THE IMPACT OF DISEASE ACTIVITY ON 5-YEAR OUTCOMES IN PATIENTS UNDERGOING TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To assess the impact of disease activity on clinical outcomes in a "real-world" cohort with neovascular age-related macular degeneration over 5 years. METHODS: Data were obtained from the prospectively defined Fight Retinal Blindness! registry. Eyes were divided into tertiles based on the proportion of visits where choroidal neovascular lesion was active (low, moderate, and high) up until 5 years. RESULTS: Data from 2,109 eyes were included. The adjusted mean (95% confidence interval) visual acuity change was -0.5 letters (-1.8 to 1.1), 1.8 letters (0.2 to 3.4), and -2.5 letters (-4.2 to -1.3) in the low, moderate, and high activity groups respectively, P < 0.001. Eyes in the low activity group were more likely to develop macular atrophy (56, 47 and 26% in the low, moderate, and high activity groups respectively, P < 0.001) but less likely to develop subretinal fibrosis (27, 35 and 42% in the low, moderate, and high activity groups respectively, P < 0.001). CONCLUSION: Eyes with higher and lower levels of disease activity had poorer outcomes than eyes with moderate activity over 5 years, apparently because of the development of subretinal fibrosis or macular atrophy.

THREE-YEAR TREATMENT OUTCOMES OF AFLIBERCEPT VERSUS RANIBIZUMAB FOR DIABETIC MACULAR EDEMA: Data from the Fight Retinal Blindness! Registry.

PURPOSE: Compare the 3-year outcomes of ranibizumab versus aflibercept in eyes with diabetic macular edema in daily practice. METHODS: This was a retrospective analysis of naive diabetic macular edema eyes starting intravitreal injections of ranibizumab (0.5 mg) or aflibercept (2 mg) from January 1, 2013 to December 31, 2017 that were collected in the Fight Retinal Blindness! Registry. RESULTS: We identified 534 eyes (ranibizumab-267 and aflibercept-267) of 402 patients. The adjusted mean (95% confidence interval) visual acuity change of +1.3 (-0.1 to 4.2) letters in the ranibizumab group and +2.4 (-0.2 to 5.1) letters (P = 0.001) in the aflibercept group at 3 years was not clinically different. However, the adjusted mean CST change seemed to remain significantly different throughout the 3-year period with higher reductions in favor of aflibercept (-87.8 [-108.3 to -67.4] µm for ranibizumab vs. -114.4 [-134.4 to -94.3] for aflibercept; P < 0.01). When baseline visual impairment was moderate (visual acuity ≤68 Early Treatment Diabetic Retinopathy Study letters), we found a faster improvement in visual acuity in eyes treated with aflibercept up until 18 months of treatment than eyes treated with ranibizumab, which then stayed similar until 36 months of treatment, whereas there was no apparent difference when baseline visual impairment was mild (visual acuity ≥69 Early Treatment Diabetic Retinopathy Study letters). The rate of serious adverse events was low. CONCLUSION: Aflibercept and ranibizumab were both effective and safe for diabetic macular edema over 3 years.

ANALYSIS OF FLUID VOLUME AND ITS IMPACT ON VISUAL ACUITY IN THE FLUID STUDY AS QUANTIFIED WITH DEEP LEARNING.

PURPOSE: To investigate quantitative differences in fluid volumes between subretinal fluid (SRF)-tolerant and SRF-intolerant treat-and-extend regimens for neovascular age-related macular degeneration and analyze the association with best-corrected visual acuity. METHODS: Macular fluid (SRF and intraretinal fluid) was quantified on optical coherence tomography volumetric scans using a trained and validated deep learning algorithm. Fluid volumes and complete resolution was automatically assessed throughout the study. The impact of fluid location and volumes on best-corrected visual acuity was computed using mixed-effects regression models. RESULTS: Baseline fluid quantifications for 348 eyes from 348 patients were balanced (all P > 0.05). No quantitative differences in SRF/intraretinal fluid between the treatment arms was found at any study-specific time point (all P > 0.05). Compared with qualitative assessment, the proportion of eyes without SRF/intraretinal fluid did not differ between the groups at any time point (all P > 0.05). Intraretinal fluid in the central 1 mm and SRF in the 1-mm to 6-mm macular area were negatively associated with best-corrected visual acuity (-2.8 letters/100 nL intraretinal fluid, P = 0.007 and -0.20 letters/100 nL SRF, P = 0.005, respectively). CONCLUSION: Automated fluid quantification using artificial intelligence allows objective and precise assessment of macular fluid volume and location. Precise determination of fluid parameters will help improve therapeutic efficacy of treatment in neovascular age-related macular degeneration.

USING MICROPERIMETRY AND LOW-LUMINANCE VISUAL ACUITY TO DETECT THE ONSET OF LATE AGE-RELATED MACULAR DEGENERATION: A LEAD Study Report.

PURPOSE: To evaluate the performance of microperimetry and low-luminance visual acuity for detecting late age-related macular degeneration (AMD) onset. METHODS: Two hundred ninety-two individuals with bilateral large drusen in the Laser Intervention in the Early Stages of AMD study underwent best-corrected visual acuity, low-luminance visual acuity, and microperimetry testing as well as multimodal imaging to detect late (neovascular or atrophic) AMD onset. The performance of the change in the measurement from baseline of each of visual function test for detecting late AMD onset was compared. RESULTS: The area under the receiver operating characteristic curve for detecting neovascular and atrophic AMD onset was not significantly different for low-luminance visual acuity (area under the receiver operating characteristic curve = 0.71 and 0.56, respectively) and microperimetry (area under the receiver operating characteristic curve = 0.82 and 0.62, respectively) compared with best-corrected visual acuity (area under the receiver operating characteristic curve = 0.57 and 0.56, respectively; P ≥ 0.126 for all). There was also only a fair degree of agreement between the three visual function measures for detecting the onset of neovascular and atrophic AMD (κ ≥ 0.24). CONCLUSION: Microperimetry, low-luminance visual acuity, and best-corrected visual acuity demonstrate limited performance for detecting the earliest onset of late AMD. It remains to be established whether they perform better than current methods designed to enable self-detection of neovascular AMD onset, such as Amsler grid testing.

Macular Atrophy in Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial Comparing Ranibizumab and Aflibercept (RIVAL Study).

PURPOSE: To investigate differences in the development of macular atrophy (MA) over 24 months between treat-and-extend (T&E) ranibizumab and aflibercept in patients with neovascular age-related macular degeneration (nAMD). DESIGN: A phase 4 randomized, partially masked, multicenter study. PARTICIPANTS: Individuals 50 years of age or older diagnosed with active, treatment-naïve subfoveal choroidal neovascularization secondary to nAMD with baseline best-corrected visual acuity (BCVA) of 23 logarithm of minimum angle of resolution letters or more. METHODS: Patients were randomized 1:1 to receive either intravitreal injections of ranibizumab 0.5 mg or aflibercept 2.0 mg and were treated according to the same reading center-guided T&E regimen after 3 initial monthly injections. MAIN OUTCOME MEASURES: The primary outcome was mean change in square root area of MA from baseline to month 24. Key secondary outcomes included number of injections and mean change in BCVA from baseline to months 12 and 24. RESULTS: Two hundred seventy-eight patients were included in the analysis (ranibizumab 0.5 mg, n = 141; aflibercept 2.0 mg, n = 137). Mean change in square root area of MA from baseline to month 24 was +0.36 mm (95% confidence interval [CI], 0.27-0.45 mm) for ranibizumab and +0.28 mm (95% CI, 0.19-0.37 mm) for aflibercept (treatment difference, +0.08 mm [95% CI, -0.05 to 0.21 mm]; P = 0.24). The proportion of patients with MA increased from 7% (10/141) to 37% (43/117) for ranibizumab and from 6% (8/137) to 32% (35/108) for aflibercept from baseline to month 24. The average number of injections received per year was similar between both groups: 9.6 (95% CI, 9.2-10.0) for ranibizumab and 9.5 (95% CI, 9.1-9.9) for aflibercept. The mean change in BCVA from baseline to month 24 was +6.6 letters (95% CI,4.7-8.5 letters) for the ranibizumab group and +4.6 letters (95% CI, 2.7-6.6 letters) for the aflibercept group ( P = 0.15). Rates of adverse events (AEs) were similar between both groups. CONCLUSIONS: No significant differences in the rate of development or growth of MA over 24 months were observed between ranibizumab and aflibercept in nAMD patients treated using an identical T&E regimen.

Focal Scleral Nodule: A New Name for Solitary Idiopathic Choroiditis and Unifocal Helioid Choroiditis.

PURPOSE: To evaluate multimodal imaging findings of solitary idiopathic choroiditis (SIC; also known as unifocal helioid choroiditis) to clarify its origin, anatomic location, and natural course. DESIGN: Multicenter retrospective observational case series. PARTICIPANTS: Sixty-three patients with SIC in 1 eye. METHODS: Demographic and clinical data were collected. Multimodal imaging included color fundus photography, OCT (including swept-source OCT), OCT angiography (OCTA), fundus autofluorescence, fluorescein and indocyanine green angiography, and B-scan ultrasonography. MAIN OUTCOME MEASURES: Standardized grading of imaging features. RESULTS: Mean age at presentation was 56 ± 15 years (range, 12-83 years). Mean follow-up duration in 39 patients was 39 ± 55 months (range, 1 month-25 years). The lesions measured a mean of 2.4 × 2.1 mm in basal diameter, were located inferior (64%) or nasal to the optic disc, and appeared yellow (53%). No systemic associations were found. The lesions all appeared as an elevated subretinal mass, with OCT demonstrating all lesions to be confined to the sclera, not the choroid. On OCT, the deep lesion margin was visible in 12 eyes with a mean lesion thickness of 0.6 mm. Overlying choroidal thinning or absence was seen in 95% (mean choroidal thickness, 28 ± 35 µm). Mild subretinal fluid was observed overlying the lesions in 9 patients (14%). Retinal pigment epithelial disruption and overlying retinal thinning was observed in 56% and 57%, respectively. OCT angiography was performed in 13 eyes and demonstrated associated choroidal and lesional flow voids. Four lesions (6%) were identified at the macula, leading to visual loss in 1 patient. One lesion demonstrated growth and another lesion showed spontaneous resolution. CONCLUSIONS: In this largest series to date, multimodal imaging of SIC demonstrated a scleral location in all patients. The yellow and white clinical appearance may be related to scleral unmasking resulting from atrophy of overlying tissues. Additional associated features included documentation of deep margin on swept-source OCT, trace subretinal fluid in a few patients, and OCTA evidence of lesional flow voids. Because of the scleral location of this lesion in every patient, a new name, focal scleral nodule, is proposed.

PREVALENCE AND RISK FACTORS FOR THE DEVELOPMENT OF PHYSICIAN-GRADED SUBRETINAL FIBROSIS IN EYES TREATED FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To assess the prevalence and incidence of and risk factors for subretinal fibrosis (SRFi) in eyes with neovascular age-related macular degeneration (nAMD) that underwent vascular endothelial growth factor inhibitor treatment for up to 10 years. METHODS: A cross-sectional and longitudinal analysis was performed on data from a neovascular age-related macular degeneration registry. The presence and location of SRFi were graded by the treating practitioner. Visual acuity, lesion characteristics (type, morphology, and activity), and treatment administered at each visit was recorded. RESULTS: The prevalence of SRFi in 2,914 eyes rose from 20.4% at year interval 0-1 to 40.7% at year interval 9 to 10. The incidence in 1,950 eyes was 14.3% at baseline and 26.3% at 24 months. Independent characteristics associated with SRFi included poorer baseline vision (adjusted odds ratio 5.33 [95% confidence interval 4.66-7.61] for visual acuity ≤35 letters vs. visual acuity ≥70 letters, P < 0.01), baseline lesion size (adjusted odds ratio 1.08 [95% confidence interval 1.08-1.14] per 1000 µm, P = 0.03), lesion type (adjusted odds ratio 1.42 [95% confidence interval 1.17-1.72] for predominantly classic vs. occult lesions, P = 0.02), and proportion of active visits (adjusted odds ratio 1.58 [95% confidence interval 1.25-2.01] for the group with the highest level of activity vs. the lowest level of activity, P < 0.01). CONCLUSION: Subretinal fibrosis was found in 40% of eyes after 10 years of treatment. High rates of lesion activity, predominantly classic lesions, poor baseline vision, and larger lesion size seem to be independent risk factors for SRFi.

SMOKING STATUS AND TREATMENT OUTCOMES OF VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To assess whether smoking status affects 1-year visual outcomes in eyes treated with vascular endothelial growth factor inhibitors for neovascular age-related macular degeneration. METHODS: Retrospective analysis of data from a prospectively designed, multicenter, observational database. Nine hundred and eighty seven treatment-naive eyes of patients with neovascular age-related macular degeneration were tracked by the Fight Retinal Blindness! outcome registry in Australia, New Zealand, Singapore, and Switzerland who had documented smoking status at baseline and commenced vascular endothelial growth factor inhibitor therapy from January 2006 to December 2016. Generalized additive models were used to display visual acuity results. RESULTS: There was a significant difference in mean improvement in visual acuity at 12 months between nonsmokers, ex-smokers, and current smokers (7.7 vs. 6.1 vs. 3.5 letters of change; P = 0.046) among patients who completed 12 months of treatment when adjusted for age, baseline visual acuity, and choroidal neovascular membrane lesion type and nested for practice. There was no significant difference in the median number of injections over 12 months of treatment by smoking status. Current smokers were a mean of 6.2 years younger than nonsmokers when they started treatment (P < 0.001). CONCLUSION: This study found inferior 12-month visual outcomes in patients who continued to smoke while receiving vascular endothelial growth factor inhibitor therapy for neovascular age-related macular degeneration.

Four-week outcomes of vascular endothelial growth factor inhibitors for neovascular age-related macular degeneration.

IMPORTANCE: To assess early outcomes of intravitreal vascular endothelial growth factor (VEGF) inhibitor treatment in neovascular age-related macular degeneration (nAMD) before patients have a chance to miss or discontinue treatment. BACKGROUND: Intravitreal VEGF inhibitors used to treat nAMD have been compared in various ways. The present study compared the 4-week responses to the first injection of either aflibercept, bevacizumab, or ranibizumab. DESIGN: Observational study. PARTICIPANTS: Treatment-naïve nAMD patients with visual acuity (VA) taken 22 to 48 days after the first treatment with an intravitreal VEGF inhibitor. METHODS: An observational study from a prospectively designed database. MAIN OUTCOME MEASURES: VA change from baseline and proportion of eyes judged active 22 to 48 days after the first treatment. RESULTS: The overall mean (95% confidence interval [CI]) VA change at 4 weeks was +3.7 (3.3, 4.0) letters. No pairwise comparisons in crude VA change or VA change after multivariate adjustment between the three agents were significant. However, after multivariate adjustment, more eyes treated with bevacizumab (90%) had active disease 4 weeks after the first injection than ranibizumab (84%; P = .013) and aflibercept (82%; P = .004). Older age, higher baseline vision and larger lesions were associated with lower VA change. CONCLUSION: There was no significant difference in VA gains amongst all three drugs but ranibizumab and aflibercept seemed to be more efficacious in quelling disease activity 4 weeks after the first treatment. VA change after the first injection was driven largely by baseline characteristics such as age, baseline VA and lesion size.

Changes in real-world treatment patterns for diabetic macular oedema from 2009 to 2019 and 5-year outcomes: Data from the Fight Retinal Blindness! Registry.

IMPORTANCE: Evaluating the treatment outcomes of diabetic macular oedema (DMO) in routine clinical practice provides data for comparison with those of clinical trials. BACKGROUND: Phase 3 clinical trials of vascular endothelial growth factor (VEGF) inhibitors for DMO have reported significant improvements in visual acuity (VA) not previously reported with laser and steroid treatments. DESIGN: Retrospective analysis of observational data from routine clinical practice. PARTICIPANTS: Eyes receiving treatments for DMO tracked in the Fight Retinal Blindness! Registry. METHODS: We analysed 510 eyes (347 patients) that started DMO treatment between 2009 and 2014. MAIN OUTCOME MEASURES: Changes in DMO treatment patterns and mean change in VA (letters logMAR) and central subfield thickness (CST) 5 years after starting treatment. RESULTS: Treatment choice for DMO changed to predominantly VEGF inhibitors from 2009 to 2014. A total of 238 eyes (47%) were followed for at least 5 years. The mean VA at the start of treatment improved from 2009 (58 letters) to 2014 (68 letters) while mean VA change at 5 years were + 4.5 and + 5.3 letters for eyes starting treatment in 2009 and 2014, respectively. The mean CST dropped from 401 µm at baseline to 314 µm at 5 years. Eyes received a median of four injections in the first, two in the second, third and fourth and three in the fifth years. CONCLUSIONS AND RELEVANCE: Changing the treatment of DMO from macular laser and intravitreal triamcinolone to VEGF inhibitors from 2011 onwards was associated with better VA outcomes, part of which were due to better VA at the start of treatment. The outcomes of treatment in eyes in real-world practice were, however, worse than those reported by clinical trials, likely because they were undertreated.

Tolerating Subretinal Fluid in Neovascular Age-Related Macular Degeneration Treated with Ranibizumab Using a Treat-and-Extend Regimen: FLUID Study 24-Month Results.

PURPOSE: To test the hypothesis that tolerating some subretinal fluid (SRF) in patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab using a treat-and-extend (T&E) regimen can achieve similar visual acuity (VA) outcomes as treatment aimed at resolving all SRF. DESIGN: Multicenter, randomized, 24-month, phase 4, single-masked, noninferiority clinical trial. PARTICIPANTS: Participants with treatment-naïve active subfoveal choroidal neovascularization (CNV). METHODS: Participants were randomized to receive ranibizumab 0.5 mg monthly until either complete resolution of SRF and intraretinal fluid (IRF; intensive arm: SRF intolerant) or resolution of all IRF only (relaxed arm: SRF tolerant except for SRF >200 µm at the foveal center) before extending treatment intervals. A 5-letter noninferiority margin was applied to the primary outcome. MAIN OUTCOME MEASURES: Mean change in best-corrected VA (BCVA), and central subfield thickness and number of injections from baseline to month 24. RESULTS: Of the 349 participants randomized (intensive arm, n = 174; relaxed arm, n = 175), 279 (79.9%) completed the month 24. The mean change in BCVA from baseline to month 24 was 3.0 letters (standard deviation, 16.3 letters) in the intensive group and 2.6 letters (standard deviation, 16.3 letters) in the relaxed group, demonstrating noninferiority of the relaxed compared with the intensive treatment (P = 0.99). Similar proportions of both groups achieved 20/40 or better VA (53.5% and 56.6%, respectively; P = 0.92) and 20/200 or worse VA (8.7% and 8.1%, respectively; P = 0.52). Participants in the relaxed group received fewer ranibizumab injections over 24 months (mean, 15.8 [standard deviation, 5.9]) than those in the intensive group (mean, 17 [standard deviation, 6.5]; P = 0.001). Significantly more participants in the intensive group never extended beyond 4-week treatment intervals (13.5%) than in the relaxed group (2.8%; P = 0.003), and significantly more participants in the relaxed group extended to and maintained 12-week treatment intervals (29.6%) than the intensive group (15.0%; P = 0.005). CONCLUSIONS: Patients treated with a ranibizumab T&E protocol who tolerated some SRF achieved VA that is comparable, with fewer injections, with that achieved when treatment aimed to resolve all SRF completely.

Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial.

PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.

RANIBIZUMAB AND AFLIBERCEPT FOR THE TREATMENT OF PIGMENT EPITHELIAL DETACHMENT IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Data from an Observational Study.

PURPOSE: To assess the effect of intravitreal ranibizumab and aflibercept on retinal pigment epithelial detachment (RPED) in patients with neovascular age-related macular degeneration. METHODS: This was a retrospective analysis of data from a prospectively designed and implemented clinical audit. Analysis included change in RPED dimensions and visual acuity in 92/233 treatment-naive eyes with neovascular age-related macular degeneration and RPED 6 months after treatment with either aflibercept or ranibizumab. RESULTS: There was no significant between-group difference in the adjusted mean change for maximum RPED height (P = 0.195), diameter (P = 0.522) or visual acuity (P = 0.836) at 6 months. Injection frequency was the only clinical variable that affected RPED height (P = 0.050) and visual acuity change for both treatment groups (P = 0.004). Around 30% of eyes in each group had complete resolution of RPED at 6 months. CONCLUSION: Eyes with neovascular age-related macular degeneration and RPED showed significant functional and anatomical responses after 6 months of intravitreal anti-vascular endothelial growth factor injections. However, we found no significant difference in anatomical response or change in visual acuity between eyes treated with ranibizumab compared with aflibercept. Larger, prospectively designed, randomized studies with longer term follow-up may identify a difference between the two drugs that we did not detect.

TWO YEAR OUTCOMES OF "TREAT AND EXTEND" INTRAVITREAL THERAPY USING AFLIBERCEPT PREFERENTIALLY FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To report 24-month outcomes of a treat and extend (T&E) regimen using aflibercept in eyes with neovascular age-related macular degeneration. METHODS: This was a database observational study that included treatment-naive eyes with neovascular age-related macular degeneration tracked by the Fight Retinal Blindness! outcome registry completing 24 months of sole monotherapy with aflibercept treatment under a T&E regimen between November 1, 2012 and January 31, 2014. Locally weighted scatterplot smoothing curves were used to display visual acuity outcomes. Main outcome measures were change in visual acuity at 24 months and number of injections and visits during the study period. RESULTS: The study population, identified by reviewing the database, consisted of 136 eyes from 123 patients completing 24 months of follow-up on aflibercept. Mean (SD) age was 77.2 (7.0) years, 59% were female. Mean visual acuity increased from 61.4 (∼20/60; SD 17.4) letters at baseline to 67.4 (∼20/45; SD 17.7) letters at 24 months (+6.0 letters [95% confidence interval: 3.3-8.5]; P < 0.001). From baseline to 24 months, the proportion of eyes with visual acuity ≥70 letters (20/40) increased (40%-58%, P < 0.001) and the proportion of eyes with visual acuity ≤35 letters (20/200) remained the same (10%; P = 0.547). Ninety-eight per cent of eyes starting with visual acuity ≥70 letters (20/40) were able to maintain this up to 24 months. From the first to the second year of treatment, the mean number of injections (7.8 [2.1] vs. 5.7 [2.6]; P < 0.001) and visits (8.7 [1.7] vs. 6.5 [2.4]; P < 0.001) decreased for eyes completing 24 months of treatment. When data from 60 eligible eyes that did not complete 2 years follow-up, along with 14 eyes that switched to ranibizumab, were included using last observation carried forward, the mean change in visual acuity from baseline was +5.6 letters (95% confidence interval: 3.3-7.7). CONCLUSION: These data indicate that eyes treated with aflibercept, as a sole therapy, in routine clinical practice with a T&E regimen can achieve good visual outcomes while decreasing the burden of treatments and clinic visits.

Myopic Choroidal Neovascularization: Review, Guidance, and Consensus Statement on Management.

TOPIC: The aim of this article is to review and compile available information on the classification, pathophysiology, and clinical features of myopic choroidal neovascularization (CNV); to describe the latest data on the management of this disease; and to present guidance. CLINICAL RELEVANCE: In the United States, myopia affects approximately 34 million people (2010), and similar figures have been reported in Europe. Pathologic myopia (PM), a possible consequence of myopia, is estimated to affect up to 3% of the global population. One of the most serious complications of PM is myopic CNV, which often leads to a sudden onset but progressive decline in central vision and is associated with a poor prognosis unless treated. Furthermore, 35% of patients with myopic CNV develop bilateral disease in the fellow eye within 8 years. Although intravitreal anti-vascular endothelial growth factor (VEGF) therapies have had a major impact on the management of patients with myopic CNV, there remain significant gaps in our understanding of this condition and how to best administer treatment. Additionally, the long-term safety and efficacy of these treatments are largely unknown. METHODS: We carried out a literature review (September 2015) of all English-language articles in PubMed resulting from searches of the following terms: "choroidal neovascularization" AND "myopia" OR "myopic macular degeneration" OR "degenerative myopia" OR "myopic maculopathy" OR "myopic retinopathy" OR "pathological myopia" OR "pathologic myopia." RESULTS: We screened a total of 566 abstracts, and 250 articles were deemed relevant for full publication review. We excluded a further 71, but an additional 44 articles were identified. This resulted in 223 articles being used to develop this review. CONCLUSIONS: Highly myopic patients experiencing a sudden loss of central vision should be referred for further examination. Once a diagnosis of myopic CNV has been confirmed, after fluorescein angiography, treatment initiation should be prompt and anti-VEGF agents considered as first-line therapy, unless contraindicated. Continued monitoring of patients is required to assess any progression or recurrence of the condition.

Twelve-Month Outcomes of Ranibizumab vs. Aflibercept for Neovascular Age-Related Macular Degeneration: Data from an Observational Study.

PURPOSE: To directly compare visual acuity (VA) outcomes with ranibizumab vs. aflibercept for eyes with neovascular age-related macular degeneration (nAMD) treated in routine clinical practice. DESIGN: Database observational study. PARTICIPANTS: Treatment-naïve eyes with nAMD tracked by the Fight Retinal Blindness outcome registry that commenced anti-vascular endothelial growth factor therapy with ranibizumab or aflibercept between December 1, 2013, and January 31, 2015. Eyes were matched at baseline for VA, age, and choroidal neovascular membrane (CNV) size. METHODS: Locally weighted scatterplot smoothing curves were used to display VA results. Eyes that switched or discontinued treatment were included with their last observation carried forward. MAIN OUTCOME MEASURES: Change in mean VA (number of letters read on a logarithm of the minimum angle of resolution chart); number of injections and visits; proportion of eyes with inactive CNV over 12 months. RESULTS: We identified 394 eyes (197 treated with ranibizumab and 197 with aflibercept) from 372 patients who received treatment from 34 practitioners. Baseline parameters were well matched. The mean (standard deviation [SD]) VA of ranibizumab-treated eyes increased from 58.6 (20.3) letters at baseline to 62.3 (23.9) (+3.7 [95% confidence interval {CI} 1.4-6.1]) letters (P = 0.001), compared with 58.9 (19.2) letters at baseline to 63.1 (21.5) (+4.26 [95% CI 2.0-6.5]) letters (P < 0.001) for eyes receiving aflibercept. The difference in change in crude VA of 0.6 letters between the 2 groups was not statistically significant (P = 0.76), nor was the difference in adjusted mean VA of the 2 groups (P = 0.26). In completers, the mean (SD) numbers of injections (8.1 [2.1] vs. 8.0 [2.3]; P = 0.27) and visits (9.6 [3.0] vs. 9.5 [3.1]; P = 0.15) did not differ between the 2 groups. The adjusted proportion of eyes in which the CNV lesion was graded as inactive during the study was similar between the eyes receiving ranibizumab and aflibercept (74% vs. 77%, respectively; P = 0.63). CONCLUSIONS: Visual acuity outcomes at 12 months did not differ between ranibizumab and aflibercept used for nAMD in this large observational study, nor was a difference in treatment frequency found.

Treatment Patterns and Visual Outcomes during the Maintenance Phase of Treat-and-Extend Therapy for Age-Related Macular Degeneration.

PURPOSE: To present the treatment patterns, disease activity, and visual outcomes of eyes in the maintenance phase of a treat-and-extend regimen for neovascular age-related macular degeneration (nAMD). To compare the maintenance phase behavior of eyes with a shorter induction phase (≤3 injections) with those requiring a longer induction phase (>3 injections). DESIGN: Database observational study. PARTICIPANTS: Eyes with nAMD receiving anti-vascular endothelial growth factor (VEGF) treatment using a treat-and-extend protocol. Persistently active eyes were excluded, as were eyes with <12 months follow-up during the maintenance phase. METHODS: Clinical information from a large prospective international voluntary registry of nAMD was analyzed. The maintenance phase was defined as starting at the first clinician-reported grading of lesion inactivity. MAIN OUTCOME MEASURES: For analyses by eye: treatment interval at first reactivation; time to first reactivation; and visual acuity change during the study period. For analyses by visit: choroidal neovascular membrane activity graded by the treating physician; time since previous injection; and visual acuity loss since previous injection (>0 letters and ≥15 letters). RESULTS: The mean change in visual acuity during the maintenance phase was +1.0 letters at 12 months -0.6 letters at 24 months and -1.5 at 36 months. Median treatment interval increased from 35 days at study entry to 63 days at 12 months and was 60 days at 36 months. 38.5% of eyes remained inactive at all observed visits during the maintenance phase (minimum 1 year follow-up, mean 945 days). The most common treatment interval at first reactivation was 8 weeks. Treatment intervals beyond 12 weeks seemed to be associated with increased risk of disease reactivation, with risk of reactivation reaching 37.4% at treatment intervals of ≥20 weeks. Eyes with a longer induction phase had worse visual outcomes in the maintenance phase, and earlier and more-frequent disease reactivation, although they received injections less frequently. CONCLUSIONS: The detailed behavior of eyes in the maintenance phase of treat-and-extend management for nAMD is presented. Visual acuity was well maintained during the study period. The most common interval at which reactivation first occurred was 8 weeks. Longer duration of induction phase was associated with worse visual acuity outcomes and earlier disease reactivation, perhaps because of undertreatment.

The role of sub-retinal fluid in determining treatment outcomes in patients with neovascular age-related macular degeneration--a phase IV randomised clinical trial with ranibizumab: the FLUID study.

BACKGROUND: With increasing experience using anti-VEGF therapy for the treatment of neovascular age-related macular degeneration (nAMD), ophthalmologists have shifted away from a "one size fits all" to an "individualised" approach based on disease activity with the aim of achieving a fluid-free retina. The FLUID study investigates the non-inferiority of a Treat and Extend (T&E) protocol of 0.5 mg ranibizumab, which allows treatment extension in the presence of incomplete resolution of sub-retinal fluid (SRF) ≤200 µm at the foveal centre relative to a T&E protocol that requires complete resolution of all retinal fluid (i.e., both SRF and intra-retinal fluid [IRF]) in patients with nAMD. METHODS/DESIGN: This 24 month, randomised, phase IV trial has completed recruitment of treatment-naïve patients randomised 1:1 to ranibizumab "intensive" treatment (complete resolution of IRF and SRF) or ranibizumab "relaxed" treatment (resolution of IRF or >200 µm SRF only at foveal centre). Patients in both arms follow a T&E regimen where extension decisions are based upon assessment of lesion activity: loss of ≥5 letters of visual acuity, new haemorrhage, presence of IRF and SRF on an optical coherence tomography (OCT) scan. The determination of SRF is conducted at a reading centre while the assessment of IRF is physician-determined. The primary endpoint is the mean change in best-corrected visual acuity (BCVA) from baseline to 24 months. Secondary endpoints include the mean change in central retinal thickness (CRT) from baseline to 12 and 24 months, the number of ranibizumab injections administered at 12 and 24 months, and the pharmacogenomic assessment of AMD Gene Consortium-identified single-nucleotide polymorphisms (SNPs) and their association with treatment response. Three hundred and forty seven (347) patients have been recruited by 16 Australian sites within approximately 16 months. A protocol to adjudicate on SRF has been established by the central reading centre and is demonstrating good concordance with investigator assessment. DISCUSSION: This study will provide important insights into retreatment criteria for managing nAMD using a T&E regimen. The current paper describes the clinical rationale for using a less intensive treatment approach using ranibizumab and details of the treatment protocol. TRIAL REGISTRATION NUMBER: NCT01972789. Date of registration: 24th October 2013.

Time to initial clinician-reported inactivation of neovascular age-related macular degeneration treated primarily with ranibizumab.

PURPOSE: To characterize in more detail routine treatment patterns of intravitreal ranibizumab for neovascular age-related macular degeneration (nAMD), we analyzed the length of time and the number of injections required until lesions with choroidal neovascularization (CNV) were first graded inactive. DESIGN: Database observational study. PARTICIPANTS: Treatment-naïve eyes receiving predominantly ranibizumab for nAMD in routine clinical practice that were tracked in the Fight Retinal Blindness! observational registry. METHODS: Eyes treated with ranibizumab were followed until CNV was first reported to be "inactive" (i.e., absence of intraretinal fluid and hemorrhages). MAIN OUTCOME MEASURES: The length of time until lesion inactivation occurred and the number of injections required. RESULTS: A total of 1096 eyes (65.8% from women) were included in the study. The median number of weeks until a lesion was graded as inactive after beginning treatment was 15 weeks. One to 3 injections were sufficient to inactivate the lesion in 61.1% of eyes. A mean change in visual acuity of +5.5 logarithm of the minimum angle of resolution letters (95% confidence interval, 4.8-6.3) was found from treatment initiation to the time that eyes were reported as inactive. In eyes with a mean treatment frequency less than every 5.3 weeks, a median of only 3 injections (mean=3.7) were required before lesions with CNV were graded as inactive, but if the mean treatment interval extended beyond 5.3 weeks, the median number of injections required increased sharply to 6 injections (mean, 7 injections). Occult lesions became inactive more slowly than classic lesions. CONCLUSIONS: Most lesions with CNV became inactive with 3 injections of ranibizumab, but a small proportion remained active for more than 12 months. Injection frequency and lesion type were the main factors that predicted the time and number of injections required to render lesions inactive.

Two-year outcomes of "treat and extend" intravitreal therapy for neovascular age-related macular degeneration.

PURPOSE: To report 24-month outcomes of anti-vascular endothelial growth factor (VEGF) therapy for treatment-naïve eyes with neovascular age-related macular degeneration (nAMD) using a treat and extend treatment regimen in routine clinical practice. DESIGN: Database observational study. PARTICIPANTS: We included treatment-naïve eyes receiving predominantly ranibizumab for nAMD in routine clinical practice treated using a treat and extend regimen that were tracked in the Fight Retinal Blindness observational registry. METHODS: A cohort of eyes treated by practitioners using exclusively a treat and extend regimen was extracted from the Fight Retinal Blindness observational registry. MAIN OUTCOME MEASURES: Change in visual acuity (VA) over 2 years and number of injections and visits. RESULTS: Data from 1198 eyes from 1011 patients receiving anti-VEGF therapy using a treat and extend regimen for treatment-naïve nAMD between January 2007 and December 2012 and with 24-month follow-up were included in the analysis. Mean VA increased by +5.3 logarithm of the minimum angle of resolution letters from 56.5 letters (20/80+1) at initial visit to 61.8 (20/60+2) letters at 24 months. Mean VA gains improved and number of injections increased with successive years from +2.7 letters for eyes commencing in 2007 after a mean of 9.7 injections in 2 years, to +7.8 letters for eyes commencing in 2012 after a mean of 14.2 injections over 2 years. The proportion of eyes with VA >20/40 increased from 27% when starting treatment to 45% after 24 months; the proportion with vision of <20/200 remained unchanged (13% initial, 11% at 24 months). Of the included eyes, 90.5% avoided a vision loss of ≥15 letters. There was an overall mean of 13.0 injections over the 24 months, 7.5 injections in the first year and 5.5 in the second year, with a mean of 14.8 clinic visits. CONCLUSIONS: These data indicate that eyes managed in routine clinical practice with a treat and extend regimen can achieve good visual outcomes while decreasing the burden of treatments and clinic visits.