|Year : 2013 | Volume
| Issue : 1 | Page : 1-6
Intravitreal double-dose ranibizumab therapy for refractory diabetic macular edema
Ahmed M Abdel Hadi, Abdel Hamid S ElHofy
Department of Ophthalmology, Faculty of Medicine, Alexandria University, Consultants at the Alexandria Vitreoretinal Center (Tertiary Referral Vitreoretinal Canter in Alexandria), Alexandria, Egypt
|Date of Web Publication||9-Dec-2013|
Ahmed M Abdel Hadi
24 FawzyMoaz Street, Safwa 5, Entrance 2, Alexandria
Source of Support: None, Conflict of Interest: None
Purpose: To evaluate the efficacy of ranibizumab (1 mg) for the treatment of refractory diabetic macular edema (DME). Materials and Methods: This prospective, consecutive, non-comparative case series included 24 eyes with refractory DME. Patients were included in the study independently of the size of the leakage area, retinal thickness, visual acuity (VA), age, metabolic control and type of diabetes mellitus. Exclusion criteria included presence of a hard exudate at the fovea, macular edema secondary to causes other than diabetic maculopathy, signs of vitreomacular traction clinically or by optical coherence tomography (OCT), proliferative diabetic retinopathy requiring treatment, history of glaucoma or ocular hypertension and macular ischemia. Patients who had intraocular/periocular steroid/antivascular endothelial growth factor injections within 6 months of the enrollment or significant media opacities were excluded. After a written informed consent was obtained, all patients were treated with three intravitreal injections, 1 month apart, of 0.1 mL (1 mg) injection of ranibizumab. Changes of retinal thickness and VA, as measured by the Snellen chart and converted to decimal equivalents, were evaluated. Results: A total of 24 eyes of 24 patients (nine females and 15 males) with non-proliferative diabetic retinopathy (12 patients; 50%) or quiescent diabetic retinopathy (12 patients; 50%) were included in the study. Their mean age and standard deviation (SD) was 45.5 ± 13.1 years (range: 27-71 years). All patients completed 6 months of follow-up. No injection-related side-effects, either locally or systemically, were observed during the follow-up period. All included patients were subjected to at least one method of treatment for DME. At baseline, the mean VA ±SD was 0.015 ± 0.008; after 1 month from the first injection, the mean VA increased to 0.019 ± 0.008 (significant increase, P = 0.0013). The VA remained the same after the second and the third injections. Six months after the third injection, the mean VA ± SD was 0.018 ± 0.009 (significant increase, P = 0.0013). The mean central retinal thickness ± SD by OCT was 526.7 ± 243.4μ at baseline. Four weeks post-operatively, a significant decrease of mean retinal thickness ± SD to 429.7 ± 187.8μ was observed. Eight weeks after the injection, the mean macular retinal thickness ± SD had further decreased to 352.2 ± 142.5μ, which is a significant difference (P = 0.001) compared with the baseline thickness. After 12 weeks, the mean retinal thickness ± SD further decreased to 333.7 ± 114.5μ (P = 0.001). Conclusion: The intravitreal injection of 1 mg of ranibizumab provides a new treatment strategy for refractory DME, which offers patients a true perspective of visual recovery. Further prospective and randomized studies will be needed to better determine which patients benefit the most and how often and in which concentration the drug should be administered.
Keywords: Intravitreal injection, ranibizumab, refractory diabetic macular edema
|How to cite this article:|
Abdel Hadi AM, ElHofy AS. Intravitreal double-dose ranibizumab therapy for refractory diabetic macular edema
. Egypt Retina J 2013;1:1-6
| Introduction|| |
Diabetic macular edema (DME) is an important cause of visual loss in the developed world. The gold standard of DME treatment has been macular laser photocoagulation,  the benefit of which was originally demonstrated in the Early Treatment Diabetic Retinopathy Study (ETDRS).  In spite of this, in a subgroup of patients, it was shown that laser therapy usually does not improve impaired vision, and many patients lose vision despite laser therapy. The recent approval of ranibizumab by the European Medicines Agency to treat visual impairment due to DME fulfills the previously unmet medical need for a treatment that can improve visual acuity (VA) in these patients.  The increasing number of patients with refractory DME (defined as patients with chronic, clinically significant DME who had in part not responded to other previous treatments such as laser photocoagulation, intravitreal injection of triamcinolone or vitrectomy)  has led to growing interest in other methods of treatment.
The use of Triamcinolone acetonide (TA), although effective as shown by many studies, has the disadvantage of accelerated cataractogenesis and steroid-induced intraocular pressure (IOP) rise,  while the use of antivascular endothelial growth factor agents is limited by a short duration of action and the need for repeated injections.  A study by Kreutzer et al.  showed that the effect of macular edema reduction in DME after a single 4-mg intravitreal triamcinolone (ivTA) injection was similar to that of three intravitreal bevacizumab injections over a 4-month period. Any form of intravitreal injection is associated with the potential risk of endophthalmitis, iatrogenic retinal tear and detachment.  Therefore, the aim of this study was to find a way of prolonging the beneficial effects of the pharmacologic agents and limit the number of injections.
Based on previous reports , showing a correlation between the recurrence of macular fluid and increasing Vascular endothelial growth factor (VEGF) levels in eyes with macular fluid secondary to neovascular Age related macular degeneration (AMD) and vein occlusions undergoing anti-VEGF therapy, it is reasonable to assume that eyes with persistent macular fluid after monthly anti-VEGF therapy have an overabundance of VEGF and an inadequate amount of anti-VEGF binding activity 1 month after an injection.
The previous deduction, together with the fact shown by previous work  that multiple intravitreal injections of ranibizumab at escalating doses ranging from 0.3 to 2.0 mg are well tolerated and biologically active through 20 weeks, we adopted a treatment strategy of injecting a double dose of ranibizumab (1 mg) intravitreally for three consecutive months in eyes with refractory DME in an attempt to maximize visual gain while decreasing the total number of injections.
| Materials and Methods|| |
This was a prospective, interventional case series conducted at a tertiary referral center in Alexandria, Egypt. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The research protocol and its amendments were approved by the Ophthalmology Department, Alexandria University Institutional Review Boards and Ethics Committees. Explanation about the procedure and its duration was given to the subject of the research in clear, understandable words. Each patient was informed about the liable reasonable risk. All patients provided written informed consent. They were especially informed about the off-label character of the dosage given for this treatment and the likelihood that additional treatments might be required. Confidentiality was assured.
All patients were referred to one specialist. Diabetic patients with the following criteria were enrolled in the study: Refractory, clinically significant macular edema, defined as patients with recent macular laser photocoagulation treatment at least 3 months or more before enrollment, with no subsequent improvement in best-corrected visual acuity (BCVA) or macular thickness assessed by optical coherence tomography (OCT). Patients were included in the study independently of the size of the leakage area, VA and age. We included cases with central retinal thickness ranging from 300 to 600μ as determined by OCT. As for the metabolic control of the included patients, all patients had HbA1c in the range of 6-7.5, which was identified by the treating physician as a sign of fair to good control. All patients suffered from type 2 diabetes mellitus.
Exclusion criteria included the presence of a hard exudate at the fovea, macular edema secondary to causes other than diabetic maculopathy, signs of vitreomacular traction clinically or by OCT, proliferative diabetic retinopathy requiring treatment, history of glaucoma or ocular hypertension and macular ischemia (enlargement of the foveal avascular zone, macular ischemia involving the central macula or more or equal than a disk diameter of capillary closure elsewhere on the macula on fluorescein angiography). Patients who had intraocular/periocular steroid/antivascular endothelial growth factor injections within 6 months of the enrollment or significant media opacities were excluded from the study.
At each visit, a complete eye examination was performed, including BCVA (BCVA) using Snellen testing, slit-lamp examination, IOP measurement, stereoscopic biomicroscopy of the central retina, retinal thickness measurement by OCT, fluorescein angiography (at the initial visit only to exclude maculae ischemia) and fundus photography or a red free image of the macular area. This was done 1 day before and 1 month after each injection, with an additional post-injection follow-up visit (1 day after the injection) to exclude any intraocular injection-related complication and a final post-injection visit at 6 months from the first dose.
Before injection, topical anesthesia was induced by applying benoxicate hydrochloride (1%) eye drops at least three times. The bulbar conjunctiva and the fornices were rinsed with povidone-iodine (Betadine; Alcon, Ft. Worth, TX, USA). Povidone-iodine was also applied to the eyelid margins and the lashes, avoiding expression of the Meibomian gland More Detailss. After application of a sterile drape, a lid speculum was inserted. Patients then received a unilateral intravitreal injection of a 0.1-mL volume containing 1.0 mg of ranibizumab using a sharp 27-gauge needle at a distance of 3.5 mm from the limbus in pseudophakic or 4.0 mm in phakiceyes. The needle was carefully removed and a sterile cotton applicator was applied to the injection site to prevent reflux. After injection, antibiotic eye drops (polymyxin and neomycin) were applied for 3 days, four times per day.
Only one eye per subject was treated. All data were collected on an MS-Excel 2000 spreadsheet (Microsoft Corporation, Redmond, WA, USA) and analyzed using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, USA). For all statistical tests, P < 0.05 was considered significant.
| Results|| |
A total of 24 eyes of 24 patients (nine females and 15 males) with non-proliferative diabetic retinopathy (12 patients; 50%) or quiescent diabetic retinopathy (i.e., with previous effective panretinal photocoagulation) (12 patients; 50%) were included in the study. The mean age and standard deviation (SD) of the patients was 45.5 ± 13.1 years (range: 27-71 years). All patients completed 6 months of follow-up. No injection-related side-effects were observed, either locally or systemically, during the follow-up period. All included patients had at least one previously applied method of treatment for DME; focal laser therapy was applied in all cases at least 3 months or more before enrollment with no improvement in vision as identified by the patients' records.
Macular thickness by OCT did not improve or improved then worsened again within 3 months of the treatment. IvTA acetonide was performed in four patients (16.6%) more than 6 months before the beginning of the study. Intravitreal bevacizumab was performed in another eight eyes (33.3%) more than 6 months before the enrollment. For assessing VA, both Snellen VA [Figure 1] and decimal form [Figure 2] were used. At baseline, the mean VA ± SD was 0.015 ± 0.008; after 1 month from the first injection, the mean VA increased to 0.019 ± 0.008 (significant increase, P = 0.0013*). The same happened after the second and the third injections. Six months after the third injection, the mean VA ± SD was 0.018 ± 0.009 (significant increase; P = 0.0013*) [Table 1].
|Table 1: Comparison between the pre- and post-injection visual acuity levels and retinal thickness values after each injection and after 6 months from the first injection|
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|Figure 1: Improvement of visual acuity (Snellen) after each injection and 6 months from the fi rst injection|
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|Figure 2: Improvement of visual acuity (decimal) after each injection and 6 months from the fi rst injection|
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The mean central retinal thickness ± SD by OCT was 526.7 ± 243.4μ at baseline. Four weeks post-operatively, a significant decrease of mean retinal thickness ± SD to 429.7 ± 187.8μ was observed. Eight weeks after the injection, the mean macular retinal thickness ± SD had further decreased to 352.2 ± 142.5μ, which is a significant difference (P = 0.001) compared with baseline. After 12 weeks, the mean retinal thickness ± SD further decreased to 333.7 ± 114.5 μ (P = 0.001). [Figure 3] summarizes the OCT-measured retinal thickness results. Changes in retinal thickness and VA were well correlated after 3 months [Figure 4], [Figure 5], [Figure 6].
|Figure 3: Simultaneous decrease of central macular thickness after each injection and 6 months from the fi rst injection|
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|Figure 4: A case with left refractory diabetic macular edema (DME) 3 months after grid laser and improvement in macular thickness and best-corrected visual acuity (BCVA) after 3-monthly ranibizumab|
injections that persisted 6 months from the fi rst injection. (a) Patient with left refractory DME after focal grid laser (BCVA: 6/36) (b) Left eye after 1 month from the fi rst injection (BCVA: 6/24) (c) The left eye after 1 month from the second injection (BCVA: 6/24) (d) After 1 month from the third injection (BCVA: 6/12) (e) Left eye 6 months from the fi rst injection (BCVA: 6/9)
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|Figure 5: A case with left refractory diabetic macular edema 6 months after intravitreal triamcinolone|
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|Figure 6: The same patient in Figure 5 after double-dose ranibizumab injections. Left hand side, 1 month from the fi rst injection, the central macular thickness (CMT) decreased by 375. Right hand side, 1 month from the third injection, the CMT reached 269μ|
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No post-injection-related complication was identified in the study group during the follow-up period (e.g., rise in IOP, anterior segment reaction, endophthalmitis).
| Discussion|| |
In the current study, we found that even in patients with chronic DME, which did not respond to other treatments such as laser photocoagulation, regular dosing protocols of antivascular endothelial growth factor, significant improvement (decrease of retinal thickness and increase of VA) was achieved after intravitreal injection of double-dose ranibizumab even after a short period.
The idea behind this protocol of treatment came from the fact that despite the success of these anti-VEGF drugs, some eyes will show little or no improvement when dosed monthly and VA may even deteriorate.  One possible explanation for the persistent or worsening macular fluid 1 month after an injection of an anti-VEGF drug would be that the level of VEGF in the vitreous exceeds the amount of anti-VEGF binding activity after 1 month from the injection. Because recent reports  of VEGF levels in eyes with exudative diseases suggest that close to a million-fold excess of VEGF binding activity is injected into the eye when a dose of either ranibizumab or bevacizumab is given at baseline, it seems reasonable to assume that these eyes may initially respond but then the drug remaining in the eye after 1 month is overwhelmed by increasing the VEGF levels as previously documented in eyes with neovascular AMD and vein occlusions.  This overabundance of VEGF may result from overexpression of VEGF, inadequate drug diffusion through the vitreous to the macula or a shorter-than-expected half-life of the drug resulting in a smaller-than-anticipated intraocular depot. This might be attributed to drug reflux through the scleral injection site or a vitreous that is either liquefied or absent, resulting in more rapid clearance of the drug.
For those patients who did not respond favorably to monthly dosing with either persistent or increasing fluid in the macula and worsening vision, it is unknown whether more frequent dosing would be beneficial. Rather than dosing more frequently, an alternative strategy would be to increase the dose of the drug and continue the monthly injections. Based on the studies that concluded that multiple intravitreal injections of ranibizumab at escalating doses ranging from 0.3 to 2.0 mg were well tolerated and biologically active in eyes with neovascular AMD through 20 weeks,  we delivered higher doses of ranibizumab by doubling the injection volume to 1.0 mL, thereby doubling the dose of ranibizumab to 1.0 mg.
In the current study, we observed a decrease in the mean retinal thickness from 526.7μ at baseline to 333.7μ after 6 months and an increase in VA - whatever the baseline VA level was - throughout the follow-up period, even after the first injection of ranibizumab (1 mg), which lasted in a significant manner till 6 months from the first injection. Moreover, no post-injection-related complication was identified in the study group during the follow-up period.
The RESOLVE study included a possibility of dose doubling that was eventually undertaken in the majority of patients receiving ranibizumab. Most patients (86%) received a dose between 0.5 and 1.0 mg inclusive during the study period. Dose doubling was included to allow for best efficacy outcomes.
In the non-randomized pilot study by Chan et al.,  they demonstrated that triple therapy (sub-Tenon triamcinolone [70 mg], intravitreal bevacizumab [1.25 mg] and focal/grid laser) in patients with refractory DME could result in sustained central fluid reduction up to 1 year; even with a single set of treatments, they showed that significant BCVA improvement was only observed in patients with a baseline BCVA of 20/100 or worse, and there were some side-effects in terms of increased incidence of IOP rise, cataract and ptosis. The side-effects were mainly associated with the sub-Tenon component of the triple therapy.
In the study by Kook et al.,  all patients with chronic diffuse DME (those patients who received various previous treatments) completed 6 months of follow-up and only 47% completed 12 months of follow-up. Within this period, 48% of the patients had received at least three intravitreal injections of bevacizumab. The mean central retinal thickness on OCT was 463μ. Throughout the follow-up period, the VA changes were not significant after 6 months but were significant after 12 months. The mean central retinal thickness (OCT) decreased to 374μ after 6 months (P = 0.001) and to 357μ after 12 months. Changes of retinal thickness and VA did not correlate with each other.
It seemed sufficient to check for VA improvement and macular thickness reduction 1 month after the injection based on the work done by Giuseppe et al.,  which showed that the mean BCVA improvement was not detectable 14-days post injection, with a significant improvement at the 28-day follow-up, with continuous improvement till 56 days post-injection. These data taken together seem to suggest that intravitreal ranibizumab would give a continuous anatomical and functional improvement until at least 14 days after the injection, with a stabilization lasting at least 28 days. Moreover, they concluded that intravitreal ranibizumab would show therapeutic effects as soon as 1 h after the injection.
A limitation of the present investigation is the short follow-up period, which did not allow for any estimation of the long-term efficacy and safety of this treatment. However, the results presented herein are promising, although we were treating patients with the refractory stage of this disease. Other limitations are the lack of a control group and the broad inclusion criteria, which were attributed to the off-label character of the protocol as mentioned above. The strengths of the present study are the prospective design and the careful follow-up. The intravitreal injection of VEGF inhibitors such asranibizumab (double the conventional dose) provides new treatment strategies for the refractory stage of DME and offers patients a true perspectiveof visual recovery. Further prospective and randomized studies are needed to better determine which patients benefit the most and how often and in which concentration the drug should be administered.
| References|| |
|1.||Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009;127:245-51. |
|2.||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. |
|3.||Bandello F, Cunha-Vaz J, Chong NV, Lang GE, Massin P, Mitchell P, et al. New approaches for the treatment of diabetic macular edema: Recommendations by an expert panel. Eye (Lond) 2012;26:485-93. |
|4.||Kook D, Wolf A, Kreutzer T, Neubauer A, Strauss R, Ulbig M, et al. Long-term effect of intravitreal Bivacizumab (Avastin) in patients with chronic diffuse macular edema. Retina 2008;28:1053-60. |
|5.||Gillies MC, Simpson JM, Billson FA, Luo W, Penfold P, Chua W, et al. Safety of an intravitreal injection of triamcinolone: Results from a randomized clinical trial. Arch Ophthalmol 2004;122:336-40. |
|6.||Kreutzer TC, Al Saeidi R, Kook D, Wolf A, Ulbig MW, Neubauer AS, et al. Comparison of intravitreal bevacizumab versus triamcinolone for the treatment of diffuse diabetic macular edema. Ophthalmologica 2010;224:258-64. |
|7.||Funk M, Karl D, Georgopoulos M, Benesch T, Sacu S, Polak K, et al. Neovascular agerelated macular degeneration: Intraocular cytokines and growth factors and the influence of therapy with ranibizumab. Ophthalmology 2009;116:2393-9. |
|8.||Funk M, Kriechbaum K, Prager F, Benesch T, Georgopoulos M, Zlabinger GJ, et al. Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. Invest Ophthalmol Vis Sci 2009;50:1025-32. |
|9.||Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N. Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology 2006;113:623. |
|10.||Rosenfeld PJ, Shapiro H, Tuomi L, Webster M, Elledge J, Blodi B; MARINA and ANCHOR Study Groups. Characteristics of patients losing vision after 2 years of monthly dosing in the phase iii ranibizumab clinical trials. Ophthalmology 2011;118:523-30. |
|11.||Zhu Q, Ziemssen F, Henke-Fahle S, Tatar O, Szurman P, Aisenbrey S, et al. Vitreous levels of bevacizumab and vascular endothelial growth factor-A in patients with choroidal neovascularization. Ophthalmology 2008;115:1750-5. |
|12.||Funk M, Kriechbaum K, Prager F, Benesch T, Georgopoulos M, Zlabinger GJ, et al. Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. Invest Ophthalmol Vis Sci 2009;50:1025-32. |
|13.||Chan CK, Lai TY, Mohamed S, Lee VY, Liu DT, Li CL, et al. Combined high-dose sub-tenon triamcinolone, intravitreal bevacizumab, and laser photocoagulation for refractory diabetic macular edema: A pilot study. Retina 2012;32:672-8. |
|14.||Querques G, Bux AV, Martinelli D, Iaculli C, Del Curatolo MV, Delle Noci N. Short -Term fluctuation of diabetic macular edema after intravitreal ranibizumab injection. Retina 2009;29:1274-81. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]