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edi tor i a l

Th e n e w e ngl a nd j o u r na l o f m e dic i n e

Treatment Choice for Diabetic Macular EdemaDaniel F. Martin, M.D., and Maureen G. Maguire, Ph.D.

Macular edema is a common cause of vision loss in patients with diabetes. Chronic elevation of serum glucose levels leads to capillary damage that results in microaneurysm formation in the retina. Leakage from these microaneurysms leads to vision loss if the fluid involves the center of the fovea. The mainstay of therapy for more than 25 years was focal laser photocoagulation applied to or near the microaneurysms.1 However, results from clinical trials of drugs that block vascular endothelial growth factor (VEGF) for the treat-ment of diabetic macular edema have led to a dramatic shift away from laser therapy to primary treatment with intravitreal injections of one of three anti-VEGF drugs: aflibercept, bevacizumab, and ranibizumab.2,3

Researchers from the Diabetic Retinopathy Clinical Research Network now report in the Journal findings from a comparative trial of drugs to treat diabetic macular edema.4 Although each of the three drugs produced substantial improve-ment in visual acuity at 1 year, there were im-portant differences in treatment effects in pre-specified subgroups. In eyes with visual acuity of 20/40 or better, there was no difference among the drugs in improvement in the visual-acuity letter score (mean improvement, 8 for each drug) or the number of injections (median, 9 for each drug) required to achieve this result. However, in eyes with visual acuity of 20/50 or worse, there was a clear advantage with aflibercept in improve-ment in the visual-acuity letter score (mean im-provement, 19) over bevacizumab (mean improve-ment, 12) or ranibizumab (mean improvement, 14), although the number of injections was similar among aflibercept (median, 10), bevacizu-mab (median, 11), and ranibizumab (median, 10).

For the entire study sample, improvement in the visual-acuity letter score was greater by 2 to

3 with aflibercept than with the other two agents. However, with a highly significant inter-action between baseline visual acuity and treat-ment effects, the overall results do not apply to patients in either subgroup.

Aflibercept and ranibizumab reduced retinal thickness more than bevacizumab in both visual-acuity subgroups, but the anatomical benefit translated into a visual-acuity benefit only in eyes with a baseline visual acuity of 20/50 or worse. The greater reduction in retinal thickness with aflibercept is consistent with the lower rate of supplemental laser treatment required in afliber-cept-treated eyes than in eyes treated with the other agents.

There were no significant differences in safety observed among the drugs, although in a post hoc analysis, there were more cardiovascular events in patients treated with ranibizumab (37 patients, 17%) than in those treated with afliber-cept (20 patients, 9%) or bevacizumab (19 pa-tients, 9%) (P = 0.01). Given the absence of dif-ferences in cardiovascular safety observed in other trials of diabetic macular edema, as well as the absence of consistent differences in car-diovascular safety in comparative trials of these drugs for the treatment of age-related macular degeneration,5-9 we agree with the authors that the difference may have been due to chance and that the topic warrants continued surveillance.

Approximately 75% of patients with diabetic macular edema in the general population present with a visual acuity of 20/40 or better.10 Because there were no significant differences in safety or efficacy among drugs in patients with this presenting visual acuity, cost becomes a major consideration in choosing therapy. Given the large difference in cost to patients per dose among bevacizumab ($50), ranibizumab ($1,200),

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and aflibercept ($1,950), bevacizumab should be considered as first-line therapy in patients with a visual acuity of 20/40 or better.

For patients who present with a visual acuity of 20/50 or worse, improvement in vision was greatest with aflibercept and similar between bevacizumab and ranibizumab. Aflibercept should be considered as first-line therapy in these patients, with bevacizumab as the alternative given the lack of a significant difference in visual outcome between bevacizumab and ranibizumab and the large difference in cost between the two drugs. The equivalence of bevacizumab and ra-nibizumab in effects on visual acuity has now been shown in different disease states, includ-ing diabetic macular edema in the current trial and neovascular age-related macular degenera-tion in several multicenter clinical trials.5-9

There are powerful forces in addition to effi-cacy and safety that affect drug selection by physicians. These include the current require-ment for a patient-specific prescription, which limits or delays access to compounded bevacizu-mab in some states; the rebates paid directly to physicians from pharmaceutical companies to reward use of a more expensive drug; and the policy of the Centers for Medicare and Medicaid Services to reimburse on the basis of a percent-age of the cost of a drug, so that the agency provides higher payments to physicians when more expensive drugs are prescribed. We believe that all financial incentives and logistic barriers to providing the least expensive drug, among drugs equivalent in safety and efficacy, should be eliminated so that patients may benefit fully from the results of this Diabetic Retinopathy Clinical Research Network trial as well as those from other comparative trials.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

From the Cleveland Clinic Cole Eye Institute, Cleveland (D.F.M.); and the Department of Ophthalmology, University of Pennsyl-vania, Philadelphia (M.G.M.).

This article was published on February 18, 2015, at NEJM.org.

1. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796-806.2. Diabetic Retinopathy Clinical Research Network. Random-ized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117:1064-77.3. Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology 2012;119:1658-65.4. The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. DOI: 10.1056/NEJMoa1414264.5. The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897-908.6. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascu-larisation: 2-year findings of the IVAN randomised controlled trial. Lancet 2013;382:1258-67.7. Kodjikian L, Souied EH, Mimoun G, et al. Ranibizumab ver-sus bevacizumab for neovascular age-related macular degenera-tion: results from the GEFAL noninferiority randomized trial. Ophthalmology 2013;120:2300-9.8. Krebs I, Schmetterer L, Boltz A, et al. A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration. Br J Ophthalmol 2013;97:266-71.9. Berg K, Pedersen TR, Sandvik L, Bragadttir R. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend pro-tocol. Ophthalmology 2015;122:146-52.10. Early Treatment Diabetic Retinopathy Study Research Group. Focal photocoagulation treatment of diabetic macular edema relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Arch Ophthalmol 1995;113:1144-55.

DOI: 10.1056/NEJMe1500351Copyright 2015 Massachusetts Medical Society.

The New England Journal of Medicine Downloaded from nejm.org on March 23, 2015. For personal use only. No other uses without permission.

Copyright 2015 Massachusetts Medical Society. All rights reserved.