Early Treatment Diabetic Retinopathy Study Letters Research Articles

2-Year Real-World Outcomes with Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: Literature Review and Meta-analysis of Patient-Relevant Outcomes.

BackgroundThe 96 weeks’ assessment from the VIEW studies provided insights into the long-term efficacy of intravitreal aflibercept (IVT-AFL) in neovascular age-related macular degeneration (nAMD) and demonstrated that it was possible to maintain long-term outcomes while moving from a fixed bimonthly regimen in Year 1 to a variable dosing regimen in Year 2. The aim of this analysis was to perform a literature review and meta-analysis assessing the use of IVT-AFL and real-world outcomes in treatment-naïve patients with nAMD treated with IVT-AFL for 2 years, as per label.MethodsA literature review and meta-analysis were performed to provide an overview of the baseline characteristics of the population, the 2-year outcomes, the associated treatment burden, and safety.ResultsEleven publications providing data from patients with nAMD who had treatment initiated with IVT-AFL between 2012 and 2016 were identified. The mean baseline age of patients was 78.62 years, with a baseline best-corrected visual acuity (BCVA) of 57.73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Patients reported a mean BCVA at 2 years of 62.55 ETDRS letters, with 47.39% of patients having a BCVA ≥ 70 ETDRS letters. Mean gain in BCVA versus baseline was + 4.49 ETDRS letters for the combined population (+ 5.91 letters for patients treated with a treat-and-extend regimen). Over the 2 years of the study, patients received an average of 12.34 injections, with a reduction in injections in Year 2 versus Year 1. The qualitative assessment of the safety data suggested that no new safety signals were identified.ConclusionPatients treated with IVT-AFL reported significant gains in visual acuity versus baseline after 2 years. The evidence identified indicates that the visual gains achieved during the first year of treatment are maintained through the second year and that these were achieved with a reduction in the mean number of IVT-AFL injections administered in Year 2 of treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40123-021-00350-5.

Clinical Characteristics and Outcomes of Eyes with Intraocular Inflammation after Brolucizumab: Post Hoc Analysis of HAWK and HARRIER

This analysis of the pivotal phase 3 HAWK and HARRIER trials aimed to provide insights on the timing of presentation, management, and outcomes of intraocular inflammation (IOI)-related adverse events (AEs), as reported by investigators in these trials. Post hoc analysis of investigator-reported IOI-related AEs in HAWK and HARRIER. Of 1088 brolucizumab-treated eyes (3 or 6 mg), 49 eyes demonstrated at least 1 IOI-related AE and were included in this analysis. Reports of IOI-related AEs were analyzed and descriptive statistics were provided for outcome measures. Incidence and description of eyes with IOI-related AEs, timing of presentation, management, clinical outcomes, and brolucizumab treatment after the first IOI-related AE. Seventy IOI-related AEs were reported in 49 eyes. Before the onset of first IOI-related AE, eyes received a mean ± standard deviation (SD) of 3.9 ± 2.2 brolucizumab injections. Median time to first IOI-related AE from the last administered brolucizumab injection was 18.0 days (interquartile range, 4.0-29.0 days). Of the 70 AEs, 61 (87.1%) were treated, most with topical corticosteroids; systemic and intraocular corticosteroids were used for 3 AEs each. Overall, inflammation resolved completely in 39 eyes (79.6%), resolved with sequelae in 5 eyes (10.2%), and did not resolve in 5 eyes (10.2%) by end-of-study (EOS). Overall, the mean ± SD best-corrected visual acuity (BCVA) change from baseline to EOS, before AE to the lowest BCVA in 3 months after AE, and from before AE to EOS were -0.84 ± 20.6 , -16.31 ± 17.6, and -0.22 ± 18.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, respectively. Of the 36 eyes (73.5%) that continued with brolucizumab therapy after the first IOI-related AE, 24 completed the trials and 12 discontinued; mean ± SD BCVA change in these eyes was 2.6 ± 17.6, 7.8 ± 13.2, and -7.7 ± 21.3 ETDRS letters, respectively, from baseline to EOS. The remaining 13 eyes (26.5%) were not treated with brolucizumab after first IOI-related AE and showed a mean ± SD BCVA change of -10.4 ± 25.5 ETDRS letters from baseline to EOS. Findings of this analysis highlight the need for continued vigilance and monitoring for any signs of IOI-related events in patients receiving brolucizumab.

Long-term outcomes of intravitreal therapy for symptomatic diabetic macular oedema in a real-world setting in Switzerland

ObjectiveTo assess the long-term visual outcomes in eyes with symptomatic diabetic macular oedema (DME) under intravitreal treatment (IVT) in a clinical routine setting.MethodsPatients with newly diagnosed DME were included in this retrospective study if they had received at least three IVTs and a follow-up period ≥ 2 years. Due to altered treatment patterns since the approval of ranibizumab for DME in 2012, patients were subdivided according to their first IVT before 2013 (group 1) or thereafter (group 2). The primary outcome measure was the evolution of best-corrected visual acuity (BCVA) over time.ResultsOf 217 eyes (191 patients) with DME, 151 eyes (117 patients) fulfilled the inclusion criteria (63 eyes in the first period, 88 in the second period). Mean follow-up time was 7.9 ± 3.1 (group 1) and 4.1 ± 1.4 years (group 2; p < 0.001). Visual gains were similar in the first year (group 1: + 5.3 ± 15.5, group 2: + 7.3 ± 12.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters; p = 0.44), but not thereafter (after 2 years in group 1: + 4.4 ± 15.0, group 2: + 8.3 ± 13.0 ETDRS letters; p = 0.038). During the first year, group 1 patients received less clinical examinations (group 1: 6.6 ± 3.3, group 2: 7.5 ± 2.1; p = 0.007) and less injections (group 1: 3.6 ± 2.7, group 2: 6.1 ± 2.7; p < 0.001).ConclusionA greater visual gain, in response to more intensive treatment during the first year, was maintained for at least 5 years in group 2 subjects. Our data confirm that in a real-world setting, early intensive treatment results in satisfying long-term visual outcomes.

Efficacy and Safety of Biosimilar FYB201 Compared with Ranibizumab in Neovascular Age-Related Macular Degeneration

This trial was conducted to investigate the clinical equivalence of the proposed biosimilar FYB201 and reference ranibizumab in patients with treatment-naive, subfoveal choroidal neovascularization caused by neovascular age-related macular degeneration (nAMD). This was a prospective, multicenter, evaluation-masked, parallel-group, 48-week, phase III randomized study. A total of 477 patients were randomly assigned to receive FYB201 (n= 238) or reference ranibizumab (n= 239). Patients received FYB201 or reference ranibizumab 0.5 mg by intravitreal (IVT) injection in the study eye every 4 weeks. The primary end point was change from baseline in best-corrected visual acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 8 weeks before the third monthly IVT injection. Biosimilarity of FYB201 to its originator was assessed via a 2-sided equivalence test, with an equivalence margin in BCVA of 3 ETDRS letters. The BCVA improved in both groups, with a mean improvement of+5.1 (FYB201) and+5.6 (reference ranibizumab) ETDRS letters at week 8. The analysis of covariance (ANCOVA) least squares mean difference for the change from baseline between FYB201 and reference ranibizumab was -0.4 ETDRS letters with a 90% confidence interval (CI) of -1.6 to 0.9. Primary end point was met as the 90% CI was within the predefined equivalence margin. Adverse events were comparable between treatment groups. FYB201 is biosimilar to reference ranibizumab in terms of clinical efficacy and ocular and systemic safety in the treatment of patients with nAMD.

Prevalence of Vitreoretinal Interface Disorders in an Australian Population: The Blue Mountains Eye Study.

PurposeTo describe the prevalence, risk factors, and associations of vitreoretinal interface (VRI) abnormalities in a population-based study of older adults.DesignCross-sectional analysis of cohort study participants.ParticipantsOf the 1149 participants (mean age, 76.1 ± 6.9 years) in the 15-year Blue Mountains Eye Study follow-up examination from 2007 through 2009, 905 (1791 eyes) had gradable time-domain or spectral-domain OCT scans of the macula from at least 1 eye.MethodsOCT scans were graded according to the International Vitreomacular Traction Study Group classification system of VRI abnormalities. Best-corrected visual acuity (BCVA) was recorded.Main Outcome MeasuresPrevalence of VRIs.ResultsOverall, 451 participants showed any VRI abnormality (49.8%). Prevalence of VRI abnormality by person was: vitreomacular adhesion (VMA), 33.6%; vitreomacular traction (VMT), 1.6%; epiretinal membrane (ERM), 21.4%; full-thickness macular hole (FTMH), 0.7%; and lamellar macular hole (LMH), 0.7%. Twenty-two percent of VMAs were focal, and 78% were broad based; 76% of VMTs were focal, and 24% were broad based. All FTMHs observed were large (>400 μm), with mean aperture size of 573 μm (range, 459–771 μm). Increased age was associated with higher ERM and lower VMA prevalence (P < 0.001 for both). Pseudophakia and myopia were associated with ERM (age- and sex-adjusted odds ratios [ORs], 1.48 [95% confidence interval (CI), 1.01–2.17] and 1.72 [95% CI, 1.05–2.81], respectively). Moderate or severe ERM and FTMH were associated with worse BCVA of 9.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% CI, 3.4–15.0 ETDRS letters; P = 0.008) and 26.0 ETDRS letters (95% CI, 10.9–41.1 ETDRS letters; P = 0.001), respectively.ConclusionsThe prevalence of VRI abnormalities is high in older individuals. Epiretinal membrane was associated with increasing age, pseudophakia, and myopia. Epiretinal membrane and FTMH may account for significant visual loss in the affected eye. This study provided useful population-based data on the prevalence of VRI abnormalities in older individuals.

Recurrent Neovascular Age-Related Macular Degeneration after Discontinuation of Vascular Endothelial Growth Factor Inhibitors Managed in a Treat-and-Extend Regimen

To investigate the recurrence rate of active macular neovascularization in patients with neovascular age-related macular degeneration (nAMD) previously followed up in a treat-and-extend (TE) regimen in which treatment had been stopped because of disease stability. Prospective cohort study. One hundred five patients with nAMD previously followed up in a TE regimen treated with aflibercept injections. All patients with a dry macula on 3 consecutive visits 12 weeks apart were eligible to participate in the study. Patients were examined at baseline and then monitored for disease recurrence 4, 6, 8, 10, and 12 months after the last injection. The proportion of patients with recurrent disease within 12 months after the last injection. Change in best-corrected visual acuity (BCVA) at the time of recurrence and after resumed therapy. Evidence of recurrent nAMD was seen in 54 of 102 patients (52.9%) after 12 months of follow-up. The mean time to recurrence after the last injection was 6.7 ± 2.2 months. The BCVA decreased from 71.7 ± 10.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline to 68.1 ± 11.1 ETDRS letters at the recurrence (P= 0.12). After treatment resumed, BCVA increased to 71.4 ± 10.0 ETDRS letters (P= not significant compared with baseline). Patients with a pigment epithelial detachment (PED) at baseline showed a 74% (14/19) recurrence rate compared with 48% (40/83) in patients without a PED (P < 0.05). Only 22 of 54 patients (40.7%) with recurrent disease showed symptoms of visual loss or metamorphopsia. Recurrent nAMD is common in previously stable patients for whom anti-VEGF injections have been suspended. It is difficult to predict which patients will experience a recurrence, and most of these patients do not show symptoms in the early stages of reactivation. Long-term follow-up is important, and early detection of recurrent disease can improve the chances for maintained visual function.

Surgery for idiopathic epiretinal membrane.

Epiretinal membrane is an abnormal sheet of avascular fibrocellular tissue that develops on the inner surface of the retina. Epiretinal membrane can cause impairment of sight as a consequence of progressive distortion of retinal architecture. To determine the effects of surgery compared to no intervention for epiretinal membrane. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, EmbaseOvid, ISRCTN registry, US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). There were no restrictions to language or year of publication. The databases were last searched on 20 May 2020. We included randomised controlled trials (RCTs) assessing surgical removal of idiopathic epiretinal membrane compared to placebo, no treatment or shamtreatment. Paired or within-person studies were included, as well as those where both eyes of a single participant were treated. We used standard methods expected by Cochrane, and assessed certainty using the GRADE system. We considered the following five outcome measures: mean change in best corrected visual acuity (BCVA) in the study eye between baseline (before randomisation), 6 months and 12 months later; proportion of people with a gain of 0.3 logMAR or more of visual acuity in the study eye as measured by a logMAR chart at a starting distance of 4 m at 6 months and 12 months after randomisation; proportion of people with a loss of 0.3 logMAR or moreof visual acuity in the study eye as measured by a logMAR chart at a starting distance of 4 m at 6 months and 12 months after randomisation; mean quality of life score at 6 months and 12 months following surgery, measured using a validated questionnaire; and any harm identified during follow-up. We included one study in the review. This was a RCT including 53 eyes of 53 participants with mild symptomatic epiretinal membraneand BCVA of 65 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Participants were randomly allocated to immediate surgery or to watchful waiting with deferred surgery if indicated by evidence of disease progression. The study was limited by imprecision owing to the small number of participants and was at some risk of bias owing to inconsistencies in the time points for outcome assessment and in the management of lens opacity. At 12 months, the visual acuity in the immediate surgery group was higher by a mean of 2.1 (95% confidence interval (CI) -2.0 to 6.2 ETDRS letters; 53 participants; low-certainty evidence) than the watchful waiting/deferred surgery group. The evidence of the effect of immediate surgery on gains of 0.3 logMAR or more of visual acuity is very uncertain (risk ratio (RR) 0.55, 95% CI 0.06 to 4.93; 53 participants; very low-certainty evidence). At 12 months, no participant in either group sustained a loss of 0.3 logMAR or more of visual acuity(53 participants; low-certainty evidence). The included study did not measure quality of life. At 12 months, no serious adverse event was identified in any participant. One participant developed chronic minimal cystoid macular oedema following immediate surgery (53 participants; low-certainty evidence). We found no RCT that directly investigated the effect of surgery compared to no intervention. For severe disabling epiretinal membrane, the lack of a RCT comparing surgery to no intervention may reflect evidence from non-randomised studies in favour of surgery; a RCT may be considered unnecessary and ethically unacceptable because a superior effect of surgery is widely accepted. For mild symptomatic epiretinal membrane, however, the value of surgery is uncertain. Low-certainty evidence from this review suggests that watchful waiting or deferred surgery may offer outcomes as favourable as immediate surgery. However, this finding needs to be confirmed in further RCTs with appropriate statistical power, masking of treatment allocation, consistent management of cataract, and measurement of outcomes including patient-reported quality of life over a more extended time frame.

Outcomes of macular buckling surgery in myopic foveal detachment eyes with and without disrupted ellipsoid zone band: a case-control study.

To compare the outcomes of macular buckling (MB) surgery between myopic foveal detachment (FD) eyes with and without ellipsoid zone (EZ) disruption. A retrospective, case-control study. Forty-four consecutive eyes from 44 patients received MB surgery for myopic FD between November 2017 and January 2019 were included. The eyes were divided into two groups according to the integrity of EZ on spectral-domain optical coherence tomography (SD-OCT): 28 eyes with disrupted EZ band and 16 eyes with intact EZ band. Main outcome measures were visual acuity and the duration of subfoveal fluid (SFF) after MB. The mean follow-up time was 17.64 ± 6.61 and 16.06 ± 5.78 months in the disrupted EZ and intact EZ group, respectively (P = 0.430). The logMAR best-corrected visual acuity (BCVA) improved significantly, from 1.13 ± 0.46 and 1.12 ± 0.39 at baseline to 0.85 ± 0.65 (P = 0.002) and 0.53 ± 0.33 (P = 0.000) for the disrupted EZ group and intact EZ group, respectively. The mean visual improvement was 15.00 ± 14.14 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for the disrupted EZ group and 26.88 ± 19.48 ETDRS letters for the intact EZ group. Significant difference was found on both final postoperative BCVA (P = 0.035) and visual improvement (P = 0.025). At 6 months, SFF remained in 53.57% (15/28) of the eyes in the disrupted EZ group and in only 12.50% (2/16) of the eyes in the intact EZ group (P = 0.018). The intact EZ group showed better functional and anatomical outcomes than the disrupted EZ group after MB surgery.

Asymmetric response to ranibizumab in mixed choroidal neovascularization in a neovascular age-related macular degeneration diagnosed on OCT angiography \u2013 case report

BackgroundTo present a case report of a patient with a mixed choroidal neovascular membrane (CNV) with an asymmetric response to ranibizumab diagnosed on optical coherence tomography angiography (OCTa).Case presentationA 61-year-old male was referred to our department in September 2017 due to decreased vision in his left eye. Best-corrected visual acuity (BCVA) was 43 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the left eye. Macular edema was present in the left eye, and a mixed CNV was identified on the OCTa. Therapy with intravitreal ranibizumab was commenced. After 5 ranibizumab injections, the BCVA was 42 ETDRS letters, and considerable intraretinal edema was still present. OCTa showed a resolution of the type 2 lesion of the mixed CNV; however, the type 1 lesion had continued to grow. The patient was then switched to intravitreal aflibercept. After 3 monthly aflibercept injections, the BCVA improved to 53 ETDRS letters, and a reduction of the edema was observed on the optical coherence tomography (OCT). OCTa showed a decrease in both the area and vessel density in the type 1 lesion of the CNV. Therapy with aflibercept was continued; however, while the intraretinal edema continued to improve, atrophy developed in the macula and the BCVA worsened to 43 ETDRS letters.ConclusionsRanibizumab nonresponse in a neovascular age-related macular degeneration is not uncommon. However, to our knowledge, this is the first described case of an asymmetric response to ranibizumab in a mixed CNV. While the type 2 lesion of the CNV reacted swiftly to the ranibizumab therapy, the type 1 lesion continued to grow. As with some other cases of ranibizumab resistance, switching to aflibercept proved effective.

End-of-Study Results for the Ladder Phase 2 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration

To report the end-of-study results from the Ladder clinical trial of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). Multicenter, randomized, active treatment-controlled phase 2 clinical trial. Patients diagnosed with nAMD with a documented response to anti-vascular endothelial growth factor treatment who received study treatment (N= 220). Patients were randomized 3:3:3:2 to treatment with the PDS filled with ranibizumab 10-mg/ml, 40-mg/ml, and 100-mg/ml formulations or monthly intravitreal ranibizumab 0.5-mg injections. End-of-study results for the time to first meeting refill criteria (first refill), mean change from baseline for best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety. At study end, the mean time on study was 22.1 months (range, 10.8-37.6 months) for all PDS patients. Median time to first refill was 8.7 months, 13.0 months, and 15.8 months, and 28.9%, 56.0%, and 59.4% of patients went 12 months or longer without meeting refill criteria in the PDS 10-mg/ml, 40-mg/ml, and 100-mg/ml treatment arms, respectively. At month 22, the observed mean BCVA change from baseline was ‒4.6 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒2.3 ETDRS letters,+2.9 ETDRS letters, and+2.7 ETDRS letters in the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg treatment arms, respectively. At month 22, the observed mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg treatment arms. No new safety signals were detected during the additional follow-up. Over a mean of 22 months on study, vision and anatomic outcomes were comparable between the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms, with a lower total number of ranibizumab treatments with the PDS. The Ladder end-of-study findings were consistent with the primary analysis, and the PDS generally was well tolerated throughout the entire study period. The PDS has the potential to reduce treatment burden in patients with nAMD while maintaining vision.

Intravitreal Aflibercept Treatment Strategies in Routine Clinical Practice of Neovascular Age-Related Macular Degeneration in Belgium: A Retrospective Observational Study.

IntroductionSTELLAR was a Belgian, multicentre, retrospective, observational chart review that described the utilization (number of injections and treatment regimen) and effectiveness of intravitreal aflibercept (IVT-AFL) in patients with anti-vascular endothelial growth factor (VEGF) treatment-naïve neovascular age-related macular degeneration (nAMD) during the first 12 months of IVT-AFL treatment.MethodsPatients initiating IVT-AFL between July 2013 and July 2017 were included in STELLAR. Primary endpoints were number of visits and IVT-AFL injections, and number of patients who received ≥ 7 versus < 7 IVT-AFL injections during the first 12 months of treatment.ResultsA total of 337 patients completed ≥ 12 months of IVT-AFL treatment. The mean number of visits and mean number of injections during the first 12 months was 9.8 and 7.1 injections, respectively (64% received ≥ 7 injections). Overall, 96% of patients received ≥ 3 initial monthly injections. Of the 337 patients, 180 received VT-AFL as needed (pro re nata), 141 received it as treat-and-extend dosing and 16 received it as fixed dosing. The proportion of patients who received treat-and-extend dosing increased year-on-year. Mean best-corrected visual acuity (BCVA) (± standard deviation) was 61.6 (± 14.9) Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline and improved by + 3.9 and + 5.7 ETDRS letters at 3 and 12 months, respectively. Mean BCVA improvement was numerically greater in patients who received ≥ 7 versus < 7 injections during the first 12 months 7 (+ 6.5 vs. + 4.4 ETDRS letters) and in patients who received ≥ 3 versus < 3 initial monthly injections (+ 5.2 vs. − 0.25 ETDRS letters [3 at months]; + 5.9 vs + 1.2 ETDRS letters [at 12 months]). No specific adverse events were reported.ConclusionMost patients in this Belgian study received ≥ 7 IVT-AFL injections during a mean of 9.8 visits over the 12 months assessed. IVT-AFL was an effective treatment for nAMD in clinical practice, with numerically higher BCVA gains in patients receiving ≥ 7 versus < 7 injections over the first 12 months and ≥ 3 versus < 3 injections in the first 3 months.Electronic supplementary materialThe online version of this article (10.1007/s40123-020-00300-7) contains supplementary material, which is available to authorized users.

Evaluation of Month-24 Efficacy and Safety of Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration

Although anti-vascular endothelial growth factor (VEGF) treatment offers better outcomes than the natural history of neovascular age-related macular degeneration (ARMD), a less burdensome, less expensive, and more durable treatment is needed. To assess the efficacy and safety of epimacular brachytherapy (EMB) for chronic, active, neovascular ARMD. The Macular Epiretinal Brachytherapy vs Ranibizumab (Lucentis) Only Treatment (MERLOT) pivotal device trial was conducted at 24 National Health Service hospitals across the UK. Patients who had neovascular ARMD and received intravitreal ranibizumab were enrolled between November 10, 2009, and January 30, 2012. Eligible patients were randomized 2:1 and were stratified by lens status and angiographic lesion type to receive either EMB plus as-needed ranibizumab or as-needed ranibizumab monotherapy. Participants were followed up monthly for 24 months and then assessed at a final visit at month 36. Masking of participants and clinicians was not possible, but best-corrected visual acuity (BCVA) and imaging were analyzed by masked assessors. Analysis followed the intent-to-treat approach. Pars plana vitrectomy with 24 Gy EMB plus as-needed ranibizumab vs as-needed ranibizumab monotherapy. Coprimary outcomes were the number of as-needed ranibizumab injections and the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA with a noninferiority margin of -5 ETDRS letters. Secondary outcomes were the percentage of participants losing fewer than 15 ETDRS letters and gaining 0 or more or 15 or more ETDRS letters and the mean change in angiographic total lesion size, choroidal neovascularization size, and foveal thickness on optical coherence tomography. Of 363 participants, 329 (90.6%) completed 24 months of follow-up (222 participants in the EMB group and 107 in the ranibizumab group). The mean (SD) age of the combined groups was 76.5 (7.4) years. The mean (SD) number of ranibizumab injections was 9.3 (6.7) in the EMB group and 8.3 (4.5) in the ranibizumab group, with a difference of 1.0 injection (95% CI, -0.3 to 2.3; P = .13). The mean (SD) BCVA change was -11.2 (15.7) ETDRS letters in the EMB group and -1.4 (10.9) ETDRS letters in the ranibizumab group, with a difference of 9.8 ETDRS letters (95% CI, -6.7 to -12.9). In the EMB group, 65.6% of participants (160 of 244) lost fewer than 15 ETDRS letters vs 86.6% (103 of 119) in the ranibizumab group, with a difference of 21% (95% CI, 12.4%-29.5%; P < .001). Microvascular abnormalities occurred in 20 of 207 eyes (9.7%) in the EMB group and 1 of 97 eyes (1.0%) in the ranibizumab group. These abnormalities occurred outside the foveal center, and there were no unexpected safety concerns. The MERLOT trial found that despite the acceptable safety of EMB, it did not reduce the number of ranibizumab injections and was associated with worse visual acuity than anti-VEGF treatment alone; these results do not support EMB use as an adjunct treatment for chronic, active neovascular ARMD. ClinicalTrials.gov Identifier: NCT01006538.

Individualizing Therapy for Neovascular Age-Related Macular Degeneration with Aflibercept (VITAL): A Two-Year Prospective, Interventional Single-Centre Trial.

AimsTo report the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) and reading performance (reading acuity and maximum reading speed (MRS) using the MNREAD test) between baseline and 24 months in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal aflibercept injections.MethodsA prospective, open-label, interventional non-randomised case series with 24 months’ duration. Patients were recruited to the study from medical retina clinics at Moorfields Eye Hospital. Intravitreal injections of 2.0 mg aflibercept in the study eye were administered using a fixed dosing regimen during the first year and a treat-and-extend treatment regimen during the second year of treatment.ResultsFifty patients were enrolled with a mean age (SD) of 78.7 (7.6) years; a mean BCVA of 62.8 ETDRS letters; mean reading acuity of 0.52 logMAR; mean maximum reading speed (MRS) of 141.3 words per minute and a central macular thickness of 322.6 µm at baseline. The mean improvement in BCVA was 6.4 letters for the 44 patients (88%) for whom data was available at 2 years. The mean improvement in reading acuity was 0.13 logMAR with an improvement in MRS of 2.9 words per minute. The mean reduction in CRT from baseline was 104.8 µm.ConclusionsAflibercept treatment of nAMD using fixed dosing in year 1 and treat and extend in year 2 leads to improvements in reading ability, visual acuity and retinal morphology which were maintained to 2 years of treatment.Trial RegistrationClinicalTrials.gov Identifier NCT02441816, the VITAL study.Electronic supplementary materialThe online version of this article (10.1007/s40123-020-00267-5) contains supplementary material, which is available to authorized users.

Neovascular glaucoma in patients with central retinal vein occlusion: A real-life study in the anti-VEGF era.

To investigate the characteristics and treatment patterns of patients developing a neovascular event (NE) in the anterior chamber secondary to central retinal vein occlusion (CRVO) in an ordinary clinical setting. In this retrospective real-life study, data from 243 eyes presenting with CRVO during 2012-2013 were collected. Maximum follow-up was 5years. All patients that developed NE were included in the analysis. Of 243 eligible patients, 72 (30%) either presented with or developed NE during the follow-up. In these 72 patients, 23 (32%) eyes already had evidence of NE at baseline. Twenty-eight eyes (39%) developed NE after discontinuation of intravitreal therapy for macular oedema (ME). In this subgroup, the NE occurred 15.6±13.8months after the baseline visit and 4.1±2.6months after the last injection. Final best-corrected visual acuity was 8.6 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the group of patients presenting with NE compared to 8.1 ETDRS letters in the group that developed NE later on. Of the patients presenting with intraocular pressure (IOP) below 30mmHg, 3/29 (10%) needed subsequent cyclodiode laser therapy compared to 35/43 (81%) patients with a baseline IOP above 30mmHg (p<0.001). In a clinical setting, many patients show evidence of NE already at the first visit. A substantial part of patients develops NE a long time after presentation, commonly a few months after discontinuation of intravitreal therapy for ME. The visual prognosis is similar for patients presenting with NE and patients developing NE during follow-up. A high baseline IOP predicts the need for subsequent pressure-lowering procedures.

Timing of Peak Vision Gains in Patients with Neovascular Age-Related Macular Degeneration Treated with Ranibizumab

To investigate whether time to peak best-corrected visual acuity (BCVA) was predictive of magnitude of BCVA changes at study end in patients with neovascular age-related macular degeneration (nAMD) who received ranibizumab and assess whether patient baseline characteristics and on-study events were predictive of time to peak BCVA. Exploratory analysis of data from HARBOR (ClinicalTrials.gov identifier, NCT00891735). Treatment-naïve patients 50 years of age or older with subfoveal nAMD. Data by ranibizumab dose were pooled; data by dosing schedule (pro re nata [PRN] and monthly) were evaluated separately. Time to peak BCVA was the monthly evaluation at which the patient's greatest gain in Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline was achieved. Early peakers achieved peak BCVA between day 7 and month 6; late peakers achieved peak BCVA between months 7 and 12, months 13 and 18, and months 19 and 24. Variables evaluated for effect of time to peakBCVA included baseline demographic and clinical characteristics, presence of persistent subretinal fluid (SRF) or intraretinal fluid (IRF), and on-study events (atrophy status, fibrosis, retinal pigment epitheliumtears). Time to peak BCVA and its predictive value for magnitude of BCVA changes and BCVA at month 24 (study end). Most patients reached peak BCVA after more than 6 months of treatment: 64% in the PRN group (301/474) and 70% in the monthly groups (327/469). Thirty-six percent and 30% of patients, respectively, peaked early, and 64% and 70%, respectively, peaked late. At month 24, early peakers on average lost vision (PRN,-1.6 ETDRS letters; monthly,-1.9 ETDRS letters). By contrast, late peakers achieved significantly better vision gains from baseline (PRN, 8.5-17.7 ETDRS letters; monthly, 10.1-18.7 ETDRS letters). No differences were found in patient characteristics, persistent SRF or IRF, or on-study events to account for the observed different outcomes between early and late peakers. In most treatment-naïve patients with nAMD, vision gains were achieved at a slower rate (>6months), and a slower response was associated with better vision outcomes after 24 months of ranibizumab. These findings suggest that continued treatment may result in greater vision improvements when consistent anti-vascular endothelial growth factor therapy is maintained over a longer period.

Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis: Phase 3 Randomized Trial

Injection of pharmacotherapy into the suprachoroidal space, between the sclera and choroid, is an alternative delivery technique developed with the rationale of providing higher drug concentrations to posterior ocular structures compared with other intraocular and periocular injection procedures. This study was conducted to evaluate the safety and efficacy of suprachoroidally injected triamcinolone acetonide formulation (CLS-TA), a suspension of triamcinolone acetonide, in improving vision among patients with noninfectious uveitis complicated by macular edema (ME). Phase 3 masked, randomized trial. One hundred sixty patients with ME secondary to noninfectious uveitis. Patients were required to have a best-corrected visual acuity (BCVA) of 5 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent, 20/800) and 70 or fewer ETDRS letters read (Snellen equivalent, 20/40) in the study eye. Patients were randomized 3:2 to suprachoroidally injected CLS-TA or sham treatment, with administrations at day 0 and week12. The primary end point was improvement from baseline of 15 or more ETDRS letters in BCVA at week 24. The secondary end point was reduction from baseline in central subfield thickness (CST) at week24. In the CLS-TA arm, 47% of patients gained 15 or more ETDRS letters in BCVA versus 16% in the control arm (P < 0.001), meeting the primary end point. Mean reductions in CST from baseline were 153 μm versus 18 μm (P < 0.001). No serious adverse events (AEs) related to treatment were reported. Corticosteroid-associated AEs of elevated intraocular pressure occurred in 11.5% and 15.6% of the CLS-TA and control groups, respectively. Cataract AE rates were comparable (7.3% and 6.3%, respectively). Patients in the CLS-TA study arm experienced clinically significant improvement in vision relative to the sham procedure, demonstrating the efficacy of suprachoroidal injection of CLS-TA for the treatment of ME in a vision-threatening disorder.

Real-world outcomes following 12\xa0months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: results from the APOLLON study

PurposeTo report the effectiveness of intravitreal aflibercept (IVT-AFL) treatment for diabetic macular edema (DME) in French clinical practice.MethodsAPOLLON (NCT02924311) was a prospective, observational cohort study of patients with DME. Effectiveness was evaluated by change from baseline in best-corrected visual acuity (BCVA) at 12 months in treatment-naïve patients (i.e., had not received any anti-vascular endothelial growth factor [anti-VEGF] agent, laser, or steroid at IVT-AFL treatment start) and previously treated patients (i.e., previously treated with anti-VEGF agents other than IVT-AFL, laser, or steroids at IVT-AFL treatment start). Secondary endpoints included change in central retinal thickness (CRT) over 12 months, frequency of injections, and proportion of patients with safety events.ResultsOf the 147 patients followed for at least 12 months and included in the effectiveness analysis, 52.4% (n = 77) were treatment-naïve and 47.6% (n = 70) were previously treated. Mean (standard deviation [SD]) BCVA score at baseline was 62.7 (14.3) Early Treatment Diabetic Retinopathy Study (ETDRS) letters in treatment-naïve patients and 60.0 (13.7) ETDRS letters in previously treated patients. At month 12, mean (SD) change in BCVA was + 7.8 (12.3) letters in treatment-naïve patients and + 5.0 (11.3) letters in previously treated patients. Mean CRT decreased in both patient cohorts. The mean (SD) number of IVT-AFL injections at month 12 was 7.6 (2.5) for treatment-naïve patients and 7.6 (2.3) for previously treated patients. Of 388 patients included in the safety analysis, ocular treatment-emergent adverse events occurred in 54.1% (n = 210) of patients.ConclusionIVT-AFL treatment was associated with improvements in functional and anatomic outcomes in both treatment-naïve and previously treated patients with DME in France.

Natural History of Geographic Atrophy Secondary to Age-Related Macular Degeneration: Results from the Prospective Proxima A and B Clinical Trials

To better characterize visual function decline and geographic atrophy (GA) progression secondary to age-related macular degeneration (AMD). Proxima A (NCT02479386)/Proxima B (NCT02399072) were global, prospective, noninterventional, observational clinical trials. Eligible patients were aged ≥50 years. Patients in Proxima A had bilateral GA without choroidal neovascularization (CNV) in either eye (N= 295). Patients in Proxima B had GA without CNV in the study eye and CNV±GA in the fellow eye (fellow eye CNV cohort, n= 168) or GA without CNV in the study eye, no CNV/GA in the fellow eye (fellow eye intermediate AMD cohort, n= 32). Changes in visual function and imaging/anatomic parameters were evaluated over time using a mixed model for repeated measurement accounting for key baseline characteristics. Prespecified end points included change in GA area from baseline, best-corrected visual acuity (BCVA) score assessed by Early Treatment Diabetic Retinopathy Study (ETDRS), and visual acuity under low-luminance (LLVA). At 24 months, adjusted mean (standard error) change in GA lesion area from baseline was 3.87 (0.15) mm2 in participants with bilateral GA (Proxima A), 3.55 (0.16) mm2 in the fellow eye CNV cohort (Proxima B), and 2.96 (0.25) mm2 in the fellow eye intermediate AMD cohort (Proxima B). Progression of GA was greater in patients with baseline nonsubfoveal (vs. subfoveal) GA lesions and tended to increase as baseline low-luminance deficit increased (all patients). Conversion to GA or CNV in the fellow eye occurred in 30% and 6.7% of participants, respectively, in the Proxima B intermediate AMD cohort at month 12. Adjusted mean (standard error) changes in BCVA and LLVA (ETDRS letters) in the study eye from baseline to 24 months were-13.88 (1.40) and-7.64 (1.20) in Proxima A,-9.49 (1.29) and-7.57 (1.26) in Proxima B fellow eye CNV cohort, and-11.48 (3.39) and-8.37 (3.02) in Proxima B fellow eye intermediate AMD cohort, respectively. The prospective Proxima A and B studies highlight the severe functional impact of GA and the rapid rate of GA lesion progression over a 2-year period, including in patients with unilateral GA at baseline.

Real-World Effectiveness and Real-World Cost-Effectiveness of Intravitreal Aflibercept and Intravitreal Ranibizumab in Neovascular Age-Related Macular Degeneration: Systematic Review and Meta-Analysis of Real-World Studies.

IntroductionTreatment of neovascular age-related macular degeneration (nAMD) has evolved with the advent of anti-vascular endothelial growth factor agents such that intravitreally administered aflibercept and ranibizumab (RBZ) have become the standard of care. Randomized clinical trials (RCTs) have demonstrated the benefits of these agents in nAMD; however, results achieved under RCT protocols may not always be replicated in clinical practice. Assessing real-world outcomes is important to estimate the effectiveness and cost-effectiveness of these two agents. Our objective was to assess the real-world effectiveness of intravitreally administered aflibercept and RBZ in treatment-naive patients with nAMD and determine the cost-effectiveness of intravitreally administered aflibercept versus RBZ in a real-world setting.MethodsA multistage approach was undertaken. A systematic literature review (SLR) was completed to identify studies describing real-world outcomes in patients with nAMD treated intravitreally with aflibercept or RBZ. A meta-analysis of data identified in the SLR generated a pooled estimate of the effectiveness of intravitreally administered aflibercept and RBZ at 52 weeks and an estimate of treatment burden (injection frequency and monitoring). The impact of treatment effect modifiers, such as baseline visual acuity (VA) and age, were corrected through a multivariable meta-regression. A Markov state transition model was developed to estimate the real-world cost-effectiveness of intravitreally administered aflibercept using results from the pooled estimates for effectiveness and treatment burden as primary inputs. The analysis considered the perspective of the French National Healthcare System.ResultsPatients treated intravitreally with aflibercept had a mean age of 79.52 years and mean baseline VA of 55.80 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. At week 52, mean VA gain was 5.30 ETDRS letters in patients reporting an average of 7.10 intravitreal injections of aflibercept and 8.65 visits (injection and/or monitoring). RBZ-treated patients were younger (77.28 years), with a lower mean baseline VA (52.81 ETDRS letters). At week 52, mean VA gain from baseline was 4.24 ETDRS letters, with an average of 5.88 injections and 10.10 visits (injection and/or monitoring). After correcting for differences in age (77.28 years) and baseline VA (52.81 ETDRS letters) and considering the current clinical practice with aflibercept and RBZ, the mean VA gain was 6.57 ETDRS letters for patients treated intravitreally with aflibercept and 4.42 ETDRS for patients treated intravitreally with RBZ. The cost-effectiveness analysis showed that intravitreally administered aflibercept is a more effective treatment option with an incremental gain in quality-adjusted life years (QALYs) (4.918 versus 4.880) and an incremental cost-effectiveness ratio (ICER) of €27,087 per QALY.ConclusionsThe analysis identified differences in the overall treatment approach and how ophthalmologists use intravitreally administered aflibercept and RBZ in clinical practice. These differences ultimately influence the mean real-world effectiveness of the two agents. Intravitreal treatment with aflibercept (injection frequency and patients follow-up) was consistent and in line with the European label recommendations. Patients treated intravitreally with aflibercept in clinical practice reported a mean gain in VA of similar magnitude to the mean VA gain reported in the pivotal RCT. Conversely, treatment with RBZ varied significantly across the different studies. On average, RBZ-treated patients reported a low injection frequency and a frequent follow-up, driven in part by the high number of patients treated with pro re nata (PRN) regimens. RBZ-treated patients reported gains in VA versus baseline; however, the magnitude of the gain in VA was not comparable to the VA gains reported in the RBZ pivotal RCT. Intravitreal treatment with aflibercept was associated with better mean VA outcomes and an incremental gain in QALYs compared with RBZ and can be considered cost-effective for the treatment of nAMD in patients in France despite a higher price for each individual intravitreal injection of aflibercept compared with RBZ.FundingBayer AG, Basel.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01147-6) contains supplementary material, which is available to authorized users.

Response to Aflibercept Therapy in Three Types of Choroidal Neovascular Membrane in Neovascular Age-Related Macular Degeneration: Real-Life Evidence in the Czech Republic

Purpose To present a cohort of treatment-naive patients with the neovascular form of age-related macular degeneration (nAMD) treated with aflibercept in a fixed regimen and evaluate the treatment response of three types of choroidal neovascular membrane (CNV)—occult (Type 1), classic (Type 2), and minimally classic (Type 4). Methods This was a multicentre, prospective, observational consecutive case series study. Patients diagnosed with three types of CNV of nAMD were treated in a fixed regimen (3 injections every 4 weeks, and then injections at 8 week intervals). The follow-up period was 48 weeks. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were measured using Early Treatment Diabetic Retinopathy Study (ETDRS) charts and spectral-domain optical coherence tomography (OCT). The measurements were taken at the baseline and then at 16, 32, and 48 weeks. Results The treatment-naive group was composed of 135 eyes of 135 patients in the study. 61 eyes had Type 1 lesions of CNV, 50 eyes had Type 2 lesions, and 24 eyes had Type 4 lesions. Mean baseline BCVA ± SD for Type 1 lesions was 56.1 ± 10.8 ETDRS letters, and then 62.2 ± 12.9 letters, 61.2 ± 13.7 letters, and 62.8 ± 15.1 letters at 16, 32, and 48 weeks, respectively. Mean baseline CRT ± SD for Type 1 lesions was 442.4 ± 194.9 μm, and then 302.5 ± 144.4 μm, 299.7 ± 128.5 μm, and 277.7 ± 106.5 μm at 16, 32, and 48 weeks, respectively. Mean baseline BCVA ± SD for Type 2 lesions was 55.6 ± 9.9 ETDRS letters, and then 62.5 ± 11.1 letters, 60.7 ± 13.0 letters, and 62.5 ± 14.2 letters at 16, 32, and 48 weeks, respectively. Mean baseline CRT ± SD. For Type 4 lesions mean baseline BCVA ± SD was 56.7 ± 9.0 ETDRS letters, and then 59.1 ± 10.6 letters, 59.5 ± 11.4 letters, and 59.2 ± 12.6 letters at 16, 32, and 48 weeks respectively. Mean baseline CRT ± SD for Type 4 lesions was 492.1 ± 187.0 μm, and then 333.3 ± 137.5 μm, 354.4 ± 175.0 μm, and 326.7 ± 122.4 μm at 16, 32, and 48 weeks respectively. All these changes were statistically significant (p < 0.005). Conclusions The primary outcome of our study is that the treatment with aflibercept in nAMD patients led to statistically significant improvement in BCVA and to a decrease in CRT throughout the follow-up period in both occult and classic types of CNV. The minimally classic type of CNV demonstrated a poorer functional and anatomical response to treatment.