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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 17  |  Issue : 1  |  Page : 35-47

Comparative study between ranibizumab and aflibercept in the management of macular edema caused by diabetes mellitus in age group more than 40 years


Department of Ophthalmology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Date of Submission27-Oct-2018
Date of Acceptance22-Apr-2019
Date of Web Publication12-Sep-2019

Correspondence Address:
Abd El-Magid M Tag El-Din
1st District Omar Zaafan Street, Building 13, Flat 602, Nasr City, Cairo 11765
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_115_18

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  Abstract 


Background Diabetic macular edema (DME) is a common cause of blindness and visual impairment in diabetic patients, which can affect the quality of life. Aflibercept and ranibizumab are used as intravitreal anti-vascular endothelial growth factor injections; both of them have a relatively safe effective treatment of DME.
Aim of the work To compare the effect of aflibercept and ranibizumab in the management of DME.
Patients and methods A prospective invasive and nonrandomized study, including 20 eyes in 20 patients, more than 40 years old, was conducted in Al-Azhar Faculty of Medicine, Cairo, with three times injections 1 month apart. Eyes were divided into two groups: group A included 10 patients who received ranibizumab 0.5 mg (0.05 ml of 10 mg/ml solution) as an intravitreal injection, and group B included 10 patients who received aflibercept 2 mg (0.05 ml of 40 mg/ml solution) as an intravitreal injection. Follow-up period was 4 months.
Results A statistically significant improvement of best-corrected visual acuity (BCVA) and central macular thickness with ranibizumab was reported over the follow-up period. There was also a statistically significant improvement of BCVA, central macular thickness, and intraocular pressure over the follow-up visits with aflibercept. Ranibizumab was more effective in BCVA correction and in the reduction of central macular thickness than aflibercept.
Conclusion Both ranibizumab and aflibercept are effective in improving the BCVA and in the reduction of central macular thickness. Ranibizumab is more effective for BCVA correction and in the reduction of central macular thickness than aflibercept
Recommendations Further studies are needed to confirm the effect of ranibizumab and aflibercept intravitreal injection on the central macular thickness and intraocular pressure.

Keywords: aflibercept, diabetic macular edema, ranibizumab


How to cite this article:
Tag El-Din AMM. Comparative study between ranibizumab and aflibercept in the management of macular edema caused by diabetes mellitus in age group more than 40 years. Al-Azhar Assiut Med J 2019;17:35-47

How to cite this URL:
Tag El-Din AMM. Comparative study between ranibizumab and aflibercept in the management of macular edema caused by diabetes mellitus in age group more than 40 years. Al-Azhar Assiut Med J [serial online] 2019 [cited 2019 Oct 20];17:35-47. Available from: http://www.azmj.eg.net/text.asp?2019/17/1/35/266729




  Introduction Top


The rise in diabetes prevalence is a global health and economic problem. Diabetic retinopathy (DR) is a serious complication of diabetes, which leads to blindness among working-age populations in developed countries [1].

The prevalence of diabetes mellitus (DM) is suspected to grow to 430 million patients by 2030, with increased risk of developing DR [2].

The prevalence of DR is still high at 40% of diabetic patients. Globally, there are approximately 93 million people with DR, 70 million with proliferative diabetic retinopathy (PDR), 21 million with diabetic macular edema (DME), and 28 million with high-risk retinopathy as PDR [3].

DR is a microangiopathy characterized by microaneurysms, capillary nonperfusion, and ischemia within the retina. It may cause several complications, such as DME and diabetic macular ischemia. In particular, capillary nonperfusion impairs the nutrition of the neuroglial tissues in the retinal parenchyma, with the resultant hypoxia increasing the risk of expression of vascular endothelial growth factor (VEGF), which promotes both angiogenic responses and vascular permeability [4].

The classic retinal changes of DR include microaneurysms, hemorrhages, venous beading, intraretinal-microvascular abnormalities, hard exudates, cotton-wool spots, and retinal neovascularization. These findings can be used to classify eyes as having one of two stages of DR [5].

Nonproliferative diabetic retinopathy

Different stages of DR with increasing severity include mild, moderate, and severe non-PDR. The identification of the DR severity level of an eye allows a prediction of risk of DR progression, threat of visual loss, and determine the appropriate treatment and recommendations including regular follow-up visits [6].

Proliferative diabetic retinopathy

PDR is the most advanced stage of DR. It is an angiogenic retinal response to the extensive ischemia from capillary occlusion. Retinal neovascularization is characterized by new vessels on the disc or new vessels elsewhere along the vascular arcades [6].

DME, a manifestation of DR, affects central vision. It affects ∼750 000 people in the United States and is a leading cause of vision loss. The costs associated with visual impairment and treatment of DME are high. The increasing prevalence of diabetes worldwide highlights the importance of DME as a global health issue [7].

The Early Treatment Diabetic Retinopathy Study (ETDRS) defined macular edema as retinal thickening and/or hard exudates within one disc diameter of the center of the macula [8].

Alteration of the blood–retinal barrier is the main pathology of this disease, characterized by loss of the pericytes and breakdown of the endothelial cell–cell junction. The animal and clinical studies indicate that DME is an inflammatory disease. Multiple chemokines and cytokines are involved in the pathogenesis of DME, with multiple cellular involvement affecting the neurovascular unit [9].

Risk factors that contribute to DME progression include increasing hyperglycemia levels, diabetic duration, severity of DR at baseline, the presence of gross proteinuria, and diastolic blood pressure [10].

The common tools for assessing macular edema are fundus biomicroscopy and fluorescein angiography. Stereoscopic examination of the fundus using the slit-lamp or on stereoscopic color fundus photographs is the standard method, as defined by the ETDRS, for evaluating macular thickening and to initiate treatment when the clinical significant macular edema is settled [11].

Optical coherence tomography (OCT) allows detailed assessment of retinal thickness and morphologic evaluation of the neurosensory retinal layers. OCT imaging has been integrated into diagnosis and management of DME in routine clinical practice and clinical trials [12].

DME is recently classified into a central involved and noncentral involved macular edema. Central involved macular edema is defined as retinal thickening in the macula that involves the central subfield zone that is 1 mm in diameter [6].

VEGF levels are elevated in the retina and vitreous of eyes with DR [13].

Since the 1980s, intravitreal injections of anti-VEGF agents have been shown to be the standard treatment for DME. In 2013, approximately 90% of retinal specialists in USA reported using intravitreal anti-VEGF therapy for initial management of vision loss from DME involving the macular center [2].

The three drugs commonly used for intravitreal VEGF inhibitors − bevacizumab, aflibercept, and ranibizumab − have been shown to be relatively safe and beneficial for the treatment of DME. The Food and Drug Administration approve only aflibercept and ranibizumab for this indication. Bevacizumab (avastin), is not approved by the Food and Drug Administration for any ocular indication and is widely used for off-label treatment of DME in repackaged aliquots containing ∼1/500th of the systemic dose used in treatment of cancer [14].


  Aim of the work Top


The aim of this study is to compare between the effect of aflibercept and ranibizumab in patients with DME which is one of the most common DR complications that leads to impairment of vision.


  Patients and methods Top


This prospective invasive nonrandomized study included 20 eyes of 20 patients. It was conducted in the Faculty of Medicine, Al-Azhar University Hospitals, Cairo, with three injections 1 month apart. Eyes in the study were divided into two groups: group A included eyes in 10 patients who received ranibizumab 0.5 mg (0.05 ml of 10 mg/ml solution) intravitreal injection, and group B included 10 eyes in 10 patients who received aflibercept 2 mg (0.05 ml of 40 mg/ml solution) intravitreal injection. Follow-up was carried out for 3 months.

Inclusion criteria

More than 40-year-old patients with DME, who need an intravitreal injection of anti-VGEF with no other factors mentioned in the exclusion criteria, were included.

Exclusion criteria

Patients with macular edema owing to other medical causes like retinal vein occlusion and choroidal neovascularization, patients with postoperative macular edema after phacoemulsification (Irvine–Gass syndrome), and patients with past history of trauma, uveitis, glaucoma, and retinal dystrophies were excluded.

All patients were subjected to visual acuity testing, unaided and aided. Slit-lamp biomicroscopy was done for evaluation of anterior segment. Intraocular pressure (IOP) measurement was done using air puff tonometer. Indirect ophthalmoscopy was done to assess media clarity and retinal pathology. Fundus fluorescein angiography was done for all patients using Topcon device preoperatively and after the third injection. OCT examination was done for all patients using Topcon 3D OCT 2000 (Topcon Corporation, Itabashi, Tokyo, Japan) preoperative, and follow-up OCT was done monthly for 3 months after each injection.

Ethical considerations

This prospective study was conducted, in accordance with the ethical standards stated in the Faculty of Medicine, Al-Azhar University. All patients signed an informed consent before surgery.

Statistical analysis

The recorded data were statistically analyzed using the statistical package for social sciences, version 20.0 (SPSS Inc., Chicago, Illinois, USA). Quantitative data were expressed in the form of mean±SD. Qualitative data were expressed as frequency and percentage.

The following tests have done: independent samples t test of significance was used when comparing between two means. One-way analysis of variance was done to compare between more than two means. χ2 test of significance was used to compare proportions between two qualitative parameters. The confidence interval was preset to 95% and the margin of error accepted was preset to 5%. So, P value was considered significant if P value less than 0.05 was considered significant. P value less than 0.001 was considered as highly significant. P value more than 0.05 was considered insignificant.


  Results Top


There was insignificant statistical difference between both groups according to the demographic data ([Table 1]).
Table 1 Comparison between both groups according to demographic data

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Differences between both groups according to best-corrected visual acuity (BCVA), central thickness, and IOP before injection were statistically insignificant ([Table 2]).
Table 2 Comparison between both groups according to best-corrected visual acuity, central thickness, and intraocular pressure before injection

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There was a statistically significant difference between both groups according to BCVA after the first injection ([Table 3]).
Table 3 Comparison between both groups according to best-corrected visual acuity, central thickness, and intraocular pressure after the first injection

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There was also a statistically significant difference between both groups according to BCVA after the second injection ([Table 4]).
Table 4 Comparison between both groups according to best-corrected visual acuity, central thickness, and intraocular pressure after second injection

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Difference between both groups according to BCVA after the third injection was statistically significant ([Table 5]).
Table 5 Comparison between both groups according to best-corrected visual acuity, central thickness, and intraocular pressure after third injection

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Improvement of BCVA and central thickness over the follow-up periods in group I was statistically significant ([Table 6]).
Table 6 The extent of differences over the periods in best-corrected visual acuity, central thickness, and intraocular pressure in group I

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There was also a statistically significant improvement of BCVA and central thickness over the follow-up periods in group II ([Table 7], [Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6],[Figure 7],[Figure 8],[Figure 9],[Figure 10],[Figure 11],[Figure 12],[Figure 13]).
Table 7 The extent of differences over the periods in best-corrected visual acuity, central thickness and intraocular pressure in group II

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Figure 1 Topcon 3D OCT device. OCT, optical coherence tomography.

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Figure 2 OCT scan of patient number 3 before injection passing through the fovea showing neurosensory detachment and overlying cystic spaces; average thickness is shown above. OCT, optical coherence tomography.

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Figure 3 OCT scan of patient number 3 showing marked improvement after the first injection. OCT, optical coherence tomography.

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Figure 4 OCT scan of patient number 3 showing more improvement after the second injection. OCT, optical coherence tomography.

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Figure 5 OCT scan of patient number 3 after the third injection. OCT, optical coherence tomography.

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Figure 6 FFA of patient number 3 before injection. FFA, fundus fluorescein angiography.

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Figure 7 FFA of patient number 3 after the third injection. FFA, fundus fluorescein angiography.

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Figure 8 OCT scan of patient number 2 before injection passing through the fovea showing diffuse macular edema. OCT, optical coherence tomography.

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Figure 9 OCT scan of patient number 2 showing marked improvement after the first injection. OCT, optical coherence tomography.

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Figure 10 OCT scan of patient number 2 showing more improvement after the second injection. OCT, optical coherence tomography.

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Figure 11 OCT scan of patient number 2 after the third injection. OCT, optical coherence tomography.

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Figure 12 FFA of patient number 2 before injection. FFA, fundus fluorescein angiography.

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Figure 13 FFA of patient number 2 after the third injection. FFA, fundus fluorescein angiography.

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  Discussion Top


DME is a well-documented, vision-threatening complication of diabetes mellitus. Previously described methods of assessing DME include contact and noncontact slit-lamp biomicroscopy, indirect fundoscopy, fluorescein angiography, and fundus stereo-photograph [11].

Regarding the economic burden of the disease, DME may lead to impairment of vision with reduction in quality of life. Patients with DME consume more healthcare resources than diabetic patients without retinal insults [15].

The etiology of DME has not been fully elucidated. Chronic hyperglycemia, the oxygen free radicals accumulation, advanced glycation end products, and high cholesterol levels have all been implicated as risk factors for the development of DME [16].

The use of OCT allows further objective evaluation of DME. In addition, OCT gives cross-sectional images of the retina that correlate well with retinal histological structure as demonstrated by light microscopy [11].

VEGF-A has been identified as a key vascular permeability factor that contributes to neovascularization and blood–retinal barrier dysfunction, making it an attractive target for pharmaceutical intervention [17].

Strict diabetic, blood pressure, and lipid control is crucial for prevention and treatment of DME. According to American Diabetes Association, glycated hemoglobin should be controlled at 6.5–7%, and blood pressure should be below 130/85 mmHg, with total lipids lower than 100 mg/dl. The goal of local eye treatment is to reduce thickness, control the progression of the disease, and improve vision. Local treatments for eyes with DME include laser photocoagulation, vitrectomy surgery, and intravitreal injection of drugs [18].

In this comparative, randomized clinical trial of DME causing decreased visual acuity, treatment with intravitreal aflibercept and ranibizumab was associated with improvement in mean visual acuity at 1 month. Improvement persisted through 3-month follow-up, with the use of a standardized retreatment protocol. On average, greater improvement was noticed with ranibizumab than with the other anti-VEGF agent.

On correlating between age and sex of patients with the effect of anti-VEGF on the BCVA and the central thickness, differences were statistically insignificant.

There was a significant improvement in the visual acuity after 1 month of ranibizumab injection (13%) with much decrease in the central thickness. After the second injection of ranibizumab, there was also a significant improvement of BCVA compared with aflibercept but it was much less than the first one (3%). The increase in the BCVA (4%) was also significant after the third injection of ranibizumab as compared with the other agent and more than the second injection.

To evaluate the long-term efficacy of ranibizumab, Schmidt-Erfurth et al. [19] reported that the patients initially treated with ranibizumab showed a considerable improvement at month 12 in BCVA compared with those treated with laser in the core phase. During the extension study, patients in the prior ranibizumab groups were able to maintain the initial BCVA gains achieved at month 12 to months 24 and 36 with individualized ranibizumab treatment.

Regarding the effect of ranibizumab on the central macular thickness, the central subfield thickness decreased from 344.80 µm to a level of 254.20 µm (average, 90.6±86 µm) after the first injection, whereas it decreased to a level of 229.90 µm (average, 45.7±4 µm) after the second injection. The third injection had the least effect on the central thickness compared with the previous two injections, as central subfield thickness decreased to a level of 226.50 µm (average, 3.4±1 µm).

Ozturk et al. [20] reported that 29 eyes were enrolled in their study in which the ranibizumab treatment increased the median BCVA from 53 to 66 ETDRS letters and decreased the median central subfield mean thickness (CSMT) from 428 µm to a level of 279 µm after 1 month of injection, which was statistically significant.

In patients treated with ranibizumab in the study reported by Schmidt-Erfurth et al. [19], the mean central retinal subfield thickness (CRST) reductions observed at the end of the core study (127.8 µm at month 12) were maintained at month 36 (142.1 µm).

Regarding the effect of aflibercept on the central thickness, the central subfield thickness decreased from 288.70 µm to a level of 244.80 µm (average, 43.9±25 µm) after the first injection, whereas it decreased to a level of 235.40 µm (average, 9.4±2 µm) after the second injection. The third injection had the least effect on the central thickness compared with the previous two injections, as central subfield thickness decreased to a level of 231.20 µm, (average, 4.2±2 µm). The improvement in the central thickness was significant over the time.

In protocol T, the central subfield thickness decreased at the 1-year visit, on average, by 169±138 µm with aflibercept and 147±134 µm with ranibizumab; the thickness was less than 250 µm in 135 of 205 (66%) eyes and 116 of 201 (58%) eyes, respectively. The relative treatment effect on central subfield thickness varied according to initial visual acuity.

Different to previous studies, our study showed more improvement in BCVA (P=0.03), which is significant, and more reduction in central macular thickness with ranibizumab than with aflibercept in accordance with the study of cost-effectiveness of ranibizumab versus aflibercept for the treatment of visual impairment owing to DME done by the UK National Institute for Health and Care Excellence [21], in which ranibizumab was dominant over aflibercept, by demonstrating lower life time costs for UK healthcare providers, as well as higher gains for patients receiving ranibizumab than for those taking aflibercept. The main drivers of the results were the higher probability of gaining 10 or more letters in BCVA with ranibizumab regimens compared with aflibercept, the greater number of injections required, and the costs associated with aflibercept versus ranibizumab treatment.These results can also be explained by presence of resistance to aflibercept in a patient who was bilaterally injected. It is not known, yet, why some patients do not respond to anti-VEGF treatment or develop into nonresponders during the course of the treatment. Tachyphylaxis has been accused to be responsible about the development of a resistance to intravitreal injections. However, the mechanisms are not clear. Genetic variants of the VEGF gene seem to alter the response to anti-VEGF treatment [22].

Regarding the effect of aflibercept on the IOP, there was a statistically significant difference over the time after the three injections as it showed reduction in IOP especially after the first one and this may be owing to the diurnal variation in IOP.

In the study by Baek et al. [23] of the long-term effects of multiple intravitreal anti-VEGF injections on the IOP, no significant change in IOP was observed.


  Conclusion Top


There is a statistically significant improvement of BCVA and central macular thickness over the time with ranibizumab and aflibercept intravitreal injections for treatment of DME. Ranibizumab showed a statistically significant improvement in BCVA and central macular thickness improvement as compared with aflibercept.

Recommendations

A large-scale and a long-term study is recommended to confirm our results for the effect of ranibizumab and aflibercept injection on BCVA, central macular thickness, and IOP, and to compare the effect of a single injection versus multiple injections. Searching for causes of resistance or delayed response to the intravitreal injections in some patients is highly recommended.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Congdon NG, Friedman DS, Lietman T. Important causes of visual impairment in the world today. JAMA 2003; 290:60–205.  Back to cited text no. 1
    
2.
Korobelnik JF, Do DV, Schmidt-Erfurth U, Boyer DS, Holz FG, Heier JS et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology 2014; 121:54–224.  Back to cited text no. 2
    
3.
Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012; 35:64–556.  Back to cited text no. 3
    
4.
Miwa Y, Murakami T, Suzuma K, Uji A, Yoshitake S, Fujimoto M et al. Relationship between functional and structural changes in diabetic vessels in optical coherence tomography angiography. Sci Rep 2016; 6:290.  Back to cited text no. 4
    
5.
Wong TY, Sun J, Kawasaki R, Ruamviboonsuk P, Gupta N, Lansingh VC et al. Guidelines on diabetic eye care: The International Council of Ophthalmology recommendations for screening, follow-up, referral, and treatment based on resource settings. Ophthalmology 2018; 125:233–241.  Back to cited text no. 5
    
6.
ICO Guidelines. Guidelines Diabetic Eye Care, 2017. Avalilable at: www.icoph.org/downloads/ICO. [Last Accessed at 2018-May-13]  Back to cited text no. 6
    
7.
Varma R, Bressler NM, Doan QV, Gleeson M, Danese M, Bower JK et al. Prevalence and risk factors for diabetic macular edema in the United States. JAMA Ophthalmol 2014; 40:132–134.  Back to cited text no. 7
    
8.
Yang XL, Liu K, Xu X. Update on treatments of diabetic macular edema. Chin Med J (Engl) 2009; 122:90–278.  Back to cited text no. 8
    
9.
Das A, McGuire PG, Rangasamy S. Diabetic macular edema: pathophysiology and novel therapeutic targets. Ophthalmology 2015; 122:1375–1394.  Back to cited text no. 9
    
10.
Stitt AW, Lois N, Medina RJ, Adamson P, Curtis TM. Advances in our understanding of diabetic retinopathy. Clin Sci (Lond) 2013; 125:1–17.  Back to cited text no. 10
    
11.
Kim BY, Smith SD, Kaiser PK. Optical coherence tomographic patterns of diabetic macular edema. Am J Ophthalmol 2006; 142:12–405.  Back to cited text no. 11
    
12.
Al-latayfeh MM, Sun JK, Aiello LP. Ocular coherence tomography and diabetic eye disease. Semin Ophthalmol 2010; 25:7–192.  Back to cited text no. 12
    
13.
Miller JW, Le Couter J, Strauss EC, Ferrara N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 2013; 120:14–106.  Back to cited text no. 13
    
14.
Arevalo JF, Lasave AF, Wu L, Diaz-Llopis M, Gallego-Pinazo R, Alezzandrini AA et al. Intravitreal bevacizumab plus grid laser photocoagulation or intravitreal bevacizumab or grid laser photocoagulation for diffuse diabetic macular edema: results of the Pan-American Collaborative Retina Study Group at 24 months. Retina 2013; 33:13–403.  Back to cited text no. 14
    
15.
Chen E, Looman M, Laouri M, Gallagher M, Van Nuys K, Lakdawalla D, Fortuny J. Burden of illness of diabetic macular edema: literature review. Curr Med Res Opin 2010; 26:1587–1597.  Back to cited text no. 15
    
16.
Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: pathogenesis and treatment. Surv Ophthalmol 2009; 54:1–32.  Back to cited text no. 16
    
17.
Zhang X, Bao S, Hambly BD, Gillies MC. Vascular endothelial growth factor-A: a multifunctional molecular player in diabetic retinopathy. Int J Biochem Cell Biol 2009; 41:2368–2371.  Back to cited text no. 17
    
18.
Breen EC. VEGF in biological control. J Cell Biochem 2007; 102:1358–1367.  Back to cited text no. 18
    
19.
Schmidt-Erfurth U, Lang GE, Holz FG, Schlingemann RO, Lanzetta P, Massin P et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology 2014; 121:1045–1053.  Back to cited text no. 19
    
20.
Ozturk BT, Kerimoglu H, Bozkurt B, Okudan S. Comparison of intravitreal bevacizumab and ranibizumab treatment for diabetic macular edema. J Ocul Pharmacol Ther 2011; 27:373–377.  Back to cited text no. 20
    
21.
UK National Institute for Health and Care Excellence (NICE) Ranibizumab for treating diabetic macular oedema. 2014. www.nice.org.uk/guidance/ta274. [Last Acceseed at 2018-Apr-2]  Back to cited text no. 21
    
22.
Abedi F, Wickremasinghe S, Richardson AJ, Makalic E, Schmidt DF, Sandhu SS et al. Variants in the VEGFA gene and treatment outcome after anti-VEGF treatment for neovascular age-related macular degeneration. Ophthalmology 2013; 120:115–121.  Back to cited text no. 22
    
23.
Baek SU, Park IW, Suh W. Long-term intraocular pressure changes after intravitreal injection of bevacizumab. Cutan Ocul Toxicol 2016; 35:310–314.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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