|Year : 2015 | Volume
| Issue : 1 | Page : 23-28
Primary intravitreal bevacizumab injection as a monotherapy versus combined intravitreal bevacizumab with argon laser photocoagulation in management of diabetic macular edema: A comparative study
Yomna Amr Alahmadawy, Rasha Mounir Eltanamly, M Ayman Khattab, Mosatafa Hamed Nabih
Department of Ophthalmology, Cairo University, Giza, Egypt
|Date of Web Publication||29-Mar-2016|
Yomna Amr Alahmadawy
No. 3, Montasser Buildings, Elharam, Giza
Source of Support: None, Conflict of Interest: None
Purpose: To assess the effectiveness of bevacizumab versus bevacizumab with macular laser photocoagulation in diabetic macular edema. Patients and Methods: Forty eyes of 31 patients with macular edema were enrolled in this study; Group A, twenty eyes received baseline three monthly injections of bevacizumab (1.25 mg/0.05 ml), then monthly reinjection according to pro re nata (PRN) regimen, and Group B, twenty eyes received one injection plus laser 1 month later, then monthly injections according to PRN regimen (? according to PRN also). Results: In Group A, no significant change in mean best-corrected visual acuity (BCVA) throughout 1 year (P = 0.165), as compared to Group B (P < 0.001). Mean BCVA in Group B at 12 months was 0.46 ± 0.30 compared with 0.75 ± 0.33 in Group A (P = 0.041).The mean number of injections in Group A was 5.55 times while in Group B was 1.4 times (P < 0.001). Conclusion: Combined treatment resulted in marked reduction of the number of injections required to control edema.
Keywords: Bevacizumab, diabetic macular edema, laser photocoagulation
|How to cite this article:|
Alahmadawy YA, Eltanamly RM, Khattab M A, Nabih MH. Primary intravitreal bevacizumab injection as a monotherapy versus combined intravitreal bevacizumab with argon laser photocoagulation in management of diabetic macular edema: A comparative study. Egypt Retina J 2015;3:23-8
|How to cite this URL:|
Alahmadawy YA, Eltanamly RM, Khattab M A, Nabih MH. Primary intravitreal bevacizumab injection as a monotherapy versus combined intravitreal bevacizumab with argon laser photocoagulation in management of diabetic macular edema: A comparative study. Egypt Retina J [serial online] 2015 [cited 2019 Oct 20];3:23-8. Available from: http://www.egyptretinaj.com/text.asp?2015/3/1/23/179349
| Introduction|| |
Diabetic macular edema (DME) is a manifestation of diabetic retinopathy that produces loss of central vision.  The standard treatment of DME is macular photocoagulation in clinically significant macular edema. 
Hypoxia triggered by diabetic vasculopathy stimulates the production of vascular endothelial growth factor (VEGF) which increases vascular permeability and leads to edema. Anti-VEGF therapy represents a useful therapeutic modality that targets the underlying pathogenesis of DME. Recently, the regimen of adding macular photocoagulation to intravitreal injections of bevacizumab, to consolidate the results and decrease the need for reinjection was adopted. 
The aim of this work was to assess the efficacy of intravitreal injection of bevacizumab as a monotherapy in DME as regard visual acuity and optical coherence tomography (OCT) thickness as compared to combined treatment with laser photocoagulation.
| Patients and Methods|| |
In this prospective, comparative, interventional study, 40 eyes of 31 patients, with clinically significant DME were randomized into two groups; Group A: Patients undergoing macular treatment using repeated bevacizumab injections and Group B: Patients undergoing macular treatment using bevacizumab injection followed by macular laser photocoagulation whether grid or focal depending on type of macular edema.
The patients were selected from the outpatient ophthalmology clinic of Kasr Al-Ainy Hospital, Cairo University. The protocol was revised and approved by ophthalmology Ethical Committee.
Any patient with clinically significant DME diagnosed by slit-lamp biomicroscopy, defined according to the Early Treatment Diabetic Retinopathy Study criteria (both diffuse and focal with or without macular ischemia) was included. Diagnosis was confirmed by baseline fundus fluorescein angiography and OCT scan.
Patients were excluded if they had proliferative diabetic retinopathy, previous treatment of macular edema, significant cataract, and glaucoma. Patients with any ocular condition that might affect macular edema or alter visual acuity during the course of the study (e.g., retinal vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass syndrome, etc.) were also excluded. Patients with uncontrolled hypertension and poor blood sugar control as evidenced by glycosylated hemoglobin (HbA1c) >10% were also excluded.
All patients underwent full medical and ophthalmic history, full ophthalmological examination, including best-corrected visual acuity (BCVA) using Snellen chart at a viewing distance of 3 meters and expressed in Decimal system. Slit-lamp examination of the anterior segment, intraocular pressure measurement using Goldmann applanation tonometry. Fundus examination was done using slit-lamp biomicroscopy and indirect ophthalmology.
Preinterventional fluorescein angiography (FFA), using Topcon TRC 50IX retinal camera (Topcon Optical Co., Tokyo, Japan) and OCT to document macular thickness and configuration of macular edema, using standard deviation (SD) OCT using line scans and macular map 5 mm was also done.
Laboratory investigations such as HbA1c, serum lipids, and kidney functions were also done for the patients.
All patients signed consent for intervention including advantages, disadvantages, and risks of possible complications especially for the intravitreal injection.
Patients received three initial, consecutive, monthly injections of 1.25 mg/0.05 ml bevacizumab, then monthly injections were received according to visual acuity and central macular thickness (CMT) by OCT. Monthly injections were discontinued if no further improvement in visual acuity or CMT. Injections were done under sterile conditions in the odds ratio.
After suspension, injections would be resumed if there was a decrease in BCVA due to DME progression confirmed by OCT. Patients were treated at monthly intervals again till the end of the follow-up period. When DME continued to progress despite monthly injections, we shifted to argon laser photocoagulation whether focal or grid according to the pattern of edema by FFA.
Intravitreal bevacizumab (IVB) injection was given, followed 3-4 weeks by macular laser photocoagulation whether focal or grid according to the pattern of edema. Injection was repeated after 3 months, provided that primary laser treatment was complete and not missing untreated lesions, according to response monitored by VA and OCT. Laser was performed using a green laser light (OPTO Advant Green Laser, Optos PLC., Dunfermline, Scotland, United Kingdom) with 100 μm spot size and with an exposure time of 100 ms. The power was adjusted by slowly increasing the laser power until a light gray-white (just visible) burn was obtained.
All the patients were examined monthly after treatment for 1 year. Examination included slit-lamp anterior segment examination, slit-lamp biomicroscopy for assessment of retinal thickening, hard exudations, development of neovessels or any other associated problems, and BCVA assessment using Snellen chart.
OCT was done 1 month after the first intervention (first 3 doses of bevacizumab in Group A/first injection plus laser in Group B) and after retreatment, otherwise it was done every 2 months. Fluorescein angiography was done when proliferative changes were suspected, and on failure to respond to laser photocoagulation, to detect untreated lesions.
Follow-up for the systemic condition of the patient regarding HbA1c, lipid profile, and kidney functions specially those who were resistant to treatment.
Primary outcomes measured were BCVA and CMT. Secondary outcomes were the occurrence of complications from either protocol.
Data were statistically described in terms of mean ± SD, range or frequencies (number of cases), and percentages when appropriate.
Shapiro-Wilk test was used to detect whether data are normally distributed or not. Most of the results have shown the nonnormal distribution of data, thus nonparametric methods were used. Comparison of numerical variables between the study groups was done using Mann-Whitney U-test for independent samples  to detect a difference in means between the two groups. Friedman test was used to compare the difference in means between three or more repeated measures within each group separately. 
For comparing categorical data, cross tabulations, and Chi-square test were performed. Fisher's Exact test was used instead when the expected frequency is <5. A probability P < 0.05 is considered to be statistically significant.
| Results|| |
Forty eyes of 31 patients were enrolled, nine patients for both eyes, 18 males, and 13 females. All of the patients completed 1-year follow-up. Twenty eyes were randomized to receive repeated bevacizumab injections (Group A), and the other twenty eyes were randomized to receive one injection of bevacizumab followed by laser photocoagulation (Group B).
Demographic data analysis
Demographic data of the patients are shown in [Table 1]. Thirteen patients (65%) in Group A and 11 patients (55%) in Group B received insulin, whereas seven patients (35%) in Group A and nine patients (45%) in Group B received oral hypoglycemic drugs with no statistical significance (P = 0.519). Ten patients (50%) in Group A and seven patients (35%) in Group B were hypertensive with no statistical significance (P = 0.337).
Initial mean BCVA (logarithm of the minimum angle of resolution [log MAR]) was 0.78 (SD ± 0.37) in Group A and 0.73 (SD ± 0.35) in Group B. No statistically significant difference in the mean visual acuity value was found at baseline (P = 0.576). The mean BCVA of both groups throughout the study is shown in [Table 2]. In Group A, there was no statistically significant change in BCVA among the follow-up visits at 1, 3, 6, and 12 months (P = 0.165) or even there was a minimal deterioration in BCVA at 6 th and 12 th month visits, while in Group B there was statistically significant improvement throughout the 1 year follow-up as shown in [Table 2] (P < 0.001).
|Table 2: Mean best corrected visual acuity (logarithm of the minimum angle of resolution) at different follow-up visits in both groups|
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The mean rate of change in BCVA (log MAR) from baseline to 12 th month was − 3.7% (negative value means a decrease in VA) in Group A, and 14.9% in Group B. Group A shows a decrease of the mean rate of change throughout different follow-up intervals unlike the improvement seen in Group B.
In Group A, 15% of patients gained only one line of BCVA on Snellen chart, 25% have gained 2 or more lines, 25% remain unchanged while 35% lost 2 or more lines of BCVA. In Group B, about 50% of patients gained more than two lines on Snellen chart, 15% gained only one line, 30% remained unchanged while only 5% lost one line of BCVA (this was the patient that developed the epiretinal membrane).
Central macular thickness
Initial mean CMT in Group A was 431 microns (SD ± 140.8), while in Group B was 394.1 microns (SD ± 101.4) with no statistically significant difference (P = 0.529). The mean CMT of both groups along the follow-up is shown in [Table 3]. In Group A, there was no statistically significant change throughout the follow-up period (P = 0.058), whereas in Group B, there was a significant change at the 1 st month with no furthermore significant change throughout the following visits (P = 0.001).
|Table 3: Mean optical coherence tomography thickness at different follow-up visits in both groups|
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In Group A, the rate of change of the mean CMT from baseline till the end of follow-up at 12 th month was 11.9% (SD ± 25.2) (decrease in thickness), in which the maximum rate of change was in the 1 st month after the first three injections by about 14.4% (SD ± 21.3); however, there was a deterioration in the mean CMT by 0.1% (SD ± 10.7) from 1 st to 3 rd month, 7.5% (SD ± 25.6) from 3 rd to 6 th months, and 0.6% (SD ± 23.4) from 6 th to 12 th months, however this reduction is of no statistical significance from one follow-up to the other.
In Group B, the rate of change of the mean CMT from baseline till the end of follow-up at 12 th month was 26.5% (SD ± 18.3) (decrease in thickness), in which the maximum rate of change was in the first month by about 19.1% (SD ± 11.6), this was followed by minimal improvement throughout the follow-up visits by 1.7% (SD ± 11.9) from 1 st to 3 rd month, 3.2% (SD ± 25.3) from 3 rd to 6 th month, and 2.5% (SD ± 13.6) from 6 th to 12 th month. Although it is clear that more reduction of macular thickness occurred in Group B at the end of 1-year follow-up, but it is of no statistical significance (P = 0.551), this was the same throughout all intervals. By the end of follow-up, 40% of patients in Group A achieved OCT thickness <300 μ as compared to 70% in Group B.
Number of injections
The mean number of injections in Group A was 5.55 times (range 3-8), while in Group B was 1.4 times (range 1-3) with a statistical significance (P < 0.001). About 70% of patients in Group A needed more than 3 injections throughout the follow-up period while in Group B about 65% of patients received only one injection.
The mean number of laser sessions given in Group B was 1.3 sessions (range 1-2). Thirty percent of patients required two sessions of laser, as indicated and confirmed by FFA.
No serious complications related to the procedures were encountered; apart from a transient rise of intraocular pressure in one patient in Group A (5%) that was controlled by antiglaucoma medication, and one patient in Group B that ended with an epiretinal membrane. The latter showed improvement of visual acuity and macular thickness after laser treatment till the 6 th -month visit, at 1 year visit the visual acuity dropped without any significant change in macular thickness.
| Discussion|| |
In recent years, alternative or adjunct treatments for DME have been studied such as intravitreal triamcinolone acetonide and inhibitors of VEGF.  Several studies showed the superiority of intravitreal injections of anti-VEGF over laser photocoagulation. 
Studies have shown no evidence from which to infer superiority of ranibizumab over bevacizumab in DME, except that bevacizumab is not licensed for management of DME, and, therefore, it is unlikely that ranibizumab would be cost-effective compared with bevacizumab. 
Few studies compared the effect of IVB as monotherapy to IVB combined with laser. In 2007, Diabetic Retinopathy Clinical Research Network evaluated the short-term safety and effect of IVB, either alone or in combination with focal photocoagulation, in the treatment of DME. Combining photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes; however, the follow-up was too short to determine if combination therapy would be beneficial in either improving visual outcome or reducing the number of intravitreal injections required. 
This study used BCVA (log MAR) and CMT using OCT as primary outcomes, and secondary outcomes were a number of injections and occurrence of complications related to the interventions.
Mean BCVA showed no statistically significant change among the follow-up visits in Group A (IVB alone) (P = 0.165) while in Group B (IVB and laser), there was statistically significant improvement throughout the 1-year follow-up (P < 0.001). Adding laser treatment to injection of bevacizumab showed better final vision, at the end of 1 year, than injection monotherapy (P = 0.04). Our results were different from those reported by Solaiman et al., who reported a nonsignificant change in the mean best-corrected visual acuity between the baseline and the end of the follow-up period in both the groups (P > 0.05). 
The results of Pan-American Collaborative Retina Study Group (PACORES) showed that primary IVB at doses of 1.25 mg or 2.5 mg with or without laser seems to provide fast stability and improvement in BCVA at 24 months. Groups A (IVB alone) and C (IVB and laser) had a statistically significant improvement from baseline BCVA at all-time points of follow-up. Conversely, in Group B (laser alone), there was no statistically significant difference from baseline BCVA until the first 6 months of treatment then BCVA improved significantly from baseline, and these changes were maintained throughout the 24 months of follow-up.
However, the PACORES study was a retrospective study, selection of patients for combined treatment (Group C) might have happened because of increased metabolic, functional, and anatomical impairment with poor glycemic control at some point in therapy. In addition, in Group A, baseline BCVA was worse, and CMT was higher that gives primary IVB alone more room for improvement to better functional and anatomical outcomes as regarding the rate of change. Other important limitation of that retrospective study is the lack of HbA1c data on nearly half of the patients in all groups. Those baseline characteristics could have biased the results and could explain why the combination of anti-VEGF therapy and laser did not result in fewer injections in combined treatment. They also reported that their sample size may have been insufficient to determine whether combined treatment was superior to laser or to anti-VEGF injections alone. 
Regarding OCT thickness, in our study, there was no statistically significant change throughout the follow-up period in Group A (P = 0.058), while in Group B there was a significant change at 1 st month with no furthermore significant change throughout the following visits (P = 0.001). The mean rate of reduction in OCT thickness at the end of follow-up was 11.9% in Group A and 26.5% in Group B which was not statistically significant. This was in contrast to what Solaiman et al. reported that within each group, the difference between the mean CMT at the baseline and at the end of the follow-up duration was statistically significant (P < 0.05). 
Furthermore, in the PACORES study, CMT improved in all treatment groups at 24 months of follow-up, although primary IVB alone produced a greater decrease in CMT than treatments in Groups B and C. 
The mean number of injections in this study was 5.55 times in Group A, while in Group B was 1.4 times. This protocol of retreatment criteria that is based on disease stability allows for reduction of the number of injections.
A number of injections in the combined group of this study did not match that of PACORS study as the total number of injections was 5.8 ± 3.2 in Group A (monotherapy) and 6.2 ± 4.9 in Group C (combined therapy). This may be attributed as mentioned before to the nature of retrospective study in baseline characteristic selection bias. Furthermore, the timing of laser application was not uniform as they used prompt and deferred laser. Prompt laser was assumed not to get the maximum effect of intravitreal injection in reducing the macular thickness. Another point of dissimilarity is that they enrolled only diffuse edema; however, in this study, focal edema was also allowed, this strengthened the role of laser treatment in our combined group due to good response of focal edema to laser treatment.
The cost-effectiveness of various modalities of interventions for newly diagnosed DME was studied, and considering the equivalent effectiveness and safety of bevacizumab and ranibizumab, bevacizumab conferred the greatest value among the studied treatment options. 
We found no major complications during our follow-up, apart from a transient rise of IOP in one patient in Group A, which was controlled by antiglaucoma medications, and another patient who developed a late epiretinal membrane in Group B due to extensive laser.  Other investigators reported on complications such as endophthalmitis, uveitis, retinal detachment, and systemic complications with anti-VEGF agents. ,
This study did not take into consideration the chronicity of DME and all cases of 1ry DME were enrolled regardless the untreated duration. Kook et al. observed a decrease in CMT and a gain in BCVA following repeated intravitreal injections of bevacizumab, even in cases with chronic diffuse ischemic DME. 
Subgroup analysis could not be done in this study to emphasize the effect of either repeated injections or combined treatment on focal and diffuse edema. Several factors that influence the visual function in eyes with macular edema, other than macular thickness, as integrity of external limiting membrane and inner and outer segments junction  and residual Muller fibers volume  were not considered in this study.
From the points of strength of this study is being a prospective study with a 1 year follow-up period. The customized regimen of injection according to patient's need depending on visual acuity and OCT using bevacizumab instead of ranibizumab to stress upon the concept of cost-benefit choice of the intravitreal drug used in the management of DME, especially in developing countries.
| Conclusion|| |
This study showed that combined treatment of IVB and laser had a significantly better outcome than IVB alone in the treatment of DME, as regards BCVA and CMT, and resulted in marked reduction of a number of injections required to control edema. Laser treatment resulted in prolonging the treatment-free interval. The rationale for the current trend of using a combination therapy is based on the fast recovery of macular anatomy/BCVA related to prompt VEGF inhibition (due to bevacizumab) associated with the long-term effects of laser (that may decrease the necessity of injections due to the sustained anti-VEGF effects of laser scars.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]