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ORIGINAL ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 2  |  Page : 37-42

Intravitreal bevacizumab alone or combined with macular laser for treatment of diabetic macular edema


Department of Ophthalmology, Benha Faculty of Medicine, Benha University, Banha, Egypt

Date of Web Publication17-Nov-2017

Correspondence Address:
Ayser Abd El-Hameed Fayed
Department of Ophthalmology, Benha Faculty of Medicine, Benha University, Banha
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/erj.erj_8_17

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  Abstract 


Purpose: We aimed to evaluate the best-corrected visual acuity (BCVA) and assess improvement of central macular thickness (CMT) in patients with diffuse diabetic macular edema (DDME) after an intravitreal injection of bevacizumab (Avastin®) alone, or followed by modified grid macular laser photocoagulation. Subjects and Methods: This was a randomized prospective interventional study that included 78 eyes of 40 patients with DDME, divided into two groups of interventions: Group A received bevacizumab (Avastin®) injections monthly for 3 months then pro re nata, and Group B received bevacizumab as Group A but followed by grid macular laser photocoagulation 2 weeks after the first injection. Patients were observed monthly for a 12-month period and their BCVA, intraocular pressure, and CMT were recorded. Results: Compared with the baseline, there was a significant decrease of CMT in both groups of patients (−138.3 ± 40.15 vs. −156.5 ± 33.47, respectively). The improvement in ME was more in the combined group than the Avastin® group (P < 0.0001). After 12-month follow-up, the mean average change in visual acuity letter score was significantly improved in both groups (P < 0.018 and < 0.002, respectively). Conclusion: Combined Avastin® and modified grid macular photocoagulation led to more stable improvement in the treatment of eyes with DDME.

Keywords: Avastin®, diffuse diabetic macular edema, photocoagulation


How to cite this article:
Shalaby UA, Soliman TT, El-Hameed Fayed AA. Intravitreal bevacizumab alone or combined with macular laser for treatment of diabetic macular edema. Egypt Retina J 2017;4:37-42

How to cite this URL:
Shalaby UA, Soliman TT, El-Hameed Fayed AA. Intravitreal bevacizumab alone or combined with macular laser for treatment of diabetic macular edema. Egypt Retina J [serial online] 2017 [cited 2017 Dec 11];4:37-42. Available from: http://www.egyptretinaj.com/text.asp?2017/4/2/37/218590




  Introduction Top


Diffuse diabetic macular edema (DDME) is a sight-threatening inconvenience of diabetic retinopathy. It is of multiple pathophysiologic mechanisms. The breakdown of inner and/or outer retinal blood barriers, which are situated in retinal capillary endothelial/retinal pigment epithelial cell tight junctions, is to be proposed to be a noteworthy reason for diabetic macular edema (DME).[1]

The treatment of DDME is more challenging than that of focal edema, which usually responds to laser photocoagulation of microaneurysms.[2]

Focal/grid laser photocoagulation (laser), the standard of administer for DME since 1985, was shown by the Early Treatment Diabetic Retinopathy Study to lessen the hazard for significant vision loss by half, but complete cessation of vision loss and/or improvements in visual acuity (VA) are rarely observed.[3]

It has been demonstrated useful in a 10-letter vision gain in 31% of patients, in a study done by the Diabetic Retinopathy Clinical Research Network, whereas 19% of laser-treated patients exhibited progressive visual loss (worsening by 2 lines after 2-year follow-up).[4]

The beneficial effect of focal/grid laser photocoagulation is believed to be caused by the induction of proliferation of both the endothelial cells in retinal capillaries and the retinal pigment epithelial cells, thus improving the efficacy of both the inner and outer blood–retina barriers. However, DDME is still having a poor visual prognosis despite macular laser therapy.[2]

All variants of vascular endothelial growth factor (VEGF) (particularly VEGF-A) have been implicated in the occurrence of increased vascular permeability by increasing the phosphorylation of endothelial tight-junction proteins [5] in ocular vascular diseases, for example, DME.[6] The currently used anti-VEGF drugs, ranibizumab and bevacizumab, are recombinant antibodies with a pan-VEGF-A-blocking activity and have shown promising effects in the treatment of DME.[7]

The anti-VEGF, bevacizumab, is a full-length humanized monoclonal antibody that blocks all forms of VEGF, and it has been reported to be effective in reducing DDME and improving the best-corrected visual acuity (BCVA) when injected intravitreally.[8],[9],[10]

However, recurrence of macular edema in bevacizumab-injected eyes was observed within a few weeks after the initial treatment.[10],[11]

Combined therapy with intravitreal bevacizumab (IVB) and sequential macular grid photocoagulation (MGP) after 2 weeks appeared to be superior to MGP or IVB alone for the treatment of DDME. However, the recurrence of macular edema after few months was evident in those eyes treated with this combined therapy.[2] Thus, it was reported that multiple injections of bevacizumab should be considered to maintain its effect in reducing DME.[9],[12]

Thus, our study was aiming to evaluate the BCVA and assess improvement of central macular thickness (CMT) in patients with DDME after an intravitreal injection of bevacizumab (Avastin ®) alone, or Avastin ® followed by modified grid macular laser photocoagulation.


  Subjects and Methods Top


Patients

Seventy-eight eyes of 40 diabetes mellitus (Type 2) patients, with diffuse macular edema (25 males and 15 females), were recruited for this prospective study, from the outpatient clinic of Ophthalmology Department, Faculty of Medicine, Benha University. Cases were collected in the period from May 2013 to June 2014. The study was approved by the Research and Ethics Committee of the University in accordance with the Helsinki Declaration of human subjects, and written informed consent was obtained from all participating patients after explaining to them all the study procedures with its benefits and hazards.

Inclusion criteria:

Patients were selected according to the following inclusion criteria:

(1) The BCVA in the study eyes ranged from 20/30 to 20/200. (2) Center-involving CSME with CMT on optical coherence tomography (OCT) of >270 μm in the central subfield. (3) Intraocular pressure (IOP) <24 mmHg. (4) Media clarity, pupillary dilation, and subject cooperation sufficient for adequate fundus imaging and (5) the ability of the patient for regular follow-up visits.

Exclusion criteria

We excluded from our study patients with macular ischemia (foveal avascular zone (FAZ) ≥1000 μm greatest linear dimension or severe perifoveal intercapillary loss on FFA). Macular edema due to a cause other than DME. Coexistent ocular disease such as a preexisting ocular condition that was likely to preclude VA improvement (e.g., foveal scar, marked cataract, amblyopia) or an ocular condition that may affect macular edema or alter VA during the course of the study (e.g., retinal vascular occlusion, ocular inflammatory disease, and neovascular glaucoma). Finally, we excluded any patients who received previous local treatment for DME, patients with proliferative diabetic retinopathy or with hemoglobin A1c (HbA1c) >10.0%, and patients with medical history of chronic renal failure requiring dialysis or kidney transplantation or blood pressure (BP) >170/100 mmHg.

Methods

All patients were subjected to complete history taking including duration and type of diabetes mellitus, duration of vision deterioration, any present or past ocular diseases or surgeries including retinal laser or intravitreal injections, and any associated systemic disease other than diabetes. Complete ophthalmological examination including BCVA using ETDRS VA chart, applanation tonometry, anterior segment, and dilated slit-lamp biomicroscopic examination (including clinical grading of lens opacity). All patients had standard color fundus photographs. Fluorescein angiography was made using Topcon TRC-50DX fundus camera. OCT imaging using ZEISS (Cirrus HD-OCT Ophthalmic Systems Inc., Humphrey Division, Dublin, CA), where retinal thickness was measured in a circle (6.0 mm in diameter) centered on the point of fixation. The central subfield macular thickness (CMT) was recorded and used for statistical analysis. All patients had their BP and HbA1c recorded.

Patients were subdivided randomly using closed envelope technique according to the line of treatment they will receive, into two groups: (i) intravitral bevacizumab group (IVB group); included 20 patients, 15 males and 5 females, with mean ages ± standard deviation (SD) of 58.45 ± 8.24 years. They received 1.25 mg bevacizumab (Avastin ®) in 0.05 ml intravitreally at baseline, 1st and 2nd month then monthly if needed “pro re nata (PRN),” the criteria for retreatment was considered if still residual edema, CMT more than 350 μ on OCT and/or unstable VA (ii) Combined laser and intravitral bevacizumab group (IVB + laser group); 20 patients, 11 males and 9 females with mean ages ± SD of 60.12 ± 7.34 years, who received repeated bevacizumab (Avastin ®) 1.25 mg in 0.05 ml intravitreally at baseline, 1st and 2nd months followed by focal/grid laser within 2 weeks from the first injection. If residual edema was still present with CMT >350 μ, patients were treated with IVB monthly till CMT ≤200 μ on OCT or no further improvement on two consecutive visits.

Patients were followed up every month for 1 year, complete ocular examination including BCVA, IOP, and CMT was recorded at each visit and any detected complications or side effects were recorded too.

Surgical technique

Laser photocoagulation: Macular grid photocoagulation was performed with an argon green laser delivering 2–3 rows of 50–100 μm spots, for 0.1 s, 100 μm apart in the parafoveal region >500 μm from the edge of the FAZ. Then, 150 μm to 200 μm spots were applied 200 μm apart to the remaining areas of retinal thickening and capillary nonperfusion. Focal leaks outside or within the zones of diffuse leakage were treated with 100 μm to 150 μm spots to achieve a mild blanching of the retinal pigment epithelium.

IVB injection was performed in the surgical theater under complete aseptic conditions, using topical anesthesia. After disinfection and draping, 0.05 mL of solution containing 1.25 mg of bevacizumab (Avastin ®; Genetech, Inc, South San Francisco, CA) was injected into the vitreous cavity using a 27-gauge needle inserted through the inferotemporal pars plana. After the injection, the optic nerve head and the IOP were assessed. Paracentesis was performed if the IOP was elevated. The patient was instructed to instill topical moxifloxacin ophthalmic solution 0.5% (Alcon Laboratories, Inc, Fort Worth, TX, USA) four times daily for 1 week after the intravitreal injection.

Statistical analysis

Demographic and clinical characteristics of forty randomized diabetic patients (20 patients) per treatment group were subjected to descriptive analysis (mean, standard deviation, and range) using the SPSS statistical software program (SPSS, version 21, Spss Inc, Chicago, ILL Company USA). The data on CMT outcome at 12 months' follow-up between the treatment groups were statistically analyzed based on two-sided 95% confidence interval (CI) is based on the t-distribution. The difference in least square means and two-sided 95% CI of mean average changes in the CMT, as well as average changes in VA from the baseline to 12 months' follow-up, was estimated by the paired t- test. Means and standard deviation were calculated for each variable. The significant differences among treatment groups were matched and the results were reflected to be significant at P < 0.05.


  Results Top


Seventy-eight eyes of 40 patients with type 2 diabetes were enrolled in this study. The demographic and clinical characteristics of all patients are summarized in [Table 1].
Table 1: Baseline demographic and clinical characteristics of all the study group of diabetic patients

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Patients were randomized into two groups: 20 patients (40 eyes) were treated with IVB (IVB group) and 20 patients (38 eyes) received IVB + laser (IVB + laser group). All eyes included in the study received IVB injections for 3 months then PRN, plus macular laser for the patients in the combined group during the 12-month follow-up period.

The demographic analysis between the treatment groups

All our patients were Caucasian, among the IVB group, 15 patients were males and 5 females with mean age ± SD, 58.45 ± 8.24 years. The duration of diabetes was an average of 12.14 ± 2.42 years. Among the IVB + Laser group, there were 11 male patients and 9 females and the mean age ± SD was 60.12 ± 7.34 years, the duration of diabetes was an average of 11.48 ± 2.98 years. There were no clinically significant differences observed at baseline between the two treatment arms, including demographic characteristics, the disease duration, BP, HbA1c, BCVA, and CMT, as demonstrated in [Table 2].
Table 2: Baseline demographic analysis between intravitreal bevacizumab group (20 patients; 40 eyes) and intravitreal bevacizumab + laser group (20 patients; 38 eyes) of diabetic patients

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Central macular thickness at the baseline and 12-month follow-up

After 12-month follow-up, the mean number of injections in IVB group was five injections while in the combined group it was only three during the whole year of follow-up. The IVB + laser group showed the highest significant decrease in CMT than that of the baseline, while the IVB-only-treated group showed the least significant change in CMT than baseline (−156.5 ± 33.47 vs. −138.3 ± 40.15, respectively). In addition, IVB + laser group showed a highly significant decrease in CMT when compared with IVB–only-treated group (P < 0.0001) as displayed in [Table 3].
Table 3: Central macular thickness outcome at 1-year follow-up of intravitreal bevacizumab group (20 patients; 40 eyes) and intravitreal bevacizumab + laser group (20 patients; 38 eyes)

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Distribution of visual acuity at baseline and 1-year follow-up

[Table 4] summarizes that the median baseline VA letter scores in IVB group and IVB + laser group were 55 and 56, respectively, with no significant differences between the two groups of patients.
Table 4: Distribution of visual acuity at baseline and 1-year follow-up in eyes of 40 diabetic patients after treatment with intravitreal bevacizumab or intravitreal bevacizumab + laser

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While after 12-month follow-up, the mean average change in VA letter score was significantly improved than that of the baseline in IVB, IVB + laser-treated groups (P < 0.018 and <0.002, respectively) [Table 5].
Table 5: Visual acuity outcome at 1-year follow-up of intravitreal bevacizumab group (20 diabetic patients) and intravitreal bevacizumab + laser group (20 diabetic patients)

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Moreover, the VA letter score showed a higher significant improvement in IVB + laser group (P < 0.007) when compared with the IVB treated group [Table 5].

Ocular adverse effects during the follow-up period

No ocular or systemic side effects recorded in both groups except three cases of subconjunctival hemorrhage at the site of injection, two cases in the combined group, and one case in the IVB group, also five cases developed significant cataract during follow-up period and phacoemulsification with IOL done for them (two cases in IVB group, three cases in the combined group), but we do not have any evident if this cataract related to age or to the IVB injection [Table 6].
Table 6: Major ocular adverse events during 1-year of follow-up of intravitreal bevacizumab group (20 patients; 40 eyes) and intravitreal bevacizumab + laser group (20 patients; 38 eyes)

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  Discussion Top


Available therapies for DME include macular laser photocoagulation, corticosteroids, and anti-VEGF drugs. However, single treatments are often not effective enough to control DME during the entire course of the disease which can be very long.[13]

In this work, we tried to highlight the significant role of combined laser and Avastin ® intravitreal injection in treating diabetic macular edema in comparison to the intravitreal Avastin ® injection.

In comparison to the baseline, there was a significant decrease of CMT in both groups of patients that was more significant in the combined group than the Avastin ® group.

After 12-month follow-up, the mean average change in VA letter score was significantly improved in both groups but more significant in the combined than in the Avastin ® only group.

These results are in consistence with the previously reported results of Seo and Park [14] who stated that IVB injection resulted in significant improvement in BCVA and reduction in central retinal thickness as early as 1 week after injection, and persisted for up to 3 months. Also in consistence with Zhang et al.[15] who concluded that combining anti-VEGF with laser photocoagulation is a complementary treatment with high efficacy in treating DME and decreasing recurrence relative to other applied methods of therapy.

In addition, it was reported that triamcinolone and bevacizumab, alone or in combination with laser photocoagulation, have produced successful results in the treatment of DME.[7],[16],[17],[18],[19]

Previously, it was documented that earlier and more frequent recurrences in the eyes treated with bevacizumab intravitral injection alone. Therefore, multiple injections of bevacizumab were required to prolong the reductive effect.[19] Studies testing the efficacy of laser after anti-VEGF therapy have shown that, once the retina has been sufficiently thinned with anti-VEGF drugs, laser photocoagulation does stabilize the retinal thickness and reduce treatment burden. However, reduction in CMT only decreased as long as anti-VEGF injections were being given.[20],[21] Besides, repeated IVB injection could provide a long-term benefit for the treatment of DDME. Performing macular grid photocoagulation once only 3 weeks subsequent to the initial IVB injection might provide a longer disease-free intervals and reduce the burden of more frequent injections.[2] And, this is the state in our study where we repeat the IVB injection for minimum three times, thus there was no any incidence of recurrence of DME all over the period of follow-up. On the other hand, many previous studies documented that adding grid laser to a regimen of intravitreal anti-VEGF injections may not improve visual outcome.[4],[22],[23] Also, more extensive focal/grid laser therapy may have contribute in reduction of the number of injections.[23],[24] And, this can explain why in our study the mean number of injection is less in combined group than in the IVB group (three versus five injections). In addition, there is a potentiation of the laser treatment, after the retina has been sufficiently thinned using anti-VEGF agents,[21] thus these results favor the effect of combined IVB and laser therapy in DME.

As regards the adverse effects, there were three cases of subconjunctival hemorrhage at the site of injection, 2 cases in the combined group, and one case in the IVB group, also five cases developed significant cataract during follow-up period. Phacoemulsification with IOL was done for them (two cases in IVB group, three cases in the combined group).


  Conclusion Top


From our results, it seems that each treatment methodology is potentiating the impact of the other because of the different modes of action, and a combined therapy may yield more favorable outcomes and may be considered superior decision for use rather than single treatment to acquire more steady and delayed change in the treatment of DME.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Mohalhal AA, Ghalwash GA. Short-term effect of a single intravitreal injection of bevacizumab (Avastin) alone, triamcinolone alone, or in combination, followed by macular grid laser photocoagulation on diffuse diabetic macular edema. J Egypt Ophthalmol Soc 2014;107:127-31.  Back to cited text no. 1
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    Tables

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



 

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