|Year : 2018 | Volume
| Issue : 3 | Page : 336-443
Intravitreal bevacizumab with prompt laser compared with steroid with prompt laser and prompt laser alone for treatment of diffuse diabetic macular edema
Ashraf A Alshayeb1, Tarek T Soliman1, Osama A Shalaby1, Amro M Abdel-Galil2
1 Department of Ophthalmology, Benha University, Benha, Egypt
2 Magrabi Eye Hospital, Al-Madina Al-Munawara; Zagazig Ophthalmology Hospital, Kingdom of Saudi Arabia
|Date of Submission||25-Jun-2016|
|Date of Acceptance||09-May-2018|
|Date of Web Publication||07-Jan-2019|
Dr. Amro M Abdel-Galil
Magrabi Eye Hospital, Al-Madina Al-Munawara
Kingdom of Saudi Arabia
Source of Support: None, Conflict of Interest: None
Aim The aim of this study was to compare the efficacy of combined intravitreal bevacizumab injection plus prompt laser versus combined intravitreal triamcinolone injection plus prompt laser and laser alone in the management of diffuse diabetic macular edema on both central macular thickness (CMT) and visual acuity.
Patients and methods Sixty patients with diabetes mellitus (type 2) with diffuse macular edema (35 males and 25 females) were recruited for this prospective, randomized, interventional study. Complete history taking, full ophthalmological examination, and CMT measurement using optical coherence tomography were done for all patients. They were subdivided randomly into three groups: laser photocoagulation group (laser group), combined laser and intravitreal bevacizumab group (IVB+laser group), and laser and intravitreal triamcinolone acetonide group (IVTA+laser group), and they were followed up every 2 months for 1 year for evaluation of their response to these treatment modalities as well as for detection of any adverse effects.
Results After 12-month follow-up, IVB+laser group showed a higher significant decrease in CMT than that occurred with the other two groups (P<0.0001). However, the laser-treated group showed the least significant change in CMT than baseline. In addition, the visual acuity letter score showed a significant improvement in the IVB+laser group (P˂0.008) than the IVTA+laser group (P<0.048). Compared with the laser-treated group, the most commonly recorded adverse effects during the period of follow-up were increased intraocular pressure and accelerated cataract formation with the need for surgery, with the highest incidence of these complications in the IVTA+laser group than the other two groups.
Conclusion Combined IVB+laser photocoagulation provided the highest and the longest efficacy in improving visual acuity and reducing CMT in treating diabetic macular edema, compared with laser group or combined IVTA+laser.
Keywords: bevacizumab, diabetic macular edema, laser, triamcinolone acetonide
|How to cite this article:|
Alshayeb AA, Soliman TT, Shalaby OA, Abdel-Galil AM. Intravitreal bevacizumab with prompt laser compared with steroid with prompt laser and prompt laser alone for treatment of diffuse diabetic macular edema. Benha Med J 2018;35:336-443
|How to cite this URL:|
Alshayeb AA, Soliman TT, Shalaby OA, Abdel-Galil AM. Intravitreal bevacizumab with prompt laser compared with steroid with prompt laser and prompt laser alone for treatment of diffuse diabetic macular edema. Benha Med J [serial online] 2018 [cited 2019 Dec 15];35:336-443. Available from: http://www.bmfj.eg.net/text.asp?2018/35/3/336/249427
| Introduction|| |
Diabetic retinopathy is a major cause of blindness in working-age persons all around the world . Its pathogenesis is complex and multifactorial, mainly owing to disruption of the blood–retinal barrier, with subsequent accumulation of fluid within the intraretinal layers of the macula . It was noted that vascular endothelial growth factor (VEGF) levels increase in the retina and vitreous of eyes with diabetic retinopathy . They increase vascular permeability by increasing the phosphorylation of tight junction proteins. Therefore, anti-VEGF therapy can represent a useful therapeutic modality that targets the underlying pathogenesis of diabetic macular edema (DME) . The purpose of DME treatment is to prevent the deterioration of visual acuity (VA) by recovering the thickened retina, and occasionally absorption of hard exudates .
Focal/grid laser photocoagulation (hereafter referred to as laser), the current standard of care in DME, is mostly associated with only vision stabilization. However, other trials have demonstrated useful vision gain (10-letter gain in 31% patients) with laser .
Corticosteroids are potent anti-inflammatory agents that inhibit the expression of VEGF, reduce the vessel permeability, prevent blood–retinal barrier breakdown, and inhibit the action of certain matrix metalloproteinases. This broad biologic activity and multiple pharmacological effects of corticosteroids support the rationale behind its use for the treatment of DME and proliferative diabetic retinopathy. Triamcinolone acetonide (TA) is the most popular among the corticosteroids being used in the management of diabetic retinopathy. TA can be administered by several routes, including intravitreal depot injection; periocular injection, posterior subtenon injection, and intravitreal implant .
Triamcinolone intravitreally alone was found to be superior to the expected untreated course in the Early Treatment Diabetic Retinopathy Study but not superior to focal/grid photocoagulation ,. However, intravitreal triamcinolone acetonide (IVTA) monotherapy has also been found to be efficacious for refractory DME and vision loss in eyes not responding to laser therapy .
The combined intravitreal treatment by either triamcinolone or an anti-VEGF drug with focal/grid photocoagulation, theoretically, is more effective than either treatment alone. It might rapidly reduce macular edema and lead to more rapid VA improvement .
Bevacizumab (Avastin) is a complete full-length humanized antibody. It binds to all biologically active subtypes of VEGF. It has been used successfully as a systemic drug in tumor therapy. Recent studies on its intravitreal injections have shown a full-thickness penetration of the retina within 24 h, which has agreat usefulness in the reduction of macular edema due to central retinal vein occlusion, fibrovascular proliferation in retinal neovascularization due to proliferative diabetic retinopathy, and choroidal neovascularization secondary to age-related macular degeneration .
In this study, we aimed at comparing the effectiveness of combined intravitreal bevacizumab (IVB) injection plus prompt laser versus combined IVTA injection plus prompt laser and laser alone in the management of diffuse DME on both central macular thickness (CMT) and VA.
| Patients and methods|| |
Sixty patients with diabetes mellitus (type 2) with diffuse macular edema (35 males and 25 females) were recruited for this randomized interventional prospective study, from the outpatient clinic of Ophthalmology, Faculty of Medicine, Benha University.
The work was approved by the Benha Ophthalmology Department Administrative and Ethical Committee meeting on April 2013. Trial setting was in Ophthalmology Department, Benha University Hospitals. The treatment intervention with its benefits and hazards was explained to each patient verbally, who were requested to sign consent if possible.
These patients were selected according to the following inclusion criteria: the best-corrected visual acuity (BCVA) in the study eye between 20/30 and 20/200; diffuse DME with CMT on optical coherence tomography (OCT) of more than 270 μm in the central subfield; media clarity, pupillary dilation, and patient cooperation sufficient for adequate fundus imaging; intraocular pressure (IOP) less than 25 mmHg; and the ability for regular follow-up visits.
Complete history taking from all patients was done, and ophthalmological examination, including BCVA using (Snellen) VA charts, was undertaken by a masked optometrist then converted to letter score for statistical analysis. Moreover, applanation tonometry and anterior segment and dilated slit-lamp biomicroscopic examination (including clinical grading of lens opacity) were performed for all patients. All patients had standard colour fundus photographs, fundus fluorescein angiography (Topcon TRC-50DX fundus camera), and OCT imaging (ZEISS cirrus HD-OCT; Ophthalmic Systems Inc., Humphrey Division, Dublin, California, USA). We measured the retinal thickness in a circle (6.0 mm in diameter) centered on the point of fixation. The CMT was recorded and used for statistical analysis, and all patients had their blood pressure (BP) and glycosylated hemoglobin (HbA1c) recorded.
We excluded from our study patients with macular ischemia (greatest linear dimension of the foveal avascular zone of at least 1000 μm or severe perifoveal intercapillary loss on fundus fluorescein angiography; macular edema due to a cause other than DME; coexistent or preexisting ocular condition that was likely to preclude VA improvement (e.g. foveal atrophy, dense subfoveal hard exudates, marked cataract, or 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, neovascular glaucoma, Irvine–Gass syndrome); any patients who received previous treatment for DME; patients with proliferative diabetic retinopathy; (vii) patients with HbA1c more than 11.0%; patients with a history of chronic renal failure, on dialysis or with kidney transplantation; and patients with BP more than 170/100 mmHg.
Patients were subdivided randomly using closed envelope technique according to the line of treatment, and they were allocated into three groups to receive the corresponding treatment protocols: laser photocoagulation group (laser group) contained 20 patients (40 eyes) who received focal/grid macular laser at baseline on one or two session and after 4 months if indicated; combined laser and intravitreal bevacizumab group (IVB+laser group) included 38 eyes of 20 patients who received bevacizumab (Avastin) 1.25 mg in 0.05 ml intravitreally at baseline and at second and fourth months followed by focal/grid laser within 2 weeks from the first injection; and lastly, the laser and intravitreal triamcinolone acetonide group (IVTA+laser group) included 37 eyes of 20 patients who received TA 4 mg in 0.1 ml at baseline and third month followed by focal/grid laser within 2 weeks from the first injection.
Patients were followed up every 2 months for 1 year. Complete ocular examination, including BCVA using Snellen chart, IOP, and CMT were recorded at each visit, and any detected complications or adverse effects were recorded as well.
- Laser photocoagulation: Macular grid photocoagulation was performed with an argon green laser delivering two to three rows of 50–100 μm spots, 100 μm apart in the parafoveal region and more than 500 μm from the edge of the foveal avascular zone. Then, 150–200 μm spots were applied 200 μm apart to the remaining areas of retinal thickening and capillary nonperfusion. Any other focal leaks were treated with 50–100 μm spots to achieve a mild blanching of the retinal pigment epithelium.
- IVB injection was performed under aseptic condition inside operating room using topical anesthetic drops, and after disinfection and draping, 0.05 ml of solution containing 1.25 mg of bevacizumab (Avastin; Genetech Inc., South San Francisco, California, USA) was injected intravitreally through the inferotemporal pars plana using a 27 G needle. 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 the topical moxifloxacin ophthalmic solution 0.5% (Alcon Laboratories Inc., Fort Worth, Texas, USA) four times daily for 1 week after the intravitreal injection.
- Intravitreal triamcinolone injection: After the patient’s eye was anesthetized with 2% lidocaine hydrochloride eye drops, and sterilized using 0.05% povidone iodine, a 4-mg (0.1 ml) triamcinolone (Kenacort-A; Bristol-Myers Squibb, Sermoneta, Latina, Italy) solution was injected to the vitreous cavity through the inferotemporal pars plana. This was followed by compressing the adjacent area for ∼10 s with a sterile cotton swab, and antibiotic eye drops were administered, The patient was instructed to instill topical moxifloxacin ophthalmic solution 0.5% (Alcon Laboratories Inc.) four times daily for 1 week after the intravitreal injection.
The primary analysis was performed on the full analysis set (FAS). All patients who received treatment injection and/or laser had postbaseline assessment for CMT. The primary end point was the difference between the average CMT and VA from baseline to 12 months. Data were statistically analyzed using the SPSS statistical software program (version 21; SPSS Inc., Chicago, Illinois, USA). Sensitivity analyses of the primary end point were performed using the average change from baseline in CMT from observed changes only in FAS, and a per-protocol set with missing data being handled in the same way as for the FAS. A sample size of 60 randomized patients per treatment group (20 patients) was allocated. The normality of distribution was tested using D’Agostino and Pearson Omnibus normality test. The statistical hypothesis testing of the average change from baseline in VA was based on the stratified Cochran–Mantel–Haenszel test using the observed values as scores and baseline VA letter score (78–74, 73–69). Two-sided 95% confidence intervals for the mean average changes in VA and for the corresponding pairwise analysis of variance (ANOVA) were calculated. The difference between treatments, were intended using the least-square means, using one-way ANOVA followed by Duncan’s test. Means and SD for each patient were calculated, and significant differences among groups were compared. The results were considered to be significant at P value less than 0.05.
| Results|| |
One hundred and fifteen eyes of 60 patients with type 2 diabetes were enrolled in this study. The mean±SD age of the patients was 60.15±8.07 years (range: 40–75 years). There were 35 (58%) male and 25 (42%) female patients. The demographic data of all patients are summarized in [Table 1].
|Table 1 Baseline demographic and clinical characteristics of all the diabetic patients in the study groups|
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The demographic analysis between the three treatment groups
Among the laser group, 14 patients were male and six were female, with mean age of 59.1 years. The duration of diabetes was an average of 12.88 years. Among the IVB+laser group, there were 11 male patients and nine female patients, and the mean age was 60.6 years. The duration of diabetes was an average of 11.58 years. In the IVTA+laser group, there were 10 male and 10 female patients, with an average age of 60.8 years and disease duration of 12.35 years ([Table 2]). Regarding demographic characteristics data, including the disease duration, BP, HbA1c, BCVA, CMT, and retinopathy grading, there was no significance difference between treatment groups. HbA1c (%) was 7.47, 7.94, and 7.24; IOP (mmHg) was 17.8, 18.95, and 18.21; phakic eyes (%) was 85, 95, and 75; pseudophakic eyes (%) was 15, 5, and 25; and CMT was 394, 399, and 400 (μm) in laser, IVB+laser, and IVTA+laser groups, respectively ([Table 2]).
|Table 2 Baseline demographic analysis between the diabetic patients of the treatment groups|
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Central macular thickness at the baseline and 12-month follow-up
As displayed in [Table 3], after 12-month follow-up, the IVB+laser group showed the highest significant decrease in CMT than that of the baseline, whereas the laser-only group showed the least significant change in CMT than baseline (−156.5±33.47 vs. −139.3±42.43, respectively). In addition, with intergroup analysis, IVB+laser group showed a highly significant decrease in CMT than that occurred with laser-only group (P<0.0001) and significant only in IVTA+laser group (P<0.016).
Distribution of visual acuity at baseline and 1-year follow-up
The median baseline VA letter scores in the laser, IVB+laser, and IVTA+laser groups, as presented in [Table 4], were 55, 56, and 54, respectively, with no significant differences between the different groups of patients.
However, after 12-month follow-up, the mean average change in VA letter score was significantly improved than that of the baseline in the laser, IVB+laser, and IVTA+laser-treated groups (P=0.019, 0.002 and 0.001, respectively) ([Table 5]). Moreover, the VA letter score showed a higher significant improvement in the IVB+laser group (P˂0.008) than the IVTA+laser group (P<0.048) in comparison with the laser-only treated group ([Table 5]).
Ocular adverse effects during the follow-up period
We found that the most commonly recorded adverse effects during the follow-up period were increased IOP of at least 10 mmHg from baseline (0, 5.3, and 49% in laser, IVB+laser, and IVTA+laser groups, respectively); IOP of at least 30 mmHg from baseline (0, 2.6, and 27% in laser, IVB+laser, and IVTA+laser groups, respectively); accelerated cataract formation with the need for surgery (5, 8, and 30% in laser, IVB+laser, and IVTA+laser groups, respectively), with the highest incidence of these complications in the IVTA+laser group than the other two groups; and endophthalmitis (0, 2.6, and 2.7% in laser, IVB+laser, and IVTA+laser groups, respectively), which was more in the IVTA+laser group ([Table 6]).
| Discussion|| |
Among the treatment strategies toward the pathogenesis of DME disease, intravitreal corticosteroids (IVTA) and intravitreal anti-VEGF (bevacizumab), alone or in combination with laser photocoagulation, have produced successful results in the treatment of DME . However, single treatments are often not effective enough to control DME during the entire course of the disease, which can be very long .
In this work, we tried to highlight the significant role of combined laser and bevacizumab intravitreal injection in treating DME in comparison with the commonly applied methods (laser or combined laser and intravitreal corticosteroid).
Our results are in agreement with a previously mentioned report by the Diabetic Retinopathy Clinical Research Network that intravitreal ranibizumab (anti-VEGF) with prompt or deferred laser therapy is more effective through at least 2 years than prompt laser treatment alone or combination therapy with IVTA and macular grid/focal treatment . Combining anti-VEGF with laser photocoagulation is a complementary treatment with high efficacy in treating DME and decreasing the recurrence through the decreasing foveal thickness that facilitates laser treatment and reduces the need for high laser energy. Bevacizumab and ranibizumab downregulate VEGF and reduce capillary permeability, thus a marked and prolonged reduction in macular thickness is achieved ,,. Similarly, IVTA decreases foveal thickness, allows more effective macular laser photocoagulation, seems to be protective, and even modulates the retinal pigment epithelium modeling after laser therapy . Although both combinations seem similar to have similar effects, the treatment regimen of VEGF inhibitors is more intense with less time between injections than that of IVTA .
Regarding the change in CMT at the 12th month, the laser-only treated group showed the least significant decrease in CMT than the other two groups, which is partially consistent with that of Lee et al. , who found the mean CMT of the macular laser grid (MLG)+IVTA group showed a more statistically significant decrease than the MLG group at the first and third months, but not in later periods of follow-up. Although the combined therapy has a prolonged effect on CMT reduction as explained above, the recurrence of ME with MLG+IVTA is explained by the fact that the therapeutic effect of triamcinolone on CMT is characterized by a curve in three phases: a fast decrease, a steady state, and relapse, where TA disappears ∼3–6 months after the absorption of the drug, and the recurrence of macular edema later on ,,,.
In addition, we found a statistically significant decrease in CMT and significant improvement of the VA between the 12-month follow-up and the baseline, which also was more significant in the IVB+laser group than the other two groups, confirming the previously reported results of Forte et al. , which mentioned a more visual and anatomical improvement in the IVB group only at 6- and 12-month follow-up in diffuse nonischemic DME. Moreover, it was in line with that of Elman et al. , who found the mean change in the VA letter score from baseline within at 1 year of follow-up was significantly greater in the ranibizumab+prompt laser group and ranibizumab+deferred laser group but not in the triamcinolone+prompt laser group compared with the sham+prompt laser group.
Previous studies , reported initial improvement (in the early 3 months, but not later on during follow-up) of CMT and VA, in either combined laser with VEGF inhibitors or with IVTA than in laser therapy alone, whereas our results confirmed the prolonged efficacy of combined laser and VEGF inhibitors through a 1 year of follow-up than the other two modalities as reported by other studies ,,.
We have observed that the most common ocular complications were increased IOP (49% >10 mmHg and 27% >30 mmHg), endophthalmitis (2.7%), and accelerated cataract (30%), which were associated with the intravitreal injection of triamcinolone more than the other groups of therapy. This is in agreement with previously reported results ,, and with that of Forte et al. , who found an association between intravitreal injection of TA and elevation of IOP, not always responding to antiglaucomatous treatment in 10.4% of the study patients. Moreover, it is in line with Elman and colleagues ,, who found IOP elevation after IVTA in 50% of study patients and accelerated cataract with cataract surgery in 59% of patients. However, it is in contrast to another study that documented an initial response to combination therapy of IVTA and laser photocoagulation with no need for additional treatment for diffuse DME for 3 years , suggesting that this combination has long-lasting effects with a lower recurrence and lower incidence of adverse effects. Moreover, our results are in contrast to another study that documents no complication that seriously affects BCVA during a 6-month follow-up period .
No other ocular or systemic adverse effect has been recorded in our study, which is in agreement with Solaiman et al. , but in contrast to Elman et al. , who reported one case of tractional retinal detachment in the ranibizumab+deferred laser group and five retinal vein occlusions (one in the sham+prompt laser group, one in each of the ranibizumab groups, and three in the triamcinolone+prompt laser group).
| Conclusion|| |
This study suggests that combined IVB+laser photocoagulation is a complementary treatment with high early and prolonged effect on improving the VA and reducing macular thickness in diffuse nonischemic DME relative to the other applied methods of therapy, with lower incidence recurrence or occurrence of ocular adverse effects within a 1-year follow-up period. However, in our study, IVTA+laser was also effective, but with more ocular adverse effects. Further large multicenter studies are required with longer follow-up periods to optimize therapy for refractory cases, which still exist even with these combination therapies.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]