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Purpose: Historically, supplemental dextrose to infusion fluid has been used to reduce the need for intraoperative lensectomies to maintain visualization during diabetic vitrectomy. Valved, small-gauge vitrectomy has reduced surgical time and decreased intraoperative fluid flow. Assessment of supplemental dextrose in modern vitrectomy is presented in this study., Methods: A retrospective cohort study of diabetic patients undergoing vitrectomy was conducted. The dextrose group received supplemental dextrose in the infusion fluid, while the nondextrose group used a standard balanced salt solution (BSS Plus). Group assignment was per surgeons' typical practice patterns. Eyes with tractional retinal detachments were also evaluated as a subgroup., Results: Three hundred thirty phakic eyes were included. Supplemental dextrose was used in 199 eyes (60.3%). One unplanned lensectomy was performed in this series, in the nondextrose group, not statistically different from the dextrose group, with zero lensectomies (P = 0.4). Cataract survival curves overlapped for all eyes and for the tractional retinal detachment subgroup., Conclusion: In modern vitrectomy, unplanned lensectomy is rare. No difference was observed in the rate of intraoperative lensectomies or overall postoperative cataract course with or without dextrose supplementation to the infusion fluid. Standard solutions appear to be adequate for infusion, even for diabetics.

Importance: Despite the effectiveness of existing anti-vascular endothelial growth factor (VEGF) therapies, a need remains for further treatment options to improve response rates and/or reduce injection or monitoring frequency in patients with diabetic macular edema (DME)., Objective: To evaluate the efficacy and safety of brolucizumab vs aflibercept dosed every 4 weeks in participants with DME., Design, Participants, and Setting: This 52-week, double-masked, phase 3 randomized clinical trial included treatment-naive adults and adults who had previously received anti-VEGF therapy. Data were collected from September 2019 to March 2020, and data were analyzed from April 2020 to February 2021., Intervention: Brolucizumab, 6 mg, intravitreal injection every 4 weeks or aflibercept, 2 mg, intravitreal injection every 4 weeks., Main Outcomes and Measures: Participants were randomized 2:1 to brolucizumab, 6 mg, or aflibercept, 2 mg. The primary end point was change from baseline in best-corrected visual acuity at week 52. Secondary end points were the proportion of participants with a 2-step improvement or greater from baseline in Diabetic Retinopathy Severity Scale score, the proportion of eyes with absence of both subretinal fluid and intraretinal fluid, change from baseline in central subfield thickness, and safety at week 52., Results: A total of 517 participants were randomized to brolucizumab (n = 346) or aflibercept (n = 171); 299 (57.8%) were male, and the mean (SD) age was 60.7 (10.2) years. Brolucizumab was noninferior to aflibercept in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score) change from baseline at week 52 (brolucizumab, 12.2-letter improvement; aflibercept, 11.0-letter improvement; difference, 1.1; 95% CI, -0.6 to 2.9; noninferiority margin, 4; P < .001). Brolucizumab was superior to aflibercept for the proportion of eyes without subretinal and intraretinal fluid (brolucizumab, 144 of 346 [41.6%]; aflibercept, 38 of 171 [22.2%]; difference, 20.0%; 95% CI, 12.5to 28.6; P < .001) and mean central subfield thickness change from baseline at week 52 (brolucizumab, -237.8 μm; aflibercept, -196.5 μm; difference, -41.4; 95% CI, -58.9 to -23.8; P < .001). Incidence of intraocular inflammation was 4.0% (14 of 346) in the brolucizumab arm and 2.9% (5 of 171) in the aflibercept arm, incidence of retinal vasculitis was 0.9% (3 of 346) and 0.6% (1 of 171), respectively, and incidence of retinal vascular occlusion was 0.3% (1 of 346) and 0.6% (1 of 171). One participant in the brolucizumab arm had retinal artery occlusion., Conclusions and Relevance: In these study participants with DME, no clinically meaningful differences in visual outcomes were noted between the brolucizumab and aflibercept arms; some superior anatomic improvements were noted in the brolucizumab arm. No new safety concerns were identified., Trial Registration: ClinicalTrials.gov Identifier: NCT03917472.

Aims: To quantify retinal vascular bed area (RVBA) in square millimetres on stereographically projected ultra-wide field (UWF) fluorescein angiography (FA) in eyes with diabetic retinopathy (DR)., Methods: A prospective, observational study. Baseline Optos 200Tx UWF FA images of 80 eyes with DR from the DAVE (NCT01552408) and RECOVERY (NCT02863354) studies were stereographically projected at the Doheny Image Reading Center to adjust for peripheral distortion. The early-phase FA frame was used to extract the retinal vasculature as a mask for calculating RVBA. The pixels of the retinal vasculature were automatically computed in square millimetres using manufacturer-provided software., Results: Eighteen of 80 diabetic eyes were excluded because image quality and contrast were insufficient for automatic extraction of the retinal vasculature from the background fluorescence. The remaining 62 eyes were included in the final analysis. In comparison with age-matched and sex-matched normal controls, eyes with DR had a higher global RVBA for the entire retina (p<0.001), and RVBA correlated with DR severity (p<0.001), with a higher RVBA in eyes with proliferative DR (66.1±16.2 mm 2 ) than in those with non-proliferative DR (56.2±16.6 mm 2 ) or in normal controls (37.2±9.9 mm 2 ). This tendency was also present in the posterior retina and mid-periphery but absent in the far-periphery. RVBA did not correlate with retinal ischaemia (p>0.05)., Conclusions: Eyes with DR harboured a larger global RVBA for the entire retina than normal controls, and RVBA appeared to indicate DR severity. However, this biomarker was not observed to be a good indicator of retinal ischaemia., Competing Interests: Competing interests: SS reported receiving grants, personal fees or non-financial support from Carl Zeiss Meditec, Optos, Allergan, Genentech, Alcon, Novartis, Roche, Regeneron, Bayer, Thrombogenics, StemCells Inc and Avalanche. MSI reported receiving grants, personal fees or non-financial support from Thrombogenics, Omeros, Boehringer Ingelheim and Genentech., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Retinal nonperfusion (RNP) is an important biomarker for diabetic retinopathy (DR). Data suggest that consistent anti-VEGF pharmacotherapy can slow RNP development. The RECOVERY trial evaluated the impact of aflibercept (Eylea, Regeneron) on RNP among eyes with proliferative DR (PDR)., Design: Prospective, randomized clinical trial with treatment crossover in the second year., Subjects: Eyes with PDR and RNP., Methods: At baseline, the subjects were randomized 1:1 to monthly (arm 1) or quarterly (arm 2) intravitreal 2 mg aflibercept. At the beginning of year 2, the treatment arms were crossed over so that the monthly-dosed subjects subsequently received quarterly dosing and the quarterly-dosed subjects subsequently received monthly dosing., Main Outcome Measures: Change in total RNP area (mm 2 ) through year 2. Secondary outcomes included Diabetic Retinopathy Severity Scale (DRSS) scores; best-corrected visual acuity; central subfield thickness; additional measures of RNP, including ischemic index (ISI); and adverse event incidence. Means and 95% confidence intervals were calculated., Results: Among all subjects, from baseline to year 2, the mean RNP increased from 235 mm 2 to 402 mm 2 (P < 0.0001), and the ISI increased from 25.8% to 50.4% (P < 0.0001). Increases in the mean RNP (P < 0.0001) and ISI (P < 0.0001) were also observed from year 1 to year 2. The mean total RNP increased from 264 mm 2 at baseline to 386 mm 2 (P < 0.0001) at year 2 in arm 1 and from 207 mm 2 at baseline to 421 mm 2 (P < 0.0001) at year 2 in arm 2 (P = 0.023, arm 1 vs. arm 2). Increases in the mean RNP for both treatment arms (P < 0.0001) were also specifically observed within year 2 (P = 0.32, arm 1 vs. arm 2). Compared with baseline, the DRSS scores at the end of year 2 improved in 82% (n = 27) of subjects and remained stable in 18% (n = 6), with no subjects experiencing worsening; at 2 years, the DRSS scores had improved by 2 or more steps in 65% (n = 11) and 81% (n = 13) of subjects in arms 1 and 2, respectively., Conclusions: Through year 2 of the RECOVERY trial, both treatment arms experienced significant increases in RNP. Despite the expansion of the RNP area in nearly all subjects, 82% of subjects demonstrated an improvement in DRSS levels from baseline, with no subjects experiencing worsening in DRSS scores., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background/aims: Quantifying microaneurysms (MAs) turnover may be an objective measure for therapeutic response in diabetic retinopathy. This study assesses changes in MA counts on ultra-widefield fluorescein angiography (UWFA) in subjects undergoing treatment with intravitreal aflibercept injection (IAI) for proliferative diabetic retinopathy (PDR) in the Intravit re al Afliber c ept for Retinal N o n-Perfusion in Proliferati v e Diab e tic R etinopath y (RECOVERY) study using an automated MA detection platform., Methods: RECOVERY is a prospective study that enrolled 40 subjects with PDR randomised 1:1 to receive 2 mg IAI every 4 weeks(q4wk) or every 12 weeks (q12wk). UWFA images were obtained at baseline, 6 months and 1 year. Images were analysed using an automated segmentation platform to detect and quantify MAs. Zones 1, 2 and 3 correspond to the macula, mid-periphery and far-periphery, respectively., Results: The q4wk cohort demonstrated a significant decline in MAs in all zones and panretinally at baseline versus month 6, baseline versus year 1, and month 6 versus year 1 (-20.0% to -61.8%; all p<0.001). In the q12wk cohort, baseline versus month 6 showed a significant decline panretinally (mean: -34.2%; p<0.001) and in zone 3 (mean -44.18%; p<0.001). Addiitonally, baseline to year 1 in the q12wk group demonstrated significant decline panretinally (mean: -47.7%; p<0.001) and in zone 3 (mean: -59.8%; p<0.001). All zones demonstrated significantly decline from month 6 to year 1 in the q12wk group., Conclusion: Therapy with IAI demonstrates significantly reduced panretinal MA counts in PDR at 1 year in both treatment groups. The use of automated platforms to detect and quantify MAs may provide a novel imaging marker for evaluating disease activity and therapeutic impact., Trial Registration Number: NCT02863354., Competing Interests: Competing interests: AB, research support—Genentech, Allergan; consulting—Genentech; CCW, research support—Adverum, Allergan, Apellis, Clearside, EyePoint, Genentech/Roch, Neurotech, Novartis, Opthea, Regeneron, Regenxbio, Samsung, Santen; consulting—Adverum, Alimera Sciences, Allegro, Allergan, Apellis, Bayer, Clearside, DORC, EyePoint, Genentech/Roche, Kodiak, Notal Vision, Novartis, ONL Therapeutics, PolyPhotonix, RecensMedical, Regeneron, Regenxbio, Santen, Takeda; SS, research support—Regeneron, Allergan, Gilead; consulting: Bausch and Lomb, Santen; patent—Leica; SVRS, research support—Carl Zeiss Meditec, consulting—Optos, CenterVue, Heidelberg Engineering, Roche/Genentech, Novartis, Allergan, Amgen, Bayer; research instruments—Carl Zeiss Meditec, Nidek, Topcon; JPE, research support—Aerpio, Alcon, Thrombogenics, Regeneron, Genentech, Novartis; consulting—Aerpio, Alcon, Allegro, Allergan, Genentech/Roche, Novartis, Thrombogenics, Leica, Zeiss, Regeneron, Santen; patent—Leica; MI, consultant: Boehringer Ingelheim, Thrombogenics, Quark, Omeros, Allergan, Amgen, Astellas, Alimera; research support—Novartis, Genentech, Clearside, Biogen. KET, HJY, MN MH, JR, no competing interests., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: This study assessed relationships between best-corrected visual acuity (BCVA), central subfield thickness (CST), and ellipsoid zone (EZ) integrity in macular edema (ME) patients., Design: Post hoc analysis of 6 clinical trials, which included verified diagnoses, protocol refractions, and reading center assessment of OCT images., Participants: Participants (n = 1063) were diagnosed with ME from retinal vein occlusion (RVO), diabetic retinopathy (DR; diabetic macular edema, DME), or noninfectious uveitis (NIU)., Methods: For CST, 2 clinical trials for each disorder were analyzed. For EZ, 3 studies across 2 disorders were analyzed., Main Outcome Measures: Primary outcomes were correlations between BCVA and CST, and between BCVA and 4 central subfield EZ grades., Results: For baseline BCVA and CST, Pearson correlation coefficients were: ME from RVO, -0.56 (774 eyes; 95% confidence interval [CI], -0.61 to -0.51; P < 0.001); DME, -0.50 (91 eyes; 95% CI, -0.64 to -0.33; P < 0.001); and ME from NIU, -0.38 (198 eyes; 95% CI, -0.49 to -0.26; P < 0.001). Regarding change from baseline to 24 weeks for both BCVA and CST, Pearson correlation coefficients were: ME from RVO, -0.35 (95% CI, -0.43 to -0.27; P < 0.001); DME, -0.30 (95% CI, -0.48 to -0.09; P = 0.006); and ME from NIU, -0.42 (95% CI, -0.53 to -0.29; P < 0.001). Acute and chronic ME showed similar baseline and 24-week change linear correlations. With lower baseline CST, a trend of decreased baseline and 24-week change correlations was found. For central subfield EZ at baseline, mean BCVA progressively worsened with each of 4 EZ grades in 185 eyes with gradable EZ (DME, 41 eyes; NIU, 144 eyes; P ≤ 0.050 for all pairwise comparisons except between normal and questionably abnormal EZ grades). Eyes with normal baseline central subfield EZ showed greater 24-week change in BCVA than those with abnormal baseline EZ (15.00 letters vs. 8.16 letters; P = 0.0005, with baseline BCVA, CST, and age as covariates)., Conclusions: Despite these correlations, CST and EZ integrity, as graded herein, account for the minority of BCVA variation in patients with ME resulting from RVO, DR, and NIU., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Evaluate the impact of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) on retinal nonperfusion (RNP) in eyes with proliferative diabetic retinopathy (PDR)., Design: Prospective, randomized clinical trial., Participants: Eyes with treatment-naïve PDR and extensive RNP without diabetic macular edema., Methods: Patients were randomized 1:1 to intravitreal 2 mg aflibercept every 4 weeks (monthly) or every 12 weeks (quarterly)., Main Outcome Measures: The primary outcome measure was change in total RNP area (in square millimeters) from baseline to year 1. Secondary outcomes included ischemic index (ISI), diabetic retinopathy severity scale (DRSS) scores, visual acuity, central retinal thickness, and adverse events. The mean and 95% confidence interval were calculated for each outcome., Results: Through 1 year, the monthly (n = 20) and quarterly (n = 20) cohorts received 11.0 and 3.95 mean aflibercept injections, and DRSS scores improved 2 steps or more in 74% and 67% of patients, respectively. Among all patients through 1 year, mean total area of RNP increased from 235 mm 2 to 266 mm 2 (P = 0.18) and ISI increased from 25.8% to 31.9% (P = 0.004). Retinal nonperfusion outcomes favored monthly dosing. Mean total RNP increased from 207 mm 2 at baseline to 268 mm 2 (P = 0.01) at 1 year in the quarterly cohort and remained stable at 264 mm 2 at baseline and 1 year (P = 0.70) in the monthly cohort (P = 0.05, monthly vs. quarterly cohorts). Although many eyes demonstrated increased areas of RNP longitudinally (n = 24 [66.7%]), this was more common with quarterly dosing (n = 14 [77.8%]), and a proportion of eyes (n = 12 [33.3%]) demonstrated localized areas of apparent reperfusion of nonperfused retina, more commonly in the monthly cohort (n = 8 [44.4%])., Conclusions: Widespread evidence of retinal reperfusion with aflibercept dosing of PDR eyes with extensive RNP was not identified, and therefore the primary outcome of the current study was not met. Nevertheless, zones of apparent reperfusion were detected in some patients, and a dose response was identified with a reduction of RNP progression with monthly compared to quarterly dosing., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To classify retinal nonperfusion regions (NPRs) in patients with diabetic macular edema (DME) and assess the relationship with severity of DME., Design: Prospective, observational case series., Methods: Forty eyes of 29 patients with treatment-naïve center-involved macular edema secondary to diabetes mellitus were included (The DAVE study, NCT01552408) in this analysis. Ultra-widefield fluorescein angiography (UWF FA) images were transmitted to the Doheny Image Reading Center, where they were corrected using stereographic projection to adjust for peripheral distortion. Two independent, certified graders manually evaluated the NPR and classified the nonperfusion as being associated with leakage or without leakage. The size of these 2 subtypes of NPR were computed in mm 2 and assessed across the entire retina and within 3 concentric retinal zones. The relationship between subtype of NPR and the severity of DME was assessed., Results: In 40 eyes with treatment-naïve DME, visual acuity was significantly correlated with central macular thickness (CMT) and macular volume (MV). The NPR with leakage was positively correlated with CMT (R = 0.408, P = .009) and MV (R = 0.399, P = .011), whereas the NPR without leakage was negatively correlated with CMT (R = -0.468, P = .002) and MV (R = -0.473, P = .002). The NPR with leakage in the posterior region was significantly greater compared to the mid-periphery and the far periphery (P < .001), whereas the NPR without leakage was significantly greater in the mid-periphery compared with the far periphery or the posterior region (P = .001)., Conclusion: In patients with DME, the severity of DME appears to be positively correlated with NPR with leakage but negatively correlated with NPR without leakage. These findings may have implications for the pathophysiology of DME and the design of protocols for targeted laser in these eyes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Objective: To determine the effect of propranolol on retinal neovascularization due to proliferative diabetic retinopathy (PDR)., Patients and Methods: For this prospective pilot, interventional, case series, patients with diabetes with PDR (n = 10 subjects; 12 eyes) were recruited at the ophthalmology clinic of the University of Wisconsin - Madison. Subjects were administered oral propranolol for 12 weeks and retinopathy and area of retinal neovascularization were monitored with fundus photography and fluorescein angiography (FA). The study's main outcome measures were photographic area of retinal neovascularization and degree of leakage on FA., Results: All eyes demonstrated stable degrees of retinal neovascularization by the end of 12 weeks., Conclusion: This dose of oral propranolol during a period of 12 weeks did not demonstrate significant effect on retinal neovascularization due to PDR. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:35-40.]., (Copyright 2018, SLACK Incorporated.)

Purpose: To investigate the clinical importance of changes in diabetic retinopathy severity score (DRSS) in patients with diabetic macular edema (DME) treated with intravitreal ranibizumab., Design: Post hoc analysis of the phase III RIDE and RISE studies of ranibizumab for treatment of DME., Participants: Four hundred sixty-eight eyes treated with ranibizumab from randomization with gradable DRSS on baseline fundus photographs., Methods: Visual and anatomic outcomes were examined in eyes grouped according to DRSS change from baseline to month 24., Main Outcome Measures: Mean best-corrected visual acuity (BCVA) letter score change, proportion of patients with 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letter score change, mean contrast sensitivity change, proportion of patients with resolved macular edema, and leakage on fluorescein angiography., Results: Most (56.8%) patients treated with ranibizumab experienced 1-step or more improvement in DRSS from baseline to month 24; 40.0% had no change, and 3.2% experienced DRSS worsening. Patients with DRSS stability or improvement had greater mean BCVA letter score changes (+15.1, +14.2, +11.3, and +11.2 letters for ≥3-step improvement, ≥2-step improvement, 1-step improvement, and no DRSS change, respectively) compared with +5.0 letters in patients who had any DRSS worsening. Best-corrected visual acuity letter score gain of 15 letters or more was more common in patients with 2-step or 3-step or more DRSS improvement (51.9% and 44.6%, respectively) compared with those with a 1-step DRSS improvement, no change, or worsening (37.9%, 39.6%, and 26.7%, respectively). A loss of 15 letters or more in BCVA was more common in patients with any DRSS worsening (13.3%) compared with patients who had stable or improved DRSS (0%-2.8%). Resolution of macular edema was more common in patients with DRSS improvement: 84.2%, 87.7%, and 92.3% of patients with 1-step, 2-step or more, and 3-step or more improvement in DRSS achieved central foveal thickness of 250 μm or less, compared with 65.2% and 53.3% of patients who had no DRSS change or any DRSS worsening., Conclusions: These findings provide further support that improvement in DRSS is a clinically important outcome that should be evaluated as a measure of treatment effectiveness in future studies of diabetic eye disease., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effect of monthly intravitreal ranibizumab on hard exudate (HE) area and the impact of HE on visual acuity (VA) outcomes in diabetic macular edema (DME) patients using data from 2 phase III clinical trials., Design: Exploratory analyses of phase III, randomized, double-masked, sham-controlled, multicenter clinical trials., Participants: Adults with DME, baseline best-corrected VA 20/40 to 20/320 Snellen equivalent, and central foveal thickness of ≥275 μm., Methods: Between the 2 studies, 759 patients with DME were randomized to receive monthly 0.3 or 0.5 mg intravitreal ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) or sham injections., Main Outcome Measures: Hard exudate area was assessed from color fundus stereophotographs both on an ordinal scale and using continuous estimates of areas within the Early Treatment Diabetic Retinopathy Study grid., Results: Data from 739 eyes were available for analysis. Mean baseline HE area was similar across treatment groups, ranging from 0.65 to 0.82 mm(2). Through month 24, the percentage of eyes without HE increased from 20.9% to 36.3% in the sham group and from 22.1% to 61.3% and 23.6% to 62.0% in the ranibizumab 0.3-mg and 0.5-mg groups, respectively. Resolution of HE became apparent sometime after month 6 in ranibizumab-treated eyes. At baseline, there was no meaningful correlation between VA and presence or absence of HE. After baseline, there also was no consistent correlation between presence or absence of HE and change in VA over time., Conclusions: In this exploratory analysis, monthly intravitreal ranibizumab resulted in significantly greater reduction of HE area compared with sham (P < 0.0001). In contrast to the rapid effects of ranibizumab on macular edema, changes in HE area were more gradual. Contrary to prior expectations, the presence and area of HE did not increase as DME resolved (either in the ranibizumab or sham groups). Importantly, baseline VA was not correlated with presence of HE, nor was the therapeutic benefit of ranibizumab on VA affected negatively by the presence of HE. These data suggest that in the context of intravitreal anti-vascular endothelial growth factor therapy, the presence of HE is not a prognostic indicator of poor visual outcomes., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity when administered for up to 3 years, evaluate the effect of delayed initiation of ranibizumab therapy on DR severity, and identify baseline patient characteristics associated with the development of proliferative DR (PDR)., Design: Exploratory analyses of phase III, randomized, double-masked, sham-controlled multicenter clinical trials., Participants: Adults with diabetic macular edema (DME) (N = 759), baseline best-corrected visual acuity 20/40 to 20/320 Snellen equivalent, and central foveal thickness ≥275 μm., Methods: Patients were randomized to monthly 0.3 or 0.5 mg ranibizumab or sham injections. Sham participants could switch to 0.5 mg ranibizumab during the third year (sham/0.5 mg crossover). Baseline risk factors were evaluated to explore potential associations with development of PDR. Time to first development of PDR was analyzed by Kaplan-Meier methods to calculate cumulative probabilities by group., Main Outcome Measures: Study eye change on the Early Treatment Diabetic Retinopathy Study severity scale and a composite clinical outcome evaluating progression to PDR based on photographic changes plus clinically important events defining PDR., Results: At month 36, a greater proportion of ranibizumab-treated eyes had ≥2- or ≥3-step DR improvement compared with sham/0.5 mg crossover. A ≥3-step improvement was achieved at 36 months by 3.3%, 15.0%, and 13.2% of sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab-treated eyes, respectively (P < 0.0001). Through 36 months, 39.1% of eyes in the sham/0.5 mg group developed PDR, as measured by composite outcome, compared with 18.3% and 17.1% of eyes treated with 0.3 or 0.5 mg ranibizumab, respectively. The presence of macular capillary nonperfusion at baseline seems to be associated with progression to PDR in ranibizumab-treated eyes but did not meaningfully influence visual acuity improvement in eyes with DME after ranibizumab therapy., Conclusions: Ranibizumab, as administered to patients with DME for 12 to 36 months in these studies, can both improve DR severity and prevent worsening. Prolonged delays in initiation of ranibizumab therapy may limit this therapeutic effect. Although uncommon, the development of PDR still occurs in a small percentage of eyes undergoing anti-vascular endothelial growth factor therapy and may be related to the presence of macular nonperfusion., (Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.)

Objective: To review the evidence regarding the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) pharmacotherapies for the treatment of diabetic macular edema (DME)., Methods: Literature searches last were conducted in September 2011, in PubMed with no date restrictions, limited to articles published in English, and in the Cochrane Library without a language limitation. The combined searches yielded 532 citations, of which 45 were deemed clinically relevant for the authors to review in full text and to assign ratings of level of evidence to each of the selected studies with the guidance of the panel methodologists., Results: At this time, there are 5 studies that provide level I evidence for intravitreal ranibizumab, alone or in combination with other treatments for DME. There is also 1 study that provides level I evidence for intravitreal pegaptanib sodium for DME. Nine studies reviewed were rated as level II, and 2 additional studies reviewed were graded as level III. Most studies do not provide information about long-term results (i.e., more than 2 years of follow-up) or the comparative efficacy of anti-VEGF pharmacotherapies., Conclusions: Review of the available literature indicates that anti-VEGF pharmacotherapy, delivered by intravitreal injection, is a safe and effective treatment over 2 years for DME. Further evidence is required to support the long-term safety of these pharmacotherapies and their comparative efficacy., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity over time in 2 phase 3 clinical trials (RIDE, NCT00473382; RISE, NCT00473330) of ranibizumab for diabetic macular edema., Methods: Participants with diabetic macular edema (n=759) were randomized to monthly sham, 0.3-mg ranibizumab, or 0.5-mg ranibizumab intravitreal injections. Macular laser was available per protocol-specified criteria. Fundus photographs, taken at baseline and periodically, were graded by a central reading center; clinical examinations were performed monthly. The main outcome measures of this report are secondary/exploratory analyses including a 2-step or more and 3-step or more change on the Early Treatment Diabetic Retinopathy Study severity scale in the study eye and a composite DR progression outcome including photographic changes plus clinically important events such as occurrence of vitreous hemorrhage or need for panretinal laser., Results: At 2 years, the percentage of participants with DR progression (worsening by ≥ 2 or ≥ 3 steps) was significantly reduced in ranibizumab-treated eyes compared with sham-treated eyes, and DR regression (improving by ≥ 2 or ≥ 3 steps) was significantly more likely. The cumulative probability of clinical progression of DR as measured by the composite outcome at 2 years was 33.8% of sham-treated eyes compared with 11.2% to 11.5% of ranibizumab-treated eyes., Conclusions: Intravitreal ranibizumab reduced the risk of DR progression in eyes with diabetic macular edema, and many ranibizumab-treated eyes experienced improvement in DR severity. Because these results are exploratory, the use of intravitreal ranibizumab specifically to reduce DR progression or cause DR regression requires further study.

Purpose: To identify factors associated with the visual acuity outcome after focal/grid photocoagulation for diabetic macular edema (DME) among eyes randomized to the focal/grid photocoagulation treatment group within the Diabetic Retinopathy Clinical Research Network (DRCR.net) trial comparing triamcinolone with focal/grid laser., Design: Multicenter, randomized, clinical trial., Participants: Three hundred thirty eyes with DME assigned to the focal/grid photocoagulation group, visual acuity 20/40 to 20/320, and optical coherence tomography (OCT) central subfield thickness > or =250 microns., Methods: Eyes were treated with a protocol-defined photocoagulation technique, which was repeated at 4-month intervals for persistent or recurrent edema. Separate logistic regression models were used to evaluate the associations of demographic, clinical, OCT, and fundus photographic variables with visual acuity improvement or worsening of > or =10 letters from baseline to 2 years. The association of the initial visual acuity outcome after treatment with the subsequent visual acuity course also was evaluated., Main Outcome Measures: Visual acuity measured with the electronic Early Treatment Diabetic Retinopathy Study method., Results: Worse baseline visual acuity was the only factor found to be associated with more frequent visual acuity improvement (P<0.001), and both greater baseline OCT-measured retinal volume (P = 0.001) and better baseline visual acuity (P = 0.009) were found to be associated with more frequent visual acuity worsening. Visual acuity outcomes were similar in eyes with and without prior macular or panretinal photocoagulation. The initial visual acuity outcome at 4 months was not generally predictive of the subsequent course. Many eyes that worsened > or =10 letters from baseline to 4 months subsequently improved, and many eyes that initially improved, subsequently worsened., Conclusions: At this time, focal/grid photocoagulation remains the standard management for DME and these results do not alter this paradigm., (Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the effect of intravitreal triamcinolone acetonide with focal/grid photocoagulation on the progression of diabetic retinopathy., Methods: We performed an exploratory analysis of participants with diabetic macular edema randomly assigned to receive laser therapy or intravitreal triamcinolone acetonide (1 or 4 mg). Fundus photographs were obtained at baseline and 1, 2, and 3 years. The main outcome measure was progression to proliferative diabetic retinopathy or worsening of 2 or more severity levels on reading-center masked assessment of 7-field fundus photographs, plus additional eyes that received panretinal photocoagulation or had a vitreous hemorrhage., Results: From July 15, 2004, through May 5, 2006, 840 eyes from 693 participants were enrolled in the study and randomly assigned to receive laser therapy (n = 330), 1 mg of triamcinolone acetonide (n = 256), or 4 mg of triamcinolone acetonide (n = 254). The cumulative probability of progression of retinopathy at 2 years was 31% (laser group), 29% (1-mg group), and 21% (4-mg group) (P = .64 in the 1-mg group and .005 in the 4-mg group compared with the laser group). These differences appeared to be sustained at 3 years., Conclusions: Intravitreal triamcinolone acetonide (4 mg) appeared to reduce the risk of progression of diabetic retinopathy. Given the exploratory nature of this analysis and because intravitreal triamcinolone adverse effects include cataract formation and glaucoma, use of this treatment merely to reduce the rates of progression of proliferative diabetic retinopathy or worsening of the level of diabetic retinopathy does not seem warranted at this time.

Objective: To report 3-year outcomes of patients who participated in a randomized trial evaluating 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone compared with focal/grid photocoagulation for treatment of diabetic macular edema., Methods: Eyes with diabetic macular edema and visual acuities of 20/40 to 20/320 were randomly assigned to focal/grid photocoagulation or 1 mg or 4 mg of triamcinolone. At the conclusion of the trial, 3-year follow-up data were available in 306 eyes., Results: Between 2 years (time of the primary outcome) and 3 years, more eyes improved than worsened in all 3 treatment groups. Change in visual acuity letter score from baseline to 3 years was +5 in the laser group and 0 in each triamcinolone group. The cumulative probability of cataract surgery by 3 years was 31%, 46%, and 83% in the laser and 1-mg and 4-mg triamcinolone groups, respectively. Intraocular pressure increased by more than 10 mm Hg at any visit in 4%, 18%, and 33% of eyes, respectively., Conclusions: Results in a subset of randomized subjects who completed the 3-year follow-up are consistent with previously published 2-year results and do not indicate a long-term benefit of intravitreal triamcinolone relative to focal/grid photocoagulation in patients with diabetic macular edema similar to those studied in this clinical trial. Most eyes receiving 4 mg of triamcinolone as given in this study are likely to require cataract surgery., Trial Registration: clinicaltrials.gov Identifier: NCT00367133.

Purpose: To compare baseline demographic, systemic, and ocular characteristics within age and racial subgroups among participants in this Diabetic Retinopathy Clinical Research Network clinical trial and to compare this cohort with other cohorts enrolled in phase 3 clinical trials for diabetic retinopathy., Methods: Thirty-six month, randomized, controlled, multicenter clinical trial of 693 participants with diabetic macular edema enrolled at 88 clinical sites in the United States. Participants were categorized into self-reported race/ethnicity subgroups and into one of three age groups: 18 to <60, 60 to <70, and 70 and older., Results: Mean age of participants was 63 years, 72% were white, and median visual acuity letter score was 62 (approximately 20/63). No substantial difference was identified between racial subgroups for any baseline variable. Older participants were more likely to have Type 2 diabetes mellitus and longer duration disease. The most frequent levels of diabetic retinopathy among 840 study eyes were moderate (level 43) to moderately severe (level 47) nonproliferative disease., Conclusion: While the racial composition of this cohort does not differ from other cohorts in large phase 3 trials that have evaluated participants with diabetic retinopathy, the inclusion of many subjects over age 70 and a better level of glycemic control are distinguishing features.