Current Eye Research, Early Online, 1–7, 2015 ! Informa Healthcare USA, Inc. ISSN: 0271-3683 print / 1460-2202 online DOI: 10.3109/02713683.2014.1002048


Dexamethasone Intravitreal Implant for Chronic Diabetic Macular Edema Resistant to Intravitreal Bevacizumab Treatment Yu¨ksel Totan1, Emre Gu¨ler2 and Fatma Betu¨l Gu¨rag˘ac¸1

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¨ zal University, Ankara, Turkey and 2Eye Clinic, Department of Ophthalmology, Medical School, Turgut O Erci¸s State Hospital, Eye Clinic, Van, Turkey

ABSTRACT Purpose: To evaluate the safety and efficacy of intravitreal dexamethasone implant (Ozurdex) in patients with chronic diabetic macular edema (DME) resistant to prior intravitreal bevacizumab (IVB) treatment. Materials and Methods: Thirty eyes of 30 patients were administered intravitreal Ozurdex and examined at baseline and 1, 3, and 6 months postinjection in this prospective study. Main outcomes were the best corrected visual acuity (BCVA, logMAR), central foveal thickness (CFT), mean cube volume (MCV), and intraocular pressure (IOP). Patients had a CFT over 275 mm (measured by OCT) and were unresponsive to 3 consecutive IVB injections. All data are presented as mean ± standard deviation. Results: The mean BCVA significantly increased from 0.56 ± 0.38 to 0.41 ± 0.27 (p50.001), and 0.44 ± 0.28 (p = 0.008) at 1 and 3 months, respectively. At months 1, 3, and 6, the mean CFT significantly decreased from 517 ± 136 mm at baseline, to 290 ± 60 mm (p50.001), 314 ± 88 mm (p50.001) and 411 ± 126 mm (p = 0.01), respectively. However, the mean CFT (p50.001) and MCV (p = 0.01) significantly increased and BCVA significantly decreased (p = 0.04) at 6 month compared to 3 month. Compared to baseline, IOP increased significantly at 1 week (p = 0.01), 1 month (p = 0.01) and 3 months (p = 0.04). However eyes with IOP higher than 21 mmHg were treated and well controlled with topical anti-glaucoma monotherapy. Macular edema recurrence occurred in 25 eyes (CFT ranged from 321 mm to 800 mm) at 6 months. Conclusion: Dexamethasone intravitreal implant may be an effective and safe alternative in treatment of chronic DME nonresponsive to regular IVB. However, its therapeutic efficacy decreases between the third and sixth months following the injection. Keywords: Anti-VEGF therapy, bevacizumab, corticosteroids, diabetic macular edema, dexamethasone implant, inflammation, Ozurdex


adhesion molecule-1, tumor necrosis factor-a, and interleukin-6; and alterations in endothelial tight junction proteins.2–4 Treatment for DME includes focal and grid laser photocoagulation of microaneurysms and areas of diffuse leakage to reduce DME.5,6 Intravitreal antiVEGF agents also show a benefit in DME, as reported in the long-term outcomes of Ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE7 and a prospective randomized trial of intravitreal bevacizumab or laser

Diabetic macular edema (DME) is the most common cause of vision loss in diabetic retinopathy. DME results from breakdown of the blood retinal barrier, leading to vascular leakage, fluid accumulation, and thickening of the macula.1 The breakdown of the blood retinal barrier involves the recruitment and adhesion of leukocytes to the retinal vascular endothelium (leukostasis); expression of inflammatory factors, such as VEGF, intercellular

Received 28 August 2014; revised 13 November 2014; accepted 17 December 2014; published online 16 January 2015 Correspondence: Emre Gu¨ler, Eye Clinic, Erci¸s State Hospital, Van Yolu Cad. No: 57, 65400 Erci¸s, Van, Turkey. Tel: +90 432 351 96 61. E-mail: [email protected]


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Y. Totan et al.

therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2.8 In cases of anti-VEGF resistant chronic DME, effectiveness of anti-VEFG treatment may not be satisfactory since inflammatory mediators other than VEGF may also have a major role in sustaining DME. Anti-VEGF agents directly inhibit the activity of vascular permeability factor VEGF while corticosteroids decrease the production and release of VEGF and other proinflammatory cytokines, block leukostasis and enhance the barrier function of vascular tight junctions.9–11 The combination of intravitreal antiVEGF and triamcinolone acetonide therapies did not yield any significant benefits in chronic DME compared to anti-VEGF monotherapy.12–14 However, it may be logical to switch anti-VEGF treatment to corticosteroids in patients with chronic DME resistant to consecutive intravitreal anti-VEGF injections because the inflammatory mediators have a major role in chronic DME other than VEFG. Dexamethasone is a potent corticosteroid that can be delivered to the back of the eye via a sustainedrelease intravitreal implant (DEX implant 0.7 mg; Ozurdex; Allergan, Inc, Irvine, CA). The implant slowly releases dexamethasone for up to 6 months.15,16 It has been reported to be effective for the treatment of persistent DME both in vitrectomized17 and non–vitrectomized eyes.18 Dexamethasone intravitreal implant has a favorable safety profile which may be explained by the slow release of a low dexamethasone dose over a period of 6 months.15,16 The purpose of this study was to evaluate anatomical and functional outcomes of intravitreal dexamethasone implant in patients with chronic DME resistant to prior bevacizumab injections.

METHODS In this prospective, non-randomized study we have evaluated a group of 30 patients unresponsive to regular intravitreal bevacizumab injections for diabetic macular edema. Inclusion criteria were age over 18 years, a best-corrected visual acuity (BCVA) between 1.0 and 0.3 (logMAR) and chronic resistant DME. We defined chronic DME as DME present for a period of 6 months or more with central foveal thickness (CFT) greater than 275 micron as measured by optical coherence tomography (OCT).7,8,19 We also defined chronic-resistant DME as chronic DME unresponsive (reduction of CFT less than 50 micron, or increase in CFT) to a minimum of three 2.5-mg intravitreal bevacizumab injections given 6 weeks apart before inclusion into the study. The exclusion criteria were a history of glaucoma, severe cataract, venous occlusions, epiretinal membrane visible by optical coherence tomography (OCT), age-related

macular degeneration, uveitis, history of cataract surgery (within the previous 6 months), YAG laser capsulotomy (within 2 months prior to the trial), previous vitrectomy, panretinal or grid laser photocoagulation (within 3 months prior to investigation), and DME previously treated with intravitreal or periocular corticosteroids injection. All patients underwent general preoperative anamnesis, cardiological examination, electrocardiogram, and blood tests that included glycosylated hemoglobin (HbA1c). An informed consent was obtained prior to the injection after they had been informed about the benefits, risks, and possible complications of the intervention. This study was approved by the Ethics Committee and was conducted in accordance with the Declaration of Helsinki. Initially, all of the patients included in the study underwent a complete ophthalmic examination, including BCVA (logMAR), intraocular pressure (IOP) measurement by Tono-Pen (Reichert Tono-Pen AVIA),20 and fundus fluorescein angiography (FFA). Central foveal thickness (CFT) and mean cube volume (MCV) was measured by spectral domain OCT (Cirrus HD OCT, Carl Zeiss Meditec Inc., Dublin, CA) and the presence of retinal thickness greater than 275 mm was verified. Intravitreal dexamethasone implant (0.7-mg implant of dexamethasone, Ozurdex; Allergan, Inc, Irvine, CA) was administered intravitreally through the pars plana using the original implanting device. After the administration, IOP and light perception were assessed. Complete ophthalmic examination, including IOP measurements was performed at first week, 1, 3, and 6 months. BCVA, CFT, and MCV measurements were performed at 1, 3, and 6 months. The main outcomes were the changes between the initial and follow up visits in the mean BCVA, CFT, MCV, and IOP measures. Statistical calculations were performed using the SPSS (version 17.0; SPSS Inc., Chicago, IL). Paired sample t-test was used to measure mean differences between pre- and post-implant values of all the parameters evaluated and obtained at different temporal follow-up points (at month 1–6). Pearson’s correlation coefficients were used to evaluate the relation of BCVA with CFT and MCV. All data are presented as mean ± standard deviation (SD). Differences were statistically significant when p50.05.

RESULTS A total of 30 eyes of 30 patients (12 males, 18 females; mean age 61.3 ± 7.3 years, range 47–76 years) with chronic resistant DME were included in the analysis. The mean duration of DME was 29.7 ± 9.5 months (range 12–44 months), and the mean HbA1c value at Current Eye Research

Dexamethasone Implant for Diabetic Macular Edema baseline was 7.4% (mean 7.4 ± 1.9). Of the 30 eyes, 12 had previous grid laser, 5 had scatter laser treatment. The average interval between the last intravitreal bevacizumab injection and dexamethasone implant application was 2 months (6 weeks to 3 months). The total mean number of the intravitreal

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TABLE 1. Demographic characteristics and medical history of the study population. No. of patients (eyes) Gender (M/F) (n) Age (years, mean ± SD) Eye (R/L) (n) Duration of DME (months, mean ± SD) HbA1c value at baseline (%, mean ± SD) Total anti-VEGF injections (mean ± SD) Previous scatter laser (n, %) Previous grid laser (n, %)

30 12/18 61.3 ± 7.3 16/14 29.7 ± 9.5 7.4 ± 1.9 6.0 ± 0.6 5 (16%) 12 (40%)

M = Male, F = Female, SD = Standard deviation, DME = Diabetic macular edema, VEGF = Vascular endothelial growth factor, R = Right, L = Left.

bevacizumab injections was 6.0 ± 0.6. Preoperative and follow-up FFA showed no cases of macular or paramacular retinal ischemia (Table 1). Statistically significant change from baseline was observed in BCVA (at 1, 3 and 6 months), CFT (at 1, 3, and 6 months), MCV (at 1, 3, and 6 months), and IOP (at 1 week, 1 and 3 months) (Table 2). BCVA significantly (p = 0.04) decreased at 6th month (0.59 ± 0.39 logMAR) compared to the mean BCVA at 3 month (0.44 ± 0.28 logMAR) (Figure 1). At the 6th month visit, the mean CFT (411 ± 126 mm, range 174–776 mm) (p50.001) was still significantly lower compared to the baseline value (517 ± 136 mm, range 324–872 mm) (p = 0.01), but significantly increased compared to the mean CFT at 3 month (314 ± 88 mm, range 186–758 mm) (Figure 2). At the last visit, the mean MCV was significantly lower than baseline value (13.6 ± 1.9 mm3) (p50.001). However, it was significantly increased to 12.1 ± 1.9 mm3 (p = 0.01) compared to the mean MCV at 3 month (11.3 ± 1.5 mm3) (Figures 3 and 4).

TABLE 2. Mean changes from baseline BCVA (logMAR), CFT, MCV, and IOP.

Baseline 1 Week 1 Month 3 Month 6 Month


CFT (mm)

0.56 ± 0.38 – 0.41 ± 0.27 (p50.001) 0.44 ± 0.28 (p = 0.008) 0.59 ± 0.39 (p = 0.39)

517 ± 136 – 290 ± 60 (p50.001) 314 ± 88 (p50.001) 411 ± 126 (p = 0.01)

MCV (mm) 13.6 ± 1.9 – 11.0 ± 1.4 (p50.001) 11.3 ± 1.5 (p50.001) 12.1 ± 1.9 (p50.001)

IOP (mmHg) 16.5 ± 3.3 18.4 ± 3.7 19.5 ± 5.3 18.5 ± 4.8 17.1 ± 4.1

(p = 0.01) (p = 0.01) (p = 0.04) (p = 0.26)

BCVA: Best corrected visual acuity, CFT: Central foveal thickness, MCV: Mean cube volume, IOP: Intraocular pressure. p50.05 was considered statistically significant.

FIGURE 1. Visual acuity changes following OZURDEX implantation. !

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Y. Totan et al.

FIGURE 2. CFT changes following OZURDEX implantation.

FIGURE 3. MCV changes following OZURDEX implantation.

A recurrence of macular edema at 6 months was observed in a total of 25 eyes with CFT ranged from 321 mm to 800 mm and mean HbA1c value of 6.8%. Three of 25 eyes showed a CFT increase to a higher level than baseline (rebound effect) at the 6-month follow-up examination and were retreated

with additional 2.5 mg intravitreal bevacizumab. These 3 patients had HbA1c values of 6.3%, 6.9% and 8.3%. Thirteen of the reminder 22 eyes were retreated with 1.25 mg of intravitreal ranibizumab, and 9 eyes with additional 2.5 mg intravitreal bevacizumab. Current Eye Research

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Dexamethasone Implant for Diabetic Macular Edema


FIGURE 4. SD-OCT retinal images in 3 patients with DME, at baseline and after treatment with Ozurdex (first, third and sixth months).

FIGURE 5. IOP changes after OZURDEX implantation.

The BCVA was not significantly correlated with CFT and MCV at 6-month follow up (r = 0.10, p = 0.58; r = 0.29, p = 0.11, respectively). IOP values were significantly higher at 1 week (p = 0.01), 1 month (p = 0.01) and 3 months (p = 0.04) compared to the baseline IOP. After 1 month, it was gradually decreased to the baseline value at 6 month (Figure 5). !

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During the follow-up period, we have found IOP higher than 21 mmHg in 4 of 30 eyes (13.3%) (The maximum value was 32 mmHg at 1 month). These eyes were treated and well-controlled with topical anti-glaucoma monotherapy. No inflammation, infection, thromboembolic events, ocular toxicity, and cataract progression (based on the ‘‘Lens Opacities


Y. Totan et al.

Classification System’’ III)21 were observed in any of the patients.

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DISCUSSION A variety of nonsurgical treatments exist for DME including intravitreal anti-VEGF and steroid therapies. Cases of DME that do not respond well to regular anti-VEGF injections may be driven by pro inflammatory cytokines other than VEGF. Furthermore, long-standing edema may be resistant to treatment and results in worse outcomes. Therefore, it may be helpful to switch from anti-VEGF therapy to steroid therapy because corticosteroids not only regulate blood flow by their vasoconstrictor effect but also mediate chronic inflammation and therefore may have a dual effect in controlling DME. In clinical practice, intravitreal steroids are rarely the initial treatment for DME due to the ocular side effects. So, the corticosteroid implants may be considered for DME when anti-VEGF treatment is contraindicated, as an adjunct to intravitreal anti-VEGF therapy in low compliant patients due to repeated anti-VEGF injections and in anti-VEGF–resistant patients. From the data through 6 months follow-up, we can see that the slow-release intravitreal dexamethasone implant shows efficacy for the treatment of DME. The peak efficacy of the implant appears to be reached at month 1 to month 3, and then decreases to month 6. This result may be explained by reduced release of the drug rather than worsening of the diabetic regulation because the included patients had a mean HbA1c value of 6.8 during follow up. In our study, 25 of 30 eyes resistant to bevacizumab treatment were also considered to have DME recurrence between 3 and 6 months after intravitreal dexamethasone implant application. The results suggested that Ozurdex does not provide a favorable injection free interval in patients resistant to previous bevacizumab treatment. The study population in the present study was difficult to treat, because duration of DME before the dexamethasone implant was 30 months, and DME had persisted in all patients despite regular intravitreal anti-VEGF injections. In some cases, BCVA was not improved although a decrease was observed in CFT and MCV. The Pearson correlation did not show any relation between those parameters. This may be most likely due to the secondary photoreceptor degeneration. Only one study in the literature evaluated the efficiency of intravitreal dexamethasone implant in patients with chronic DME unresponsive to three monthly 1.25 mg intravitreal bevacizumab injections.18 They have reported significant improvement

in BCVA at month 2 and in CFT at month 1, 2 and 3. In our study, we have detected improvements in both CFT and BCVA for 3 months postoperatively, then a tendency toward the loss of improvement in CFT and BCVA between 3 and 6 months possibly due to reduced steroid release. According to our study results, it is reasonable to switch to corticosteroids as an adjuvant therapy in anti-VEGF resistant chronic DME. However, the CFT again increased markedly and almost to the baseline value in some patients at 6-month visit because these patients generally have chronic inflammation for lifetime. Another reason for the increased CFT may be the chronic ischemia, however follow up FFA did not show any cases of ischemia in our cases. So, another randomized study could give a more definite suggestion on whether the second dexamethasone implant or an anti-VEGF agent would be more beneficial at this point. In addition, pars planavitrectomy may also be useful in the treatment of these chronic DME patients. The mechanism for the effect of vitrectomy on DME may involve both release of vitreomacular traction and increased diffusion of advanced glycation end products, VEGF, and other cytokines away from the retina. Recently, GENEVA study reported that the dexamethasone intravitreal implant (Ozurdex) was associated with a very low ocular risk profile.16 In the current study, a limited rise in IOP was noticed in 4 patients, and successfully managed with topical medication. Cataract progression was not observed during the follow up. No cases of major adverse effects including inflammation, infection, thromboembolic events, or ocular toxicity regarding use of dexamethasone intravitreal implant were observed. We have to acknowledge that this study has some limitations. In particular, a limited number of eyes were evaluated with a short follow-up period. However, this study suggests that dexamethasone intravitreal implant may present a good alternative in the management of DME unresponsive to regular intravitreal anti-VEGF injections. We also have observed that its efficacy has remarkably been decreased between month 3 and 6 following administration. Therefore, it is recommended to do earlier control to detect the recurrent diabetic macular edema and to try with new dexamethasone implant or switch back to bevacizumab based on the clinician preference and patient characteristics.

DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content writing of the paper. The authors declare no proprietary interests or research funding. Current Eye Research

Dexamethasone Implant for Diabetic Macular Edema

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Dexamethasone Intravitreal Implant for Chronic Diabetic Macular Edema Resistant to Intravitreal Bevacizumab Treatment.

To evaluate the safety and efficacy of intravitreal dexamethasone implant (Ozurdex) in patients with chronic diabetic macular edema (DME) resistant to...
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