Original Paper

Ophthalmologica

Ophthalmologica 2014;231:141–146 DOI: 10.1159/000356413

Received: July 2, 2013 Accepted after revision: September 13, 2013 Published online: December 19, 2013

Dexamethasone Intravitreal Implant for Treatment of Patients with Persistent Diabetic Macular Edema Marco Dutra Medeiros a Maurizio Postorino a Rafael Navarro a José Garcia-Arumí a, b Carlos Mateo a Borja Corcóstegui a a

Instituto de Microcirugia Ocular and b Hospital Universitario Vall d’Hebron, Barcelona, Spain

Key Words Diabetes · Refractory macular edema · Ozurdex

ment with a dexamethasone implant safely reduced DME and improved visual acuity in a difficult-to-treat patient population with long-standing refractory DME. © 2013 S. Karger AG, Basel

© 2013 S. Karger AG, Basel 0030–3755/13/2313–0141$38.00/0 E-Mail [email protected] www.karger.com/oph

Introduction

Diabetic macular edema (DME) is the main cause of mild to moderate visual loss in diabetic retinopathy [1]. Laser photocoagulation has been considered, for a long time, as the reference option for treatment of DME, based on the results of the Early Treatment Diabetic Retinopathy Study clinical trial [2, 3]. Various studies highlighted the expression of vascular endothelial growth factor (VEGF) as a key factor in the development of DME [4, 5]. This has recently been documented by randomized clinical trials, which led to considering intravitreal anti-VEGF as one of the most recent additions to the armamentarium against DME [6, 7]. Glucocorticoids such as dexamethasone exert their anti-inflammatory effects by influencing multiple signal transduction pathways, including VEGF [8–11]. By binding to cytoplasmic glucocorticoid receptors, corticosteroids in high doses increase the activation of anti-inflammatory genes, whereas at low concentrations they have a Marco Dutra Medeiros, MD Instituto de Microcirurgia Ocular Calle Josep María Lladó No. 3 E–08035 Barcelona (Spain) E-Mail marcodutramedeiros @ gmail.com

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Abstract Purpose: To report the 6-month anatomical and best-corrected visual acuity (BCVA) response after primary intravitreal dexamethasone implantation (Ozurdex®) in patients with refractory diabetic macular edema (DME). Methods: Retrospective review of the medical records of 58 patients with decreased visual acuity, due to refractory DME, who underwent a single injection of Ozurdex between November 2010 and January 2012, at the Instituto de Microcirurgia Ocular, Barcelona, Spain. Results: At baseline, the mean foveal thickness (FT) was 543.24 ± 156.51 μm. Mean (±SD) values of FT did decrease to 346.82 ± 123.74 μm at month 1 and 341.12 ± 129.64 μm at month 3. Data on the 6-month followup showed a mild increase to 420.16 ± 152.15 μm. All of the FT reduction outcomes were statistically significant, with respect to baseline data (p = 0.0001). The baseline BCVA data was 0.66 ± 0.36 logarithm of the minimum angle of resolution (logMAR). The mean BCVA improved to 0.52 ± 0.32 logMAR (p = 0.0001) and 0.44 ± 0.27 logMAR (p = 0.0001) after 1 and 3 months, respectively. At the last visit (6-month follow-up), the mean BCVA increased to 0.51 ± 0.31 logMAR (p = 0.0001). Conclusions: In this study, intravitreal treat-

Subjects and Methods We retrospectively reviewed the medical records of 67 patients with decreased visual acuity, due to refractory DME, who underwent a single injection of Ozurdex between November 2010 and January 2012, at the Instituto de Microcirurgia Ocular, Barcelona, Spain. Of these patients, 58 patients were enrolled in the study. Key inclusion criteria included previous treatment with antiVEGF agents, other intraocular steroids or laser photocoagulation with only a partial response to the previous treatments. Refractory DME was defined as persistent ME with foveal thickness (FT) more than 250 μm by spectral-domain optical coherence tomography, lasting for at least 90 days after laser or intravitreal antiVEGF/steroid treatment. Exclusion criteria were diagnosis of uncontrolled systemic disease, glaucoma, elevated intraocular pressure (IOP), epiretinal membrane or vitreomacular traction in the study eye that could prevent improvement in visual acuity as well as any intraocular

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Ophthalmologica 2014;231:141–146 DOI: 10.1159/000356413

injection, intraocular surgery, or laser treatment in the study eye within the previous 3 months. Informed consent was obtained from all patients in agreement with the Declaration of Helsinki for research involving human subjects. At baseline, all patients underwent a complete ophthalmic evaluation, including best-corrected visual acuity (BCVA) using standardized Early Treatment Diabetic Retinopathy Study charts, tonometry, fluorescein angiography and spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec Inc., Dublin, Calif., USA) with FT measurement. Patients received a dexamethasone implant in the study eye at the baseline visit (day 1). A single-use applicator with a 22-gauge needle was used to place a dexamethasone implant in the vitreal chamber through a self-sealing scleral injection. All injections were performed in the operating room. All of them returned to our institution at regular intervals after the surgical procedure for ocular and systemic follow-up. Patients were seen at outcome assessment study visits on day 2 and at months 1, 3 and 6. All patients were monitored for any local or systemic adverse effects during the whole study. The primary efficacy outcome measure was the change from baseline in BVCA and in FT from baseline to month 6. Statistical calculations were performed using the Statistical Package for Social Sciences (version 19.0; SPSS Inc., Chicago, Ill., USA). Mean changes from baseline FT and BCVA (converted to the logarithm of the minimum angle of resolution, logMAR) were analyzed using paired t tests. A two-tailed test with an alpha level of 0.05 was used for all comparisons. We report our results herein.

Results

During the inclusion period of the study, refractory DME that had undergone dexamethasone implantation was identified in 67 patients. Of these patients, 58 patients were enrolled in the study. Baseline characteristics of patients and study eyes are listed in table 1. The mean age of patients was 64 years. Thirty-nine (68%) of the patients were male. Patients had previously been exposed to a variety of treatments for diabetic retinopathy and DME (table 2). The current occurrence of DME had been previously treated with anti-VEGF therapy in 44 (75.9%) patients, with intravitreal triamcinolone acetonide in 39 (67.2%), with focal laser therapy in 51 (87.9%) and with panretinal photocoagulation in 43 (74.1%). Forty-one percent (24 patients) had undergone a pars plana vitrectomy before entering the study. At baseline, the mean FT was 543.24 ± 156.51 μm. Mean (±SD) values of FT did decrease to 346.82 ± 123.74 μm at month 1 and 341.12 ± 129.64 μm at month 3. Data Dutra Medeiros/Postorino/Navarro/ Garcia-Arumí/Mateo/Corcóstegui

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role in the suppression of activated inflammatory genes [9, 12]. Therefore, a drug release profile that consists of an initial phase of high concentration of dexamethasone, followed by a second phase of lower concentration, may continue to contribute to the anti-inflammatory action of dexamethasone for the duration of the implant. The dexamethasone implant (Ozurdex®; Allergan Inc., Irvine, Calif., USA) is a novel approach approved by the United States Food and Drug Administration and by the European Union for the intravitreal treatment of macular edema after branch or central retinal vein occlusion and for the treatment of noninfectious uveitis affecting the posterior segment of the eye [13]. However, there is evidence for efficacy in multiple clinical situations, including DME, ME associated with uveitis or Irvine-Gass syndrome, DME in vitrectomized eyes, persistent ME and noninfectious vitritis [13–20]. Dexamethasone implantation resulted in sustained levels of dexamethasone and biological activity for 6 months, with peak levels of drug over the first 2 months [16–18]. Compared with published data describing other routes of administration of dexamethasone analogues, several results demonstrate a few advantages of this implant [21]. Key features of the drug delivery system are the sustained-release formulation of the poly(lactic acid-coglycolic acid) matrix material, which dissolves completely in vivo, and the singleuse applicator for intravitreal placement [22]. The primary purpose of this study was to evaluate the effectiveness of a single intravitreal injection of Ozurdex, over 6 months in diabetic patients with persistent DME. The patient population included severe cases that had not responded to multiple previous therapies.

Table 1. Baseline demographics and clinical features of study eyes Sex 

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58

H M H H H H H H H H H M H M M H H M M M H M M H M H M M H H H H H M M H H H H H H H H M H H H H H H M M M H M H H H

Age, years

BCVA baseline

month 1

month 3

month 6

baseline

month 1

month 3

month 6

60 66 64 40 70 59 66 66 66 66 64 78 82 59 66 63 56 62 84 65 65 65 62 58 61 62 77 77 68 70 81 64 46 65 65 78 78 57 72 72 66 61 75 62 68 71 65 68 32 59 24 60 63 66 36 46 62 59

0.70 0.70 0.20 1.00 0.50 0.40 0.80 0.80 0.70 0.70 0.40 0.40 1.30 0.30 0.70 1.00 0.70 0.70 0.70 1.00 0.70 1.00 0.10 0.50 1.30 0.70 2.00 1.00 0.70 0.70 0.50 1.00 1.00 1.10 1.30 0.40 0.80 0.18 0.50 0.40 0.50 0.20 0.50 0.20 0.30 0.70 0.20 1.30 0.50 0.40 0.20 0.50 0.80 0.20 0.70 0.70 0.50 0.50

0.50 0.70 0.20 0.80 0.50 0.40 0.30 0.40 0.40 0.40 0.20 0.30 1.00 0.20 0.70 0.80 0.50 0.50 0.50 0.50 0.40 1.00 0.10 0.30 1.00 0.80 1.60 1.00 0.70 0.70 0.30 1.00 0.70 1.00 1.30 0.30 0.80 0.10 0.18 0.20 0.30 0.40 0.20 0.18 0.30 0.70 0.20 0.50 0.40 0.40 0.10 0.40 0.70 0.18 0.20 0.70 0.40 0.40

0.40 0.50 0.20 0.70 0.70 0.40 0.40 0.40 0.50 0.30 0.20 0.20 0.70 0.18 0.50 0.80 0.40 0.30 0.50 0.50 0.20 0.40 0.10 0.20 1.00 0.70 1.30 0.80 0.50 0.70 0.30 0.50 0.70 0.40 1.30 0.30 0.80 0.10 0.20 0.20 0.20 0.40 0.20 0.18 0.20 0.70 0.18 0.70 0.30 0.40 0.10 0.30 0.50 0.18 0.18 0.70 0.40 0.20

0.20 0.50 0.20 0.70 0.50 0.40 0.40 0.70 0.50 0.50 0.50 0.40 1.00 0.30 1.00 1.00 0.40 0.30 0.40 0.50 0.20 1.00 0.18 0.40 0.80 0.70 1.30 0.80 0.50 0.80 0.40 0.40 0.70 0.40 1.30 0.30 1.30 0.10 0.20 0.18 0.18 0.50 0.20 0.18 0.18 0.70 0.20 0.70 0.30 0.40 0.10 0.40 0.70 0.18 0.50 1.00 0.50 0.20

512.00 686.00 501.00 638.00 695.00 523.00 762.00 696.00 688.00 616.00 643.00 746.00 525.00 273.00 535.00 889.00 480.00 507.00 333.00 437.00 597.00 552.00 462.00 543.00 835.00 419.00 925.00 523.00 346.00 264.00 625.00 276.00 510.00 658.00 764.00 541.00 603.00 334.00 560.00 607.00 826.00 526.00 599.00 354.00 422.00 692.00 497.00 416.00 411.00 283.00 369.00 524.00 460.00 438.00 611.00 567.00 581.00 303.00

332.00 218.00 419.00 367.00 545.00 444.00 181.00 193.00 457.00 407.00 265.00 432.00 536.00 267.00 387.00 654.00 329.00 233.00 238.00 347.00 323.00 315.00 411.00 387.00 672.00 344.00 778.00 367.00 166.00 234.00 248.00 231.00 184.00 336.00 219.00 258.00 451.00 268.00 264.00 443.00 314.00 351.00 403.00 306.00 337.00 478.00 321.00 460.00 221.00 273.00 257.00 397.00 332.00 426.00 236.00 292.00 338.00 224.00

261.00 459.00 272.00 173.00 419.00 434.00 233.00 243.00 677.00 587.00 634.00 457.00 211.00 267.00 328.00 566.00 279.00 211.00 232.00 320.00 322.00 307.00 323.00 334.00 602.00 311.00 643.00 322.00 156.00 234.00 242.00 288.00 259.00 402.00 207.00 312.00 430.00 206.00 254.00 245.00 306.00 317.00 496.00 273.00 276.00 397.00 322.00 514.00 237.00 273.00 306.00 370.00 290.00 431.00 588.00 173.00 316.00 238.00

303.00 450.00 354.00 456.00 476.00 507.00 321.00 352.00 643.00 612.00 756.00 717.00 411.00 222.00 361.00 866.00 299.00 239.00 283.00 372.00 344.00 387.00 352.00 585.00 698.00 356.00 699.00 411.00 178.00 256.00 502.00 311.00 567.00 477.00 301.00 536.00 631.00 249.00 309.00 336.00 325.00 318.00 529.00 401.00 274.00 481.00 402.00 529.00 310.00 287.00 317.00 411.00 321.00 496.00 596.00 229.00 428.00 230.00

Intravitreal Implant for Macular Edema

FT, μm

Ophthalmologica 2014;231:141–146 DOI: 10.1159/000356413

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Patient No.

Month 1

Month 3

Month 6

–50 –100 –150 –200 –250

0.7

0.66

0.6 0.52

0.5

0.51 0.44

0.4 0.3 0.2 0.1 0

Baseline

Month 1

Month 3

Month 6

Fig. 1. Mean changes from baseline FT in the study eye.

Fig. 2. Mean changes from baseline BCVA in the study eye.

Table 2. History of posterior segment procedures in the study

No anecdotal IOP elevation was observed throughout the study. No serious ocular and systemic adverse events were observed.

eye Posterior segment procedure

Patients (n = 58, 100%) with any previous treatment for DME

Pars plana vitrectomy Focal laser Panretinal photocoagulation Intravenous anti-VEGF Intravenous triamcinolone

24 (41.4%) 51 (87.9%) 43 (74.1%) 44 (75.9%) 39 (67.2%)

on the 6-month follow-up showed a mild increase to 420.16 ± 152.15 μm. All of the FT reduction outcomes were statistically significant, with respect to baseline data (p = 0.0001). The mean (±SD) change from baseline FT thickness was 196.41 μm (a decrease value of 36%) at month 1, and 202.12 μm (decrease value of 37%) and 123.09 μm (decrease value of 23%) at months 3 and 6, respectively (fig. 1). A statistically significant improvement in BCVA was also seen at month 1 after treatment with a dexamethasone implant and at each subsequent follow-up visit (fig. 2). The baseline BCVA data was 0.66 ± 0.36 logMAR. The mean BCVA improved to 0.52 ± 0.32 logMAR (p  = 0.0001) and 0.44 ± 0.27 logMAR (p = 0.0001) after 1 and 3 months, respectively. At the last visit (6-month followup), the mean BCVA increased to 0.51 ± 0.31 logMAR (p = 0.0001). 144

Ophthalmologica 2014;231:141–146 DOI: 10.1159/000356413

Discussion

In the current study, intravitreal treatment with a dexamethasone implant safely reduced ME and improved visual acuity in a difficult-to-treat patient population with long-standing refractory DME. Both mean FT and mean BCVA had improved from baseline by 1 month after treatment with a dexamethasone implant, and the improvement remained statistically significant throughout the 6-month study. The peak effectiveness of dexamethasone implants was seen at 3  months after injection, when the mean FT had decreased by 37%, and the mean BCVA improved to 0.44 ± 0.27 logMAR from baseline. Most recently, two studies evaluated the efficacy of a dexamethasone intravitreous drug delivery system in persistent ME secondary to diabetes. In the first clinical trial, Haller et al. [14] demonstrated that, in eyes with DME treated with dexamethasone intravitreous drug delivery 0.7 mg, BCVA and FT significantly improved at 3 months when compared with the observation group. Interestingly, they found that the BCVA improvement was no longer significant at 6 months. Unfortunately, this randomized trial did not investigate the corresponding change in FT at the same time point. This may be due to the different outcome measures between the two studies. In fact, in our study Dutra Medeiros/Postorino/Navarro/ Garcia-Arumí/Mateo/Corcóstegui

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Baseline FT

Change in BCVA from baseline (logMAR)

Mean change in FT from baseline (μm)

0

we investigated the mean BCVA changes at different time points, while in their randomized trial the authors investigated the proportion of eyes that achieved an improvement in BCVA of 10 letters or more, compared with the observation group. In the second study, Zucchiatti et al. [23] showed that a single intravitreal injection of Ozurdex produced improvement in BCVA and FT in eyes with persistent DME. Such an improvement was evident from the third day to the first month after injection, peaked at the third month and was no more significant 6 months after the injection. Similarly, our data are consistent with the results named above. The target population in the current study was difficult to treat because it included severe cases of long-standing DME that had failed to respond to previous therapy with pars plana vitrectomy, focal laser and/or pharmacotherapy, most commonly intravitreal injection of the corticosteroid triamcinolone acetonide or the anti-VEGF therapy. In fact, one third of the patients underwent previous triple therapy. In these cases, the potential for improvement in vision was likely limited by secondary functional and structural changes related to chronic edema. Treatment of DME has evolved to encompass a combination of multi-target therapeutic approaches. In the past decades, corticosteroids have raised interest in the treatment of DME due to their anti-inflammatory effects, and because they inhibit the synthesis of VEGF and reduce vascular permeability. However, due to safety concerns [24] (i.e. IOP elevation and cataract progression), in the last few years, the use of corticosteroids has been drastically reduced in most developed countries. Recently, the safety profile of Ozurdex, which is currently an approved treatment for retinal vein occlusion, has been reported in the GENEVA study [13]. Dexamethasone intravitreal implants were well tolerated and demonstrated an acceptable safety profile in this study. No anecdotal IOP elevation nor cataract progression were observed throughout the study. The implant does not need to be removed because the copolymer slowly biodegrades into carbon dioxide and water and is absorbed over time. Twenty-four patients had undergone a pars plana vitrectomy before entering in the current study. The improvement in central retinal thickness and BCVA seen in this sample was similar to the improvement seen in the remaining nonvitrectomized patients with persistent macular edema. The results of the present study demonstrate that a dexamethasone implant may be an effective and well-tolerated treatment for DME in vitrectomized

patients, even in severe cases that have failed to respond to previous therapies. Our data are consistent with those from a recent analysis of the earlier publication addressing this issue [15, 18]. Advantages of dexamethasone implants over intravitreal triamcinolone acetonide in vitrectomized eyes include a longer duration of action and absence of postinjection ‘visual clouding’ and floater-like symptoms. Our study has several limitations – in that it is shortterm, open-label, uncontrolled, retrospective and evaluates a small study population – that preclude any estimation of the long-term efficacy or safety of intravitreal Ozurdex. Another limitation was that information about the status of the underlying diabetes in the sample was not recorded. Therefore, the extent to which diabetes control and blood glucose concentrations may have affected patient outcomes in the study is unknown. However, our 6-month findings provide useful comparisons with the results from other studies [14, 23]. So far, a literature review indicates that the single injection of the implant is well tolerated and produces meaningful improvements in ME and visual acuity that persist through 6 months. The available 6-month data also indicate that this implant confers much less of a risk of ocular hypertension than do other forms of intraocular steroid therapy. However, future longer-term trials are needed to evaluate the efficacy and safety data in patients who receive multiple injections. According to our results, the recent dexamethasone implant Ozurdex 0.7 mg will probably be a useful addition to our local armamentarium in the treatment of persistent DME given its efficacy, safety and ease of use in the outpatient setting and support the conducting of clinical trials in this patient population.

Intravitreal Implant for Macular Edema

Ophthalmologica 2014;231:141–146 DOI: 10.1159/000356413

Conclusion

In this study, intravitreal treatment with a dexamethasone implant safely reduced central retinal thickness and improved visual acuity from baseline by 1 month after treatment, in a difficult-to-treat patient population with refractory DME. The improvement remained statistically significant throughout the 6-month study.

None of the listed authors have any conflicting financial interest related to this paper, current and over the past 5 years.

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Disclosure Statement

References

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Dexamethasone intravitreal implant for treatment of patients with persistent diabetic macular edema.

To report the 6-month anatomical and best-corrected visual acuity (BCVA) response after primary intravitreal dexamethasone implantation (Ozurdex®) in ...
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