasone in Retinal Vein Occlusion with Macular Edema) showed that the visual gain was significantly higher in the treatment groups compared with controls, but this benefit was associated with a higher incidence of ocular hypertension .
The most common current treatment option for macular edema due to BRVO is intravitreal anti-VEGF injections.
Bevacizumab, although not FDA approved for intravitreal use, is used off label. Many case series showed that bevacizumab has good visual and anatomic outcomes in the treatment of macular edema after BRVO ,,,.
Ranibizumab was the first anti-VEGF to be used in a large randomized, controlled study in the treatment of BRVO. The BRAVO study (Ranibizumab for the Treatment of Macular Edema after Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety) showed that monthly ranibizumab injections were more effective functionally and anatomically than sham treatment. However, in this study laser was a rescue treatment, so it did not show superiority over macular grid laser treatment .
Aflibercept is a 115-kDa soluble receptor fusion protein that blocks VEGF and placental growth factor . Aflibercept has more binding affinity for VEGF than that of either bevacizumab or ranibizumab , and it also has a longer duration of action ,. Recently, the Study to assess the clinical efficacy and safety of intravitreal aflibercept injection in patients with branch retinal vein occlusion (VIBRANT) study was the first study to compare anti-VEGF treatment with laser. This study compared intravitreal aflibercept (IVA) in the treatment of macular edema secondary to BRVO to macular grid photocoagulation which was the standard treatment. The aflibercept group followed a strict, fixed monthly regimen. Overall, monthly aflibercept provided significantly better functional and anatomic results at 24 weeks than grid laser photocoagulation. During the next 6 months, injections were given every 8 weeks. The visual outcome was maintained until the 1-year follow-up visit ,.
The aim of the present study was to evaluate the results of IVA in the treatment of newly diagnosed symptomatic BRVO with macular edema, given in a pro-re-nata (PRN) regimen which is different from the fixed monthly dose regimen of the VIBRANT study to decrease the treatment burden.
| Patients and methods|| |
This prospective interventional study was conducted in accordance with the tenets of the Declaration of Helsinki. The study was approved by the Alexandria University Ethics Committee. Informed consent was obtained from all study patients before participating in the study.
Treatment-naive patients with macular edema due to BRVO were treated with aflibercept as the only treatment.
The inclusion criteria used in this study were age more than 18 years, symptomatic BRVO causing edema involving the center of the macula, best corrected visual acuity (BCVA) of 0.1 or better on the decimal visual acuity (VA) chart, central macular thickness (CMT) of more than 300 μm measured by spectral domain OCT, and duration of symptoms of less than 6 months.
Exclusion criteria included any previous treatment for BRVO, other chorioretinal diseases (e.g. diabetic retinopathy, hypertensive retinopathy, and age-related macular degeneration), any intraocular surgery within the last 6 months, uncontrolled glaucoma, or any other cause for diminution of vision.
At baseline, all patients were subjected to a detailed history taking. Complete ophthalmological examination included slit-lamp biomicroscopy with a 90 D lens. BCVA was determined using a decimal VA chart.
Fundus photography and fluorescein angiography were performed using a Kowa VX-10α Fundus camera (Kowa Company Ltd, Nagoya, Japan).
OCT examination was performed through a dilated pupil using a commercially available spectral domain Cirrus HD-OCT Model 4000 (Carl Zeiss Meditec Inc., Dublin, California, USA).
The patients received IVA (2.0 mg in 0.05 ml, Eylea; Bayer, Berlin, Germany).
Follow-up examinations were performed monthly after the first injection for 6 months. At each visit, complete examination and OCT evaluation were performed with recording of the BCVA and CMT.
At the monthly follow-up visits, additional aflibercept injections were given according to a PRN regimen. Retreatment criteria were persistent intraretinal/subretinal fluid with CMT of more than 300 μm, or an increase in CMT compared with the baseline.
The outcome measures were the change in VA from baseline at month 6 and the change in CMT from the baseline at month 6.
Decimal BCVA was converted to logarithm of the minimal angle of resolution (logMAR) values for statistical analysis.
The data were collected and entered into a personal computer. Statistical analysis was done using the Statistical Package for the Social Sciences (SPSS/version 21; LEAD Technology, North Carolina, USA) software. Arithmetic mean and SD were determined for numerical data and t-test was used to compare the two groups. To find the association between two variables, Spearman’s correlation coefficient test was used. The level of significance was 0.05.
| Results|| |
This study included 25 patients (16 men and nine women) with symptomatic macular edema secondary to BRVO. The age of the patients ranged from 42 to 75 years, with a mean of 61.12 years ([Table 1]).
Among the 25 patients, 21 were treated for hypertension and two patients were treated for diabetes mellitus. Four patients were treated for primary open angle glaucoma.
The duration of diminution of vision ranged from 10 to 50 days, with a mean of 21.8 days.
The location of the BRVO was superior in 19 patients and inferior in six patients.
The fluorescein angiography showed good capillary perfusion in 18 patients and areas of capillary nonperfusion (>5 disk diameter) in seven patients.
The baseline logMAR BCVA ranged from 0.495 to 1.00, with a mean of 0.790±0.16. The baseline CMT ranged from 370 to 879 μm, with a mean of 538.84±186.96 μm. OCT showed cystoid macular edema in all 25 cases, whereas epiretinal membrane was present in seven cases and subretinal fluid in four cases.
The BCVA improved from a baseline mean of 0.790±0.16 to a mean of 0.244±0.22 at the 6-month visit. This improvement was statistically significant at all time points starting from the first month ([Table 2] and [Figure 1]).
|Table 2 Comparison between visual acuity (logarithm of the minimal angle of resolution) at different periods of follow-up|
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|Figure 1 Comparison between VA (logMAR) at different period of follow up.|
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The mean CMT on spectral domain OCT decreased from 538.84±186.96 µm at presentation to 284.680±68.22 µm at the 6-month visit. This improvement was also statistically significant at all the monthly visits starting from the first month ([Table 3] and [Figure 2]).
|Table 3 Comparison between central macular thickness at different periods of follow-up|
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[Figure 3],[Figure 4],[Figure 5],[Figure 6] show two patients at baseline and at the end of follow-up.
|Figure 3 A patient with BRVO at baseline. The central thickness is 585 µm with cystic intraretinal edema. The visual acuity is 6/36. BRVO, branch retinal vein occlusion.|
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|Figure 4 The same patient with BRVO at 6-month visit. The central thickness improved from 585 µm with cystic intraretinal edema to 237 µm with resolution of the cystoid macular edema. The visual acuity improved from 6/36 to 6/6. BRVO, branch retinal vein occlusion.|
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|Figure 5 A patient with BRVO at baseline. The central thickness is 480 µm with cystoid edema and vitreomacular traction. The visual acuity is 6/18. BRVO, branch retinal vein occlusion.|
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|Figure 6 The same patient with BRVO at the end of follow-up. The central thickness improved from 480 µm to 286 µm with resolution of the cystoid edema and partial release of vitreomacular traction. The visual acuity improved from 6/18 to 6/9. BRVO, branch retinal vein occlusion.|
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As regards the factors associated with BCVA at the end of follow-up: better final BCVA was significantly correlated with younger age at presentation (R=0.478, P=0.016), better presenting BCVA (R=0.628, P=0.001), and less CMT at baseline (R=0.671, P=0.0001).
[Table 4] shows the number of cases that required injections at different time points in the study. There were three patients who needed only one injection, two patients needed two injections, and four patients needed three injections. There were no cases of macular edema recurrence (need to retreat after the injections were stopped according to the retreatment criteria) during the follow-up period.
|Table 4 Number of cases injected (central macular thickness >300 µm) at different periods of the study|
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In this case series, there were no severe ocular or systemic side effects. No cases of retinal or iris neovascularization were recorded.
| Discussion|| |
The standard treatment of macular edema due to BRVO was macular grid laser photocoagulation. The branch vein occlusion study compared macular grid laser photocoagulation to observation. The results showed significant visual improvement in the treatment group after 3 years . Nowadays, the Royal College of Ophthalmologists’ guidelines  suggest that grid laser photocoagulation is not the treatment of choice for macular edema after BRVO except if the patient refuses or is not a good candidate for anti-VEGF treatment.
VEGF is a key mediator produced due to hypoxia. It is a leading cause of macular edema after BRVO. The use of FDA approved anti-VEGF agents such as ranibizumab and aflibercept was found to produce anatomic and visual benefits .
Aflibercept intravitreal injection was tested in the landmark prospective randomized trial (VIBRANT study) in the treatment of macular edema after BRVO compared with grid laser photocoagulation. The results showed better visual outcomes with injections of IVA every 4 weeks for 24 weeks as compared with the standard grid laser treatment. In the next 24 weeks, the interval between injections was extended to 8 weeks and the visual benefit was well maintained. Subgroup analyses found that at week 52 significantly more aflibercept-treated patients than macular laser photocoagulation-treated patients had a VA equal to or better than 20/40. In addition, the proportion of eyes with dry retina (i.e. absence of intraretinal and subretinal fluid under the foveal center) was also significantly higher in aflibercept recipients compared with macular laser photocoagulation recipients .
In the landmark studies that evaluated ranibizumab and aflibercept in the treatment of macular edema after either central or branch vein occlusion, the patients were given at the beginning 6 monthly intravitreal injections. After these initial six loading doses, variable treatment schedules were followed ,.
The fixed regimen used in the VIBRANT study produced very good results but it is difficult to adopt in real-life practice. Also, it is known that macular edema after retinal vein occlusion is not in most cases a chronic condition compared with exudative age-related macular degeneration or diabetic macular edema ,,.
In the current study, we evaluated the 6-month results of IVA in the treatment of 25 patients with previously untreated newly diagnosed macular edema secondary to BRVO. The treatment regimen was a single injection followed by a PRN regimen. The BCVA significantly improved from baseline logMAR of 0.790±0.16 to 0.244±0.22 at the end of follow-up. The anatomic results on OCT showed that CMT decreased significantly from 538.84±186.96 µm at presentation to 284.680±68.22 µm at the end of follow-up.
In this study, cases of macular edema due to BRVO occlusion were only included. Cases of CRVO were excluded, as BRVO cases may have a less severe course than CRVO cases. This was shown in the number of patients who needed only three monthly injections or less. In addition, we had no cases of macular edema recurrence during the period of follow-up.
Sakanishi et al.  reported a retrospective study with only 1-month follow-up using one injection of aflibercept for macular edema after BRVO. Their cases were classified into two groups: a treatment-naive group subsequently treated with aflibercept and a switching group initially treated with ranibizumab and then switched to aflibercept because of the recurrence of macular edema. In the treatment-naive group, the BCVA significantly improved from a logMAR value of 0.49 (20/62) at preinjection to 0.34 (20/44) at 1-week post-IVA and 0.27 (20/37) at 1-month post-IVA. Regarding the CMT of treatment-naïve patients, the mean CMT decreased from 559.0 µm at preinjection to 269.2 µm at 1-week post-IVA and 204.2 µm at 1-month after aflibercept injection.
Ozkaya et al.  published the results of a retrospective case series of aflibercept injections after retinal vein occlusion. They included both central vein occlusion and BRVO cases and treatment-naive and persistent macular edema after treatments other than aflibercept. Initially, treatment-naive patients received a loading dose of three consecutive monthly injections, then the patients were planned to be followed monthly, and an intravitreal injection of aflibercept was repeated as needed. They reported failure to perform monthly follow-up visits due to poor compliance. The interval between visits ranged from 1 to 3 months. In BRVO cases, the mean baseline central retinal thickness was 493±119 µm. It decreased to 349±137 µm at the 12-month visit. The VA in the BRVO group improved from 0.87±0.56 logMAR at baseline to 0.70±0.65 at the 12-month visit .As regards the value of the loading dose in macular edema after BRVO, Miwa et al.  performed a prospective study to compare the 12-month efficacy of a single initial intravitreal ranibizumab injection followed by a PRN regimen with that of three initial monthly ranibizumab injections followed by a PRN regimen in patients with macular edema due to BRVO. Their results showed that at the end of 1 year of follow-up, both regimens achieved similar anatomic and visual outcomes. This study, although concerning ranibizumab, shows that the loading dose is not mandatory in the treatment of macular edema after branch vein occlusion . In the current study, patients were given an initial IVA injection followed by a PRN regimen with no loading doses.
The main limitations of this study are the small number of cases and the relatively short follow-up duration. A large prospective study comparing aflibercept with ranibizumab in the treatment of macular edema after BRVO is needed.
In conclusion, this prospective study showed the favorable results of IVA injections in the management of treatment-naive macular edema after BRVO. The treatment regimen was different from the large randomized controlled trials; nevertheless, the visual and anatomic results were still satisfactory.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Rogers S, McIntosh RL, Cheung N, Lim L, Wang JJ, Mitchel P et al.
The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology 2010; 117:313–319.
Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol 2008; 126:513–518.
Adedokun L, Burke C. Cost-effectiveness of ranibizumab versus aflibercept for macular edema secondary to branch retinal vein occlusion: a UK healthcare perspective. Adv Ther 2016; 33:116–128.
[No authors listed]. Argon laser photocoagulation for macular edema in branch vein occlusion. Branch Vein, Occlusion Study Group. Am J Ophthalmol 1984; 98:271–282.
Park SP, Ahn JK. Changes of aqueous vascular endothelial growth factor and interleukin-6 after intravitreal triamcinolone for branch retinal vein occlusion. Clin Exp Ophthalmol 2008; 36:831–835.
Scott IU, Ip MS, vanVeldhuisen PC, Oden NL, Blodi BA, Fisher M et al.
SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol 2009; 127:1115–1128.
Haller JA, Bandello F, Belfort Jr R, Blumenkranz MS, Gillies M, Heier J et al.
OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010; 117:1134–1146.
Haller JA, Bandello F, Belfort Jr R, Blumenkranz MS, Gillies M, Heier J et al.
OZURDEX GENEVA Study Group. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011; 118:2453–2460.
Donati S, Barosi P, Bianchi M, Al Oum M, Azzolini C. Combined intravitreal bevacizumab and grid laser photocoagulation for macular edema secondary to branch retinal vein occlusion. Eur J Ophthalmol 2012; 22:607–614.
Moradian S, Faghihi H, Sadeghi B, Piri N, Ahmadieh H, Soheilian M et al.
Intravitreal bevacizumab vs. sham treatment in acute branch retinal vein occlusion with macular edema: results at 3 months (report 1). Graefes Arch Clin Exp Ophthalmol 2011; 249:193–200.
Ehlers JP, Decroos FC, Fekrat S. Intravitreal bevacizumab for macular edema secondary to branch retinal vein occlusion. Retina 2011; 31:1856–1862.
Russo V, Barone A, Conte E, Prascina F, Stella A, Noci ND. Bevacizumab compared with macular laser grid photocoagulation for cystoid macular edema in branch retinal vein occlusion. Retina 2009; 29:511–515.
Campochiaro PA, Heier JS, Feiner L, Gray S, Saroj N, Rundle AC et al.
BRAVO Investigators. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary endpoint results of a phase III study. Ophthalmology 2010; 117:1102–1112.
Holash J, Davis S, Papadoupoulos N, Croll SD, Ho L, Russell M et al.
VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 2002; 99:11393–11398.
Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E et al.
Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012; 15:171–185.
Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008; 92:667–668.
Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M et al.
Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 2001; 7:575–583.
Campochiaro PA, Clark WL, Boyer DS, Heier JS, Brown DM, Vitti R et al.
Intravitreal aflibercept for macular edema following branch retinal vein occlusion: the 24-week results of the VIBRANT study. Ophthalmology 2015; 122:538–544.
Clark WL, Boyer DS, Heier JS, Brown DM, Haller JA, Vitti R et al.
Intravitreal aflibercept for macular edema following branch retinal vein occlusion: 52-week results of the VIBRANT study. Ophthalmology 2016; 123:330–336.
The Royal College of Ophthalmologists. Retinal vein occlusion (RVO) guidelines. 2015. Available at: http://www.rcophth.ac.uk/
. [Accessed 14 February 2017].
Hoy SM. Aflibercept: a review in macular oedema secondary to branch retinal vein occlusion. Drugs Aging 2017; 34:393–400.
Augustin AJ, Sahel JA, Cerulli L, Texier-Richard B, Buchholz PM, Kobelt G. Treating retinal vein occlusions in France, Germany, and Italy: an analysis of treatment patterns, resource consumption, and costs. Eur J Ophthalmol 2012; 22:776–784.
Bhagat N, Goldberg MF, Gascon P, Bell W, Haberman J, Zarbin MA. Central retinal vein occlusion: review of management. Eur J Ophthalmol 1999; 9:165–180.
Glacet-Bernard A, Coscas G, Zourdani A, Soubrane G, Souied EH. Steroids and macular edema from retinal vein occlusion. Eur J Ophthalmol 2011; 21(Suppl 6):S37–S44.
Sakanishi Y, Usui-Ouchi A, Tamaki K, Mashimo K, Ito R, Ebihara N. Short-term outcomes in patients with branch retinal vein occlusion who received intravitreal aflibercept with or without intravitreal ranibizumab. Clin Ophthalmol 2017; 11:829–834.
Ozkaya A, Tulu B, Garip R. Aflibercept in macular edema secondary to retinal vein occlusion: a real life study. Saudi J Ophthalmol 2017; 31:211–215.
Miwa Y, Muraoka Y, Osaka R, Ooto S, Murakami T, Suzuma K et al.
Ranibizumab for macular edema after branch retinal vein occlusion: one initial injection versus three monthly injections. Retina 2017; 37:702–709.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]