ORIGINAL ARTICLES
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 30, Number 9, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2014.0010
Dexamethasone Intravitreal Implant in Vitrectomized Versus Nonvitrectomized Eyes for Treatment of Patients with Persistent Diabetic Macular Edema Marco Dutra Medeiros,1,2 Micol Alkabes,1,3 Rafael Navarro,1 Jose´ Garcia-Arumı´,1,4 Carlos Mateo,1 and Borja Corco´stegui1
Abstract
Purpose: To compare the 6-month anatomic and best-corrected visual acuity (BCVA) response after sustainedrelease dexamethasone (DEX) intravitreal implant between nonvitrectomized and vitrectomized eyes with persistent diabetic macular edema (DME). Methods: Retrospective, comparative, and consecutive 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. Then, we divided patients into 2 groups: 24 eyes who had undergone standard pars plana vitrectomy (vitrectomized group), and 34 eyes that were not operated on (nonvitrectomized group). Outcomes measured were BCVA and foveal thickness (FT) at baseline and at months 1, 3, and 6. Results: Twenty-four of 58 eyes had prior vitrectomy (41%). Statistically significant improvement in BCVA also was seen at 1 month after treatment with a DEX implant and at each subsequent follow-up visit, in either groups (P < 0.05). All of the FT reduction outcomes were statistically significant in both groups, with respect to baseline data (P < 0.05). There were no statistically significant differences in BCVA and FT between nonvitrectomized and vitrectomized eyes at any time point (P < 0.05). Conclusion: In this study, the clinical findings were similar between nonvitrectomized and vitrectomized eyes. Intravitreal treatment with a DEX implant safely reduced DME and improved visual acuity in both groups. No statistically significant differences were found between the 2 groups regarding FT and BCVA.
Introduction
P
ars plana vitrectomy (PPV) is beneficial in many conditions, including diabetic retinopathy (DR), diabetic macular edema (DME), retinal detachment, macular holes, macular pucker, and vitreous hemorrhage. In DR, both the delivery of oxygen to the retina and the removal of inflammatory mediators of DME, such as vascular endothelial growth factor (VEGF), from the retina are improved after vitrectomy.1 PPV effectively treats DME associated with vitreomacular traction, but several authors have also documented excellent results following surgery for fovea involving diffuse DME without apparent vitreomacular traction.2–6 However, for many patients, the chronic and recurrent nature of retinal diseases requires continued drug therapy after surgical procedure.7–9 Experience with
VEGF10 and a number of drugs, including triamcinolone acetonide,11,12 amphotericin B,13 and 5-fluorouracil,14 suggests that some drugs are cleared more rapidly in vitrectomized eyes. Indeed, further intravitreal pharmacologic treatment of posterior segment disease may be less effective after removal of the vitreous. Drug clearance from the vitreous cavity is more rapid in vitrectomized eyes, limiting drug exposure to the retina and reducing treatment success and options. Therefore, differences in pharmacokinetics between nonvitrectomized and vitrectomized eyes may influence the clinical effectiveness of drug therapy. Glucocorticoids such as DEX exert their anti-inflammatory effects by influencing multiple signal transduction pathways, including VEGF.15–18 By binding to cytoplasmic glucocorticoid receptors, corticosteroids in high doses increase the activation of anti-inflammatory genes, whereas at
1
Department of Retina, Instituto de Microcirugia Ocular, Barcelona, Spain. Central Lisbon Hospital Center, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal. University Eye Clinic, San Giuseppe Hospital, Universita` di Milano, Milan, Italy. 4 Hospital Universitario Vall d’Hebron, Barcelona, Spain. 2 3
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Table 1. Patient no. 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
Baseline Demographics and Clinical Features in the Nonvitrectomized Group
Sex
Age (years)
BCVA Baseline
BCVA Month 1
BCVA Month 3
BCVA Month 6
Foveal thickness Baseline
Foveal thickness Month 1
Foveal thickness Month 3
Foveal thickness Month 6
M M M M M M F M F F M M F F F F M M M M M M M F M M M M F F F M F M
70 59 66 66 66 66 78 82 59 66 63 56 84 62 77 77 68 81 46 78 78 61 75 62 71 65 68 32 24 60 63 66 36 59
0.50 0.40 0.80 0.80 0.70 0.70 0.40 1.30 0.30 0.70 1.00 0.70 0.70 0.10 2.00 1.00 0.70 0.50 1.00 0.40 0.80 0.20 0.50 0.20 0.70 0.20 1.30 0.50 0.20 0.50 0.80 0.20 0.70 0.50
0.50 0.40 0.30 0.40 0.40 0.40 0.30 1.00 0.20 0.70 0.80 0.50 0.50 0.10 1.60 1.00 0.70 0.30 0.70 0.30 0.80 0.40 0.20 0.18 0.70 0.20 0.50 0.40 0.10 0.40 0.70 0.18 0.20 0.40
0.70 0.40 0.40 0.40 0.50 0.30 0.20 0.70 0.18 0.50 0.80 0.40 0.50 0.10 1.30 0.80 0.50 0.30 0.70 0.30 0.80 0.40 0.20 0.18 0.70 0.18 0.70 0.30 0.10 0.30 0.50 0.18 0.18 0.20
0.50 0.40 0.40 0.70 0.50 0.50 0.40 1.00 0.30 1.00 1.00 0.40 0.40 0.18 1.30 0.80 0.50 0.40 0.70 0.30 1.30 0.50 0.20 0.18 0.70 0.20 0.70 0.30 0.10 0.40 0.70 0.18 0.50 0.20
695.00 523.00 762.00 696.00 688.00 616.00 746.00 525.00 273.00 535.00 889.00 480.00 333.00 462.00 925.00 523.00 346.00 625.00 510.00 541.00 603.00 526.00 599.00 354.00 692.00 497.00 416.00 411.00 369.00 524.00 460.00 438.00 611.00 303.00
545.00 444.00 181.00 193.00 457.00 407.00 432.00 536.00 267.00 387.00 654.00 329.00 238.00 411.00 778.00 367.00 166.00 248.00 184.00 258.00 451.00 351.00 403.00 306.00 478.00 321.00 460.00 221.00 257.00 397.00 332.00 426.00 236.00 224.00
419.00 434.00 233.00 243.00 677.00 587.00 457.00 211.00 267.00 328.00 566.00 279.00 232.00 323.00 643.00 322.00 156.00 242.00 259.00 312.00 430.00 317.00 496.00 273.00 397.00 322.00 514.00 237.00 306.00 370.00 290.00 431.00 588.00 238.00
476.00 507.00 321.00 352.00 643.00 612.00 717.00 411.00 222.00 361.00 866.00 299.00 283.00 352.00 699.00 411.00 178.00 502.00 567.00 536.00 631.00 318.00 529.00 401.00 481.00 402.00 529.00 310.00 317.00 411.00 321.00 496.00 596.00 230.00
BCVA, best-corrected visual acuity; F, female; M, male.
low concentrations they have a role in the suppression of activated inflammatory genes.16,19 The DEX implant (Ozurdex; Allergan, Inc., Irvine, CA) is a novel approach approved by the United States Food and Drug Administration (FDA) and by European Union (EU) 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.20 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.15–22 The objective of this study was to compare the ocular effectiveness profile of a single intravitreal injection of Ozurdex in nonvitrectomized and vitrectomized eyes of diabetic patients with DME. The patient population included severe cases that had not responded to multiple previous therapies.
Methods Enrollment of study subjects We retrospectively reviewed the medical records of 67 consecutive 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. Then, we divided patients into 2 groups: 24 eyes who had undergone standard PPV (vitrectomized group), and 34 eyes that were not operated on (nonvitrectomized group). Baseline characteristics of patients and study eyes, in either group, are listed in Tables 1 and 2. All patients had been previously exposed to a variety of treatments for DR and DME. Key inclusion criteria included previous treatment with anti-VEGF agents, other intraocular steroids or laser photocoagulation with only a partial response to the previous treatments (Tables 3 and 4). Refractory DME was defined as persistent ME with foveal thickness (FT) 250 mm by spectral domain optical coherence tomography (SDOCT), lasting for at least 90 days after laser or intravitreal anti-VEGF/steroid treatment. Exclusion criteria were diagnosis of uncontrolled systemic disease, glaucoma, elevated intraocular pressure, epiretinal membrane or vitreomacular traction in the study eye that could prevent improvement in visual acuity as well as any intraocular injection, intraocular surgery, or laser treatment in the study eye within the previous 3 months.
INTRAVITREAL IMPLANT FOR MACULAR EDEMA
Table 2. Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
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Baseline Demographics and Clinical Features in the Vitrectomized Group
Sex
Age (years)
BCVA Baseline
BCVA Month 1
BCVA Month 3
BCVA Month 6
Foveal thickness Baseline
Foveal thickness Month 1
Foveal thickness Month 3
Foveal thickness Month 6
M F M M M M M M M M M F F M M M F F M F M F M M
60 66 59 68 64 40 64 57 46 62 64 65 65 72 72 66 62 65 65 65 58 61 70 62
0.70 0.70 0.40 0.30 0.20 1.00 0.40 0.18 0.70 0.50 1.00 1.10 1.30 0.50 0.40 0.50 0.70 1.00 0.70 1.00 0.50 1.30 0.70 0.70
0.50 0.70 0.40 0.30 0.20 0.80 0.20 0.10 0.70 0.40 1.00 1.00 1.30 0.18 0.20 0.30 0.50 0.50 0.40 1.00 0.30 1.00 0.70 0.80
0.40 0.50 0.40 0.20 0.20 0.70 0.20 0.10 0.70 0.40 0.50 0.40 1.30 0.20 0.20 0.20 0.30 0.50 0.20 0.40 0.20 1.00 0.70 0.70
0.20 0.50 0.40 0.18 0.20 0.70 0.50 0.10 1.00 0.50 0.40 0.40 1.30 0.20 0.18 0.18 0.30 0.50 0.20 1.00 0.40 0.80 0.80 0.70
512.00 686.00 283.00 422.00 501.00 638.00 643.00 334.00 567.00 581.00 276.00 658.00 764.00 560.00 607.00 826.00 507.00 437.00 597.00 552.00 543.00 835.00 264.00 419.00
332.00 218.00 273.00 337.00 419.00 367.00 265.00 268.00 292.00 338.00 231.00 336.00 219.00 264.00 443.00 314.00 233.00 347.00 323.00 315.00 387.00 672.00 234.00 344.00
261.00 459.00 273.00 276.00 272.00 173.00 634.00 206.00 173.00 316.00 288.00 402.00 207.00 254.00 245.00 306.00 211.00 320.00 322.00 307.00 334.00 602.00 234.00 311.00
303.00 450.00 287.00 274.00 354.00 456.00 756.00 249.00 229.00 428.00 311.00 477.00 301.00 309.00 336.00 325.00 239.00 372.00 344.00 387.00 585.00 698.00 256.00 356.00
Informed consent was obtained from all patients in agreement with the Declaration of Helsinki for research involving human subjects.
Examination At baseline, all patients underwent a complete ophthalmic evaluation, including best corrected visual acuity (BCVA) using standardized ETDRS charts, tonometry, fluorescein angiography and SD-OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dublin, CA) with FT measurement.
Intravitreal sustained-release dexamethasone device A dexamethasone intravitreal implant (DEX implant, 0.7 mg) consists of a biodegradable copolymer of polylacticco-glycolic acid containing micronized DEX, which is slowly released. DEX implant resulted in sustained levels of DEX and biological activity for 6 months, with peak levels of drug over the first 2 months.23–25 Compared with the published data describing other routes of administration of DEX analogues, several results demonstrate a few advantages of this implant.20–29
up. Patients were seen at outcome assessment study visits at 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 outcome measure was the change from baseline in BVCA and in FT from baseline to month 6, in both groups.
Statistical analysis Statistical calculations were performed using the Statistical Package for Social Sciences (version 19.0; SPSS, Inc., Chicago, IL). Patients’ ETDRS BCVA were transferred from their records and converted to a logarithm of the minimal angle of resolution (logMAR) scale for analysis. Mean changes from baseline FT and BCVA were analyzed using paired t-tests, in both groups. Additionally, functional and anatomic final differences between nonvitrectomized and
Treatment Patients received a DEX implant in the study eye at the baseline visit (Day 1). A single-use applicator with a 22gauge needle was used to place a DEX 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-
FIG. 1. Mean changes from baseline best-corrected visual acuity (BCVA) in both groups.
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Table 3. History of Posterior Segment Procedures in the Study Eye, in the Nonvitrectomized Group Posterior segment procedure PPV Focal laser Panretinal photocoagulation IV anti-VEGF IV triamcinolone
Number of patients (n = 34) 100% Any previous treatment for DME n (%) None 31 (91.2%) 26 (76.5%) 25 (73.5%) 24 (70.6%)
PPV, pars plana vitrectomy; IV, intravitreal; DME, diabetic macular edema; Anti-VEGF, anti-vascular endothelial growth factor.
vitrectomized eyes were determined using the independent samples Student’s t-test. A 2-tailed test with an alpha level of 0.05 was used for all comparisons.
injection (Fig. 2). These significant changes continued throughout the 6-month follow-up, but the 3- and 6-month follow-ups did not differ statistically from the 1-month followup in either group. Baseline mean FT was 544.00 – 157.09 mm (nonvitrectomized group) and 542.16 – 159.07 mm (ppv group). In the nonvitrectomized group, mean (SD) values of FT did decrease to 363.08 – 139.05 mm (P = 0.0001) at month 1 and to 364.67 – 135.06 mm (P = 0.0001) at month 3. Data on the 6-month follow-up showed a mild increase to 449.61 – 157.31 mm (P = 0.0001). In the vitrectomized group the mean FT decreased to 323.79 – 96.22 mm (P = 0.0001) at 1 month, 307.75 – 116.17 mm ( p = 0.0001) at 3 months and increased to 378.42 – 136.98 mm (P = 0.0001) at 6 months. All of the FT reduction outcomes were statistically significant, with respect to baseline data. No statistically significant differences in FT were found between the 2 dose groups (Table 5). No serious ocular and systemic adverse events were observed.
Results During the inclusion period of the study, refractory DME that had undergone DEX implant was identified in 67 patients. Of these patients, 58 patients were enrolled in the study. Figure 1 depicts the mean logMAR BCVA for both groups at 4 different time points: baseline, 1, 3, and 6 months. Statistically significant improvements in the mean logMAR BCVA were seen in both groups within 30 days after the intravitreal DEX injection. These significant changes continued throughout the 6-month follow-up, regarding to baseline. In the non-operated group (n = 34), the mean baseline logMAR BCVA was 0.65 – 0.38 logMAR. The mean BCVA improved to 0.48 – 0.31 logMAR (P = 0.0001), 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 0.52 – 0.31 logMAR (P = 0.004). In the vitrectomized group (n = 24), the mean baseline logMAR BCVA of 0.69 – 0.32 improved to 0.56 – 0.33 at 1 month (P = 0.0001), 0.44 – 0.29 at 3 months (P = 0.0001), and 0.48 – 0.32 at 6 months (P = 0.001). In both groups, there was further significant improvement in the mean logMAR BCVA between the 1- and 3-month follow-ups that was sustained up to 6 months (P = 0.0001). However, the 3- and 6-month follow-ups did not differ statistically from the 1-month follow-up, in either group. No statistically significant differences in logMAR BCVA were found between the 2 dose groups (Table 3). Statistically significant improvements in mean FT were seen in both groups within 1 month after the initial DEX implant
Discussion In this study, we have reported similar vitreoretinal DEX effectiveness after administration of the 0.7-mg DEX implant in nonvitrectomized and vitrectomized eyes. Both mean FT and mean BCVA had improved from baseline by 1 month after treatment with a DEX implant, and the improvement remained statistically significant throughout the 6-month study, in both groups. The functional peak effectiveness of DEX implants was seen at 3 months after injection in either group, when mean FT improved to 307.75 – 116.17 mm from baseline in the vitrectomized group and to 364.67 – 135.06 (m in the nonoperated on group. There were no statistically significant differences in BCVA and FT between nonvitrectomized and vitrectomized eyes at any time point (P < 0.05). The improvement in FT seen in the operated eyes was more pronounced in relation to the improvement seen in the remaining nonvitrectomized patients with persistent macular edema, albeit not statistically significant. Over the past 3 decades, we have addressed the DME issue by using focal and grid pattern laser photocoagulation as
Table 4. History of Posterior Segment Procedures in the Study Eye, in the Vitrectomized Group Posterior segment procedure PPV Focal laser Panretinal photocoagulation IV anti-VEGF IV triamcinolone
Number of patients (n = 24) 100% Any previous treatment for DME n (%) 24 (100%) 20 (83.3%) 17 (70.8%) 19 (79.2%) 15 (62.5%)
FIG. 2. Mean changes from baseline foveal thickness in both groups.
INTRAVITREAL IMPLANT FOR MACULAR EDEMA
Table 5.
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Dexamethasone Intravitreal Implant in Vitrectomized Versus Nonvitrectomized Eyes for Treatment of Patients with Persistent Diabetic Macular Edema BCVA mean
Baseline 1 month 3 months 6 months
FT mean
NON VIT
VIT
P-value
NON VIT
VIT
P-value
0.65 – 0.38 0.48 – 0.31 0.44 – 0.27 0.52 – 0.31
0.69 – 0.32 0.56 – 0.33 0.44 – 0.29 0.48 – 0.32
0.681 0.367 0.863 0.637
544.00 – 157.09 mm 363.08 – 139.05 mm 364.67 – 135.06 mm 449.61 – 157.31 mm
542.16 – 159.07 mm 323.79 – 96.22 mm 307.75 – 116.17 mm 378.42 – 136.98 mm
0.965 0.237 0.100 0.079
NON VIT, nonvitrectomized group; VIT, vitrectomized group; FT, foveal thickness.
well as intravitreal injections of corticosteroids and most recently, intravitreal injections of anti-VEGF drugs. PPV has been shown to be useful in the treatment of DME in some patients.2–6,30–34 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.1,31–33 These findings suggest that sustained drug delivery with an implant could be particularly useful in vitrectomized eyes, thus enhancing and boosting the primary effect of vitrectomy. The DRCR.net trial prospectively enrolled 241 eyes with treatment-resistant DME.35 At 6 months after vitrectomy, the mean FT decreased from 412 to 278 mm. Eyes with greater preoperative thickness, an epiretinal membrane, and vitreomacular traction achieved greater thinning. Although the average VA (20/80) of the entire cohort did not change, BCVA improvement was seen in eyes with worse baseline vision (P < 0.001) and in those requiring the removal of ERMs (P = 0.006). These authors concluded that vitrectomy may have a role in eyes with vitreomacular abnormalities, but they could not recommend vitrectomy for eyes without traction. This study reported valuable information but, unfortunately, no information regarding the utility of early, primary vitrectomy for DME. In accordance, a systematic review and meta-analysis of published, randomized, controlled trial data was conducted by Simunovic et al. to systematically review and evaluate the available data regarding the efficacy of vitrectomy for DME.36 Seven studies compared vitrectomy with the natural history of diabetic maculopathy, with laser, or with intravitreal corticosteroid injection. Four studies compared vitrectomy with internal limiting membrane peeling to vitrectomy alone. One of the latter 4 studies was the only to investigate vitrectomy in patients with vitreomacular traction. Meta-analysis suggests a structural and possibly functional superiority of vitrectomy over observation at 6 months. Vitrectomy also appears superior to laser in terms of structural, but not functional, outcomes at 6 months. At 12 months, vitrectomy offers no structural benefit and a trend toward inferior functional outcomes when compared with laser. Actually, there is little clinical evidence to support vitrectomy as an intervention for DME in the absence of epiretinal membrane or vitreomacular traction. Intravitreal delivery of corticosteroids27,37–43 and antiVEGF antibodies44–48 are addressing many of the problems associated with conventional therapies for the treatment of retinal diseases. Studies in rabbits have shown that the vit-
reous half-life of triamcinolone acetonide (TA) after intravitreal injection is reduced in eyes after PPV compared with nonvitrectomized eyes.11,12 Vitrectomy has also been shown to affect the intraocular concentration of TA after intravitreal injection in human eyes.49,50 In a vitrectomized eye, the vitreous would be removed, and less-viscous liquid would fill the space, increasing intravitreal circulation. This pathophysiological process leads to a much faster corticosteroid absorption in the vitrectomized eye than in the normal eye. An implant that provides sustained drug release and is both safe and effective may be the best option for therapy. Moreover, an earlier study40 examining the in vivo release of DEX sodium m-sulfobenzoate from a biodegradable poly (lactic acid) (PLA) implant suggests that the pharmacokinetics of DEX may be different in nonvitrectomized and vitrectomized eyes. In this earlier study conducted in rabbit eyes, the release of DEX from the PLA implant (which has chemical similarities with the DEX implant) was 2.5 times more rapid in vitrectomized eyes than in nonvitrectomized eyes. In contrast, the release of DEX from the DEX implant in a more recent study was similar between nonvitrectomized and vitrectomized eyes in rabbit eyes.25 These results suggest that DEX implants may be particularly useful in the treatment of inflammation and macular edema in vitrectomized eyes. Our data are consistent with those obtained from this later experimental study carried out by Chang-Lin et al. In our study, a near complete subtotal vitrectomy was performed in all patients. Given that the completeness of vitrectomy may influence the rate of clearance of many drugs,10–12 the extent of vitrectomy should be considered when comparing findings between nonvitrectomized and vitrectomized eyes. Regarding the efficacy of a DEX intravitreal drug-delivery system in persistent ME secondary to diabetes, Haller et al.21 demonstrated that, in eyes with DME treated with DEX implant, BCVA and FT significantly improved at 3 months when compared with the observation group. Interestingly, they found that 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. Most recently, 4 interventional case series studies addressed this issue. In the first study, Zucchiatti et al.29 showed that a single intravitreal injection of Ozurdex produced improvement in BCVA and FT in eyes with persistent DME. Such improvement was evident from the third day to the first month after injection, peaked at the third month and was no more significant at 6 months. Analogously, Rishi
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et al.51 undertook another retrospective study, enrolling 18 patients with refractory DME. All patients experienced a significant reduction in FT compared with baseline levels at month 1. The maximum reduction in FT was seen at month 1, followed by reappearance of clinically significant ME at month 4. In 2013, Pacella et al. performed a prospective interventional case series to assess the efficacy of DEX implant, over a 6-month follow-up period.52 Ozurdex produced substantial improvement in BCVA and significant reduction of FT from day 3. The peak efficacy of the implant appears to be reached at month 1 through to month 3, then slowly decreases from month 4 to 6. Similarly, we performed a retrospective interventional case series study to evaluate the effectiveness of a single intravitreal injection of Ozurdex, over 6 months in patients with persistent DME.53 Both mean FT and mean BCVA improved from baseline by 1 month after treatment and remained statistically significant throughout the 6-month study. The peak effectiveness of DEX implants was seen at 3 months after injection when mean FT had decreased by 37%. 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, this clinical application has been mitigated and the use of corticosteroids has been drastically reduced in most developed countries, in the last few years, due to safety concerns.54 Recently, the safety profile of Ozurdex, which is currently an approved treatment for retinal vein occlusion, has been reported in the GENEVA study.20 DEX intravitreal implants have demonstrated an acceptable safety profile in several studies.20,55 The implant does not need to be removed because the copolymer slowly biodegrades into carbon dioxide and water and is absorbed over time. To our knowledge, there have been no differences on the relative effectiveness of DEX implants in pseudophakic versus phakic eyes. Further studies will be needed to ascertain whether the effects of DEX implants are affected by lens status. Our study has several limitations–in that it is short-term, open-label, 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 study population was not recorded. So far, no study, comparing the difference in BCVA and FT (qualitative and quantitative measures, respectively), between vitrectomized and nonvitrectomized eyes has been reported targeting the DME issue. This study has demonstrated similar effectiveness of DEX in nonvitrectomized and vitrectomized eyes after the administration of a 0.7-mg DEX implant. According to our results, the recent DEX 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, even in the operated on patients.
Author Disclosure Statement All the listed authors agree with the submission of this article and none of them have any conflicting financial interests related to it, current and over the past 5 years.
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References 1. Stefa´nsson, E. Physiology of vitreous surgery. Graefes Arch. Clin. Exp. Ophthalmol. 247:147–163, 2009. 2. Doi, N., Sakamoto, T., Sonoda, Y., et al. Comparative study of vitrectomy versus intravitreous triamcinolone for diabetic macular edema on randomized paired eyes. Graefes Arch. Clin. Exp. Ophthalmol. 250:71–78, 2012. 3. Kumagai, K., Furukawa, M., Ogino, N., Larson, E., Iwaki, M., and Tachi, N. Long-term follow-up of vitrectomy for diffuse nontractional diabetic macular edema. Retina. 29:464–472, 2009. 4. Hoerauf, H., Bruggemann, A., Muecke, M., et al. Pars plana vitrectomy for diabetic macular edema. Internal limiting membrane delamination vs posterior hyaloid removal. A prospective randomized trial. Graefes Arch. Clin. Exp. Ophthalmol. 249:997–1008, 2011. 5. Hartley, K.L., Smiddy, W.E., Flynn, H.W., Jr., and Murray, T.G. Pars plana vitrectomy with internal limiting membrane peeling for diabetic macular edema. Retina. 28:410– 419, 2008. 6. Yanyali, A., Bozkurt, K.T., Macin, A., Horozoglu, F., and Nohutcu, A.F. Quantitative assessment of photoreceptor layer in eyes with resolved edema after pars plana vitrectomy with internal limiting membrane removal for diabetic macular edema. Ophthalmologica. 226:57–63, 2011. 7. Laidlaw, D.A. Vitrectomy for diabetic macular oedema. Eye. 22:1337–1341, 2008. 8. Androudi, S., Ahmed, M., Fiore, T., Brazitikos, P., and Foster, C.S. Combined pars plana vitrectomy and phacoemulsification to restore visual acuity in patients with chronic uveitis. J. Cataract. Refract. Surg. 31:472–478, 2005. 9. Arrigg, P.G., and Cavallerano, J. The role of vitrectomy for diabetic retinopathy. J. Am. Optom. Assoc. 69:733–740, 1998. 10. Lee, S.S., Ghosn, C., Yu, Z., et al. Vitreous VEGF clearance is increased after vitrectomy. Invest. Ophthalmol. Vis. Sci. 51:2135–2138, 2010. 11. Chin, H.S., Park, T.S., Moon, Y.S., and Oh, J.H. Difference in clearance of intravitreal triamcinolone acetonide between vitrectomized and nonvitrectomized eyes. Retina. 25:556–560, 2005. 12. Schindler, R.H., Chandler, D., Thresher, R., and Machemer, R. The clearance of intravitreal triamcinolone acetonide. Am. J. Ophthalmol. 93:415–417, 1982. 13. Doft, B.H., Weiskopf, J., Nilsson-Ehle, I., and Wingard, L.B., Jr. Amphotericin clearance in vitrectomized versus nonvitrectomized eyes. Ophthalmology. 92:1601–1605, 1985. 14. Jarus, G., Blumenkranz, M., Hernandez, E., and Sossi, N. Clearance of intravitreal fluorouracil: normal and aphakic vitrectomized eyes. Ophthalmology. 92:91–96, 1985. 15. Abraham, S.M., Lawrence, T., Kleiman, A., et al. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J. Exp. Med. 203:1883–1889, 2006. 16. Barnes, P.J. Corticosteroid effects on cell signalling. Eur. Respir. J. 27:413–426, 2006. 17. Saklatvala, J. Glucocorticoids: do we know how they work? Arthritis Res. 4:146–150, 2002. 18. Walker, B.R. Glucocorticoids and cardiovascular disease. Eur. J. Endocrinol. 157:545–559, 2007. 19. Nauck, M., Karakiulakis, G., Perruchoud, A.P., Papakonstantinou, E., and Roth, M. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur. J. Pharmacol. 341:309–315, 1998.
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20. Haller, J.A., Bandello, F., Belfort, R., Jr., Blumenkranz, M.S., Gillies, M., Heier, J., Loewenstein, A., Yoon, Y.H., Jacques, M.L., Jiao, J., Li, X.Y., Whitcup, S.M.; Ozurdex GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 117:1134–1146, 2010. 21. Haller, J.A., Kuppermann, B.D., Blumenkranz, M.S., Williams, G.A., Weinberg, D.V., Chou, C., Whitcup, S.M.; Dexamethasone DDS Phase II Study Group. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch. Ophthalmol. 128:289–296, 2010. 22. Boyer, D.S., Faber, D., Gupta, S., Patel, S.S., Tabandeh, H., Li, X.Y., Liu, C.C., Lou, J., Whitcup, S.M.; Ozurdex Champlain study group. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina. 31:915–923, 2011. 23. Chang-Lin, J.E., Attar, M., Acheampong, A.A., Robinson, M.R., Whitcup, S.M., Kuppermann, B.D., and Welty, D. Pharmacokinetics and pharmacodynamics of a sustainedrelease dexamethasone intravitreal implant. Invest. Ophthalmol. Vis. Sci. 52:80–86, 2011. 24. Saraiya, N.V., and Goldstein, D.A. Dexamethasone for ocular inflammation. Expert. Opin. Pharmacother. 12:1127– 1131, 2011. 25. Chang-Lin, J.E., Burke, J.A., Peng, Q., Lin, T., Orilla, W.C., Ghosn, C.R., Zhang, K.M., Kuppermann, B.D., Robinson, M.R., Whitcup, S.M., and Welty, D.F. Pharmacokinetics of a sustained-release dexamethasone intravitreal implant in vitrectomized and nonvitrectomized eyes. Invest. Ophthalmol. Vis. Sci. 52:4605–4609, 2011. 26. Lowder, C., Belfort, R., Jr., Lightman, S., Foster, C.S., Robinson, M.R., Schiffman, R.M., Li, X.Y., Cui, H., Whitcup, S.M.; Ozurdex HURON Study Group. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch. Ophthalmol. 129:545–553, 2011. 27. Kuppermann, B.D., Blumenkranz, M.S., Haller, J.A., Williams, G.A., Weinberg, D.V., Chou, C., Whitcup, S.M.; Dexamethasone DDS Phase II Study Group. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch. Ophthalmol. 125:309–317, 2007. 28. Kodama, M., Numaga, J., Yoshida, A., et al. Effects of a new dexamethasone-delivery system (Surodex) on experimental intraocular inflammation models. Graefes Arch. Clin. Exp. Ophthalmol. 241:927–933, 2003. 29. Zucchiatti, I., Lattanzio, R., Querques, G., Querques, L., Del Turco, C., Cascavilla, M.L., and Bandello, F. Intravitreal dexamethasone implant in patients with persistent diabetic macular edema. Ophthalmologica. 228:117–122, 2012. 30. Gandorfer, A., Messmer, E.M., Ulbig, M.W., and Kampik, A. Resolution of diabetic macular edema after surgical removal of the posterior hyaloid and the inner limiting membrane. Retina. 20:126–133, 2000. 31. Patel, J.I., Hykin, P.G., Schadt, M., et al. Pars plana vitrectomy for diabetic macular oedema: OCT and functional correlations. Eye (Lond). 20:674–680, 2006. 32. Yanyali, A., Horozoglu, F., Celik, E., and Nohutcu, A.F. Long-term outcomes of pars plana vitrectomy with internal limiting membrane removal in diabetic macular edema. Retina. 27:557–566, 2007. 33. Diabetic Retinopathy Clinical Research Network Writing Committee. Vitrectomy outcomes in eyes with diabetic
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macular edema and vitreomacular traction. Ophthalmology. 117:1087–1093, 2010. Bhagat, N., Grigorian, R.A., Tutela, A., and Zarbin, M.A. Diabetic macular edema: pathogenesis and treatment. Surv. Ophthalmol. 54:1–32, 2009. Diabetes Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 118:609–614, 2011. Simunovic, M.P., Hunyor, A.P., and Ho, I.V. Vitrectomy for diabetic macular edema: a systematic review and metaanalysis. Can. J. Ophthalmol. 49:188–195, 2014. Callanan, D.G., Jaffe, G.J., Martin, D.F., Pearson, P.A., and Comstock, T.L. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch. Ophthalmol. 126:1191–1201, 2008. Enyedi, L.B., Pearson, P.A., Ashton, P., and Jaffe, G.J. An intravitreal device providing sustained release of cyclosporine and dexamethasone. Curr. Eye Res. 15:549–557, 1996. Jaffe, G.J., Martin, D., Callanan, D., Pearson, P.A., Levy, B., and Comstock, T. Fluocinolone acetonide implant (Retisert) for noninfectious poste- rior uveitis: thirty-fourweek results of a multicenter randomized clinical study. Ophthalmology. 113:1020–1027, 2006. Morita, Y., Ohtori, A., Kimura, M., and Tojo, K. Intravitreous delivery of dexamethasone sodium m-sulfobenzoate from poly(DL-lactic acid) implants. Biol. Pharm. Bull. 21: 188–190, 1998. Silva-Cunha, A., Fialho, S.L., Naud, M.C., and Behar-Cohen, F. Poly-epsilon-caprolactone intravitreous devices: an in vivo study. Invest. Ophthalmol. Vis. Sci. 50:2312–2318, 2009. Xu, J., Wang, Y., Li, Y., et al. Inhibitory efficacy of intravitreal dexamethasone acetate-loaded PLGA nanoparticles on choroidal neovascularization in a laser-induced rat model. J. Ocul. Pharmacol. Ther. 23:527–540, 2007. Zhang, L., Li, Y., Zhang, C., Wang, Y., and Song, C. Pharmacokinetics and tolerance study of intravitreal injection of dexamethasone-loaded nanoparticles in rabbits. Int. J. Nanomed. 4:175–183, 2009. Antoszyk, A.N., Tuomi, L., Chung, C.Y., and Singh, A. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age- related macular degeneration (FOCUS): year 2 results. Am. J. Ophthalmol. 145:862–874, 2008. Chakravarthy, U., Adamis, A.P., Cunningham, E.T., Jr., et al. Year 2 efficacy results of 2 randomized controlled clinical trials of pegap- tanib for neovascular age-related macular degeneration. Ophthalmology. 113:1508 e1501– e1525, 2006. Kook, D., Wolf, A., Kreutzer, T., et al. Long-term effect of intravitreal bevacizumab (Avastin) in patients with chronic diffuse diabetic macular edema. Retina. 28:1053–1060, 2008. Singerman, L.J., Masonson, H., Patel, M., et al. Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial. Br. J. Ophthalmol. 92:1606–1611, 2008. Yeh, P.T., Yang, C.M., Lin, Y.C., Chen, M.S., and Yang, C.H. Bevacizumab pretreatment in vitrectomy with silicone oil for severe diabetic retinopathy. Retina. 29:768–774, 2009. Beer, P.M., Bakri, S.J., Singh, R.J., et al. Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology. 110:681–686, 2003. Gisladottir, S., Loftsson, T., and Stefansson, E. Diffusion characteristics of vitreous humour and saline solution fol-
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low the Stokes Einstein equation. Graefes Arch. Clin. Exp. Ophthalmol. 247:1677–1684, 2009. Rishi, P., Rishi, E., Kuniyal, L., and Mathur, G. Short-term results of intravitreal dexamethasone implant (OZURDEX()) in treatment of recalcitrant diabetic macular edema: a case series. Oman. J. Ophthalmol. 5:79–82, 2012. Pacella, E., Vestri, A.R., Muscella, R., et al., Preliminary results of an intravitreal dexamethasone implant (Ozurdex) in patients with persistent diabetic macular edema. Clin. Ophthalmol. 7:1423–1428, 2013. Dutra Medeiros, M., Postorino, M., Navarro, R., et al., Dexamethasone intravitreal implant for treatment of patients with persistent diabetic macular edema. Ophthalmologica. 231:141–146, 2014. Diabetic Retinopathy Clinical Research Net- work (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris, F., Glassman AR, Hartnett, E., Ip MS, Kim JE, Kollman C: Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal tri-
amcinolone for diabetic macular edema. Arch. Ophthalmol. 127:245–251, 2009. 55. Gallego-Pinazo, R., Herna´ndez-Martinez, P., Herva´s-Ontiveros, A., et al., Local safety concerns of repeated dexamethasone intravitreal implant (Ozurdex) for macular diseases. J. Ocul. Dis. Ther. 1:10–14, 2013.
Received: February 16, 2014 Accepted: August 14, 2014 Address correspondence to: Dr. Marco Dutra Medeiros Department of Retina Instituto de Microcirugia Ocular No. 3, Calle Josep Maria Llado´ Barcelona 08035 Spain E-mail: [email protected]
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 30, Number 9, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2014.0010
Dexamethasone Intravitreal Implant in Vitrectomized Versus Nonvitrectomized Eyes for Treatment of Patients with Persistent Diabetic Macular Edema Marco Dutra Medeiros,1,2 Micol Alkabes,1,3 Rafael Navarro,1 Jose´ Garcia-Arumı´,1,4 Carlos Mateo,1 and Borja Corco´stegui1
Abstract
Purpose: To compare the 6-month anatomic and best-corrected visual acuity (BCVA) response after sustainedrelease dexamethasone (DEX) intravitreal implant between nonvitrectomized and vitrectomized eyes with persistent diabetic macular edema (DME). Methods: Retrospective, comparative, and consecutive 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. Then, we divided patients into 2 groups: 24 eyes who had undergone standard pars plana vitrectomy (vitrectomized group), and 34 eyes that were not operated on (nonvitrectomized group). Outcomes measured were BCVA and foveal thickness (FT) at baseline and at months 1, 3, and 6. Results: Twenty-four of 58 eyes had prior vitrectomy (41%). Statistically significant improvement in BCVA also was seen at 1 month after treatment with a DEX implant and at each subsequent follow-up visit, in either groups (P < 0.05). All of the FT reduction outcomes were statistically significant in both groups, with respect to baseline data (P < 0.05). There were no statistically significant differences in BCVA and FT between nonvitrectomized and vitrectomized eyes at any time point (P < 0.05). Conclusion: In this study, the clinical findings were similar between nonvitrectomized and vitrectomized eyes. Intravitreal treatment with a DEX implant safely reduced DME and improved visual acuity in both groups. No statistically significant differences were found between the 2 groups regarding FT and BCVA.
Introduction
P
ars plana vitrectomy (PPV) is beneficial in many conditions, including diabetic retinopathy (DR), diabetic macular edema (DME), retinal detachment, macular holes, macular pucker, and vitreous hemorrhage. In DR, both the delivery of oxygen to the retina and the removal of inflammatory mediators of DME, such as vascular endothelial growth factor (VEGF), from the retina are improved after vitrectomy.1 PPV effectively treats DME associated with vitreomacular traction, but several authors have also documented excellent results following surgery for fovea involving diffuse DME without apparent vitreomacular traction.2–6 However, for many patients, the chronic and recurrent nature of retinal diseases requires continued drug therapy after surgical procedure.7–9 Experience with
VEGF10 and a number of drugs, including triamcinolone acetonide,11,12 amphotericin B,13 and 5-fluorouracil,14 suggests that some drugs are cleared more rapidly in vitrectomized eyes. Indeed, further intravitreal pharmacologic treatment of posterior segment disease may be less effective after removal of the vitreous. Drug clearance from the vitreous cavity is more rapid in vitrectomized eyes, limiting drug exposure to the retina and reducing treatment success and options. Therefore, differences in pharmacokinetics between nonvitrectomized and vitrectomized eyes may influence the clinical effectiveness of drug therapy. Glucocorticoids such as DEX exert their anti-inflammatory effects by influencing multiple signal transduction pathways, including VEGF.15–18 By binding to cytoplasmic glucocorticoid receptors, corticosteroids in high doses increase the activation of anti-inflammatory genes, whereas at
1
Department of Retina, Instituto de Microcirugia Ocular, Barcelona, Spain. Central Lisbon Hospital Center, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal. University Eye Clinic, San Giuseppe Hospital, Universita` di Milano, Milan, Italy. 4 Hospital Universitario Vall d’Hebron, Barcelona, Spain. 2 3
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Table 1. Patient no. 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
Baseline Demographics and Clinical Features in the Nonvitrectomized Group
Sex
Age (years)
BCVA Baseline
BCVA Month 1
BCVA Month 3
BCVA Month 6
Foveal thickness Baseline
Foveal thickness Month 1
Foveal thickness Month 3
Foveal thickness Month 6
M M M M M M F M F F M M F F F F M M M M M M M F M M M M F F F M F M
70 59 66 66 66 66 78 82 59 66 63 56 84 62 77 77 68 81 46 78 78 61 75 62 71 65 68 32 24 60 63 66 36 59
0.50 0.40 0.80 0.80 0.70 0.70 0.40 1.30 0.30 0.70 1.00 0.70 0.70 0.10 2.00 1.00 0.70 0.50 1.00 0.40 0.80 0.20 0.50 0.20 0.70 0.20 1.30 0.50 0.20 0.50 0.80 0.20 0.70 0.50
0.50 0.40 0.30 0.40 0.40 0.40 0.30 1.00 0.20 0.70 0.80 0.50 0.50 0.10 1.60 1.00 0.70 0.30 0.70 0.30 0.80 0.40 0.20 0.18 0.70 0.20 0.50 0.40 0.10 0.40 0.70 0.18 0.20 0.40
0.70 0.40 0.40 0.40 0.50 0.30 0.20 0.70 0.18 0.50 0.80 0.40 0.50 0.10 1.30 0.80 0.50 0.30 0.70 0.30 0.80 0.40 0.20 0.18 0.70 0.18 0.70 0.30 0.10 0.30 0.50 0.18 0.18 0.20
0.50 0.40 0.40 0.70 0.50 0.50 0.40 1.00 0.30 1.00 1.00 0.40 0.40 0.18 1.30 0.80 0.50 0.40 0.70 0.30 1.30 0.50 0.20 0.18 0.70 0.20 0.70 0.30 0.10 0.40 0.70 0.18 0.50 0.20
695.00 523.00 762.00 696.00 688.00 616.00 746.00 525.00 273.00 535.00 889.00 480.00 333.00 462.00 925.00 523.00 346.00 625.00 510.00 541.00 603.00 526.00 599.00 354.00 692.00 497.00 416.00 411.00 369.00 524.00 460.00 438.00 611.00 303.00
545.00 444.00 181.00 193.00 457.00 407.00 432.00 536.00 267.00 387.00 654.00 329.00 238.00 411.00 778.00 367.00 166.00 248.00 184.00 258.00 451.00 351.00 403.00 306.00 478.00 321.00 460.00 221.00 257.00 397.00 332.00 426.00 236.00 224.00
419.00 434.00 233.00 243.00 677.00 587.00 457.00 211.00 267.00 328.00 566.00 279.00 232.00 323.00 643.00 322.00 156.00 242.00 259.00 312.00 430.00 317.00 496.00 273.00 397.00 322.00 514.00 237.00 306.00 370.00 290.00 431.00 588.00 238.00
476.00 507.00 321.00 352.00 643.00 612.00 717.00 411.00 222.00 361.00 866.00 299.00 283.00 352.00 699.00 411.00 178.00 502.00 567.00 536.00 631.00 318.00 529.00 401.00 481.00 402.00 529.00 310.00 317.00 411.00 321.00 496.00 596.00 230.00
BCVA, best-corrected visual acuity; F, female; M, male.
low concentrations they have a role in the suppression of activated inflammatory genes.16,19 The DEX implant (Ozurdex; Allergan, Inc., Irvine, CA) is a novel approach approved by the United States Food and Drug Administration (FDA) and by European Union (EU) 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.20 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.15–22 The objective of this study was to compare the ocular effectiveness profile of a single intravitreal injection of Ozurdex in nonvitrectomized and vitrectomized eyes of diabetic patients with DME. The patient population included severe cases that had not responded to multiple previous therapies.
Methods Enrollment of study subjects We retrospectively reviewed the medical records of 67 consecutive 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. Then, we divided patients into 2 groups: 24 eyes who had undergone standard PPV (vitrectomized group), and 34 eyes that were not operated on (nonvitrectomized group). Baseline characteristics of patients and study eyes, in either group, are listed in Tables 1 and 2. All patients had been previously exposed to a variety of treatments for DR and DME. Key inclusion criteria included previous treatment with anti-VEGF agents, other intraocular steroids or laser photocoagulation with only a partial response to the previous treatments (Tables 3 and 4). Refractory DME was defined as persistent ME with foveal thickness (FT) 250 mm by spectral domain optical coherence tomography (SDOCT), lasting for at least 90 days after laser or intravitreal anti-VEGF/steroid treatment. Exclusion criteria were diagnosis of uncontrolled systemic disease, glaucoma, elevated intraocular pressure, epiretinal membrane or vitreomacular traction in the study eye that could prevent improvement in visual acuity as well as any intraocular injection, intraocular surgery, or laser treatment in the study eye within the previous 3 months.
INTRAVITREAL IMPLANT FOR MACULAR EDEMA
Table 2. Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
711
Baseline Demographics and Clinical Features in the Vitrectomized Group
Sex
Age (years)
BCVA Baseline
BCVA Month 1
BCVA Month 3
BCVA Month 6
Foveal thickness Baseline
Foveal thickness Month 1
Foveal thickness Month 3
Foveal thickness Month 6
M F M M M M M M M M M F F M M M F F M F M F M M
60 66 59 68 64 40 64 57 46 62 64 65 65 72 72 66 62 65 65 65 58 61 70 62
0.70 0.70 0.40 0.30 0.20 1.00 0.40 0.18 0.70 0.50 1.00 1.10 1.30 0.50 0.40 0.50 0.70 1.00 0.70 1.00 0.50 1.30 0.70 0.70
0.50 0.70 0.40 0.30 0.20 0.80 0.20 0.10 0.70 0.40 1.00 1.00 1.30 0.18 0.20 0.30 0.50 0.50 0.40 1.00 0.30 1.00 0.70 0.80
0.40 0.50 0.40 0.20 0.20 0.70 0.20 0.10 0.70 0.40 0.50 0.40 1.30 0.20 0.20 0.20 0.30 0.50 0.20 0.40 0.20 1.00 0.70 0.70
0.20 0.50 0.40 0.18 0.20 0.70 0.50 0.10 1.00 0.50 0.40 0.40 1.30 0.20 0.18 0.18 0.30 0.50 0.20 1.00 0.40 0.80 0.80 0.70
512.00 686.00 283.00 422.00 501.00 638.00 643.00 334.00 567.00 581.00 276.00 658.00 764.00 560.00 607.00 826.00 507.00 437.00 597.00 552.00 543.00 835.00 264.00 419.00
332.00 218.00 273.00 337.00 419.00 367.00 265.00 268.00 292.00 338.00 231.00 336.00 219.00 264.00 443.00 314.00 233.00 347.00 323.00 315.00 387.00 672.00 234.00 344.00
261.00 459.00 273.00 276.00 272.00 173.00 634.00 206.00 173.00 316.00 288.00 402.00 207.00 254.00 245.00 306.00 211.00 320.00 322.00 307.00 334.00 602.00 234.00 311.00
303.00 450.00 287.00 274.00 354.00 456.00 756.00 249.00 229.00 428.00 311.00 477.00 301.00 309.00 336.00 325.00 239.00 372.00 344.00 387.00 585.00 698.00 256.00 356.00
Informed consent was obtained from all patients in agreement with the Declaration of Helsinki for research involving human subjects.
Examination At baseline, all patients underwent a complete ophthalmic evaluation, including best corrected visual acuity (BCVA) using standardized ETDRS charts, tonometry, fluorescein angiography and SD-OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dublin, CA) with FT measurement.
Intravitreal sustained-release dexamethasone device A dexamethasone intravitreal implant (DEX implant, 0.7 mg) consists of a biodegradable copolymer of polylacticco-glycolic acid containing micronized DEX, which is slowly released. DEX implant resulted in sustained levels of DEX and biological activity for 6 months, with peak levels of drug over the first 2 months.23–25 Compared with the published data describing other routes of administration of DEX analogues, several results demonstrate a few advantages of this implant.20–29
up. Patients were seen at outcome assessment study visits at 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 outcome measure was the change from baseline in BVCA and in FT from baseline to month 6, in both groups.
Statistical analysis Statistical calculations were performed using the Statistical Package for Social Sciences (version 19.0; SPSS, Inc., Chicago, IL). Patients’ ETDRS BCVA were transferred from their records and converted to a logarithm of the minimal angle of resolution (logMAR) scale for analysis. Mean changes from baseline FT and BCVA were analyzed using paired t-tests, in both groups. Additionally, functional and anatomic final differences between nonvitrectomized and
Treatment Patients received a DEX implant in the study eye at the baseline visit (Day 1). A single-use applicator with a 22gauge needle was used to place a DEX 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-
FIG. 1. Mean changes from baseline best-corrected visual acuity (BCVA) in both groups.
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Table 3. History of Posterior Segment Procedures in the Study Eye, in the Nonvitrectomized Group Posterior segment procedure PPV Focal laser Panretinal photocoagulation IV anti-VEGF IV triamcinolone
Number of patients (n = 34) 100% Any previous treatment for DME n (%) None 31 (91.2%) 26 (76.5%) 25 (73.5%) 24 (70.6%)
PPV, pars plana vitrectomy; IV, intravitreal; DME, diabetic macular edema; Anti-VEGF, anti-vascular endothelial growth factor.
vitrectomized eyes were determined using the independent samples Student’s t-test. A 2-tailed test with an alpha level of 0.05 was used for all comparisons.
injection (Fig. 2). These significant changes continued throughout the 6-month follow-up, but the 3- and 6-month follow-ups did not differ statistically from the 1-month followup in either group. Baseline mean FT was 544.00 – 157.09 mm (nonvitrectomized group) and 542.16 – 159.07 mm (ppv group). In the nonvitrectomized group, mean (SD) values of FT did decrease to 363.08 – 139.05 mm (P = 0.0001) at month 1 and to 364.67 – 135.06 mm (P = 0.0001) at month 3. Data on the 6-month follow-up showed a mild increase to 449.61 – 157.31 mm (P = 0.0001). In the vitrectomized group the mean FT decreased to 323.79 – 96.22 mm (P = 0.0001) at 1 month, 307.75 – 116.17 mm ( p = 0.0001) at 3 months and increased to 378.42 – 136.98 mm (P = 0.0001) at 6 months. All of the FT reduction outcomes were statistically significant, with respect to baseline data. No statistically significant differences in FT were found between the 2 dose groups (Table 5). No serious ocular and systemic adverse events were observed.
Results During the inclusion period of the study, refractory DME that had undergone DEX implant was identified in 67 patients. Of these patients, 58 patients were enrolled in the study. Figure 1 depicts the mean logMAR BCVA for both groups at 4 different time points: baseline, 1, 3, and 6 months. Statistically significant improvements in the mean logMAR BCVA were seen in both groups within 30 days after the intravitreal DEX injection. These significant changes continued throughout the 6-month follow-up, regarding to baseline. In the non-operated group (n = 34), the mean baseline logMAR BCVA was 0.65 – 0.38 logMAR. The mean BCVA improved to 0.48 – 0.31 logMAR (P = 0.0001), 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 0.52 – 0.31 logMAR (P = 0.004). In the vitrectomized group (n = 24), the mean baseline logMAR BCVA of 0.69 – 0.32 improved to 0.56 – 0.33 at 1 month (P = 0.0001), 0.44 – 0.29 at 3 months (P = 0.0001), and 0.48 – 0.32 at 6 months (P = 0.001). In both groups, there was further significant improvement in the mean logMAR BCVA between the 1- and 3-month follow-ups that was sustained up to 6 months (P = 0.0001). However, the 3- and 6-month follow-ups did not differ statistically from the 1-month follow-up, in either group. No statistically significant differences in logMAR BCVA were found between the 2 dose groups (Table 3). Statistically significant improvements in mean FT were seen in both groups within 1 month after the initial DEX implant
Discussion In this study, we have reported similar vitreoretinal DEX effectiveness after administration of the 0.7-mg DEX implant in nonvitrectomized and vitrectomized eyes. Both mean FT and mean BCVA had improved from baseline by 1 month after treatment with a DEX implant, and the improvement remained statistically significant throughout the 6-month study, in both groups. The functional peak effectiveness of DEX implants was seen at 3 months after injection in either group, when mean FT improved to 307.75 – 116.17 mm from baseline in the vitrectomized group and to 364.67 – 135.06 (m in the nonoperated on group. There were no statistically significant differences in BCVA and FT between nonvitrectomized and vitrectomized eyes at any time point (P < 0.05). The improvement in FT seen in the operated eyes was more pronounced in relation to the improvement seen in the remaining nonvitrectomized patients with persistent macular edema, albeit not statistically significant. Over the past 3 decades, we have addressed the DME issue by using focal and grid pattern laser photocoagulation as
Table 4. History of Posterior Segment Procedures in the Study Eye, in the Vitrectomized Group Posterior segment procedure PPV Focal laser Panretinal photocoagulation IV anti-VEGF IV triamcinolone
Number of patients (n = 24) 100% Any previous treatment for DME n (%) 24 (100%) 20 (83.3%) 17 (70.8%) 19 (79.2%) 15 (62.5%)
FIG. 2. Mean changes from baseline foveal thickness in both groups.
INTRAVITREAL IMPLANT FOR MACULAR EDEMA
Table 5.
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Dexamethasone Intravitreal Implant in Vitrectomized Versus Nonvitrectomized Eyes for Treatment of Patients with Persistent Diabetic Macular Edema BCVA mean
Baseline 1 month 3 months 6 months
FT mean
NON VIT
VIT
P-value
NON VIT
VIT
P-value
0.65 – 0.38 0.48 – 0.31 0.44 – 0.27 0.52 – 0.31
0.69 – 0.32 0.56 – 0.33 0.44 – 0.29 0.48 – 0.32
0.681 0.367 0.863 0.637
544.00 – 157.09 mm 363.08 – 139.05 mm 364.67 – 135.06 mm 449.61 – 157.31 mm
542.16 – 159.07 mm 323.79 – 96.22 mm 307.75 – 116.17 mm 378.42 – 136.98 mm
0.965 0.237 0.100 0.079
NON VIT, nonvitrectomized group; VIT, vitrectomized group; FT, foveal thickness.
well as intravitreal injections of corticosteroids and most recently, intravitreal injections of anti-VEGF drugs. PPV has been shown to be useful in the treatment of DME in some patients.2–6,30–34 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.1,31–33 These findings suggest that sustained drug delivery with an implant could be particularly useful in vitrectomized eyes, thus enhancing and boosting the primary effect of vitrectomy. The DRCR.net trial prospectively enrolled 241 eyes with treatment-resistant DME.35 At 6 months after vitrectomy, the mean FT decreased from 412 to 278 mm. Eyes with greater preoperative thickness, an epiretinal membrane, and vitreomacular traction achieved greater thinning. Although the average VA (20/80) of the entire cohort did not change, BCVA improvement was seen in eyes with worse baseline vision (P < 0.001) and in those requiring the removal of ERMs (P = 0.006). These authors concluded that vitrectomy may have a role in eyes with vitreomacular abnormalities, but they could not recommend vitrectomy for eyes without traction. This study reported valuable information but, unfortunately, no information regarding the utility of early, primary vitrectomy for DME. In accordance, a systematic review and meta-analysis of published, randomized, controlled trial data was conducted by Simunovic et al. to systematically review and evaluate the available data regarding the efficacy of vitrectomy for DME.36 Seven studies compared vitrectomy with the natural history of diabetic maculopathy, with laser, or with intravitreal corticosteroid injection. Four studies compared vitrectomy with internal limiting membrane peeling to vitrectomy alone. One of the latter 4 studies was the only to investigate vitrectomy in patients with vitreomacular traction. Meta-analysis suggests a structural and possibly functional superiority of vitrectomy over observation at 6 months. Vitrectomy also appears superior to laser in terms of structural, but not functional, outcomes at 6 months. At 12 months, vitrectomy offers no structural benefit and a trend toward inferior functional outcomes when compared with laser. Actually, there is little clinical evidence to support vitrectomy as an intervention for DME in the absence of epiretinal membrane or vitreomacular traction. Intravitreal delivery of corticosteroids27,37–43 and antiVEGF antibodies44–48 are addressing many of the problems associated with conventional therapies for the treatment of retinal diseases. Studies in rabbits have shown that the vit-
reous half-life of triamcinolone acetonide (TA) after intravitreal injection is reduced in eyes after PPV compared with nonvitrectomized eyes.11,12 Vitrectomy has also been shown to affect the intraocular concentration of TA after intravitreal injection in human eyes.49,50 In a vitrectomized eye, the vitreous would be removed, and less-viscous liquid would fill the space, increasing intravitreal circulation. This pathophysiological process leads to a much faster corticosteroid absorption in the vitrectomized eye than in the normal eye. An implant that provides sustained drug release and is both safe and effective may be the best option for therapy. Moreover, an earlier study40 examining the in vivo release of DEX sodium m-sulfobenzoate from a biodegradable poly (lactic acid) (PLA) implant suggests that the pharmacokinetics of DEX may be different in nonvitrectomized and vitrectomized eyes. In this earlier study conducted in rabbit eyes, the release of DEX from the PLA implant (which has chemical similarities with the DEX implant) was 2.5 times more rapid in vitrectomized eyes than in nonvitrectomized eyes. In contrast, the release of DEX from the DEX implant in a more recent study was similar between nonvitrectomized and vitrectomized eyes in rabbit eyes.25 These results suggest that DEX implants may be particularly useful in the treatment of inflammation and macular edema in vitrectomized eyes. Our data are consistent with those obtained from this later experimental study carried out by Chang-Lin et al. In our study, a near complete subtotal vitrectomy was performed in all patients. Given that the completeness of vitrectomy may influence the rate of clearance of many drugs,10–12 the extent of vitrectomy should be considered when comparing findings between nonvitrectomized and vitrectomized eyes. Regarding the efficacy of a DEX intravitreal drug-delivery system in persistent ME secondary to diabetes, Haller et al.21 demonstrated that, in eyes with DME treated with DEX implant, BCVA and FT significantly improved at 3 months when compared with the observation group. Interestingly, they found that 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. Most recently, 4 interventional case series studies addressed this issue. In the first study, Zucchiatti et al.29 showed that a single intravitreal injection of Ozurdex produced improvement in BCVA and FT in eyes with persistent DME. Such improvement was evident from the third day to the first month after injection, peaked at the third month and was no more significant at 6 months. Analogously, Rishi
714
et al.51 undertook another retrospective study, enrolling 18 patients with refractory DME. All patients experienced a significant reduction in FT compared with baseline levels at month 1. The maximum reduction in FT was seen at month 1, followed by reappearance of clinically significant ME at month 4. In 2013, Pacella et al. performed a prospective interventional case series to assess the efficacy of DEX implant, over a 6-month follow-up period.52 Ozurdex produced substantial improvement in BCVA and significant reduction of FT from day 3. The peak efficacy of the implant appears to be reached at month 1 through to month 3, then slowly decreases from month 4 to 6. Similarly, we performed a retrospective interventional case series study to evaluate the effectiveness of a single intravitreal injection of Ozurdex, over 6 months in patients with persistent DME.53 Both mean FT and mean BCVA improved from baseline by 1 month after treatment and remained statistically significant throughout the 6-month study. The peak effectiveness of DEX implants was seen at 3 months after injection when mean FT had decreased by 37%. 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, this clinical application has been mitigated and the use of corticosteroids has been drastically reduced in most developed countries, in the last few years, due to safety concerns.54 Recently, the safety profile of Ozurdex, which is currently an approved treatment for retinal vein occlusion, has been reported in the GENEVA study.20 DEX intravitreal implants have demonstrated an acceptable safety profile in several studies.20,55 The implant does not need to be removed because the copolymer slowly biodegrades into carbon dioxide and water and is absorbed over time. To our knowledge, there have been no differences on the relative effectiveness of DEX implants in pseudophakic versus phakic eyes. Further studies will be needed to ascertain whether the effects of DEX implants are affected by lens status. Our study has several limitations–in that it is short-term, open-label, 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 study population was not recorded. So far, no study, comparing the difference in BCVA and FT (qualitative and quantitative measures, respectively), between vitrectomized and nonvitrectomized eyes has been reported targeting the DME issue. This study has demonstrated similar effectiveness of DEX in nonvitrectomized and vitrectomized eyes after the administration of a 0.7-mg DEX implant. According to our results, the recent DEX 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, even in the operated on patients.
Author Disclosure Statement All the listed authors agree with the submission of this article and none of them have any conflicting financial interests related to it, current and over the past 5 years.
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Received: February 16, 2014 Accepted: August 14, 2014 Address correspondence to: Dr. Marco Dutra Medeiros Department of Retina Instituto de Microcirugia Ocular No. 3, Calle Josep Maria Llado´ Barcelona 08035 Spain E-mail: [email protected]
