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MEDICAL RETINA FEATURE STORY

D

iabetic macular edema (DME) is the maincause (27%) of mild to moderate visual loss indiabetic patients,1 and the diffuse form ofDME (Figure 1) is often difficult to treat using

conventional therapy. Using a combination of therapiesmay reduce the treatment burden in these patients.

Vascular ischemic injury and hypoxia cause the releaseof several growth factors (vascular endothelial growthfactor [VEGF], transforming growth factor [TGF]-beta,connective tissue growth factor [CTGF], and platelet-derived growth factor [PDGF]), which can increase vas-cular permeability and are potential etiologic factors inthe development of DME.2 Inflammationspecificallymacrophages and complement system activationhasbeen shown to result in a loss of pericytes in the diabeticvasculature and in further expression of growth factors.3

This finding provided the rationale to perform a studyevaluating the efficacy of combination therapy with atopical nonsteroidal antiinflammatory drug (NSAID) inthe treatment of diffuse DME.

STUDY DESIGN

To assess the role of topical NSAIDs in the treatmentof refractory diffuse DME, we performed a comparativerandomized prospective study, in which treatment witha topical NSAID was combined with intravitreal beva-cizumab (Avastin, Genentech) and dexamethasone.4 Weenrolled 29 patients (29 eyes) who had refractory DME,

randomizing each to placebo, or 1 of 3 commerciallyavailable topical NSAIDs: bromfenac (Bromday, ISTAPharmaceuticals), nepafenac (Nevanac, AlconLaboratories Inc.), or ketorolac tromethamine (AcularLS, Allergan Inc.). All patient data was subject to theguidelines of our local institutional review board.

All 29 patients had persistent edema despite 2 ormore sessions of focal or grid laser photocoagulation,and all had at least a single intraocular bevacizumabinjection at least 2 months prior to study entry. Atstudy entry, all patients were treated with an injectionof 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 intravit-real injections of both drugs were given as needed forthe following reasons: 1) worsening of visual acuity, or2) 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

Combination Therapy

for Diffuse DMEBY KEITH A. WARREN, MD

Figure 1. Fundus photo showing diffuse diabetic macular

edema.

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

TABLE 1. PATIENT DEMOGRAPHICS

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placebo, or one of the 3 commercially available topicalNSAIDs, which were used according to product labelinginstructions. Demographics of the full cohort and exclu-

sion criteria can be seen in Tables 1 and 2.

RESULTS

All test groups demonstrated an improvement invisual acuity at all time points tested. Adding a topicalNSAID, however, did not result in any additional visualimprovement. Mean improvement in visual acuity was9 ETDRS letters, or 2 ETDRS lines, from pretreatment20/83 to posttreatment 20/54. All groups did best atthe earliest time point (3 months), which correspondswith previous findings regarding the use of a steroid.There was then a small reduction in visual acuity, fol-

lowed by stability through the remainder of the study.All groups also had reduced retinal thickening with

patients who received a topical NSAID demonstrating astatistically significant greater reduction in retinal thick-ness compared with those who received placebo. Themean pretreatment retinal thickness was approximately531 m. After treatment, the mean thickness for patientsin the placebo group was 363 m, and for those receivinga topical NSAID it was 262 m (Figures 2 and 3).

Interestingly, all patients required additional intravitrealinjections to maintain visual acuity or reduction in retinalthickness. The NSAID groups, however, appeared to

require less frequent intravitreal injections than did theplacebo group. The mean number of injections in theplacebo group was 3.62 injections over the 12-monthassessment period, vs 2.6 injections in the NSAID groupstaken together. The bromfenac and nepafenac groupsconsistently required the fewest number of additionalintravitreal injections.

There was a gradual increase in intraocular pressure(IOP) over the duration of the study. Mean pretreat-ment IOP was about 16 mm Hg vs 19 mm Hg at theend 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.

SUMMARY

Combination therapy consisting of an anti-VEGF agent,a corticosteroid and a topical NSAID may reduce thetreatment burden in DME. All of the NSAIDs used in thisstudy 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 burdenwas less in patients treated with a NSAID in this study.We believe that combination therapy with NSAIDs andanti-VEGF agents warrants further evaluation and investi-gation as a treatment option for some patients with dif-fuse 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 con-

sultant 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 Ital iana della Retina meeting. September 21-25, 2011; Rome.

Figure 2. Optical coherence tomography (OCT) of a study

patient prior to use of combination therapy with nepafenac.

Figure 3. OCT of a study patient shows a markedly reduced

retinal thickness at 6 weeks after combination therapy with

nepafenac.

Any topical NSAID, intraocular steroid, or anti-VEGFinjection 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.

TABLE 2. EXCLUSION CRITERIA