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Combination Therapy for Diffuse DME

iabetic macular edema (DME) is the main cause (27%) of mild to moderate visual loss in diabetic patients,1 and the diffuse form of DME (Figure 1) is often difficult to treat using conventional therapy. Using a combination of therapies may reduce the treatment burden in these patients. Vascular ischemic injury and hypoxia cause the release of several growth factors (vascular endothelial growth factor [VEGF], transforming growth factor [TGF]-beta, connective tissue growth factor [CTGF], and plateletderived growth factor [PDGF]), which can increase vascular permeability and are potential etiologic factors in the development of DME.2 Inflammationspecifically macrophages and complement system activationhas been shown to result in a loss of pericytes in the diabetic vasculature and in further expression of growth factors.3 This finding provided the rationale to perform a study evaluating the efficacy of combination therapy with a topical nonsteroidal antiinflammatory drug (NSAID) in the treatment of diffuse DME.

Figure 1. Fundus photo showing diffuse diabetic macular edema.

TABLE 1. PATIENT DEMOGRAPHICS Sex 17 men/12 women (59% male) Mean age 59.2 years (3978 years) Duration DM 17.3 years (732 years) Duration DME 11.7 months (623 months) HbA1c 7.8% (5.99.7%) Pre Rx VA 24 ETDRS letters (438 letters) Pre Rx OCT 531 m (701284 m) Pre Rx IOP 16.4 mm Hg (1122 mm Hg) DM = diabetes mellitus; DME = diabetic macular edema; Rx = treatment; VA = visual acuity; OCT = optical coherence tomography; IOP = intraocular pressure

STUDY DE SI GN To assess the role of topical NSAIDs in the treatment of refractory diffuse DME, we performed a comparative randomized prospective study, in which treatment with a topical NSAID was combined with intravitreal bevacizumab (Avastin, Genentech) and dexamethasone.4 We enrolled 29 patients (29 eyes) who had refractory DME, randomizing each to placebo, or 1 of 3 commercially available topical NSAIDs: bromfenac (Bromday, ISTA Pharmaceuticals), nepafenac (Nevanac, Alcon Laboratories Inc.), or ketorolac tromethamine (Acular LS, Allergan Inc.). All patient data was subject to the guidelines of our local institutional review board. All 29 patients had persistent edema despite 2 or more sessions of focal or grid laser photocoagulation, and all had at least a single intraocular bevacizumab injection at least 2 months prior to study entry. At study entry, all patients were treated with an injection of bevacizumab (1.25 mg) and dexamethasone (200 g). The injections were repeated in all patients monthly for

2 additional doses (total of 3 doses). Additional intravitreal injections of both drugs were given as needed for the following reasons: 1) worsening of visual acuity, or 2) retinal thickness increase of 100 m or greater. To assess the effect of the addition of an NSAID, the patients were divided into 4 groups and randomized to


TABLE 2. EXCLUSION CRITERIA Any topical NSAID, intraocular steroid, or anti-VEGF injection within 2 months of study entry Any focal laser treatment within 3 months of study entry HbA1C of 11 or greater within 3 months of study entry or known history of steroid responsiveness.
Figure 2. Optical coherence tomography (OCT) of a study patient prior to use of combination therapy with nepafenac.

placebo, or one of the 3 commercially available topical NSAIDs, which were used according to product labeling instructions. Demographics of the full cohort and exclusion criteria can be seen in Tables 1 and 2. RE SULTS All test groups demonstrated an improvement in visual acuity at all time points tested. Adding a topical NSAID, however, did not result in any additional visual improvement. Mean improvement in visual acuity was 9 ETDRS letters, or 2 ETDRS lines, from pretreatment 20/83 to posttreatment 20/54. All groups did best at the earliest time point (3 months), which corresponds with previous findings regarding the use of a steroid. There was then a small reduction in visual acuity, followed by stability through the remainder of the study. All groups also had reduced retinal thickening with patients who received a topical NSAID demonstrating a statistically significant greater reduction in retinal thickness compared with those who received placebo. The mean pretreatment retinal thickness was approximately 531 m. After treatment, the mean thickness for patients in the placebo group was 363 m, and for those receiving a topical NSAID it was 262 m (Figures 2 and 3). Interestingly, all patients required additional intravitreal injections to maintain visual acuity or reduction in retinal thickness. The NSAID groups, however, appeared to require less frequent intravitreal injections than did the placebo group. The mean number of injections in the placebo group was 3.62 injections over the 12-month assessment period, vs 2.6 injections in the NSAID groups taken together. The bromfenac and nepafenac groups consistently required the fewest number of additional intravitreal injections. There was a gradual increase in intraocular pressure (IOP) over the duration of the study. Mean pretreatment IOP was about 16 mm Hg vs 19 mm Hg at the end of the study. Six patients, 2 in the placebo group, 2 in the ketorolac group, and 2 in the nepafenac group, required topical glaucoma medication to decrease IOP.

Figure 3. OCT of a study patient shows a markedly reduced retinal thickness at 6 weeks after combination therapy with nepafenac.

SUMM ARY Combination therapy consisting of an anti-VEGF agent, a corticosteroid and a topical NSAID may reduce the treatment burden in DME. All of the NSAIDs used in this study reduced the treatment burden, but bromfenac and nepafenac provided the greatest reduction. Combination therapy resulted in a reduction in retinal thickness and improved vision. The treatment burden was less in patients treated with a NSAID in this study. We believe that combination therapy with NSAIDs and anti-VEGF agents warrants further evaluation and investigation as a treatment option for some patients with diffuse DME. Keith A. Warren, MD, is founder and CEO of Warren Retina Associates, PA, in Overland Park, KS. Dr. Warren states that he serves as a consultant and speaker for Alcon Laboratories, Inc., Dutch Ophthalmic, and Genentech. He may be reached at +1 913 339 6970; fax: +1 913 339 6974; or via email at kwarren@warrenretina.com.
1. Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. Ophthalmology. 1995;102(1):7-16. 2. Praidou A, Androudi S, Brazitikos P, Karakiulakis G, Papakonstantinou E, Dimitrakos S. Angiogenic growth factors and their inhibitors in diabetic retinopathy. Curr Diabetes Rev. 2010;6(5):304-312. 3. Gerl VB, Bohl J, Pitz S, Stoffelns B, Pfeiffer N, Bhakdi S. Extensive deposits of complement C3d and C5b-9 in the choriocapillaris of eyes of patients with diabetic retinopathy. Invest Ophthalmol Vis Sci. 2002;43(4):1104-1108. 4. Warren KA. Combination therapy for diffuse macular edema (DME). Paper presented at the Retina Society and the Societa Italiana della Retina meeting. September 21-25, 2011; Rome.