Long-Term Results of Pro Re Nata Regimen of Aflibercept Treatment in Persistent Neovascular Age-Related Macular Degeneration

correlative data after injection of a VEGF-neutralizing protein as a type of control, because that type of injection can only specifically reduce 1 protein, VEGF. This was informative because 2 proteins, MMP-9 and IGFBP-3, which were reduced after dexamethasone implant, were also reduced after injection of a VEGF antagonist; thus, their reduction cannot be attributed to the direct pharmacologic activity of dexamethasone. Instead, MMP-9 and IGFBP-3 may be produced by edematous retina and reduction in edema by any means may indirectly reduce them. This allowed us to eliminate these 2 proteins from consideration as contributors to DME. Fifth, they speculate that because many of our subjects had chronic/recurrent DME, they had permanent damage to retinal capillaries with incurable pathology. Some subjects had complete elimination of intraretinal fluid and some had marked improvement, indicating that many of the subjects did not have irreversible edema. Some subjects had little reduction in edema after dexamethasone implant or injection of a VEGF-neutralizing protein and it is possible that these subjects have permanent damage to retinal vessels that prevents a response to any therapeutic, but it is also possible that the duration of treatment was insufficient to see an optimal response or the eyes of these patients may contain pro-permeability factors that are not reduced by a dexamethasone implant. Sixth, they speculate that pro-permeability factors may differ between patients with chronic/recurrent DME and those with recent-onset DME. It is reasonable to hypothesize that chronic/recurrent edema may cause increased production and/or release of pro-permeability factors (and our findings with regard to MMP-9 and IGFBP-3 support that), but our study did not compare vasoactive proteins in recent-onset vs chronic/recurrent DME and there are no published data that provide insight regarding this issue. Finally, they suggest that efficacy of any treatment depends primarily on the duration of DME at the time treatment is started. It is clear that delay in treatment onset can have a negative impact on visual outcomes,1 but studies examining the effect of baseline characteristics on visual outcomes indicate that it is not the only factor influencing prognosis.2,3 There are some patients who have a suboptimal response despite timely treatment onset. From a practical standpoint, there are many patients with chronic/recurrent DME who are seen in clinical practice and it is important to identify the vasoactive proteins that contribute and hopefully this will help identify new treatments to improve outcomes in these patients. PETER A. CAMPOCHIARO GULNAR HAFIZ TAHREEM A. MIR ADRIENNE W. SCOTT INGRID ZIMMER-GALLER SYED M. SHAH ADAM S. WENICK CHRISTOPHER J. BRADY

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IAN HAN LINGMIN HE ROOMASA CHANNA DAVID POON CATHERINE MEYERLE MARY BETH ARONOW AKRIT SODHI JAMES T. HANDA SALEEMA KHERANI YONG HAN RAAFAY SOPHIE GUOHUA WANG JIANG QIAN

Baltimore, Maryland

SEE THE ORIGINAL ARTICLE FOR ANY DISCLOSURES OF THE authors.

REFERENCES

1. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013;120(10):2013–2022. 2. Sophie R, Lu N, Campochiaro PA. Predictors of functional and anatomic outcomes in patients with diabetic macular edema treated with ranibizumab. Ophthalmology 2015;122(7): 1395–1401. 3. Bressler SB, Qin H, Beck RW, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranizumab. Arch Ophthalmol 2012;130:1153–1161.

Long-Term Results of Pro Re Nata Regimen of Aflibercept Treatment in Persistent Neovascular Age-Related Macular Degeneration EDITOR: WE READ WITH GREAT INTEREST THE ARTICLE ‘‘LONG-TERM

Results of Pro Re Nata Regimen of Aflibercept Treatment in Persistent Neovascular Age-Related Macular Degeneration,’’ by Muftuoglu and associates.1 In their recent retrospective study, the authors have clearly demonstrated the usefulness and efficacy of intravitreal aflibercept injections on a pro re nata basis for the management of neovascular age-related macular degeneration. However, we do have a few comments to make in view of the conclusions made in the study. In the current study, close to 50% of the eyes showed no improvement in terms of resolution of fluid with asneeded injections of aflibercept. These eyes were treated with 3 consecutive monthly injections of aflibercept and

AMERICAN JOURNAL OF OPHTHALMOLOGY

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significant reduction in central macular thickness, maximal retinal thickness, maximal pigment epithelial detachment height, and maximal subretinal fluid height were achieved, thus suggesting the pro re nata regimen showed no superiority to regimens described in the VIEW 1 and 2 trials.2 Cho and associates3 showed only 18% of the eyes were dry with a single intravitreal aflibercept injection. Repeated injections of aflibercept showed no significant visual acuity gain, probably owing to the chronicity of neovascular membrane and macular atrophy.4 Baseline optical coherence tomography indicators like increased central subfield thickness, presence of intraretinal cysts, presence of pigment epithelial detachment, and subfoveal thickening indicate poor prognosis to treatment with intravitreal aflibercept.5 To conclude, the decision to switch from ranibizumab and/or bevacizumab injections to intravitreal aflibercept injections in patients with multiple recurrences or persistent fluid must also be based on the baseline OCT features, baseline visual acuity, and chances of visual acuity gain. RAMESH VENKATESH PRACHI ABHISHEK DAVE SHALINI SINGH PRACHI GURAV GAGANJEET GUJRAL

Delhi, India FUNDING/SUPPORT: NO FUNDING OR GRANT SUPPORT. Financial disclosures: The following authors have no financial disclosures: Ramesh Venkatesh, Prachi Abhishek Dave, Shalini Singh, Prachi Gurav, and Gaganjeet Gujral. The authors attest that they meet the current ICMJE criteria for authorship.

REFERENCES

1. Muftuoglu IK, Arcinue CA, Tsai FF, et al. Long-term results of pro re nata regimen of aflibercept treatment in persistent neovascular age-related macular degeneration. Am J Ophthalmol 2016; 167:1–9. 2. Heier JS, Brown DM, Chong V, et al. VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012; 119(12):2537–2548. 3. Cho H, Shah CP, Weber M, Heier JS. Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab. Br J Ophthalmol 2013;97(8):1032–1035. 4. Munk MR, Ceklic L, Ebneter A, et al. Macular atrophy in patients with long-term anti-VEGF treatment for neovascular age-related macular degeneration. Acta Ophthalmol 2016; http://dx.doi.org/10.1111/aos.13157. 5. Chatziralli I, Nicholson L, Vrizidou E, et al. Predictors of outcome in patients with neovascular age-related macular degeneration switched from ranibizumab to 8-weekly aflibercept. Ophthalmology 2016;123(8):1762–1770.

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REPLY WE THANK VENKATESH AND ASSOCIATES FOR THEIR INTER-

est in our article and for their comments. They noted that 50% of eyes did not show resolution of fluid while receiving as-needed aflibercept injections. In our study, 87% of eyes became completely dry at some point, 50% of eyes achieved a completely dry retina following 3 consecutive everyother-month aflibercept injections, and 32% of eyes gained 1 or more lines of vision at last follow-up. Therefore, the response rate was better than mentioned by them. Also, it is important to note that the patients in our study were not treatment-naı¨ve patients; all were previously treated with either bevacizumab or ranibizumab.1 In the VIEW 1–2 studies,2 every-other-month aflibercept treatment reduced treatment burden while maintaining noninferiority to monthly ranibizumab in treatment-naı¨ve patients. Thus, it would be inappropriate to make direct comparisons of the treatment regimens between the 2 studies. Interestingly, as mentioned in our article, the CATT trial demonstrated that 51.5% of the ranibizumab group and 67.4% of the bevacizumab group treated monthly had persistent fluid.3 While our study suggests that many of the patients may achieve retinal dryness and improved vision after switching to a regimen using aflibercept, there will still be a number of patients who do not. We thank Venkatesh and associated for their suggestion; we agree that the decision to switch treatment regimens for patients is a clinical decision that should be based on the visual prognosis, which may be guided by baseline optical coherence tomography characteristics, such as preserved outer retinal integrity and vision at baseline; however, our results suggest that aflibercept still is effective treatment in eyes with persistent and recurrent neovascular age-related macular degeneration. ILKAY KILIC MUFTUOGLU

La Jolla, California, and Istanbul, Turkey CHERYL A. ARCINUE MOSTAFA ALAM RAOUF GABER NATALIA CAMACHO QISHENG YOU FRANK F. TSAI WILLIAM R. FREEMAN

La Jolla, California SEE THE ORIGINAL ARTICLE FOR ANY DISCLOSURES OF THE authors.

REFERENCES

1. Muftuoglu IK, Arcinue CA, Tsai FF, et al. Long-term results of pro re nata regimen of aflibercept treatment in persistent

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