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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 4  |  Page : 1123-1130

Efficacy of intravitreal injection of aflibercept in the treatment of neovascular age-related macular degeneration


Department of Ophthalmology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission10-Oct-2019
Date of Decision06-Nov-2020
Date of Acceptance12-Nov-2020
Date of Web Publication24-Dec-2020

Correspondence Address:
Basant M. M. Doma
MBBCh, Department of Ophthalmology, Faculty of Medicine, Menoufia University, Shebin El kom, Menoufia 31733
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_321_19

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  Abstract 


Objectives
To evaluate the visual and anatomical outcomes following intravitreal injection of aflibercept in patients with neovascular age-related macular degeneration (AMD).
Background
Neovascular AMD is considered a principal cause of visual impairment worldwide. It is associated with choroidal neovascularization, which causes exudation that affects vision. Early clinical trials showed that intravitreal injection of anti-vascular endothelial growth factor agents is associated with significant improvement of visual outcomes in the majority of eyes. Aflibercept is an anti-vascular endothelial growth factor agent that recently gained approval for treating neovascular AMD.
Patients and methods
This prospective study conducted at Menoufia University Hospitals, included 60 eyes of 46 patients with treatment–naïve neovascular AMD. The patients received 3monthly aflibercept intravitreal injections. The best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure were measured at diagnosis and after each injection. Also, the patients were asked to fill the 25-item National Eye Institute Visual Function Questionnaire at baseline and at the end of the study.
Results
The mean BCVA improved from 0.061 (decimal fraction) to 0.081 after the third injection (P < 0.001). The mean CMT significantly decreased from 484.07 μm at baseline to 331.1 μm after the third injection (P < 0.001). No significant changes in intraocular pressure were observed during the study. There was a significant improvement in total score and some subscale scores of the 25-item National Eye Institute Visual Function Questionnaire.
Conclusion
Intravitreal aflibercept in neovascular AMD is associated with increased BCVA and reduced CMT. In addition, intravitreal aflibercept possibly has a benefit of improving the quality of vision-related functions.

Keywords: aflibercept, age-related macular degeneration, 25-item National Eye Institute Visual Function Questionnaire, vascular endothelial growth factor


How to cite this article:
El Sobky HM, Basiony AI, Doma BM. Efficacy of intravitreal injection of aflibercept in the treatment of neovascular age-related macular degeneration. Menoufia Med J 2020;33:1123-30

How to cite this URL:
El Sobky HM, Basiony AI, Doma BM. Efficacy of intravitreal injection of aflibercept in the treatment of neovascular age-related macular degeneration. Menoufia Med J [serial online] 2020 [cited 2021 Apr 19];33:1123-30. Available from: http://www.mmj.eg.net/text.asp?2020/33/4/1123/304503




  Introduction Top


Age-related macular degeneration (AMD) is a degenerative disease related to aging and affects the macula. As the population ages, worldwide prevalence of AMD is rising with 288 million people projected to have either early or late manifestations of AMD by 2040. It tends to be divided into two forms: atrophic (dry) and neovascular (wet). The neovascular form represents the more severe form of the disease and stands for roughly 90% of legal blindness caused by the disease[1],[2].

The neovascular AMD is defined by the presence of choroidal neovascularization (CNV) which represents the growth of new weak blood vessels from the choriocapillaris. These blood vessels extend beneath the retina or the retinal pigment epithelium (RPE) with subsequent accumulation of leaking fluids or blood in the subretinal space[3].

There is substantial proof that vascular endothelial growth factor (VEGF) plays an important role in CNV development by promoting angiogenesis. Anti-VEGF therapy is currently the treatment of choice for neovascular AMD, aiming mainly at suppressing the activity of the CNV and reducing vascular permeability to prevent further visual acuity deterioration caused by retinal edema[4],[5].

Aflibercept is the most recent anti-VEGF to gain approval by the Food and Drug Administration in November 2011 based on the results of VIEW 1 and VIEW 2 trials. This particular anti-VEGF agent neutralizes not only all the VEGF-A isoforms but also two other members of the VEGF family, VEGF-B and placental growth factor[6].

This study aimed at evaluating the visual and anatomical outcomes of intravitreal injection of aflibercept in patients with treatment–naïve neovascular AMD attending the Ophthalmology Department at Menoufia University Hospital.


  Patients and methods Top


This was a prospective study conducted at the Ophthalmology Department at Menoufia University Hospital from April 2018 to June 2019. The study was approved by the Ethics Committee of Menoufia Medical School. All patients provided written informed consent before initiating this study. The study was conducted on 60 eyes of 46 patients, who have not received any intravitreal injections before (treatment–naïve).

Inclusion criteria

All patients who had been diagnosed were with treatment–naïve CNV caused by neovascular AMD. Active subfoveal CNV lesions (classic and occult) and juxtafoveal CNV causing retinal edema that affect the fovea also were included. Best-corrected visual acuity (BCVA) less than 6/24 on the Snellen chart or 0.25 on the decimal fraction chart.

Exclusion criteria

Exclusion criteria were: CNV caused by any ocular cause other than neovascular AMD. Eyes with permanent structural damage to the central fovea such as fibrosis or retinal pigment epithelial tear involving the fovea. Ocular pathology (dense cataract, uveitis, glaucoma, diabetic retinopathy). History of ocular surgery (glaucoma surgery, pars plana vitrectomy, focal or grid laser photocoagulation to the macula). History of previous intravitreal injections in the treated eye.

Examination

Preoperatively all patients were subjected to history taking including: medical history, history of ocular operations, or previous intravitreal injections. Evaluation of quality of vision: patients were asked to complete the Arabic version of the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The scores of the NEI VFQ-25 questionnaire were calculated according to scoring protocols released by the developers of the instrument[7].

Ophthalmic examination including BCVA measured on Snellen chart and was converted to decimal fraction for statistical purpose. Examination of the anterior segment was done using diffuse and oblique illumination techniques of slit-lamp biomicroscopy to exclude the presence of media opacity that may prevent optical coherence tomography (OCT) capture like corneal opacity or dense cataract. Intraocular pressure (IOP) measurement was done using Goldman applanation tonometry. Fundus examination was done using slit-lamp biomicroscopy and Volk + 78 D lens. Fundus fluorescein angiography was performed to identify the location and type of lesions and to confirm the activity of the CNV membrane using Topcon fundus camera. CNV activity detected by dye leakage and its location determined according to its site in relation to the fovea as follows: extrafoveal (>200 μm from the foveal center), juxtafoveal (1–199 μm from the foveal center), or subfoveal (involving the foveal center). OCT: SD-OCT was performed on all patients with the help of Heidelberg Engineering (Heidelberg, Germany) to detect the location of the CNV and the associated retinal morphological changes including retinal edema and subretinal fluid. Central macular thickness (CMT) values were obtained using the integrated software, and this was the distance between the vitreoretinal interface and the anterior surface of the RPE.

Intravitreal injection of aflibercept

All patients received three consecutive monthly intravitreal injections of 2 mg (0.05 ml) of aflibercept (Eylea; Bayer Healthcare Pharmaceuticals, Berlin, Germany). Broad-spectrum topical antibiotic eye drops, Gatifloxacin 0.3% (Tymer Jamjoom Pharmaceuticals, Jeddah, Saudi Arabia, imported by: MultiPharma) instilled in the eye to be injected for 3 days before injection. All intravitreal injections were performed under sterilized conditions in the operating room. The study eye was sterilized with povidone-iodine (5%) drops. Injection was performed under topical anesthesia by benoxinate hydrochloride 0.4% drops (Benox, EIPICO, Tenth of Ramadan City - 1st Industrial Zone B1, Egypt; Egyptian Int. Pharmaceutical Industries, Egypt). Aflibercept was injected intravitreally in the lower-temporal part of pars plana (~3.5 mm in the pseudophakic eye - 4 mm in the phakic eye from the limbus) using insulin syringe. A sterile cotton-tipped applicator was rolled over the site of the injection as the needle is removed to minimize vitreous prolapse and reflux of the injected material.

Postoperative follow-up

After 24 h all patients are examined to evaluate IOP and to exclude any complications. Patients were followed up every 4 weeks to measure, BCVA using Snellen's chart, IOP using applanation tonometer, fundus examination using slit-lamp biomicroscopy and Volk +78 D lens. OCT was done 4 weeks after each injection to assess the changes in CMT with the help of Heidelberg Engineering. All OCT examinations at baseline and follow-up were done at the same line of scan using the follow-up mode. The main outcome measures were the changes between baseline and last follow-up visit (4 weeks after the third injection) in BCVA and CMT. The secondary outcome measures were the changes in NEI VFQ-25 scores between baseline and last follow-up visit (4 weeks after the third injection).

Statistical analysis

Data were collected and submitted to statistical analysis using Statistical Program for Social Sciences, version 20 (SPSS Inc., Chicago, Illinois, USA). The following statistical tests and parameters were used. Student's t test was performed to compare results before and after intervention. Comparing parametric data over time was done using repeated measures analysis of variance. Comparing nonparametric data over time was done using Friedman's test. P value less than 0.05 is considered significant.


  Results Top


The study included 60 eyes of 46 patients with treatment–naïve neovascular AMD. The patients' mean age was 67.56 ± 8.14 years with a range of 53–87 years [Table 1].
Table 1: Demographic data of the study population

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The mean BCVA was 0.061 (decimal fraction) at baseline (range, 0.01–0.16). It was improved after the first intravitreal aflibercept injection to 0.091 and after the third injection, it became 0.081 (P < 0.001) [Table 2] and [Figure 1].
Table 2: Comparison of the mean best-corrected visual acuity, central macular thickness, and intraocular pressure values at baseline and after each aflibercept injection

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Figure 1: Graph showing changes in BCVA from baseline and after each injection. BCVA, best-corrected visual acuity.

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CMT decreased from 484.07 ± 143.7 μm at baseline to 394.7 ± 95.7, 360.7 ± 89.2, and 331.1 ± 88.3 μm after 1, 2, and 3 injections, respectively (P < 0.001) [Table 2], [Figure 2] and [Figure 3].
Figure 2: Graph showing changes in CMT from baseline and after each injection. CMT, central macular thickness.

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Figure 3: A 73-year-old male patient with subfoveal CNV with spongy-like macular edema denoting activity. CMT decreased from 574 μm at baseline to 316 μm after the loading dose of aflibercept. CMT, central macular thickness; CNV, choroidal neovascularization.

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There was a mild increase in IOP occurred following intravitreal aflibercept but within the normal range; this increase was statistically nonsignificant (P = 0.076) [Table 2].

There were no ocular or systemic side effects noted during the follow-up time.

In correlation analysis, BCVA showed a negative correlation to CMT only before treatment initiation (r=-0.443, P = 0.005), but no correlation was found at the end of the study (r=-0.207, P = 0.119) [Table 3].
Table 3: Correlation between central macular thickness, best.corrected visual acuity, and intraocular pressure at baseline and after the third aflibercept injection

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The mean total score of the NEI VFQ-25 for the studied patients was 45.30 ± 18.72, which showed significant improvement after the three injections of aflibercept to become 54.19 ± 19.29 (P = 0.031). The highest scores at baseline were recorded for ocular pain, color vision, and social functioning subscales, while the lowest scores at baseline were found in driving, general vision, near and distance activities subscales. According to the subscales of the questionnaire, there was a significant improvement in general vision, near activities, distance activities, mental health, role difficulties, and dependency subscales, while, there was no significant improvement in color vision, ocular pain, driving, and peripheral vision [Table 4].
Table 4: Changes in total score and subscales of 25-item National Eye Institute Visual Function Questionnaire between baseline and after the third aflibercept injection

Click here to view



  Discussion Top


Neovascular AMD which is characterized by the growth of CNV beneath the RPE is considered one of the leading causes of blindness among the elderly. CNV leads to leakage from new blood vessels and can cause edema and disorders in retinal architecture eventually causing blurred and distorted vision. If left untreated, the area of neovascularization can expand rapidly leading to the development of fibrous scarring[8].

Anti-VEGF agents are considered the main treatment line for neovascular AMD. Anti-VEGF agents have substantially improved vision in patients with neovascular AMD[9].

Aflibercept is a soluble recombinant fusion protein that binds to all VEGF-A isoforms with a significantly higher binding affinity when compared with other monoclonal anti-VEGF antibodies. Besides that, aflibercept also blocks other proangiogenic factors such as VEGF-B and placental growth factor[10].

Aflibercept gained Food and Drug Administration approval to be used for treating neovascular AMD in 2011. The current approved treatment schedule for aflibercept consists of a loading dose of initial 2 mg monthly injections for 3 months followed by bimonthly injections[11].

The current study aimed at evaluation of the effects of aflibercept on BCVA and CMT in patients with treatment–naïve neovascular AMD attending the Ophthalmology Department at Menoufia University Hospital.

Mean BCVA was improved from 0.061 at baseline to 0.081 after the third injection which is a statistically significant improvement. There was a statistically significant decrease in mean CMT which improved from 484.07 μm at baseline to 331.1 μm after the third injection.

After 3 monthly injections of intravitreal aflibercept, BCVA improved in 86.6% of the study population and remained stable at the baseline measure in 13.3% of the study population as follows: two eyes at 0.1 and four eyes at 0.05, while two (3.3%) eyes showed a decrease in BCVA from 0.08 to 0.05.

These results are, in general, in agreement with many key studies assessing intravitreal aflibercept in the treatment of neovascular AMD including VIEW 1, CLEAR-IT phase II, and the RAINBOW studies.

In CLEAR-IT phase II (CLinical Evaluation of Anti-angiogenesis in the Retina Intravitreal Trial), the patients enrolled in the study were randomized into five groups to receive an intravitreal injection of aflibercept. Each group consists of ~30 patients. The first two groups received monthly aflibercept injections of 0.5 or 2 mg for a total of four treatments, while the remaining three groups received aflibercept injections every 3 months with doses of 0.5, 2, or 4 mg, respectively, for a total of two treatments. At the end of the study, BCVA and CRT showed significant improvement in all treatment groups. However, the groups that were randomized to monthly doses of 0.5 or 2 mg showed profound improvements and more consistent effects[12].

VIEW 1 and VIEW2 studies (VEGF Trap-Eye: investigation of efficacy and safety in wet AMD) randomized the patients in the study to 1: 1: 1: 1 ratio to receive the following regimens: 0.5 or 2 mg aflibercept every month (0.5q4) or (2q4); 2 mg aflibercept bimonthly (2q8) after three injections at week 0, 4, and 8; or monthly injection of 0.5 mg ranibizumab (Rq4). All treatment groups exhibited rapid improvement in BCVA after the first injection. On the anatomical level, central retinal thickness in ranibizumab and aflibercept treatment groups demonstrated significantly lower values compared with the baseline[13].

The RAINBOW (Real-life use of intravitreal aflibercept In France – Observational study in wet AMD) study also highlighted a significant improvement in BCVA as the mean change of BCVA (SD) in patients who received a loading dose was 5.5 (15.0) letters. In addition to that, the RAINBOW study reported a significant decrease in CRT which was manifest by month 3 and sustained through month 12[14].

Our findings were also similar to the results of Unsal and Cubuk's retrospective study which reported that the proportion of eyes that had improvement in vision was 86.8 and 10.5% achieved maintenance of vision. They also reported significant improvement of BCVA in the third month and the last follow-up visit compared with the baseline (0.98 ± 0.56LogMAR at baseline vs. 0.76 ± 0.36 and 0.57 ± 0.31 after third month and the last follow-up visit, respectively)[15]. On the other hand, they reported that this improvement was not significant in the first 2 months while in the current study, a significant improvement in BCVA was found after the first aflibercept injection (0.061 ± 003 decimal units at baseline vs. 0.091 ± 0.1after the first injection). Although Unsal and Cubuk reported a significant decrease in mean CMT from 327.9 ± 56.5 μm at baseline to 284.3 ± 55.2 μm after 3 months which, in general, agrees with the results of the current study, they highlighted that this decrease began in the third month of the study. On the contrary the current study stated a significant decrease in mean CMT starting from the first month[15].

The significant improvement in BCVA and central retinal thickness after the loading dose was also observed by Lázaro and colleagues in their retrospective study. They found that the mean BCVA (ETDRS) showed significant improvement after the loading dose (50.5 ± 14.5 vs. 39.6 ± 14.7). Also, the central retinal thickness was significantly diminished in neovascular AMD patients who received a loading dose of intravitreal aflibercept (239.6 ± 0.52 vs. 370.3 ± 117 μm)[16].

Similarly, Almuhtaseb et al.[17] also reported a significant improvement of the BCVA and diminished CMT after the loading dose of aflibercept.

This was also compatible with the results of Ito et al.[18], Ono et al.[19], Udaondo and García-delpech[20], and Castro-navarro and Cervera-taulet[21] who reported that BCVA was significantly improved after the loading phase. They also reported a significant decrease of CMT from baseline values after administration of the loading dose of aflibercept in treatment–naïve patients of neovascular AMD.

On the other hand, there was a study published in 2015 which stated that aflibercept intravitreal injection in treatment–naïve patients with neovascular AMD in a real-life clinical setting resulted in small and nonsignificant improvements in BCVA and CMT (letters scores at baseline and after loading dose were 62.55 ± 22.20 and 68.91 ± 8.51, respectively). This may be due to the limited size of that study as the number of eyes in the aflibercept-treated group was only 11 eyes. Moreover, the baseline CMT of patients receiving aflibercept was significantly lower compared with our study (352.50 ± 168.51 vs. 484.07 ± 143.7 μm)[22].

Also, a recent study that reviewed the clinical records of 126 eyes with neovascular AMD treated with either intravitreal ranibizumab or aflibercept in a real-world setting came up with the result that BCVA showed no significant difference between baseline and the follow-up visits at month 3, 6, or 12 after the first injection, but regarding CMT at month 3, 6, and 12 it was all found to be considerably much less than that at baseline[23].

There was a significant negative correlation between BCVA (decimal fraction) and CMT at baseline findings, which means that when CMT increased the BCVA decreased. In contrast, this correlation after the third injection was found to be insignificant which means that improvement of BCVA is not influenced by changes in CMT. This agrees with Bolz et al.[24], who found that baseline visit CRT values correlated significantly to BCVA values only in the baseline visit. This correlation was found to be not significant at the visits following treatment initiation.

According to the effect of aflibercept intravitreal injection on IOP, there was a mild increase in IOP that occurred following intravitreal aflibercept but within the normal range this increase was statistically nonsignificant (14.1 ± 2.4) and the first, second, and third months after the injection (14.2 ± 2.4, 14.5 ± 2.6, and 14.7 ± 2.8), respectively. That is compatible with results of an analysis conducted in patients enrolled in VIEW 1 and VIEW 2 trials comparing intravitreal aflibercept injection with intravitreal ranibizumab. This analysis found that the extent of raised IOP in the aflibercept group was lower than in the ranibizumab group[25].

Also, the studies that performed a close follow-up of IOP following intravitreal aflibercept reported a transient rise in IOP immediately after the intravitreal injection that returned to normal within 30 min [26–28].

In our study, there was a significant improvement of the total score of NEI VFQ-25 from 45.30 ± 18.72 at baseline to 54.19 ± 19.29 after the third injection. The highest scores at baseline were recorded for ocular pain, color vision, and social functioning subscales, while the lowest scores at baseline were found in driving, general vision, and near and distance activities subscales. In addition, there was an improvement in general vision, near and distant activities, mental health, dependency, and role difficulties subscales of the NEI VFQ-25. However, there was no significant improvement in subscales of color vision, ocular pain, driving, and peripheral vision.

On agreement with the current study, the analysis of data from phase 3 VIEW 1 and VIEW 2 studies which has been carried out to evaluate the effect of intravitreal aflibercept injection on visual function in wet (AMD) found that there was clinically meaningful improvement that was most obvious for the subscales of mental health, general vision, near and distance activities, role difficulties, and dependency[29].


  Conclusion Top


In conclusion, intravitreal injection of aflibercept in patients with treatment–naïve CNV caused by AMD is thought to be an efficient treatment. It was associated with significant improvement in BCVA and decreased retinal thickness as detected by OCT. In addition, aflibercept possibly has a benefit of improving the quality of vision-related functions. However, further studies with a larger number of patients and longer follow-up time is needed to assess the long-term effects of aflibercept.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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