Visual Outcomes Associated With Patterns of Macular Edema Resolution in Central Retinal Vein Occlusion Treated With Anti-Vascular Endothelial Growth Factor Therapy: A Post Hoc Analysis of the Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO) Trial.

IMPORTANCE: It is unclear how visual outcomes vary between patterns of macular edema (ME) resolution in eyes with central retinal vein occlusion (CRVO). OBJECTIVE: To assess best-corrected visual acuity (BCVA) outcomes at 100 weeks based on macular fluid resolution patterns by 52 and 100 weeks among patients receiving anti-vascular endothelial growth factor therapy for CRVO-related ME. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analysis of the prospective, 3-arm, double-masked, randomized noninferiority trial Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO), which evaluated intravitreal aflibercept (2.0 mg/0.05 mL), bevacizumab (1.25-mg/0.05 mL), or ranibizumab (0.5 mg/0.05 mL) over 100 weeks in adult patients (18 years and older) with CRVO-related ME with BCVA Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 19 to 78 in the study eye (approximate Snellen equivalent, 20/400 to 20/32, respectively) from December 2014 to December 2016 at 44 UK National Health Service ophthalmology departments. A total of 140 of 154 eyes were randomized to aflibercept, 144 of 154 randomized to bevacizumab, and 141 of 155 randomized to ranibizumab. Data were analyzed from January 2019 to March 2019. EXPOSURES: Persistent ME included eyes with central subfield thickness (CST) 320 µm or greater, and persistently dry macula (no ME) included eyes with CST less than 320 µm at 52 and 100 weeks. Recurrent ME included eyes that did not meet the criteria for persistently dry or wet. If CST was missing, the closest intervening visit was carried forward. MAIN OUTCOMES AND MEASURES: Adjusted mean BCVA at 100 weeks. RESULTS: The mean (SD) age of the 425 included participants was 69.2 (12.7) years, and 243 participants (57.2%) were men. A total of 425 eyes from 425 participants were included. By 100 weeks, 117 eyes (28.5%) were persistently dry, 44 (10.7%) were persistently wet (with ME), and 250 (60.8%) had recurrent ME. Persistent ME at 100 weeks was associated with worse VA compared with dry macula (adjusted difference, -10.98 ETDRS letters; 95% CI, -16.19 to -5.76; P < .001) and recurrent ME (adjusted difference, -5.39 letters; 95% CI, -10.15 to -0.64; P = .03). By 52 weeks, individuals with persistent ME also had poorer 100-week BCVA compared with individuals with dry macula (adjusted difference, -7.39; 95% CI, -11.72 to -3.05; P < .001) and recurrent ME (adjusted difference, -3.92; 95% CI, -8.05 to 0.20; P = .06). By 100 weeks, more eyes treated with bevacizumab had persistently wet macula than those treated with aflibercept (26 of 140 [18.6%] vs 7 of 134 [5.2%]; difference, 13.3%; 95% CI, 5.9 to 20.8; P < .001) or ranibizumab (11 of 137 [8%]; difference, 10.5%; 95% CI, 2.7 to 18.4; P = .01). CONCLUSIONS AND RELEVANCE: These findings suggest that attempts should be made to maintain persistently fluid-free macula for optimal visual acuity outcomes.

Intravitreal ranibizumab versus aflibercept versus bevacizumab for macular oedema due to central retinal vein occlusion: the LEAVO non-inferiority three-arm RCT.

BACKGROUND: Licensed ranibizumab (0.5 mg/0.05 ml Lucentis®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea®; Bayer AG, Leverkusen, Germany) and unlicensed bevacizumab (1.25 mg/0.05 ml Avastin®; F. Hoffmann-La Roche AG, Basel, Switzerland) are used to treat macula oedema due to central retinal vein occlusion, but their relative clinical effectiveness, cost-effectiveness and impact on the UK NHS and Personal Social Services have never been directly compared over the typical disease treatment period. OBJECTIVE: The objective was to compare the clinical effectiveness and cost-effectiveness of three intravitreal antivascular endothelial growth factor agents for the management of macula oedema due to central retinal vein occlusion. DESIGN: This was a three-arm, double-masked, randomised controlled non-inferiority trial. SETTING: The trial was set in 44 UK NHS ophthalmology departments, between 2014 and 2018. PARTICIPANTS: A total of 463 patients with visual impairment due to macula oedema secondary to central retinal vein occlusion were included in the trial. INTERVENTIONS: The participants were treated with repeated intravitreal injections of ranibizumab (n = 155), aflibercept (n = 154) or bevacizumab (n = 154). MAIN OUTCOME MEASURES: The primary outcome was an increase in the best corrected visual acuity letter score from baseline to 100 weeks in the trial eye. The null hypothesis that aflibercept and bevacizumab are each inferior to ranibizumab was tested with a non-inferiority margin of -5 visual acuity letters over 100 weeks. Secondary outcomes included additional visual acuity, and imaging outcomes, Visual Function Questionnaire-25, EuroQol-5 Dimensions with and without a vision bolt-on, and drug side effects. Cost-effectiveness was estimated using treatment costs and Visual Function Questionnaire-Utility Index to measure quality-adjusted life-years. RESULTS: The adjusted mean changes at 100 weeks in the best corrected visual acuity letter scores were as follows - ranibizumab, 12.5 letters (standard deviation 21.1 letters); aflibercept, 15.1 letters (standard deviation 18.7 letters); and bevacizumab, 9.8 letters (standard deviation 21.4 letters). Aflibercept was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference 2.23 letters, 95% confidence interval -2.17 to 6.63 letters; p = 0.0006), but not superior. The study was unable to demonstrate that bevacizumab was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference -1.73 letters, 95% confidence interval -6.12 to 2.67 letters; p = 0.071). A post hoc analysis was unable to demonstrate that bevacizumab was non-inferior to aflibercept in the intention-to-treat population (adjusted mean best corrected visual acuity difference was -3.96 letters, 95% confidence interval -8.34 to 0.42 letters; p = 0.32). All per-protocol population results were the same. Fewer injections were required with aflibercept (10.0) than with ranibizumab (11.8) (difference in means -1.8, 95% confidence interval -2.9 to -0.8). A post hoc analysis showed that more bevacizumab than aflibercept injections were required (difference in means 1.6, 95% confidence interval 0.5 to 2.7). There were no new safety concerns. The model- and trial-based cost-effectiveness analyses estimated that bevacizumab was the most cost-effective treatment at a threshold of £20,000-30,000 per quality-adjusted life-year. LIMITATIONS: The comparison of aflibercept and bevacizumab was a post hoc analysis. CONCLUSION: The study showed aflibercept to be non-inferior to ranibizumab. However, the possibility that bevacizumab is worse than ranibizumab and aflibercept by 5 visual acuity letters cannot be ruled out. Bevacizumab is an economically attractive treatment alternative and would lead to substantial cost savings to the NHS and other health-care systems. However, uncertainty about its relative effectiveness should be discussed comprehensively with patients, their representatives and funders before treatment is considered. FUTURE WORK: To obtain extensive patient feedback and discuss with all stakeholders future bevacizumab NHS use. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13623634. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 38. See the NIHR Journals Library website for further project information.

The eye functions like a camera. The retina, at the back of the eye, is the camera film, and the centre, the macula, allows us to see fine details. Approximately 6500 people each year in England and Wales are affected by fluid leaking out of congested tiny blood vessels, causing macular swelling or oedema. The cause is blockage of the main vein that normally drains blood from the retina. Three drugs, injected into the eye in tiny amounts every 4­8 weeks, have been shown to improve the vision of people with this condition. Two drugs, ranibizumab (0.5 mg/0.05 ml Lucentis^®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea^®; Bayer AG, Leverkusen, Germany), are licensed for UK use, but the third, bevacizumab (1.25 mg/0.05 ml Avastin^®; F. Hoffmann-La Roche AG, Basel, Switzerland), is not, even though it is much cheaper and used extensively worldwide. To our knowledge, no trials have compared the three drugs over the typical 2-year treatment period. This multicentre, Phase III, double-masked, randomised controlled non-inferiority trial comparing the clinical effectiveness and cost-effectiveness of intravitreal therapy with ranibizumab (Lucentis) versus aflibercept (Eylea) versus bevacizumab (Avastin) for macular oedema due to central retinal Vein Occlusion (LEAVO) was designed to compare ranibizumab, aflibercept and bevacizumab in this type of macular oedema. The trial showed that all three drugs improved vision a lot, but bevacizumab improved vision to a slightly lesser degree than the other two drugs. All patients should be aware of these findings before considering their treatment options. A comparison of the costs and benefits of ranibizumab, aflibercept and bevacizumab, using data from the trial and other sources, found that all three led to similar improvements in quality of life. Because aflibercept and ranibizumab are so much more expensive, they may be poor value for money. If patients, their representatives and funders all agree, it may be possible to treat this type of macular oedema with bevacizumab, which is cheaper, keeping the other agents available if needed.

Predictors of Visual Acuity Outcomes after Anti-Vascular Endothelial Growth Factor Treatment for Macular Edema Secondary to Central Retinal Vein Occlusion.

PURPOSE: To evaluate whether baseline demographic, clinical, and OCT characteristics predict visual acuity (VA) outcomes in patients receiving anti-vascular endothelial growth factor (VEGF) therapy for macular edema (ME) due to central retinal vein occlusion (CRVO). DESIGN: Post hoc analysis of the randomized noninferiority trial (Lucentis, Eylea, Avastin in CRVO) LEAVO Study from December 12, 2014, to December 16, 2016, carried out across 44 UK National Health Service ophthalmology departments. PARTICIPANTS: Data on 267 participants with a baseline best-corrected mean visual acuity (BCVA) range of 19 to 78 Early Treatment Diabetic Retinopathy Study letter score (approximate Snellen equivalent, 20/32 to 20/320) who had central subfield thickness (CST) ≥ 320 µm on Spectralis OCT (Heidelberg Engineering) were analyzed. METHODS: Study participants were randomized to receive repeated intravitreal injections of ranibizumab (0.5 mg/50 µl), aflibercept (2.0 mg/50 µl), or bevacizumab (1.25 mg/50 µl), and a protocol-driven pro re nata re-treatment regimen at 4 to 8 weekly visits was followed up to week 100 after 4 mandated 4-weekly loading injections. MAIN OUTCOME MEASURES: Change in BCVA and percentage of patients gaining ≥ 10 letters and achieving BCVA letter score > 70 letters at 52 and 100 weeks. RESULTS: The analysis was adjusted for treatment effects and confirmed by sensitivity analysis. Age ≥ 75 years is a poor predictor for all 3 visual outcomes. Lower baseline BCVA predicted 10-letter gainers and higher gains in BCVA, although it is a poor predictor of achieving > 70 Early Treatment Diabetic Retinopathy Study letters. None of the baseline OCT morphologic characteristics except ellipsoid zone (EZ) integrity influenced any visual outcomes. Both baseline CST and total macular volume showed a nonlinear relation to 10-letter gainers, with CST > 900 µm being a poor prognostic indicator. Baseline CST and macular volume did not predict mean change in BCVA or BCVA > 70 letters at 52 and 100 weeks. The sensitivity analysis conclusions after removing iCRVO were similar. CONCLUSIONS: At presentation, younger age, higher baseline BCVA, and a definitely intact subfoveal EZ are predictors of BCVA score > 70 letters at 100 weeks.

Retinal Nonperfusion Characteristics on Ultra-Widefield Angiography in Eyes With Severe Nonproliferative Diabetic Retinopathy and Proliferative Diabetic Retinopathy.

Importance: Threshold of retinal nonperfusion for the development of proliferative diabetic retinopathy (PDR) is unclear. Objectives: To identify a threshold of retinal nonperfusion for the presence of retinal neovascularization and the distribution and area of retinal nonperfusion in eyes with severe nonproliferative diabetic retinopathy (NPDR), PDR, neovascularization of the optic disc (NVD), and retinal neovascularization elsewhere (NVE). Design, Setting, and Participants: This cross-sectional image analysis study was performed between September 24, 2018, and October 24, 2018, at a multicenter national study in the United Kingdom. Baseline images were obtained from 2 completed randomized clinical trials (Ranibizumab for Diabetic Macular Edema Panretinal Photocoagulation [RDP] study and Clinical Efficacy of Intravitreal Aflibercept vs Panretinal Photocoagulation for Best Corrected Visual Acuity in Patients With Proliferative Diabetic Retinopathy at 52 Weeks [CLARITY] study). The RDP study recruited eyes with severe NPDR between April 1, 2014, and December 31, 2015, and the CLARITY study recruited eyes with PDR between August 22, 2014, and November 20, 2015. Ultra-widefield angiography images of eyes with no prior panretinal photocoagulation treatment were included. Main Outcomes and Measures: The total area of retinal nonperfusion, the area of posterior pole retinal nonperfusion, and the area of peripheral retinal nonperfusion were measured. Results: A total of 92 patients (92 eyes) were included in the study: 59 in the PDR group (mean [SD] age, 42 [15] years; 20 female [33.9%]) and 33 in the NPDR group (mean [SD] age, 63 [10] years; 3 female [9.1%]). Forty eyes had NVE and 19 had NVD with or without NVE. We identified a retinal nonperfusion threshold of 118.3 disc areas (DA) with a specificity of 84.9% (95% CI, 68.1% to 94.9%) for PDR. The median area of retinal nonperfusion was 67.8 DA (95% CI, 44.2 to 107.3 DA) in the NPDR eyes and 147.9 DA (95% CI, 127.4 to 173.5 DA) for eyes with proliferative changes, with a difference of 69.0 DA (95% CI, 42.2 to 97.7 DA; P < .001). No difference was found in the median area of posterior nonperfusion between NPDR and PDR, with a difference of 0 DA (95% CI, -6.7 to 5.2 DA; P = .56). As for peripheral nonperfusion, NPDR eyes measured 64.1 DA and PDR eyes measured 130.6 DA, with a difference of 70.8 DA (95% CI, 48.4 to 94.9 DA; P < .001). Eyes with NVD had the largest total area of retinal nonperfusion, with a difference of 65.1 DA (95% CI, 28.6 to 95.8 DA; P < .001) compared with eyes with only NVE. Conclusions and Relevance: These findings suggest eyes with at least 107.3 DA of nonperfusion are at risk of proliferative disease, and eyes with NVD have the largest area of retinal nonperfusion.

Mechanistic Evaluation of Panretinal Photocoagulation Versus Aflibercept in Proliferative Diabetic Retinopathy: CLARITY Substudy.

Purpose: The purpose of this study was to study the effects of panretinal photocoagulation (PRP) and intravitreal aflibercept on retinal vessel oxygen saturations, area of retinal nonperfusion, and area of neovascularization in proliferative diabetic retinopathy. Methods: This is a prospective randomized single center study. Forty patients with proliferative diabetic retinopathy were randomized to PRP or intravitreal aflibercept treatment for 52 weeks. Retinal oximetry and ultra-widefield angiography were performed at baseline and week 52. Ultra-widefield color fundus imaging was performed at baseline, week 12, and week 52. The outcomes were retinal arterio-venous oximetry differences (AVD), area of retinal nonperfusion, and area of neovascularization in disc areas (DA). Results: The AVD in the PRP group increased from 36.7% at baseline to 39.7%, whereas it decreased from 33.4% to 32.5% in the aflibercept group. The difference in AVD between groups at week 52 was 4.0% (95% confidence interval, -0.08, 8.8; P = 0.10). The baseline mean area of retinal nonperfusion of 125.1 DA and 131.2 DA in the PRP and aflibercept groups increased to 156.1 DA and 158.4 DA, respectively, at week 52 (P = 0.46). The median baseline area of neovascularization decreased from 0.98 DA to 0.68 DA in the PRP group and from 0.70 DA to 0 DA in the aflibercept group at week 12 (P = 0.019). At week 52, this measured 0.24 DA in the PRP group and 0 DA in the aflibercept group (P = 0.45). Conclusions: Intravitreal aflibercept achieved an earlier and complete regression of neovascularization in proliferative diabetic retinopathy compared with PRP. There were no significant differences in global change in intravascular oxygen saturation or areas of retinal nonperfusion between the two groups by 52 weeks.

Clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (acronym CLARITY): a multicentre phase IIb randomised active-controlled clinical trial.

INTRODUCTION: Proliferative diabetic retinopathy (PDR) is the main cause of severe visual loss in people with diabetes mellitus. The standard treatment for this condition is panretinal photocoagulation (PRP). This laser treatment is inherently destructive, with predictable adverse effects on visual function, and a safer alternative is required. Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors can induce short-term regression of retinal neovascularisation. The aim of this randomised controlled trial is to determine the efficacy, safety and cost-effectiveness of intravitreal aflibercept, an inhibitor of VEGF-A, VEGF-B and placental growth factor (PLGF), in PDR, and to investigate the impact on local oxygenation. METHODS AND ANALYSIS: This is a phase IIb randomised controlled single-masked multicentre clinical trial to determine the impact of repeated intravitreal aflibercept injections in the treatment and prevention of PDR. 220 participants with treatment-naïve or treated but active retinal neovascularisation in at least one eye will be randomly allocated 1:1 to intravitreal aflibercept injections or PRP for a period of 52 weeks. The primary outcome is the change in best-corrected visual acuity in the study eye at 52 weeks. Secondary outcomes include changes from baseline in other visual functions, anatomical changes and cost-effectiveness. Ocular and non-ocular adverse events will also be reported over 52 weeks. ETHICS AND DISSEMINATION: The study has been approved by the National Research Ethics Service (NRES) committee with respect to scientific content and compliance with applicable research and human subjects' regulations. Findings will be reported through scientific publications and research conferences. The results of this study will provide clinical evidence for the feasibility, efficacy safety and cost-effectiveness of intravitreal aflibercept for PDR. TRIAL REGISTRATION NUMBER: ISRCTN 32207582.

Three-year visual outcome and injection frequency of intravitreal ranibizumab therapy for neovascular age-related macular degeneration.

BACKGROUND: To assess the 3-year visual outcome and injection frequency for patients on ranibizumab for neovascular age-related macular degeneration (NV-AMD). METHODS: Retrospective case-note review of 174 treatment-naïve eyes of 156 patients with NV-AMD with 3-year follow-up was done at specific time points closest to 12, 24 and 36 months. RESULTS: The median baseline visual acuity (VA) of 50 Early Treatment Diabetic Retinopathy Study letters (mean 48.2 ± 16.9) improved significantly to 55 (mean 51.2 ± 18.7) by the end of 12 months (p = 0.04). At 24 months, the median letter score remained unchanged at 55 (mean 50.4 ± 20.8; p = 0.14 as compared to baseline) and at 36 months, the median VA was 54 letters (mean 49.1 ± 21.7; p = 0.34 compared to baseline). The mean numbers of injections were 4.8 ± 2.2 at 1 year, 7.8 ± 4.2 at 2 years (2.9 in the second year) and 10.2 ± 6.2 at the end of the third year (2.4 in the third year). CONCLUSION: Our study demonstrates the efficacy of a variable dosing regimen of ranibizumab for the treatment of NV-AMD. The mean gain in VA is inversely proportional to the baseline VA and did not correlate with the number of injections.