|Year : 2013 | Volume
| Issue : 3 | Page : 194-198
Long-term effect of intravitreal dexamethasone implant (Ozurdex) in the treatment of resistant diabetic macular edema
Abdelrahman G Salman
Department of Ophthalmology, Ain Shams University, Cairo, Egypt
|Date of Submission||25-Jan-2013|
|Date of Acceptance||30-Mar-2013|
|Date of Web Publication||28-Feb-2014|
Abdelrahman G Salman
Ain Shams University, 1195 Cairo
Source of Support: None, Conflict of Interest: None
To evaluate the long-term safety and efficacy of Ozurdex in patients with resistant diabetic macular edema.
A comparative, randomized, prospective, interventional case series.
Patients and methods
Fifteen patients with bilateral resistant diabetic macular edema were enrolled in this study. Eyes were randomized into right eyes that received intravitreal dexamethasone implant 0.7 mg (Ozurdex) and left eyes that received intravitreal bevacizumab injection 1.25 mg/0.05 ml. Outcome measures included the change in the best-corrected visual acuity (BCVA), the central macular thickness (CMT) on optical coherence tomography, and the intraocular pressure at 6 and 12 months after injection. Repeated injections were given in both groups when needed.
The mean age of patients was 52.7 ± 2.1 years. The mean duration of diabetes mellitus was 15.2 years. In the Ozurdex group, the preoperative mean CMT was 535.2 μm, which improved to 198 and 230 μm at 6 and 12 months, respectively, and the preoperative mean BCVA was 0.80 log MAR units, which improved to 0.30 and 0.40 log MAR units at 6 and 12 months, respectively, with mean number of injections of 1.8 (range, 1-3) over 1 year. The intravitreal bevacizumab injection group improved from a mean preoperative CMT of 562.4 to 212 and 266 μm at 6 and 12 months, respectively, and the preoperative mean BCVA was 0.70 log MAR units, which improved to 0.30 and 0.40 log MAR units at 6 and 12 months, respectively, with mean number of injections of 5.4 (range, 4-8) over 1 year.
Ozurdex is an effective and safe alternative tool in the management of resistant diabetic macular edema. It can be considered as an off-label treatment with less frequent injection than intravitreal bevacizumab injection. Larger multicenter studies with a longer follow-up period are required.
Keywords: Bevacizumab, dexamethasone, diabetic macular edema, intravitreal implant, Ozurdex
|How to cite this article:|
Salman AG. Long-term effect of intravitreal dexamethasone implant (Ozurdex) in the treatment of resistant diabetic macular edema. J Egypt Ophthalmol Soc 2013;106:194-8
|How to cite this URL:|
Salman AG. Long-term effect of intravitreal dexamethasone implant (Ozurdex) in the treatment of resistant diabetic macular edema. J Egypt Ophthalmol Soc [serial online] 2013 [cited 2020 Feb 21];106:194-8. Available from: http://www.jeos.eg.net/text.asp?2013/106/3/194/127404
| Introduction|| |
The main treatment options for diabetic macular edema (DME) are laser photocoagulation and it is still the gold standard treatment ,. However, the prevention of visual decline is not always uniform, and some patients can be refractory to laser treatment. In addition, this mode of therapy is associated with moderate visual loss, a diminished visual field, and reduced color vision and contrast sensitivity ,.
Other modalities for treatment such as intravitreal bevacizumab (IVB) have been used successfully in the treatment of DME; however, multiple injections are needed and its effect is usually transient in cases of resistant DME ,.
Intravitreal injections of triamcinolone acetonide have produced benefits in patients with DME, ,but several adverse events such as high intraocular pressures (IOP) and cataract have been reported 9.
Among corticosteroids, dexamethasone is one of the most potent, with an anti-inflammatory activity that is six-fold greater than that of triamcinolone and 30-fold greater than cortisol ,,. By delivering a drug directly into the vitreous cavity, the blood-eye barriers are circumvented and intraocular therapeutic levels can be achieved with minimal risk of systemic toxicity. This route of administration typically results in a short half-life unless the drug can be delivered using a formulation capable of providing sustained release ,,.
Previous studies demonstrated that dexamethasone in a biodegradable drug delivery system (Ozurdex) gradually releases the total dose of dexamethasone over several months after insertion into the vitreous. It was recently approved by the US Food and Drug Administration for treatment of macular edema following retinal vein occlusion and posterior uveitis ,. However, its potential role in the management of DME has not been reported yet.
The purpose of our study was to evaluate the long-term safety and efficacy of off-label use of 0.7 mg dexamethasone intravitreal implant (Ozurdex) in patients with resistant DME in comparison with IVB use in the other eye as a comparative arm.
| Patients and methods|| |
A comparative, randomized, prospective, interventional case series of 15 patients presenting with resistant bilateral DME who were older than 18 years, had a best-corrected visual acuity (BCVA) of 6/9 to 6/60, had persistent clinically significant macular edema involving the center of the fovea 4 or more months after one or more treatments for focal or grid macular laser photocoagulation with good systemic control, and who gave informed consent were enrolled in the study.
After acceptance by the hospital medical and ethical committee, written informed consents were obtained from all patients after explanation of the possible side effects and risk benefits of off-label use of the injections.
Exclusion criteria included a difference in the BCVA between both eyes of more than one line or a central macular thickness (CMT) difference of more than 50 μm, a history of corticosteroid-responsive IOP increase, cataract extraction or other intraocular surgery or injection within 3 months and any other laser treatment within 1 month (including YAG laser capsulotomy), and any other ocular disease or systemic steroid use.
At baseline, eyes were randomized into right eyes that received intravitreal 0.7 mg dexamethasone implant (Ozurdex; Allergan Inc., Irvine, California, USA) and left eyes that received intravitreal antivascular endothelial growth factor (VEGF) bevacizumab (Avastin, Genentech Inc., South San Francisco, California, USA) 1.25 mg/0.05 ml injections.
History was taken from all patients. Clinical ophthalmological examination included BCVA, IOP measurement, anterior segment examination including evaluation of the lens status, dilated fundus examination, and optical coherence tomography (OCT) for CMT and fundus fluorescein angiography (FFA) at baseline, 1, 6, and 12 months after injections. All patients were examined on postoperative day 1 for BCVA, anterior chamber reaction, IOP, and fundus evaluation by indirect ophthalmoscopy.
Outcome measures included safety and change in BCVA, CMT in OCT, macular leakage on FFA, and the IOP for each treatment group from baseline to 6 and 12 months after injection.
Patients received further identical doses of Ozurdex implant in the right eye or IVB in the left eye if BCVA was less than 6/24 or CMT was more than 250 μm.
Technique of Ozurdex implantation
Patients underwent Ozurdex implant (∼6 mm long) in the operating room under topical anesthesia using the 22 G sutureless applicator device. Under aseptic conditions, the cap is removed carefully from the applicator. The safety tab is pulled straight off the applicator without twisting or flexing it. The long axis of the applicator is held parallel to the limbus, and the sclera is engaged at an oblique angle with the bevel of the needle up to create a shelved scleral path, 4 mm away from limbus. The needle-tip is advanced within the sclera for about 1 mm, then redirected towards the center of the eye and advanced until the penetration of sclera is completed and the vitreous cavity is entered. The needle should not be advanced past the point where the sleeve touches the conjunctiva. The actuator button is slowly depressed until an audible click is noted. Before withdrawing the applicator from the eye, one should ensure that the actuator button is fully depressed and has locked flush with the applicator surface. The needle is removed in the same direction while entering the vitreous cavity. The fundus is examined carefully .
All patients received topical ciprofloxacin 0.3% eye drops for 3 days before and six times/day for 5 days after injection.
All data were recorded in preformatted data collection forms and analyzed; the software used to perform statistical calculations was SPSS, version 17.0 (SPSS Inc., Chicago, Illinois, USA). Student's t-test for paired data was used to compare preoperative and postoperative data. P value less than 0.05 was considered as statistically significant and P less than 0.001 as highly significant.
| Results|| |
The mean age was 52.7 ± 2.1 years (range 46-78 years); 10 male and five female patients were included. The mean duration of diabetes mellitus was 19.2 ± 2.6 years. Systemic control of diabetes mellitus was good as assessed by FBS/PPBS and HbA1c.
The mean CMT and BCVA preoperatively and postoperatively after 6 and 12 months in both the Ozurdex group and the IVB group are showed in [Table 1].
In the Ozurdex group, the preoperative mean CMT was 535.2 μm, which improved to 198 and 230 μm at 6 and 12 months, respectively, which was statistically highly significant (P < 0.001). This CMT reduction in OCT began as early as 1 week after Ozurdex injection, with peak effect after 60 ± 10 days. The preoperative mean BCVA was 0.80 log MAR units and improved to 0.30 and 0.40 log MAR units at 6 and 12 months, respectively, which was statistically significant (P < 0.05). In eight eyes (53.3%), there was a two-line improvement, and four eyes (26.7%) showed a three-line improvement. This improvement in BCVA started at 30 days and was maximum after 60 days. Two implants were required in eight eyes (53.33%) and three implants were required in two eyes (13.33%). The mean number of injections was 1.8 (range, 1-3) over 1 year [Table 1].
|Table 1: Clinical features and follow-up of patients undergoing treatment|
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The IVB group improved from the mean preoperative CMT of 562.4 to 212 and 266 μm at 6 and 12 months, respectively, which was statistically highly significant (P < 0.001).This reduction of CMT in OCT began as early as 1 week after IVB injection, with the peak after 15 ± 5 days. The preoperative mean BCVA was 0.70 log MAR units and improved to 0.30 and 0.40 log MAR units at 6 and 12 months, respectively, which was statistically significant (P < 0.05). In seven eyes (46.7%), there was a two-line improvement and three eyes (20%) showed a three-line improvement. Only one eye (6.7%) lost one line of preoperative BCVA. This improvement in BCVA started at 15-30 days and was maximum at 30-60 days The mean number of injections was 5 (range, 4-8) over 1 year, and all eyes needed four or more injections [Table 1].
FFA showed an absence of leakage in 12 eyes (80%) in the Ozurdex group and 11 eyes (73.3%) in the IVB group at both the 6- and the 12-month follow-up, with ischemic changes in one eye in the Ozurdex group and in one eye in the IVB group.
Among both groups, there was a statistically significant difference in the frequency of injection (P < 0.05), but no statistically significant differences in the improvement of BCVA or CMT or FFA leakage between both Ozurdex and IVB after 1 year of follow-up (P > 0.05) [Figure 1].
In the Ozurdex group, the IOP increased by 10 mmHg or more from baseline in one eye (6.7%) and by less than 10 mmHg in two eyes (13.3%). The IOP reached a peak at 3-4 weeks and decreased steadily over the next 2 months with topical antiglaucoma eye drops. In the IVB group, there was no increase in the IOP.
Over 12 months, cataract progression occurred in two eyes (13.3%) that received three Ozurdex implant injections versus one of the IVB-treated eyes (6.7%), and the difference was statistically not significant (P > 0.05). Phacoemulsification with PC-IOL was performed when the DME had totally and definitively vanished, or treated, if the opacification prevents any correct fundus visualization or if it generates further visual acuity (VA) decrease.
Transient subconjunctival hemorrhage occurred at the injection site in two eyes in the Ozurdex group. Patients also reported snake-like floaters in the right eye in one patient. Transient conjunctival hyperemia, eye pain, and anterior chamber cell and flare were recorded in both groups. No endophthalmitis, vitreous haemorrhage, or serious systemic or ocular treatment-related adverse events occurred in any patient.
| Discussion|| |
Ozurdex has been recently approved by FDA for the treatment of macular edema following retinal vein occlusion (RVO) and uveitis ,.
To our knowledge, there are no published data about the long-term effect of Ozurdex in resistant DME described so far in the literature.
The continuous release of medication maintains a consistent level of the drug within the eye over an extended period, eliminating the need for monthly or bimonthly injections, as might be necessary with intravitreal anti-VEGF agents ,.
The dexamethasone implant releases the drug by diffusion in a biphasic manner, with higher doses for up to 6 weeks followed by lower doses for up to 6 months. Copolymer lactic acid and glycolic acid is biocompatible, and it is metabolized into carbon dioxide and water inside the eye. Thus, sequential implants can be placed without the need for surgical removal .
Our study enrolled 15 patients with resistant bilateral DME, and we excluded any patient with a difference of more than one line in the BCVA between both eyes or a CMT difference of more than 50 μm for reliability of the comparison between both methods of treatment. Eyes randomized into right eyes received Ozurdex 0.7 mg and left eyes received IVB 1.25 mg/0.05 ml.
The decrease in CMT was highly significant in both groups (P < 0.001). In the Ozurdex group, the CMT reduction started as early as 1 week and lasted up to180 days, with the greatest improvement after 60 ± 10 days, whereas five eyes did not require another injection and the effect lasted up to 1 year. This was in agreement with other studies ,. In IVB, the reduction of CMT in OCT began as early as 1 week after IVB injection, with a peak after 15 ± 5 days, and all eyes needed four or more injections. This was in agreement with other studies ,,.
The mean improvement in BCVA was statistically significant in both groups (P < 0.05). An improvement of BCVA by three lines occurred in four eyes (26.7%) in the Ozurdex group and three eyes (20%) showed a three-line improvement in the IVB group, with earlier improvement in the IVB group and a more prolonged effect of Ozurdex. This was in agreement with other studies on Ozurdex , and IVB 6, 18, 19.
The mean postinjection BCVA after 1 year showed improvement in both groups, but was not as significant as the reduction in CMT at the same timeline. This could be explained by the fact that these eyes had chronic, resistant DME since more than 15 years, which could have led to irreversible changes in the macula.
There were no statistically significant differences in the improvement of CMT, BCVA, or FFA leakage between both Ozurdex and IVB after 1 year of follow-up (P > 0.05).
Ozurdex needed two implants in eight eyes (53.33%) and three implants in two eyes (13.33%). The mean was 1.8 implants (range, 1-3) over 1 year, whereas five eyes (33.33%) did not require another injection. This showed that the peak effect of the drug was in between 1 and 6 months, which is comparable to eyes with macular edema secondary to central retinal vein occlusion (CRVO), branch vein occlusion (BRVO), posterior or intermediate uveitis where the drug effect lasts for 6 months 13,14. However, in IVB group, the mean number of injections was 5.4 (range, 4-8) over 1 year, and all eyes (100%) needed four or more injections, and this was in agreement with other studies that found an average of 5.8 (range, 1-15) injections over 1 year 6, 18, 19.
The improvement in visual acuity and reduction of CMT on OCT seen initially tends to wane off in some cases in both groups. Hence, repeated injections may be necessary to maintain visual improvement and to control macula edema, and a 4-6 months' dosing interval could probably be used in Ozurdex implants versus monthly or bimonthly injection in IVB guided by visual acuity, OCT, and FFA in resistant DME. This limitation of anti-VGEF drugs explains why these drugs do not treat the underlying cause of the problem, that is macular hypoxia, and thus recurrence of macular edema occurs within a few weeks once the anti-VGEF drug is cleared from the vitreous, 6, whereas Ozurdex controls DME by two mechanisms: first it acts as an anti-VEGF drug and it also sensitizes the telengectatic blood vessels to the circulating catecholamines ,.
In three patients (20%) in the Ozurdex group, a transient increase in IOP occurred, which was controlled with topical antiglaucoma eye drops over the next 2 months. This was comparable to other studies that found an increase in IOP of 6% at baseline to 24% ,. In the IVB group, there was no increase in the IOP; this was in agreement with other studies; 6 this higher incidence in the Ozurdex group was due to the dexamethasone effect.
Over 12 months, cataract progression occurred in two eyes (13.37%) that received two or three Ozurdex implants versus one of the IVB-treated eyes (6.7%), which was statistically not significant (P > 0.05). This was comparable to other studies ,,.
Hence, Ozurdex implants are an additional pharmacologic agent suitable for resistant DME patients who are unwilling or unable to tolerate more frequent intravitreal injections required for anti-VEGF therapy or for patients who have demonstrated intolerance or resistant DME following anti-VEGF therapy, particularly those who are already pseudophakic and not steroid responders.
| Conclusion|| |
Ozurdex is an effective and safe alternative tool in the management of resistant DME. It can be considered as an off-label treatment in resistant DME with less frequent injection than IVB; more than one implant is required to control resistant DME over the long run. A larger multicenter study with a longer follow-up period is required.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
| References|| |
|1.||Schatz H, Madeira D, McDonald HR, Johnson RN. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol 1991; 109:1549-1551. |
|2.||Lardenoye CW, van Schooneveld MJ, Frits TW, Rothova A. Grid laser photocoagulation for macular oedema in uveitis or the Irvine-Gass syndrome. Br J Ophthalmol 1998; 82:1013-1016. |
|3.||Morgan CM, Schatz H. Atrophic creep of the retinal pigment epithelium after focal macular photocoagulation. Ophthalmology 1989; 96:96-103. |
|4.||Roider J. Laser treatment of retinal diseases by subthreshold laser effects. Semin Ophthalmol 1999; 14:19-26. |
|5.||Mehta S, Blinder KJ, Shah GK, Kymes SM, Schlief SL, Grand MG. Intravitreal bevacizumab for the treatment of refractory diabetic macular edema. Ophthalmic Surg Lasers Imaging 2010; 41:323-329. |
|6.||Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, Sanchez JG, Wu L, Maia M, et al. Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology 2007; 114:743-750. |
|7.||Leopold IH In: Sears M, Tarkkanen. A eds Nonsteroidal and steroidal anti-inflammatory agents. Surgical pharmacology of the eye 1985; New York, NY: Raven Press; 83-133. |
|8.||Nauck M, Karakiulakis G, Perruchoud A, Papakonstantinou E, Roth M. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur J Pharmacol 1998; 341:309-315. |
|9.||Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008; 115:1447-1449. |
|10.||Kwak HW, D′Amico DJ. Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection. Arch Ophthalmol 1992; 110:259-266. |
|11.||Maxwell DP Jr, Brent BD, Diamond JG, Wu L. Effect of intravitreal dexamethasone on ocular histopathology in a rabbit model of endophthalmitis. Ophthalmology 1991; 98:1370-1375. |
|12.||Kuppermann BD, Blumenkranz MS, Haller JA, Williams GA, Weinberg DV, Chou C, et al.Dexamethasone DDS Phase II Study Group Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol 2007; 125:309-317. |
|13.||Haller JA, Bandello F, Belfort R Jr, et al. OZURDEX® GENEVA Study Group Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010; 117:1134-1146. |
|14.||Lowder C, Belfort R, Lightman S, Foster CS, Robinson MR, Schiffman RM, et al.for the Ozurdex® HURON Study Group Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011; 129:545-553. |
|15.||Moritera T, Ogura Y, Honda Y, Wada R, Hyon SH, Ikada Y. Microspheres of biodegradable polymers as a drug-delivery system in the vitreous. Invest Ophthalmol Vis Sci 1991; 32:1785-1790. |
|16.||Fialho SL, Rego MB, Siqueira RC, Jorge R, Haddad A, Rodrigues AL, et al. Safety and pharmacokinetics of an intravitreal biodegradable implant of dexamethasone acetate in rabbit eyes. Curr Eye Res 2006; 31:525-534. |
|17.||Chang-Lin JE, Attar M, Acheampong AA, Robinson MR, Whitcup SM, Kuppermann BD, et al. Pharmacokinetics and pharmacodynamics of the sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci 2011; 52:80-86. |
|18.||L Wu, MA Martínez-Castellanos, H Quiroz-Mercado, Arevalo JF, Berrocal MH, Farah MH, et al. ′Twelve-month safety of intravitreal injections of bevacizumab (Avastin® ): results of the Pan-American Collaborative Retina Study Group (PACORES)′. Graefes Arch Clin Exp Ophthalmol 2008; 246:81-87. |
|19.||JF Arevalo, JG Sanchez, L Wu, Maia M, Alezzandrini AA, Brito M, et al. ′Primary intravitreal bevacizumab for diffuse diabetic macular edema. The Pan-American Collaborative Retina Study Group at 24 months′. Ophthalmology 2009; 116:1488-1497. |