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We appreciate the interest Jung et al expressed in our article.1Adrean S.D. Chaili S. Ramkumar H. et al.Consistent long-term therapy of neovascular age-related macular degeneration managed by 50 or more anti-VEGF injections using a treat-extend-stop protocol.Ophthalmology. 2018; 125: 1047-1053Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar We agree with many points discussed in their letter and would like to clarify and expand on their discussion. This long-term retrospective study may indeed demonstrate a survivor benefit, and we likewise agree that patients with end-stage disease will unlikely benefit from further treatment, so treatments should be stopped. However, this survivor benefit is not unique to any particular management protocol studied and these patients are typically excluded in randomized clinical trials owing to baseline visual acuity and lesion characteristics. Retrospective studies by Haddad et al2Haddad W.M. Minous F.L. Legeai J. et al.Long-term outcomes and incidence of recurrence of neovascularization in treated exudative age-related macular degeneration.Retina. 2017; 37: 951-961Crossref PubMed Scopus (16) Google Scholar and Peden et al3Peden M.C. Suñer I.J. Hammer M.E. et al.Long-term outcomes in eyes receiving fixed-interval dosing of anti-vascular endothelial growth factor agents for wet age-related macular degeneration.Ophthalmology. 2015; 122: 803-808Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar using an as-needed or monthly fixed schedule, respectively, excluded eyes with end-stage disease such as subfoveal geographic atrophy or fibrovascular scarring. In our study, we included eyes with subfoveal geographic atrophy, and those were 4 of the 7 eyes with a visual acuity of <20/200. This finding likely decreased our overall visual outcomes; however, these patients were included because they received >50 injections. We did not have any patients with fibrovascular scarring since their disease process was stabilized with anti-vascular endothelial growth factor therapy, long before 50 injections were reached. Patients were also included regardless of baseline vision, including 28% of patients with vision of ≥20/40. Many of these patients would also be excluded from clinical trials. Although this potentially limited visual acuity gains in our study, it may better reflect outcomes in clinical practice.1Adrean S.D. Chaili S. Ramkumar H. et al.Consistent long-term therapy of neovascular age-related macular degeneration managed by 50 or more anti-VEGF injections using a treat-extend-stop protocol.Ophthalmology. 2018; 125: 1047-1053Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Jung et al discussed that many trials exhibited decreased visual acuity over time, after initially successful anti-vascular endothelial growth factor therapy. We likewise demonstrated some visual decline from 6.5 to 8.0 years of follow-up, with visual gains decreasing from +9.7 to +8.7 letters.1Adrean S.D. Chaili S. Ramkumar H. et al.Consistent long-term therapy of neovascular age-related macular degeneration managed by 50 or more anti-VEGF injections using a treat-extend-stop protocol.Ophthalmology. 2018; 125: 1047-1053Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar The goal of this study was to assess patients who had long-term therapy and we describe the treat-extend-stop (TES) protocol because this is our management strategy for neovascular age-related macular degeneration. Vision was examined after the 50th injection as a point of constancy owing to variability in treatment extension times. We also demonstrated that these patients required consistent injections to suppress disease activity. In fact, at the 51st visit, 78.9% of patients were being treated at 6-week intervals or less, decreasing to just 63.4% at final follow-up. Patients were requiring 9.6 injections per year on average at the 51st visit, and 8.1 injections per year at final follow-up. In a different study using the TES protocol, we demonstrated that 37.3% of eyes successfully completed the protocol to treatment cessation at approximately 3 years.4Adrean S.D. Chaili S. Grant S. et al.Recurrence rate of choroidal neovascularization in neovascular age-related macular degeneration managed with a treat–extend–stop protocol.Ophthalmology Retina. 2018; 2: 225-230Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Patients were monitored at a maximum of 12-week intervals without treatment and 29.4% of eyes experienced disease recurrence at an average of 14 months.4Adrean S.D. Chaili S. Grant S. et al.Recurrence rate of choroidal neovascularization in neovascular age-related macular degeneration managed with a treat–extend–stop protocol.Ophthalmology Retina. 2018; 2: 225-230Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Average vision improved from 20/70 to 20/50 (approximately +7.5 Early Treatment of Diabetic Retinopathy Study [ETDRS] letters). Visual acuity then decreased to 20/60 at the time of recurrence, but recovered to 20/50 upon re-initiation of the TES protocol with an average follow-up of 5 years.4Adrean S.D. Chaili S. Grant S. et al.Recurrence rate of choroidal neovascularization in neovascular age-related macular degeneration managed with a treat–extend–stop protocol.Ophthalmology Retina. 2018; 2: 225-230Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar These results are comparable with monthly fixed dosing with decreased treatment burden3Peden M.C. Suñer I.J. Hammer M.E. et al.Long-term outcomes in eyes receiving fixed-interval dosing of anti-vascular endothelial growth factor agents for wet age-related macular degeneration.Ophthalmology. 2015; 122: 803-808Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar and seem to be superior to long-term extension studies of randomized clinical trials or retrospective studies using an as-needed protocol.2Haddad W.M. Minous F.L. Legeai J. et al.Long-term outcomes and incidence of recurrence of neovascularization in treated exudative age-related macular degeneration.Retina. 2017; 37: 951-961Crossref PubMed Scopus (16) Google Scholar, 5Rofagha S. Bhisitkul R.B. Boyer D.S. et al.Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP).Ophthalmol. 2013; 120: 2292-2299Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar For example, the SEVEN-UP study5Rofagha S. Bhisitkul R.B. Boyer D.S. et al.Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP).Ophthalmol. 2013; 120: 2292-2299Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar reported that 46.2% of eyes achieved >20/100 vision by the end of the study, with 68% of eyes having persistent exudation and 48% of eyes demonstrating angiographic leakage, yet only 46% of eyes were receiving ongoing treatment. These results illustrate that undertreatment of disease using the as-needed method may lead to increased breakthrough disease or minirecurrences. Over the long term, this cycle may result in significantly worse vision, even when studies exclude end-stage disease (-8.4 letters at 7.75 years vs 12 months; Haddad et al2Haddad W.M. Minous F.L. Legeai J. et al.Long-term outcomes and incidence of recurrence of neovascularization in treated exudative age-related macular degeneration.Retina. 2017; 37: 951-961Crossref PubMed Scopus (16) Google Scholar). Although many other retrospective studies did not examine baseline choroidal neovascularization lesions,2Haddad W.M. Minous F.L. Legeai J. et al.Long-term outcomes and incidence of recurrence of neovascularization in treated exudative age-related macular degeneration.Retina. 2017; 37: 951-961Crossref PubMed Scopus (16) Google Scholar, 3Peden M.C. Suñer I.J. Hammer M.E. et al.Long-term outcomes in eyes receiving fixed-interval dosing of anti-vascular endothelial growth factor agents for wet age-related macular degeneration.Ophthalmology. 2015; 122: 803-808Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar we agree with Jung et al that future investigations of baseline lesion characteristics within this study population, for example, the proportion of patients with type-1 choroidal neovascularization, may elucidate neovascular age-related macular degeneration populations more suited for long-term management using the TES protocol. In summary, the TES protocol likely achieves an appropriate balance to manage neovascular age-related macular degeneration over the long term by providing visual results comparable with a fixed treatment regimen and superior to as-needed dosing, while decreasing the number of visits and treatments. Re: Adrean et al.: Consistent long-term therapy of neovascular age-related macular degeneration managed by 50 or more anti-VEGF injections using a treat-extend-stop protocol (Ophthalmology. 2018;125:1047-1053)OphthalmologyVol. 125Issue 12PreviewWe read with interest the report by Adrean et al1 regarding the treat-extend-stop (TES) protocol for the long-term treatment of neovascular age-related macular degeneration (nAMD). Based on their results, the authors conclude that the TES protocol is likely to maintain or improve vision in eyes requiring long-term intravitreal anti-vascular endothelial growth factor therapy. However, we believe clinicians should consider certain methodologic aspects of their study design before accepting its conclusions and applying this regimen in their own practices. Full-Text PDF