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 Table of Contents    
ORIGINAL ARTICLE
Year : 2018  |  Volume : 11  |  Issue : 3  |  Page : 248-253  

Evaluation of intravitreal bevacizumab as monotherapy and in combination with macular grid laser photocoagulation in diffuse diabetic macular edema


Department of Ophthalmology, University College of Medical Sciences and GTB Hospital, Delhi University, New Delhi, India

Date of Web Publication29-Oct-2018

Correspondence Address:
Dr. Gopal K Das
Department of Ophthalmology, University College of Medical Sciences and GTB Hospital, Delhi University, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ojo.OJO_196_2016

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   Abstract 


BACKGROUND AND OBJECTIVE: The objective of the study was to compare the efficacy of intravitreal bevacizumab (IVB) as monotherapy versus combination with modified macular grid (MMG) laser photocoagulation in the primary treatment of diffuse diabetic macular edema (DDME).
MATERIALS AND METHODS: A prospective randomized trial was carried out in sixty eyes with DDME after Institutional Ethical clearance. Group A received three doses of IVB at a 1-month interval. Group B received MMG in addition to IVB. Complete examination including best-corrected visual acuity (BCVA) (Snellen's), central macular thickness (CMT) using spectral domain-optical coherence tomography was carried out at 0, 1, 4, 8, 12, and 24 weeks.
RESULTS: mean CMT at baseline, 12 and 24 weeks in Group A was 401 (±76), 280 (±49), and 307 (±46) and in Group B, 405 (±73), 237 (±33), and 242 (±45), respectively. Group B had significantly greater reductions (P < 0.001) from 12 weeks onward. BCVA and contrast sensitivity showed improvements with no significant difference.
CONCLUSION: Combined therapy has more advantage in primary DDME by reducing CMT on longer follow-up.

Keywords: Antivascular endothelial growth factor, bevacizumab, central macular thickness, diabetes macular edema, macular grid laser photocoagulation


How to cite this article:
Das GK, Sahu PK, L. Biakthangi LV, Jain D. Evaluation of intravitreal bevacizumab as monotherapy and in combination with macular grid laser photocoagulation in diffuse diabetic macular edema. Oman J Ophthalmol 2018;11:248-53

How to cite this URL:
Das GK, Sahu PK, L. Biakthangi LV, Jain D. Evaluation of intravitreal bevacizumab as monotherapy and in combination with macular grid laser photocoagulation in diffuse diabetic macular edema. Oman J Ophthalmol [serial online] 2018 [cited 2018 Dec 12];11:248-53. Available from: http://www.ojoonline.org/text.asp?2018/11/3/248/244315




   Introduction Top


Diabetes is a highly prevalent disease worldwide,[1] and in India[2] especially in the working age group. The loss of vision, due to diabetes, is commonly attributed to diabetic macular edema (DME),[3] which accounts for 12% of new cases of blindness each year[4] with heavy impact in terms of functional impairment and handicap, impaired quality of life, social burden, and economic loss.[5]

Macular grid photocoagulation has been the main treatment employed for diffuse DME.[6] However, it results in only 50% reduction in risk of vision loss[6],[7],[8],[9],[10] and a significant gain in vision is uncommon.[6] The use of intravitreal steroids for DME has been limited by the high incidence of cataract, rise in intraocular pressure (IOP), and risk of endophthalmitis.[11],[12] Recently, studies on antivascular endothelial growth factor (anti-VEGFs) have shown promising results in diffuse DME when compared with laser monotherapy or with intravitreal steroids.[13],[14] However, the main limitation of anti-VEGF is their short duration of action which necessitates repeated injection. Combination of anti-VEGF and laser photocoagulation may be beneficial (laser may have more effect on a prethinned retina with prior anti-VEGF, thus requiring lesser energy and reducing collateral damage) and may even decrease the requirement of repeated injections. This study has been carried out to compare the efficacy between intravitreal bevacizumab (IVB) monotherapy versus combined treatment of IVB and macular grid laser photocoagulation


   Materials and Methods Top


This study was conducted in sixty eyes of 36 diabetics recruited from the Outpatient Department of Guru Teg Bahadur Hospital, Delhi, with the following inclusion criteria:

  1. Diabetes mellitus type 1or 2, with diffuse diabetic macular edema (DDME). (Diffuse macular edema is defined as having two or more disk areas of retinal thickening involving the center of the macula)
  2. Central macular thickness (CMT) >300 μm, on spectral domain-optical coherence tomography (SD-OCT)
  3. Good metabolic control (HbA1c <7.5 and blood pressure <140/90).


The exclusion criteria were significant media opacity, proliferative diabetic retinopathy, previous ocular surgery, any prior treatment for macular edema, traction maculopathy, ischemic maculopathy, the presence of any other macular pathology, history of coronary artery disease/stroke, or history of glaucoma.

Institutional Ethical clearance from University College of Medical Sciences Medical Board was ensured. A written informed consent was taken from all included participants. All patients underwent complete eye examination including best-corrected visual acuity (BCVA, Snellens), IOP measurement (Goldmann's Applanation tonometry), fundus imaging digital camera fluorescein angiography (Visu Cam–lite, Carl Zeiss Inc., Germany), and SD-OCT. CMT was measured using SD-OCT (Cirrus, 4000, Carl Zeiss Inc., Germany). Contrast sensitivity (CS) using Pelli Robson CS chart and 10-2 visual field using Humphrey automated Perimetry (Carl Zeiss, Meditech) were also documented.

The subjects were randomized and allocated to one of the following groups:

  • Group A: IVB Group (who were administered three doses of IVB 1.25 mg in 0.05 ml, at 1 month interval).


Under all aseptic precautions, intravitreal injections of Bevacizumab 1.25 mg in 0.05 ml were administered under topical anesthesia, 3–4 mm from the limbus. Postprocedure evaluation was done immediately and then on the next day. Broad-spectrum antibiotic eye drops were continued up to the 3rd day. Any additional medication was given as per individual assessment and department protocol.

  • Group B: Combined Group (IVB and Macular Grid Laser photocoagulation) received modified macular grid (MMG) photocoagulation just before the second IVB injection after measurement of CMT, in addition to the three doses of IVB 1.25 mg in 0.05 ml, at 1 month interval.


After obtaining informed written consent, MMG photocoagulation was carried out with frequency doubled neodymium: yttrium aluminum garnet laser according to the ETDRS protocol (100–200 μm in diameter, with width spacing of 1–2 burns, exposure time of 0.1–0.2 s, and a laser power of 100–150 mW was delivered). Minimally white laser burns were created over the entire areas with thicknesses of ≥300 μm, as documented on OCT scans. The papillomacular bundle, the central area (up to 500 μm from the center of the fixation point), and the nonedematous retina were avoided.

For both groups, before each setting, preliminary local examination of eye was conducted including BCVA and IOP. Fundus examination was recorded at each follow-up at week 1, 4, 8, 12, and 24. Macular thickness using OCT was assessed at 1st, 2nd, 3rd, and 6th month in both groups. CS and perimetry were also performed in the 3rd and 6th month of follow-up and repeat fundus fluorescein angiography at 6 months of follow-up. Any adverse effects of therapy were documented in each follow-up.


   Results Top


The two groups had no significant difference in age [Table 1], gender [Table 2], glycosylated hemoglobin level [Table 3], and duration of diabetes [Table 4].
Table 1: Age comparison between groups

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Table 2: Gender distribution

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Table 3: Glycosylated hemoglobin level comparison between the two groups

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Table 4: Duration of diabetes comparison among the two groups

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Both the groups showed a decreasing trend of mean CMT till 3-month follow-up after which a gradual slow-increasing trend in noticed at 6 months [Table 5], [Figure 1] and [Figure 2]. The difference in mean CMT between the two groups at each follow-up was compared, and the mean CMT at baseline was found to be significant at 12 weeks and 24 weeks only (P < 0.001) between the two groups [Table 5]. In both groups, the mean CMT difference a 1, 4, 8, 12, and 24 weeks were all statistically significant when compared to the baseline mean CMT (P < 0.001) [Table 6] and [Table 7]. In both groups, the mean CMT at 4, 8, 12, and 24 weeks were also all statistically significant when compared to 1-week mean CMT [Table 6] and [Table 7]. In Group B (combined treatment), unlike Group A, the mean CMT was still significant when 4 weeks compared with 12 and 24 weeks of follow-up [Table 7].
Table 5: Mean central macular thickness in different follow-up

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Figure 1: Trend in mean central macular thickness over time

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Figure 2: Comparison of central macular thickness of individual eyes of Group A and B at baseline and 24 weeks

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Table 6: Comparison of mean central macular thickness in different follow-ups within Group A

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Table 7: Comparison of mean central macular thickness in different follow-up within Group B

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In terms of visual outcome, both groups showed improving trends over time [Figure 3] and [Figure 4]. In Group A (IVB group), change in mean BCVA was significant when compared to baseline at 4 weeks, 8 weeks, 12 weeks, and 24 weeks (P < 0.001) [Table 8]. Within Group B, mean BCVA change from baseline was significant at 8, 12, and 24 weeks. The difference in the mean BCVA between the two groups at each follow-up was not statistically significant. At 24 weeks, when compared to baseline, seven eyes (24.1%) had gain of three Snellen's line in Group A compared to eight eyes (25.9%) in group B. Five eyes (17.2%) in Group A had loss of two Snellen's line as compared to four eyes (14.8%) in Group B [Table 9].
Figure 3: Trend in mean best-corrected visual acuity over time

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Figure 4: Comparison of best corrected visual acuity of individual eyes of both groups at baseline and 24 weeks

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Table 8: Mean best-corrected visual acuity (in logarithm of the minimum angle of resolution) at different follow-ups

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Table 9: Gain or loss of best corrected visual acuity at 24 weeks

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There was an improving trend in CS with time. The change in mean log CS was significant when baseline was compared to both 12 weeks and 24 weeks in both groups (P < 0.001) [Table 10]. Furthermore, both groups had no significant difference in mean log CS in each follow-up (P = 0.959).
Table 10: Comparison of mean contrast sensitivity at different follow-ups

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There was also no significant change in mean IOP when compared within the individual groups at different follow-up (P = 260). Two eyes from Group A (IVB Group) deteriorated in staging of retinopathy. The rest other eyes did not show any changes in staging from baseline. There were no serious adverse effects encountered in any of the eyes in both groups in this study during the follow-up period which necessitated deferral of intravitreal injections. On further follow–up, beyond 6 months, two patients underwent cataract surgery from IVB group and one patient in IVB group underwent trabeculectomy within 1 year. There were no systemic adverse effects noticed in any of the subjects.


   Discussion Top


Bevacizumab is often preferred over ranibizumab in DDME due to easier availability and lower cost per injection (per patient) and has been widely used, especially in the Indian population. Indirect comparison of the efficacy of anti-VEGF using the Bucher method[15] did not demonstrate statistically significant differences between bevacizumab and ranibizumab or bevacizumab and Aflibercept. Recently, it has been seen that IVB with laser photocoagulation yielded improved visual outcomes, better anatomy, and treatment cost over monotherapy in ARMD.[16] It is possible for this additive effect to exist in DME as well. Hence, this study has been formulated to evaluate any additional benefit of combined treatment over monotherapy.

A search on world literature showed only a handful of studies on IVB for primary DME with only one study (Solaiman et al.[17]) comparing its efficacy with laser photocoagulation. To our knowledge, this is the only study with a preplanned three injections scheduled in both groups (only one other study had preplanned three injections, but it was done for refractory DME[18]). An extensive systemic review by the Canadian Agency of Drug and Technologies[19] on IVB on DME revealed four other trials comparing IVB and laser (with or without intravitreal triamcinolone acetonide) which met standard criteria. Solaiman et al.[17] noted improvement in BCVA significant only at 3 months between IVB and combined group (P < 0.05). Six months after either one injection of IVB or laser photocoagulation, there was no significant improvement; however, vision did not deteriorate from baseline. In our study, significant improvement in mean BCVA was seen in both groups when compared to the baseline. However, this difference was not significant when compared between the two groups in each follow-up. Total 17.9% had deterioration of one or more lines at week 24 whereas 59.2% showed a gain of one or more lines. Nearly 17.9% did not have any change in vision at 6 months.

Analysis of the five major trials on IVB[19] showed that mean change in CMT did not significantly differ at week 6, and at week 24, laser outperformed IVB. Median CMT which was reported in two trials (Michaelides et al.[18] and DCRN[20]) did not differ between monotherapy of either IVB and laser. In our study, CMT showed decreasing trends till 3 months followed by a gradual slow-increasing trend at 6 months in both group, significant when compared to baseline in each follow-up. Combined group had significantly lower CMT at 12 weeks and 24 weeks when compared to IVB group.


   Conclusion Top


Our study which compared IVB as monotherapy against combined therapy with laser photocoagulation, found both treatment to be similarly efficacious in terms of improvement in BCVA and CS. The advantage of combined group was reflected in a significantly lesser CMT on longer follow-up, without any increase in adverse effects. Whether this benefit translates to a decrease in the requirement for repeated injections in future needs to be further studied.

Acknowledgments

The authors would like to thank our colleagues who provided insight and expertise that greatly assisted the research. We are also immensely grateful to the technical staff for their assistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
World Health Organization. Diabetes Fact Sheet Number 312. Available from: http://www.who.int/mediacentre/factsheets/fs312/en/. [Last updated on 2018 Jan 11; Last accessed on 2015 Nov 03].  Back to cited text no. 1
    
2.
Raman R, Rani PK, Reddi Rachepalle S, Gnanamoorthy P, Uthra S, Kumaramanickavel G, et al. Prevalence of diabetic retinopathy in India: Sankara Nethralaya diabetic retinopathy epidemiology and molecular genetics study report 2. Ophthalmology 2009;116:311-8.  Back to cited text no. 2
    
3.
Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. Ophthalmology 1998;105:998-1003.  Back to cited text no. 3
    
4.
Centers for Disease Control and Prevention (CDC). Blindness caused by diabetes – Massachusetts, 1987-1994. MMWR Morb Mortal Wkly Rep 1996;45:937-41.  Back to cited text no. 4
    
5.
Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology 1995;102:647-61.  Back to cited text no. 5
    
6.
Photocoagulation for diabetic macular edema. Early treatment diabetic retinopathy study report number 1. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol 1985;103:1796-806.  Back to cited text no. 6
    
7.
Photocoagulation for diabetic macular edema: Early treatment diabetic retinopathy study report no 4. The Early Treatment Diabetic Retinopathy Study Research Group. Int Ophthalmol Clin 1987;27:265-72.  Back to cited text no. 7
    
8.
Olk RJ. Modified grid argon (blue-green) laser photocoagulation for diffuse diabetic macular edema. Ophthalmology 1986;93:938-50.  Back to cited text no. 8
    
9.
Olk RJ. Argon green (514 nm) versus krypton red (647 nm) modified grid laser photocoagulation for diffuse diabetic macular edema. Ophthalmology 1990;97:1101-12.  Back to cited text no. 9
    
10.
Striph GG, Hart WM Jr., Olk RJ. Modified grid laser photocoagulation for diabetic macular edema. The effect on the central visual field. Ophthalmology 1988;95:1673-9.  Back to cited text no. 10
    
11.
Cunha-Vaz J, Ashton P, Iezzi R, Campochiaro P, Dugel PU, Holz FG, et al. Sustained delivery fluocinolone acetonide vitreous implants: Long-term benefit in patients with chronic diabetic macular edema. Ophthalmology 2014;121:1892-903.  Back to cited text no. 11
    
12.
Callanan DG, Gupta S, Boyer DS, Ciulla TA, Singer MA, Kuppermann BD, et al. Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology 2013;120:1843-51.  Back to cited text no. 12
    
13.
Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118:615-25.  Back to cited text no. 13
    
14.
Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Ranibizumab for diabetic macular edema: Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789-801.  Back to cited text no. 14
    
15.
Paccola L, Costa RA, Folgosa MS, Barbosa JC, Scott IU, Jorge R. Intravitreal triamcinolone versus bevacizumab for treatment of refractory diabetic macular oedema (IBEME study). Br J Ophthalmol 2008;92:76-80.  Back to cited text no. 15
    
16.
Ladas ID, Kotsolis AI, Papakostas TD, Rouvas AA, Karagiannis DA, Vergados I, et al. Intravitreal bevacizumab combined with photodynamic therapy for the treatment of occult choroidal neovascularization associated with serous pigment epithelium detachment in age-related macular degeneration. Retina 2007;27:891-6.  Back to cited text no. 16
    
17.
Solaiman KA, Diab MM, Dabour SA. Repeated intravitreal bevacizumab injection with and without macular grid photocoagulation for treatment of diffuse diabetic macular edema. Retina 2013;33:1623-9.  Back to cited text no. 17
    
18.
Michaelides M, Fraser-Bell S, Hamilton R, Kaines A, Egan C, Bunce C, et al. Macular perfusion determined by fundus fluorescein angiography at the 4-month time point in a prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (Bolt study): Report 1. Retina 2010;30:781-6.  Back to cited text no. 18
    
19.
Fortin P, Mintzes B, Innes M. A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema. Canadian Agency for Drugs and Technologies in Health; May, 2012. CADTH Rapid Response Reports. Available from: http://www.ncbi.nlm.gov/pbmedhealthPMH0061068/. [Last accessed on 2014 Nov 15].  Back to cited text no. 19
    
20.
Browning DJ, Glassman AR, Aiello LP, Beck RW, Brown DM, Fong DS, et al. Diabetic Retinopathy Clinical Research Network: Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology [Internet] 2007Mar; 114:525-36.  Back to cited text no. 20
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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