Publications by authors named "Namrata Saroj"

40 Publications

Intravitreal Aflibercept Injection vs Sham as Prophylaxis Against Conversion to Exudative Age-Related Macular Degeneration in High-risk Eyes: A Randomized Clinical Trial.

JAMA Ophthalmol 2021 Mar 18. Epub 2021 Mar 18.

Retina Vitreous Associates Medical Group, Los Angeles, California.

Importance: Anti-vascular endothelial growth factor (VEGF) agents may provide a prophylactic effect in high-risk eyes with intermediate dry age-related macular degeneration (AMD) against conversion to exudative AMD (eAMD), lowering the risk of vision loss.

Objective: To evaluate intravitreal aflibercept injection (IAI) as prophylaxis against the conversion to eAMD in high-risk eyes at 24 months.

Design, Setting, And Participants: This single-masked, sham-controlled, randomized clinical trial performed at 4 US clinical sites enrolled patients with intermediate AMD in 1 eye (study eye), defined as presence of more than 10 medium drusen (≥63 to <125 μm), at least 1 large druse (≥125 μm), and/or retinal pigmentary changes, and eAMD in the fellow eye. Patients were treated from June 23, 2015, to March 13, 2019.

Interventions: Intravitreal aflibercept injection (2 mg) or sham quarterly injection for 24 months (1:1 randomization).

Main Outcomes And Measures: The primary end point was the proportion of patients with conversion to eAMD at month 24 characterized by development of choroidal neovascularization, as assessed by leakage on fluorescein angiography and fluid on spectral-domain optical coherence tomography by an independent masked reading center.

Results: Of 128 patients enrolled, 127 (63 in the IAI group and 64 in the sham group) were included in the primary analysis (68 men [53.5%]; mean [SD] age, 76.5 [8.1] years). Baseline demographic and clinical characteristics were balanced between the groups. By month 24, 6 patients (9.5%) in the IAI group and 7 (10.9%) in the sham group developed eAMD (P = .98). Patients with a history of eAMD for longer than 2 years in their fellow eye at baseline showed a lower rate of conversion to eAMD in the study eye compared with those with a history of eAMD for 2 years or less in the fellow eye. Safety was consistent with previous studies involving intravitreal anti-VEGF injections.

Conclusions And Relevance: In this evaluation of quarterly anti-VEGF exposure as prophylaxis to reduce conversion of eyes with high-risk dry AMD to eAMD, the rates of conversion were not lower in the IAI group compared with the sham treatment group at month 24. Understanding the mechanism of conversion to eAMD and therapies that could prevent this event remains an important unmet need.

Trial Registration: ClinicalTrials.gov Identifier: NCT02462889.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.0221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974836PMC
March 2021

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy.

Ophthalmology 2021 Mar 9. Epub 2021 Mar 9.

Objective: Evaluate clinical characteristics of eyes that developed investigator-determined new-onset exudative age-related macular degeneration (eAMD) during the FILLY trial.

Design: Post-hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA).

Subjects: 246 subjects with GA secondary to AMD.

Intervention: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month (EOM) for 12 months followed by a 6-month off-treatment period.

Main Outcome Measures: Time of onset of new eAMD in the study eye; history of eAMD in the fellow eye; presence of double layer sign (DLS) on structural optical coherence tomography (OCT) in the study eye; changes in retinal anatomy by structural OCT and fluorescein angiography (FA); and changes in visual acuity.

Results: Exudation was reported in 26 study eyes across all treatment groups over 18 months. Mean time to diagnosis of eAMD was 256 days (range: 31 to 555). Overall, a higher proportion of subjects with a history of eAMD in the fellow eye (P=0.016) and a DLS in the study eye at baseline (P=0.0001) developed eAMD. Among study eyes that developed eAMD, 18/26 (69%) had a history of fellow eye eAMD and 19/26 (73.1%) had a DLS at baseline, compared to 72/217 (33%) (P=0.0003) and 70/215 (32.5%) (P<0.0001)respectively, of study eyes that did not develop eAMD. All 21 subjects with structural OCT imaging at the time of eAMD diagnosis had subretinal fluid and/or intraretinal cysts, consistent with exudation. Among 17 subjects who received FA at the time of eAMD diagnosis, 10 had detectable MNV, all occult lesions. Development of eAMD did not appear to have an appreciable impact on visual acuity, and all subjects responded to anti-VEGF therapy.

Conclusions: Intravitreal injections of pegcetacoplan slowed the rate of GA growth and were associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. eAMD appeared to be associated with the presence of baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.
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http://dx.doi.org/10.1016/j.ophtha.2021.02.025DOI Listing
March 2021

Impact of Baseline Characteristics on Geographic Atrophy Progression in the FILLY Trial Evaluating the Complement C3 Inhibitor Pegcetacoplan.

Am J Ophthalmol 2021 Mar 3. Epub 2021 Mar 3.

Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina. Electronic address:

Purpose: To evaluate the effect of select baseline characteristics on geographic atrophy (GA) progression in eyes receiving intravitreal pegcetacoplan or sham.

Design: Phase 2 multicenter, randomized, single-masked, sham-controlled trial.

Methods: Patients with GA received 15 mg pegcetacoplan monthly or every other month (EOM), or sham injection monthly or EOM for 12 months. Primary efficacy endpoint was change in GA lesion size (square root) from baseline. Post hoc analysis evaluated the effects of age; gender; lesion size, focality, and location (extrafoveal vs foveal); pseudodrusen status; best corrected visual acuity (BCVA); and low luminance deficit (LLD) on GA progression at month 12.

Results: Of 246 randomized patients, 192 with 12-month data were included in this analysis. Overall mean (standard deviation) change in lesion size (mm) was 0.26 (0.17) (P < .01), 0.27 (0.27) (P < .05), and 0.36 (0.21) in the monthly pegcetacoplan (n = 67), EOM pegcetacoplan (n = 58), and sham (n = 67) groups, respectively. In univariate analysis, patients with extrafoveal lesions (P < .001), BCVA ≥ 20/60 (P = .001), and larger LLD (P = .002) had greater mean changes in lesion size. Multivariate analysis confirmed significant association of extrafoveal lesions (P = .001) and larger LLD (P = .023) with GA progression. Monthly and EOM pegcetacoplan significantly reduced progression (P < .05) when controlling for these risk factors.

Conclusions: Extrafoveal lesions and larger LLD are potential risk factors for GA progression. Pegcetacoplan treatment significantly controlled GA progression even after accounting for these risk factors.
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http://dx.doi.org/10.1016/j.ajo.2021.02.031DOI Listing
March 2021

Increasing Incidence and Prevalence of Common Retinal Diseases in Retina Practices Across the United States.

Ophthalmic Surg Lasers Imaging Retina 2021 Jan;52(1):29-36

Background And Objective: To provide an updated estimate of incidence and prevalence of the foremost retinal diseases in the U.S.

Patients And Methods: Retrospective study of the Vestrum Health Database evaluating eyes with diagnoses of wet or dry age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy (DR), branch or central retinal vein occlusion (BRVO; CRVO) from January 2014 to December 2019 across 58 retina practices.

Results: Of the 3,086,791 eyes examined, 490,881 (15.9%) had dry AMD, 294,041 (9.5%) wet AMD, 270,703 (8.8%) DME, 254,690 (8.3%) DR without DME, 73,617 (2.4%) BRVO, and 50,670 (1.6%) CRVO. Dry AMD had the highest incidence. These diseases comprised 61.0% of total prevalence and 54.3% of incidence among patients at the retina practices analyzed.

Conclusions: Based on a diverse database, these diseases comprised the majority of U.S. retina practice cases, with increasing annual incidences. AMD is the most common diagnosis, then diabetic eye disease. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:29-36.].
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http://dx.doi.org/10.3928/23258160-20201223-06DOI Listing
January 2021

Outcomes by Baseline Choroidal Neovascularization Features in Age-Related Macular Degeneration: A Post Hoc Analysis of the VIEW Studies.

Ophthalmol Retina 2021 Feb 9;5(2):141-150. Epub 2020 Jul 9.

Regeneron Pharmaceuticals, Inc., Tarrytown, New York.

Purpose: To assess the influence of baseline choroidal neovascularization (CNV) features on visual change and fluid resolution after anti-vascular endothelial growth factor (VEGF) treatment of eyes with neovascular age-related macular degeneration (nAMD).

Design: Post hoc analysis of 52-week data from the phase 3 Vascular Endothelial Growth Factor VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (AMD) Studies (VIEW) 1 and 2 clinical trials.

Participants: One thousand eight hundred four patients with nAMD.

Methods: Integrated data from VIEW 1 and 2 of 1804 eyes receiving intravitreal aflibercept injections (IAIs) 2 mg every 4 weeks, IAIs 2 mg every 8 weeks after 3 initial monthly doses, and ranibizumab every 4 weeks with documented baseline CNV type, total area, and leakage area were analyzed. Time to an event and cumulative incidence were evaluated by Kaplan-Meier analysis, and relative risks were estimated using proportional hazards analysis.

Main Outcomes Measures: Cumulative incidence of time to first sustained vision gain of 15 or more Early Treatment Diabetic Retinopathy Study letters, vision loss of more than 5 Early Treatment Diabetic Retinopathy Study letters from baseline, as well as first sustained absence of retinal fluid and intraretinal fluid as evaluated by OCT with respect to CNV type, total CNV, and leakage area.

Results: Eyes with predominantly classic CNV (mean best-corrected visual acuity [BCVA], 48.2 letters at baseline) showed a higher incidence rate of first sustained gain of 15 letters or more than eyes with occult CNV (mean BCVA, 57.9 letters at baseline; P < 0.01). Eyes with occult CNV at baseline showed higher incidence rates of first sustained absence of retinal fluid and of intraretinal fluid than eyes with predominantly classic CNV (both P < 0.01). With increasing baseline CNV total area and leakage area, the incidence rate of first sustained gain of 15 letters or more decreased.

Conclusions: This post hoc analysis provided additional evidence for the role of baseline CNV features (CNV type, total area, and leakage area) in influencing visual and anatomic outcomes in eyes with nAMD after anti-VEGF treatment.
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http://dx.doi.org/10.1016/j.oret.2020.07.003DOI Listing
February 2021

Impact of Systemic Dipeptidyl Peptidase-4 Inhibitor Use in Diabetic Macular Edema.

Ophthalmic Surg Lasers Imaging Retina 2020 04;51(4):226-234

Background And Objective: To evaluate impact of baseline systemic dipeptidyl peptidase-4 (DPP-4) inhibitor use in diabetic macular edema (DME).

Patients And Methods: This was a post hoc exploratory analysis of previously completed randomized, controlled clinical trials (VISTA and VIVID) in patients with DME evaluating intravitreal aflibercept injection (IAI) every 4 weeks (2q4) or every 8 weeks (2q8) or macular laser photocoagulation.

Results: Overall, a small number of patients (12.2% [n = 35], 9.7% [n = 28], and 15.4% [n = 44]) in the laser control, 2q4, and 2q8 groups reported baseline DPP-4 inhibitor use. There were no differences in changes from baseline in best-corrected visual acuity, central subfield thickness, or rates of 2-or-greater-step improvement in Diabetic Retinopathy Severity Scale score based on DPP-4 inhibitor use within each treatment group.

Conclusion: DPP-4 inhibitor use at baseline did not influence the magnitude of visual and anatomic benefit in patients with DME being treated with IAI or laser. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:226-234.].
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http://dx.doi.org/10.3928/23258160-20200326-04DOI Listing
April 2020

Prevention of Macular Edema in Patients With Diabetic Retinopathy Undergoing Cataract Surgery: The PROMISE Trial.

Ophthalmic Surg Lasers Imaging Retina 2020 03;51(3):170-178

Background And Objective: To determine the safety and efficacy of intravitreal aflibercept injection (IAI) in patients with diabetic retinopathy (DR) in the prevention of macular edema (ME) following cataract surgery.

Patients And Methods: This phase 2, prospective, interventional, single-masked, randomized trial at a single academic center included 30 patients who were 18 years of age or older with nonproliferative DR and undergoing cataract surgery with phacoemulsification. Patients received 2 mg intravitreal aflibercept (0.05 mL) or sham injection during cataract surgery. Main outcome measures included treatment adverse events (AEs), best-corrected visual acuity (BCVA), and incidence of ME (defined as presence of cystoid abnormalities as detected by optical coherence tomography at any follow-up visit), a 30% or greater increase from preoperative baseline in central subfield macular thickness, or a BCVA decrease of more than 5 ETDRS letters from Day 7 due to retinal thickening.

Results: There were similar incidences of AEs between the two groups and no clinically serious ocular AEs in either group. The IAI group had fewer ME events at Day 14 (13% vs. 53%; P = .022), but there was no significant difference in ME events at Day 30 (27% vs. 60%; P = .057), Day 60 (27% vs. 60%; P = .057), or Day 90 (40% vs. 67%; P = .161). Compared to the study group, the control group had a significantly greater increase in central subfield thickness (CST) at Day 30 (50.05 μm vs. 7.95 μm; P = .040) and Day 60 (56.45 μm vs. 3.02 μm; P = .010). However, the difference in CST between groups was no longer significant at Day 90 (50.31 μm vs. 18.48 μm; P = .12). There were no significant differences in BCVA gains between the IAI and sham group at the end of the follow-up period (Day 90, ETDRS letters: 9.88 vs. 8.52; P = .66).

Conclusions: Use of IAI in patients with DR for prevention of ME following cataract surgery showed no significant AEs. Although there were significant differences in ME incidence and retinal thickness at periods of time, there was no clinically meaningful benefit in terms of VA. Further larger trials are needed to validate these findings. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:170-178.].
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http://dx.doi.org/10.3928/23258160-20200228-06DOI Listing
March 2020

Impact of Posterior Vitreous Detachment on Treatment Outcomes in Diabetic Macular Edema.

Ophthalmol Retina 2020 04 9;4(4):452-454. Epub 2019 Dec 9.

Wills Eye Hospital, Philadelphia, Pennsylvania; Thomas Jefferson University, Philadelphia, Pennsylvania; Mid Atlantic Retina, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.oret.2019.12.002DOI Listing
April 2020

Outcomes in Patients with Diabetic Macular Edema Requiring Cataract Surgery in VISTA and VIVID Studies.

Ophthalmol Retina 2020 05 4;4(5):481-485. Epub 2019 Nov 4.

Regeneron Pharmaceuticals, Inc, Tarrytown, New York.

Purpose: To evaluate the impact of cataract surgery on visual and anatomic outcomes in patients with diabetic macular edema treated with intravitreal aflibercept injection (IAI) or laser control and who did not require rescue therapy.

Design: Post hoc analysis of 2 phase 3 trials, Study of Intravitreal Aflibercept Injection in Patients with Diabetic Macular Edema (VISTA) and Intravitreal Aflibercept Injection in Vision Impairment Due to DME (VIVID).

Participants: Fifty-four patients (laser treatment, n = 11; IAI, n = 43) who underwent cataract surgery during the study period.

Methods: In VISTA and VIVID, patients received IAI 2 mg every 4 weeks, IAI 2 mg every 8 weeks after 5 monthly doses, or laser control through week 100. Starting at week 24, if rescue treatment criteria were met, IAI patients received laser therapy, and laser therapy patients received IAI 2 mg every 8 weeks (after 5 monthly doses). Patients who received rescue treatment before cataract surgery were excluded.

Main Outcome Measures: Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) in the laser control and pooled IAI groups before and after cataract surgery.

Results: The cumulative incidence of cataract surgery did not depend on treatment group assignment (rate ratio, = 1.517; 95% confidence interval, 0.782-2.944; P = 0.2174). At the last study visit before surgery, BCVA was 62.2 and 56.9 letters and CRT was 342 μm and 301 μm in the laser control and IAI groups, respectively. At the first study visit after cataract surgery, BCVA was improved significantly in both the laser control and IAI groups to 73.5 letters (P = 0.010 compared with last visit before surgery) and 67.2 letters (P < 0.001 compared with last visit before surgery), respectively. Corresponding change in CRT was a modest increase to 364 μm (P > 0.05 compared with last visit before surgery) and 359 μm (P = 0.013 compared with last visit before surgery), respectively.

Conclusions: Incidence of cataract surgery was similar in both treatment groups. Despite a modest worsening in CRT after cataract surgery, BCVA was improved in both treatment groups.
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http://dx.doi.org/10.1016/j.oret.2019.10.015DOI Listing
May 2020

Changes in neovascular activity following fixed dosing with an anti-vascular endothelial growth factor agent over 52 weeks in the phase III VIEW 1 and VIEW 2 studies.

Br J Ophthalmol 2020 09 11;104(9):1223-1227. Epub 2019 Dec 11.

Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA.

Background/aims: To understand changes in disease activity as assessed by leakage and retinal fluid status in patients with neovascular age-related macular degeneration (nAMD) receiving fixed dosing with an anti-vascular endothelial growth factor (anti-VEGF) agent.

Methods: In the phase III VIEW 1 (NCT00509795) and VIEW 2 (NCT00637377) studies, eyes with nAMD were treated with intravitreal aflibercept or ranibizumab. Independent, masked reading centres determined the presence/absence of leakage (fluorescein angiography) and retinal fluid (optical coherence tomography) at baseline, week 24 and week 52. In this integrated, post hoc analysis of the VIEW studies, the relationship between leakage/fluid status and best-corrected visual acuity (BCVA) was assessed. The impact of baseline lesion type (predominantly classic (PC), minimally classic (MC), occult) was also evaluated. Data from all treatment groups were pooled.

Results: 2373 eyes were included in this analysis. At baseline, 95.4% of eyes presented with both leakage and fluid. By week 52, leakage and fluid were present in 16.0% of eyes. Mean BCVA gains at week 52 were numerically greater in eyes without leakage and fluid versus eyes with both leakage and fluid (10.3 vs 9.2 letters). At week 52, 11.6%, 15.3% and 20.1% of eyes with PC, MC and occult lesions, respectively, had both leakage and fluid present.

Conclusion: In this post hoc analysis, fixed dosing with an anti-VEGF agent over 52 weeks eliminated disease activity (absence of both leakage and fluid) in most eyes. The effect of anti-VEGF treatment on leakage/fluid status favoured PC versus occult lesions.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315021DOI Listing
September 2020

Higher-Order Assessment of OCT in Diabetic Macular Edema from the VISTA Study: Ellipsoid Zone Dynamics and the Retinal Fluid Index.

Ophthalmol Retina 2019 12 6;3(12):1056-1066. Epub 2019 Jul 6.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio; Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.

Purpose: To investigate retinal fluid features and ellipsoid zone (EZ) integrity dynamics on spectral-domain OCT (SD-OCT) in eyes with diabetic macular edema (DME) treated with intravitreal aflibercept injection (IAI) in the VISTA-DME study.

Design: A post hoc subanalysis of a phase III, prospective clinical trial.

Participants: Eyes received either IAI 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly doses (2q8).

Methods: All eyes from the VISTA Phase III study in the IAI groups imaged with the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) were included. The OCT macular cube datasets were evaluated using a novel software platform to generate retinal layer and fluid boundary lines that were manually corrected for assessment of change in EZ parameters and volumetric fluid parameters from baseline. The retinal fluid index (i.e., proportion of the retinal volume consisting of cystic fluid) was also calculated at each time point.

Main Outcome Measures: The feasibility of volumetric assessment of higher-order OCT-based retinal parameters and its correlation with best-corrected visual acuity (BCVA).

Results: Overall, 106 eyes of 106 patients were included. Specifically, 52 eyes of 52 patients were included in the IAI 2q4 arm, and 54 eyes of 54 patients were included in the IAI 2q8 arm. Ellipsoid zone integrity metrics significantly improved from baseline to week 100, including central macular mean EZ to retinal pigment epithelium (RPE) thickness (2q4: 26.6 μm to 31.6 μm, P < 0.001; 2q8: 25.2 μm to 31.4 μm, P < 0.001). At week 100, central macular intraretinal fluid volume was reduced by >65% (P < 0.001) and central macular subretinal fluid volume was reduced by >99% in both arms (P < 0.001). Central macular retinal fluid index (RFI) significantly improved in both arms (2q4: 17.9% to 7.2%, P < 0.001; 2q8: 19.8% to 4.2%, P < 0.001). Central macular mean EZ-RPE thickness (i.e., a surrogate for photoreceptor outer segment length) and central RFI were independently correlated with BCVA at multiple follow-up visits.

Conclusions: Intravitreal aflibercept injection resulted in significant improvement in EZ integrity and quantitative fluid metrics in both 2q4 and 2q8 arms and correlated with visual function.
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http://dx.doi.org/10.1016/j.oret.2019.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899163PMC
December 2019

Incidence of New Choroidal Neovascularization in Fellow Eyes of Patients With Age-Related Macular Degeneration Treated With Intravitreal Aflibercept or Ranibizumab.

JAMA Ophthalmol 2019 Jul 11. Epub 2019 Jul 11.

Vitreous Retina Macula Consultants of New York, New York.

Importance: Incidence of conversion to neovascular age-related macular degeneration (nAMD) in untreated fellow eyes of patients who are treated for nAMD in 1 eye with anti-vascular endothelial growth factor agents provides important prognostic information to clinically manage patients.

Objective: To investigate the association of treatment assignment (intravitreal aflibercept vs ranibizumab) and baseline characteristics with fellow eye conversion to nAMD in the VEGF (Vascular Endothelial Growth Factor) Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) studies.

Design, Setting, And Participants: This post hoc analysis of the VIEW 1 and VIEW 2 studies (randomized, double-masked, active-controlled, multicenter, 96-week, phase 3 trials comparing the efficacy and safety of intravitreal aflibercept in 2457 patients with treatment-naive eyes with nAMD) analyzed a subgroup of participants treated for nAMD in 1 eye who had untreated fellow eyes without neovascularization at baseline. All participants in the VIEW studies were included in 1 of 4 groups: ranibizumab, 0.5 mg, every 4 weeks; aflibercept, 2 mg, every 4 weeks; aflibercept, 0.5 mg, every 4 weeks; or aflibercept, 2 mg, every 8 weeks after 3 injections at 4-week intervals. Data collection in the VIEW studies occurred from July 2007 to August 2011; the data analysis presented in this report took place from April 2016 to November 2018.

Interventions: Patients received no treatment in the fellow eyes unless after conversion to nAMD, when any treatment approved by heath authorities was given per the investigators' discretion.

Main Outcomes And Measures: Incidence of conversion to nAMD in patients with untreated fellow eyes that had not had clinical signs of neovascularization at baseline.

Results: A total of 1561 participants were included in this analysis. At 96 weeks, 375 patients (24.0%) experienced cases of conversion to neovascular disease in the fellow eye, including 107 of the 399 individuals who received ranibizumab, 0.5 mg, every 4 weeks; 93 of the 387 individuals who received aflibercept, 2 mg, every 4 weeks; 84 of the 387 individuals who received aflibercept, 0.5 mg, every 4 weeks; and 91 of the 388 individuals who received aflibercept, 2 mg, every 8 weeks after 3 doses at 4-week intervals. The rates were 18.1, 16.2, 14.7, and 16.0 per 100 patient-years at risk at week 96, respectively. On multivariate analysis, fellow eye conversion was associated with increasing patient age (per 10 years) at baseline (hazard ratio [HR], 1.20 [95% CI, 1.05-1.36]), female sex (HR, 1.32 [95% CI, 1.06-1.63]), intraretinal fluid in the study eye at baseline (HR, 1.28 [95% CI, 1.02-1.61]), and increasing choroidal neovascularization lesion size (per 10 mm2) in the study eye at baseline (HR, 1.29 [95% CI, 1.06-1.57]). Rates of fellow eye conversion were similar with either of the treatments.

Conclusions And Relevance: In this secondary analysis of randomized clinical trial data, patients with active nAMD in 1 eye appeared to have a high risk for fellow eye conversion. Such patients should be monitored closely.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.1947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624808PMC
July 2019

Impact of Baseline Retinal Nonperfusion and Macular Retinal Capillary Nonperfusion on Outcomes in the COPERNICUS and GALILEO Studies.

Ophthalmol Retina 2019 07 27;3(7):553-560. Epub 2019 Feb 27.

Department of Ophthalmology, University of Sydney, Sydney, Australia; Western Sydney Local Health Network, Sydney, Australia; Centre for Vision Research, Westmead Institute for Medical Research, Sydney, Australia; Sydney West Retina Pty Ltd, Sydney, Australia.

Purpose: To evaluate the impact of baseline retinal capillary nonperfusion (RNP) and macular retinal capillary nonperfusion (MNP) status on outcomes at week 24 (W24).

Design: Post hoc analyses of 2 phase 3, randomized, double-masked, multicenter, sham-controlled studies.

Participants: Three hundred sixty-six patients with macular edema secondary to central retinal vein occlusion randomized in COPERNICUS and GALILEO.

Methods: We randomized patients 3:2 to receive intravitreal aflibercept 2 mg every 4 weeks or sham injections until W24. RNP and MNP were assessed by a masked independent reading center.

Main Outcome Measures: Proportion of patients with 10 disc areas (DA) or more of RNP and any degree of MNP at W24, relative risks of 10 DA or more of RNP or any degree of MNP at W24 developing, change from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) by baseline RNP and MNP status, and relationship between baseline RNP and MNP status.

Results: At baseline, 24.6% of patients showed 10 DA or more of RNP and 72.6% showed MNP, regardless of baseline RNP status. At W24, the pooled proportions of patients in the intravitreal aflibercept and sham groups with 10 DA or more of RNP were 11.6% and 29.0%, respectively (P = 0.0001); the respective proportions with any degree of MNP were 61.2% and 79.5% (P = 0.0008). Relative risks and 95% confidence intervals for intravitreal aflibercept versus sham were 0.4 (0.25-0.62) for 10 DA or more of RNP and 0.8 (0.68-0.90) for MNP, indicating a lower risk for these outcomes with intravitreal aflibercept than with sham. Mean BCVA change was greater in intravitreal aflibercept- versus sham-treated eyes, with less than 10 DA and 10 DA or more of RNP at baseline (+17.5 vs. +0.8 letters and +18.3 vs. -4.1 letters, respectively) and with and without baseline MNP (+15.7 vs. +0.3 letters and +17.1 vs. +0.4 letters, respectively). Agreement between baseline RNP and MNP status was low (κ = 0.12). The proportions of patients with 1 or more ocular serious adverse event in the intravitreal aflibercept- and sham-treated groups, respectively, were 3.2% and 11.3%.

Conclusions: At W24, visual and anatomic improvements, including perfusion status, were greater in eyes treated with intravitreal aflibercept than in eyes treated with sham, regardless of baseline RNP or MNP status.
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http://dx.doi.org/10.1016/j.oret.2019.02.010DOI Listing
July 2019

Lipid-Lowering Medications Are Associated with Lower Risk of Retinopathy and Ophthalmic Interventions among United States Patients with Diabetes.

Am J Ophthalmol 2019 11 10;207:378-384. Epub 2019 Jun 10.

Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California, USA. Electronic address:

Purpose: To evaluate the impact of lipid-lowering medications on diabetic retinopathy and diabetic complications requiring intervention in the US population.

Design: Retrospective cohort analysis.

Methods: Administrative insurance claims were drawn from the Truven MarketScan Commercial Claims and Encounters databases. Population consisted of beneficiaries with type 2 diabetes mellitus (T2DM). Main outcome measurements were any signs of diabetic retinopathy, as measured by diagnosis codes for nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), or diabetic macular edema (DME) and procedure codes for retinopathy treatments (anti-VEGF injections, laser therapy, and vitrectomy).

Results: A population of 269,782 patients diagnosed with T2DM between 2008 and 2015 were analyzed. A total of 99,233 patients (37%) were undergoing treatment with lipid-lowering medications. Approximately 6% of patients taking lipid-lowering medications had a diagnosis code for NPDR, PDR, or DME or a procedural code for intravitreal injections, pars plana vitrectomy (PPV) or laser treatment in their record following diagnosis with diabetes compared to 6.5% of patients who did not take lipid-lowering medications (P < 0.01). In adjusted time-to-event analyses, patients who took lipid-lowering medications prior to diagnosis of T2DM were less likely to progress to any retinopathy diagnosis (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.55-0.65) and less likely to receive any treatment for retinopathy (HR, 0.81; 95% CI, 0.78-0.84). These findings were significant at the aggregate level, at the individual level of diagnosis (NPDR HR, 0.63; 95% CI, 0.57-0.69; PDR HR, 0.45; 95% CI, 0.37-0.54; and DME HR, 0.39; 95% CI, 0.33-0.45), and at the level of each treatment category (anti-VEGF injection HR, 0.81; 95% CI, 0.78-0.84; laser HR, 0.62; 95% CI, 0.47-0.81; and vitrectomy HR, 0.71; 95% CI, 0.59-0.85).

Conclusions: This study found consistent evidence that patients taking lipid-lowering medications were less likely to develop NPDR, PDR, or DME and modest evidence that these patients are less likely to receive intravitreal injections of anti-VEGF medication, laser treatments, or vitrectomy. The study validates the findings of studies that have used claims databases in East Asia in relatively homogeneous populations to estimate an association between statin use and retinopathy, replicating them in a US context in a large commercial claims database.
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http://dx.doi.org/10.1016/j.ajo.2019.05.029DOI Listing
November 2019

Outcomes of Diabetic Macular Edema Eyes with Limited Early Response in the VISTA and VIVID Studies.

Ophthalmol Retina 2018 06 19;2(6):558-566. Epub 2017 Dec 19.

Retina-Vitreous Associates Medical Group, Beverly Hills, California.

Purpose: To evaluate benefit of continued treatment in diabetic macular edema (DME) eyes showing a limited early response to treatment.

Design: Post hoc analysis of VISTA and VIVID.

Participants: 818 patients (eyes) with DME.

Methods: Eyes with baseline central subfield thickness (CST) of ≥300 μm that received 2-mg intravitreal aflibercept injection (IAI) every 4 weeks (2q4) or every 8 weeks after 5 monthly injections (2q8) or laser control treatment were included in this analysis if they showed a limited early response at week 12 after 3 monthly injections or a single laser treatment at baseline, as defined by those who met: anatomic criteria (CST reduction ≤10% and CST >300 μm); visual criteria (best-corrected visual acuity [BCVA] gain <5 letters); or both. Least square (LS) means repeated measures were used to compare outcomes between initial (baseline-week 12) and later (weeks 16-100) periods within each treatment group.

Main Outcome Measures: Visual outcomes of eyes with limited early response through week 100.

Results: In the anatomic subgroup, mean BCVA gains with 2q4 (n = 41) and 2q8 (n = 31) from baseline were 4.3 and 6.6 letters at week 12 and 8.6 and 8.5 letters at week 100, respectively. Corresponding LS mean differences for BCVA gains between initial and later periods were 3.0 (P = 0.0026) and 3.6 letters (P = 0.0017), respectively. In the visual subgroup, mean BCVA gains with 2q4 (n = 53) and 2q8 (n = 49) from baseline were 0.4 and 0.3 letters at week 12 and 6.1 and 4.1 letters at week 100, respectively. Corresponding LS mean differences for BCVA gains between initial and later periods were 5.0 (P < 0.0001) and 3.1 letters (P = 0.0008), respectively. In the combined subgroup, only a small percentage of IAI-treated eyes (<7%) met criteria. Regardless of type of limited early response, continued laser treatment did not result in additional BCVA gains through week 100.

Conclusions: Significant vision improvements were observed through week 100 with continued IAI treatment in a small number of DME eyes that showed a limited early response after 3 monthly IAI.
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http://dx.doi.org/10.1016/j.oret.2017.10.014DOI Listing
June 2018

Impact of Baseline Characteristics on Treatment Response to Intravitreal Aflibercept Injection for Wet Age-Related Macular Degeneration.

Ophthalmol Retina 2018 07 27;2(7):676-683. Epub 2017 Dec 27.

Department of Ophthalmology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.

Purpose: To determine whether wet age-related macular degeneration (AMD) treatment outcomes within prespecified patient subgroups were consistent with overall study results. Additionally, this subanalysis investigated whether there were any relationships between baseline characteristics and evaluated treatment outcomes.

Design: Post hoc subanalysis of The VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2, 2 similarly designed prospective, multicenter, double-masked, active-controlled, parallel-group, randomized clinical trials.

Participants: Two thousand four hundred twelve patients with an active subfoveal choroidal neovascularization (CNV) lesion of any subtype secondary to AMD.

Methods: Primary and key secondary visual end points at week 52 were examined to explore the consistency of effect among prespecified subgroups of 5 baseline characteristics: age, best-corrected visual acuity (BCVA), lesion type, lesion size, and central retinal thickness (CRT). Additionally, within-group analyses were conducted to determine whether the mean changes in BCVA and CRT at 52 weeks were associated positively or negatively with the baseline characteristics of interest.

Main Outcome Measures: Consistency of treatment outcomes among prespecified subgroups of baseline characteristics.

Results: For each baseline characteristic, tests for interaction within each prespecified subgroup and among the subgroups were not significant, suggesting that relative visual outcomes for each treatment arm were consistent with overall study outcomes. Within-group analysis revealed a significant association between baseline age, BCVA, and lesion size with BCVA outcomes at 52 weeks; namely, older age, greater BCVA, and larger lesion size were associated with lower mean BCVA gains at 52 weeks.

Conclusions: Patients in all subgroups of baseline age, BCVA, lesion type, lesion size, and CRT experienced visual outcomes consistent with those of the overall study population. Additionally, baseline older age, better BCVA, and larger CNV lesion size were found to be associated independently with lower mean BCVA gains after 52 weeks of anti-vascular endothelial growth factor therapy. The influence of baseline age, BCVA, and CNV lesion size on treatment outcomes is consistent with other reports from large, prospective trials in wet AMD.
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http://dx.doi.org/10.1016/j.oret.2017.10.017DOI Listing
July 2018

Longitudinal Retinal Perfusion Status in Eyes with Diabetic Macular Edema Receiving Intravitreal Aflibercept or Laser in VISTA Study.

Ophthalmology 2019 08 1;126(8):1171-1180. Epub 2019 Apr 1.

Regeneron Pharmaceuticals, Inc., Tarrytown, New York.

Purpose: To evaluate changes in retinal perfusion status with intravitreal aflibercept injection (IAI) and laser treatment in the phase 3 VISTA study of patients with diabetic macular edema (DME).

Design: Post hoc analysis of a double-masked, randomized, active-controlled, phase 3 trial.

Participants: Patients with center-involved DME in the study eye.

Methods: VISTA randomized 466 patients to laser, IAI 2 mg every 4 weeks (2q4), or IAI 2 mg every 8 weeks after 5 monthly doses (2q8). One eye per patient was enrolled in the study. Retinal perfusion status was evaluated by fluorescein angiography based on the presence or absence of retinal nonperfusion (RNP) in quadrants intersecting at the optic nerve head by a masked independent reading center at weeks 24, 52, 72, and 100. Visual and anatomic outcomes were evaluated at all visits. In patients who received rescue treatment, data were censored from the time rescue treatment was given.

Main Outcome Measures: Change in perfusion status from baseline through week 100.

Results: At week 100, the proportion of eyes with improvement in retinal perfusion (defined as a reduction from baseline in the total number of quadrants in which RNP is present) in the laser control, 2q4, and 2q8 groups was 14.6%, 44.7%, and 40.0%, respectively. The proportion of eyes that experienced worsening in retinal perfusion (defined as an increase from baseline in the total number of quadrants in which RNP is present) at week 100 in the laser control, 2q4, and 2q8 groups was 25.0%, 9.0%, and 8.6%, respectively.

Conclusion: Post hoc analysis of the phase 3 VISTA study in patients with DME provides evidence that regular IAI dosing not only can slow worsening of retinal perfusion associated with diabetic retinopathy but also may be able to improve retinal perfusion in some cases by decreasing zones of RNP.
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http://dx.doi.org/10.1016/j.ophtha.2019.03.040DOI Listing
August 2019

Difference in Treatment Effect Between Intravitreal Aflibercept Injection and Laser by Baseline Factors in Diabetic Macular Edema.

Ophthalmic Surg Lasers Imaging Retina 2019 03;50(3):167-173

Background And Objective: To evaluate the effect of baseline factors on differences in vision gains with intravitreal aflibercept injection (IAI) versus laser control in patients with diabetic macular edema (DME).

Patients And Methods: This was an integrated post-hoc subanalysis of two phase 3 trials (VISTA, VIVID) in patients with DME. Least square (LS) mean differences of patients treated with IAI compared to laser control in best-corrected visual acuity (BCVA) change from baseline at week 100 were evaluated for association with baseline demographics and baseline systemic disease characteristics.

Results: At week 100, LS mean differences in BCVA change from baseline with IAI compared to laser control were not significant for association with baseline age, gender, and race or status of glycosylated hemoglobin, body mass index, renal impairment, hypertension, cerebrovascular disease, and ischemic heart disease.

Conclusion: Vision gains with IAI were significantly greater than laser control and were not influenced by demographics and systemic disease control at baseline. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:167-173.].
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http://dx.doi.org/10.3928/23258160-20190301-06DOI Listing
March 2019

Extended (Every 12 Weeks or Longer) Dosing Interval With Intravitreal Aflibercept and Ranibizumab in Neovascular Age-Related Macular Degeneration: Post Hoc Analysis of VIEW Trials.

Am J Ophthalmol 2019 04 19;200:161-168. Epub 2019 Jan 19.

Retina-Vitreous Associates Medical Group, Beverly Hills, California, USA. Electronic address:

Purpose: To evaluate outcomes and disease characteristics in eyes with neovascular age-related macular degeneration that received intravitreal aflibercept injection (IAI) and ranibizumab every 12 weeks or longer (≥q12 weeks) or less than every 12 weeks (
Design: Post hoc analysis of randomized clinical trial data.

Methods: In year 1, eyes received ranibizumab q4 weeks (Rq4), IAI 2 mg q4 weeks (2q4), or IAI 2 mg q8 weeks after 3 monthly injections (2q8). In year 2, eyes received pro re nata treatment, with mandatory treatment at least q12 weeks.

Results: At week 96, 218 (42.5%), 284 (53.9%), and 245 (47.9%) eyes treated with Rq4, 2q4, and 2q8, respectively, received treatment at ≥q12-week intervals and 295 (57.5%), 243 (46.1%), and 266 (52.1%) eyes at <12q-week intervals during the second year. Baseline occult-type choroidal neovascularization (CNV) (P = .0156) and retinal fluid (P < .0001) and leakage (P < .0001) at week 52 were associated with
Conclusions: Baseline CNV type other than occult and absence of retinal fluid and leakage at week 52 were significantly associated with ≥q12-week dosing. Vision improvements at week 52 following a year of fixed dosing with ranibizumab and IAI were maintained at week 96 in eyes that received treatment ≥q12 weeks and
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http://dx.doi.org/10.1016/j.ajo.2019.01.005DOI Listing
April 2019

Efficacy and Safety of Sarilumab for the Treatment of Posterior Segment Noninfectious Uveitis (SARIL-NIU):: The Phase 2 SATURN Study.

Ophthalmology 2019 03 11;126(3):428-437. Epub 2018 Oct 11.

Byers Eye Institute, Stanford University, Palo Alto, California. Electronic address:

Purpose: To assess efficacy and safety of sarilumab, a human anti-interleukin-6 receptor antibody, for treatment of posterior segment noninfectious uveitis (NIU).

Design: Randomized, double-masked, placebo-controlled, phase 2 study.

Participants: Fifty-eight patients (eyes) with noninfectious intermediate, posterior, or panuveitis.

Methods: Eyes received treatment every 2 weeks for 16 weeks with subcutaneous sarilumab 200 mg or placebo.

Main Outcome Measures: The primary end point was the proportion of patients with ≥2-step reduction in vitreous haze (VH) on the Miami scale or with a reduction of systemic corticosteroids (prednisolone or equivalent) to a dose of <10 mg/day at week 16. Primary end point was based on VH evaluation by a central reading center. Investigator evaluation of VH was a prespecified, planned secondary analysis.

Results: At week 16, proportion of patients taking sarilumab or placebo with ≥2-step reduction in VH or corticosteroid dose <10 mg/day was 46.1% vs. 30.0% (P = 0.2354) based on central reading center assessment of VH and 64.0% vs. 35.0% (P = 0.0372) based on investigator assessment of VH, respectively. In the subgroup of eyes with VH grade ≥2 at baseline, the mean VH reduction from baseline to week 16 was significantly greater with sarilumab vs. placebo regardless of assessment by the central reading center (-2.1 [n = 11] vs. -1.7 [n = 3], respectively; P = 0.0255) or investigator (-2.5 [n = 19] vs. -1.2 [n = 11], respectively; P = 0.0170). The mean best-corrected visual acuity gain from baseline to week 16 was greater with sarilumab vs. placebo in the overall population (8.9 vs. 3.6 letters, respectively; P = 0.0333) and in the subgroup of eyes with central subfield thickness (CST) ≥300 μm at baseline (12.2 [n = 13] vs. 2.1 [n = 7] letters, respectively; P = 0.0517). Corresponding changes in CST were -46.8 vs. +2.6 μm (P = 0.0683) in the overall population and -112.5 [n = 13] vs. -1.8 [n = 6] μm (P = 0.1317) in the subgroup of eyes with CST ≥300 μm at baseline, respectively. The most common ocular adverse events were worsening of uveitis (0 [placebo] and 3 [sarilumab] patients) and retinal infiltrates (1 [placebo] and 2 [sarilumab] patients).

Conclusions: Subcutaneous sarilumab may provide clinical benefits in the management of NIU of the posterior segment, especially in eyes with uveitic macular edema.
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http://dx.doi.org/10.1016/j.ophtha.2018.09.044DOI Listing
March 2019

Effects of Repeated Intravitreal Aflibercept Injection on the Corneal Endothelium in Patients With Age-Related Macular Degeneration: Outcomes From the RE-VIEW Study.

Cornea 2018 May;37(5):596-601

Regeneron Pharmaceuticals, Inc., Tarrytown, NY.

Purpose: The effects of repeated intravitreal aflibercept injection (IAI) on the corneal endothelium were studied in patients with unilateral neovascular age-related macular degeneration.

Methods: RE-VIEW was a phase 4, open-label, single-arm, multicenter study. Patients received IAI every 8 weeks after 3 monthly doses. Slit-lamp biomicroscopy was performed at all study visits. The central corneal endothelial health was evaluated by specular microscopy in the treated versus untreated fellow eyes at baseline and weeks 24 and 52.

Results: No slit-lamp abnormalities were noted in 154 enrolled patients (eyes). Baseline versus 52-week mean (±SD) endothelial morphometric values (n = 118) for the treated versus untreated fellow eyes were respectively as follows: endothelial cell density was 2410 ± 364 versus 2388 ± 384 cells/mm at baseline and remained unchanged at 2401 ± 353 versus 2376 ± 364 cells/mm at 52 weeks (P = 0.87); the coefficient of variation was 33.5 ± 4.4% versus 34.0 ± 5.0% at baseline and remained unchanged at 34.2 ± 4.7% versus 34.1 ± 4.9% at 52 weeks (P = 0.18); the percentage of hexagonal cells was 59.5 ± 5.8% versus 59.6 ± 6.4% at baseline and remained unchanged at 59.5 ± 6.0% versus 59.5 ± 5.8% at 52 weeks (P = 0.96).

Conclusions: Repeated IAI for 52 weeks had no apparent corneal endothelial toxicity noted on specular microscopy in patients treated for neovascular age-related macular degeneration.
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http://dx.doi.org/10.1097/ICO.0000000000001535DOI Listing
May 2018

Integrated results from the COPERNICUS and GALILEO studies.

Clin Ophthalmol 2017 23;11:1533-1540. Epub 2017 Aug 23.

Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA.

Objectives: To report on the efficacy and safety of intravitreal aflibercept in patients with macular edema secondary to central retinal vein occlusion (CRVO) in an integrated analysis of COPERNICUS and GALILEO.

Patients And Methods: Patients were randomized to receive intravitreal aflibercept 2 mg every 4 weeks or sham injections until week 24. From week 24 to week 52, all intravitreal aflibercept-treated patients in both studies and sham-treated patients in COPERNICUS were eligible to receive intravitreal aflibercept based on prespecified criteria. In GALILEO, sham-treated patients continued to receive sham treatment through week 52.

Results: At week 24, mean gain in best-corrected visual acuity and mean reduction in central retinal thickness were greater for intravitreal aflibercept-treated patients compared with sham, consistent with individual trial results. At week 52, after 6 months of intravitreal aflibercept as-needed treatment in COPERNICUS, patients originally randomized to sham group experienced visual and anatomic improvements but did not improve to the extent of those initially treated with intravitreal aflibercept, while the sham group in GALILEO did not improve over week 24 mean best-corrected visual acuity scores. Ocular serious adverse events occurred in <10% of patients.

Conclusion: This analysis of integrated data from COPERNICUS and GALILEO confirmed that intravitreal aflibercept is an effective treatment for macular edema following CRVO.
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http://dx.doi.org/10.2147/OPTH.S140665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574701PMC
August 2017

Baseline Factors Affecting Changes in Diabetic Retinopathy Severity Scale Score After Intravitreal Aflibercept or Laser for Diabetic Macular Edema: Post Hoc Analyses from VISTA and VIVID.

Ophthalmology 2018 01 29;125(1):51-56. Epub 2017 Jul 29.

Cleveland Clinic Cole Eye Institute, Cleveland, Ohio. Electronic address:

Purpose: To evaluate whether select baseline systemic and ocular factors influence ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score at week 100 in VISTA and VIVID.

Design: Post hoc analysis of 2 similarly designed phase 3 trials, VISTA and VIVID.

Participants: Total of 456 patients with center-involved diabetic macular edema (DME).

Methods: VISTA and VIVID randomized 872 DME patients to receive intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or macular laser photocoagulation. This post hoc analysis evaluated the influence of select baseline factors on ≥2-step DRSS score improvement by logistic regression in an integrated VISTA and VIVID dataset using observed cases (n = 456) with patients in each treatment group divided into tertiles based on each characteristic.

Main Outcome Measures: Proportion of patients with ≥2-step improvement in DRSS score from baseline at week 100 by age, duration of diabetes, hemoglobin A1c (HbA1c), body mass index (BMI), best-corrected visual acuity (BCVA), central subfield thickness (CST), and DRSS score.

Results: At week 100, 10.1%, 34.3%, and 37.6% of patients in the laser, 2q4, and 2q8 groups experienced a ≥2-step DRSS score improvement, respectively. Age, duration of diabetes, HbA1c, BMI, BCVA, and CST had no impact on the ability to achieve ≥2-step improvement in DRSS score. Initial DRSS score was the only factor significantly associated with ≥2-step DRSS score improvement in all treatment groups at weeks 24, 52, 76, and 100. Relatively higher proportions of IAI-treated patients with worse BCVA or thicker CST experienced ≥2-step DRSS score improvement compared with those with better BCVA or thinner CST, respectively, but these associations were not statistically significant.

Conclusion: A strong association was present between baseline DRSS score and ≥2-step DRSS score improvement at week 100 for DME patients in VISTA and VIVID.
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http://dx.doi.org/10.1016/j.ophtha.2017.06.029DOI Listing
January 2018

Outcomes of Diabetic Macular Edema Patients by Baseline Hemoglobin A1c: Analyses from VISTA and VIVID.

Ophthalmol Retina 2017 Sep - Oct;1(5):382-388. Epub 2017 Apr 17.

Ocular Imaging Research and Reading Center, Omaha, Nebraska.

Purpose: To examine the relationship between glycemic control at baseline and response to anti-vascular endothelial growth factor treatment for diabetic macular edema (DME).

Design: Post hoc analysis of 2 similarly designed phase III trials, VISTA and VIVID.

Participants: Patients with central-involved DME.

Methods: Both VISTA and VIVID compared efficacy and safety of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for DME. Current analysis focused on comparison within each treatment group in an integrated VISTA and VIVID dataset. Baseline hemoglobin A1c (HbA1c) was partitioned into 4 quartiles: 4.5% to <6.7% (n = 233), 6.7% to <7.4% (n = 206), 7.4% to <8.6% (n = 209), and 8.6% to <14.7% (n = 208). Outcomes were analyzed by mixed model for repeated measures. Intragroup differences were quantified by a regression model.

Main Outcome Measures: Change from baseline best-corrected visual acuity (BCVA), central subfield thickness (CST), and HbA1c.

Results: In the IAI group, mean BCVA improvement from baseline did not depend on baseline HbA1c at week 52 (P = 0.1852), but seemed to be dependent at week 100 (P = 0.0425). The mean CST reduction from baseline was independent of baseline HbA1c at both weeks 52 (P = 0.1857) and 100 (P = 0.7346). Mean HbA1c change from baseline in IAI group was small across all HbA1c quartiles. In the laser group, the mean BCVA gain decreased with increasing baseline HbA1c at both weeks 52 (P = 0.0421) and 100 (P = 0.0001). Similarly, the mean CST decrease was greater with decreasing baseline HbA1c, at both weeks 52 (P = 0.0065) and 100 (P = 0.0162). The mean HbA1c change from baseline in the laser group was minimal across HbA1c quartiles, although glycemic control tended to worsen in upper quartiles.

Conclusions: The benefit of IAI in patients with DME was less dependent on their presenting glycemic status as opposed to laser.
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http://dx.doi.org/10.1016/j.oret.2017.02.003DOI Listing
April 2017

Long-term Safety and Visual Outcome of Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: VIEW 1 Extension Study.

Ophthalmol Retina 2017 Jul - Aug;1(4):304-313. Epub 2017 Mar 18.

Palmetto Retina Center, West Columbia, South Carolina. Electronic address:

Purpose: To assess the long-term safety and vision change in patients who received intravitreal aflibercept injection (IAI) for neovascular age-related macular degeneration in an extension study after completing VIEW 1 trial.

Design: Prospective, open-label, multicenter, extension study.

Participants: Three hundred twenty-three patients.

Methods: In VIEW 1, 1217 patients were randomized to receive fixed dosing of 0.5 mg IAI every 4 weeks (0.5q4), 2 mg IAI every 4 weeks (2q4), 2 mg IAI every 8 weeks after 3 initial monthly dosing (2q8), or 0.5 mg ranibizumab every 4 weeks (Rq4) from baseline through week 52, followed by modified quarterly injections of the same dose of anti-vascular endothelial growth factor agent from weeks 52 to 96. After completing VIEW 1 at week 96, patients (n = 323) enrolled in an extension study and received 2 mg IAI on a modified quarterly injection schedule followed by at least an every 8-week dosing through week 212.

Main Outcome Measures: Long-term safety and vision change in patients followed for a median duration of 116 weeks in the extension study (total follow-up time of 212 weeks from the VIEW 1 baseline).

Results: Patients enrolled in the extension study gained a mean of 10.2 letters from the VIEW 1 baseline at week 96. These patients largely maintained vision over the extension study with a mean gain of 7.1 letters from the VIEW 1 baseline to week 212. The proportion of patients who lost ≥15 letters from the VIEW 1 extension baseline was 8.2% at week 212. Mean number of injections was 12.9 (range, 1-41) in the extension study. The most common serious ocular adverse event was endophthalmitis (0.9%). The overall incidence of Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events was 6.2%.

Conclusions: Vision gains achieved with anti-vascular endothelial growth factor therapy in VIEW 1 were largely maintained by continued treatment with IAI 2 mg in the extension study. Anti-vascular endothelial growth factor injections (including 4 years of IAI 2 mg) were well-tolerated with no new safety signals compared with the known profile of IAI.
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http://dx.doi.org/10.1016/j.oret.2017.01.004DOI Listing
March 2017

Intravitreal Aflibercept Injection in Eyes With Substantial Vision Loss After Laser Photocoagulation for Diabetic Macular Edema: Subanalysis of the VISTA and VIVID Randomized Clinical Trials.

JAMA Ophthalmol 2017 Feb;135(2):107-114

Ophthalmic Consultants of Boston, Boston, Massachusetts.

Importance: Information on the effect of anti-vascular endothelial growth factor therapy in eyes with diabetic macular edema (DME) with vision loss after macular laser photocoagulation is clinically valuable.

Objective: To evaluate visual and anatomic outcomes in a subgroup of macular laser photocoagulation treatment control (hereafter laser control) eyes with substantial vision loss receiving treatment with intravitreal aflibercept injection.

Design, Setting, And Participants: This investigation was a post hoc analysis of a subgroup of laser control eyes in 2 phase 3 trials-VISTA (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) and VIVID (Intravitreal Aflibercept Injection in Vision Impairment Due to DME)-in a multicenter setting. One hundred nine laser control eyes with center-involving DME were included.

Interventions: Treatment with intravitreal aflibercept injection (2 mg) every 8 weeks after 5 monthly doses with sham injections on nontreatment visits starting at week 24 was initiated on meeting prespecified criteria of at least a 10-letter visual acuity loss at 2 consecutive visits or at least a 15-letter visual acuity loss from the best previous measurement at 1 visit and vision not better than at baseline.

Main Outcomes And Measures: Visual and anatomic outcomes in a subgroup of laser control eyes receiving treatment with intravitreal aflibercept injection.

Results: Through week 100, a total of 63 of 154 eyes (40.9%) in VISTA and 46 of 133 eyes (34.6%) in VIVID initially randomized to laser control received treatment with intravitreal aflibercept injection. The median time from week 24 to the first intravitreal aflibercept injection treatment was 34.0 (VISTA) and 83.5 (VIVID) days. In this subgroup, the mean (SD) visual gain from baseline to week 100 was 2.2 (12.5) (VISTA) and 3.8 (10.1) (VIVID) letters. At the time of intravitreal aflibercept injection initiation, these eyes had a mean (SD) loss of 11.0 (10.1) (VISTA) and 10.0 (6.5) (VIVID) letters from baseline, and they subsequently gained a mean (SD) of 17.4 (9.7) (VISTA) and 13.6 (8.6) (VIVID) letters from the initiation of treatment with intravitreal aflibercept injection through week 100. There was a minimal mean change in central subfield thickness from baseline in these eyes at the time of intravitreal aflibercept injection initiation (an increase of 3.9 μm in VISTA and a decrease of 3.0 μm in VIVID), after which further mean (SD) reductions of 285.6 (202.6) μm (VISTA) and 313.4 (181.9) μm (VIVID) occurred through week 100.

Conclusions And Relevance: Intravitreal aflibercept injection improves visual and anatomic outcomes in eyes experiencing substantial vision loss after macular laser photocoagulation treatment for DME.

Trial Registration: clinicaltrials.gov Identifiers: NCT01363440 and NCT01331681.
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http://dx.doi.org/10.1001/jamaophthalmol.2016.4912DOI Listing
February 2017

Differential Response to Anti-VEGF Regimens in Age-Related Macular Degeneration Patients with Early Persistent Retinal Fluid.

Ophthalmology 2016 09 28;123(9):1856-64. Epub 2016 Jun 28.

Ophthalmic Consultants of Boston, Boston, Massachusetts.

Purpose: To compare the effect of intravitreal aflibercept or ranibizumab drug type and frequency on visual acuity outcomes in eyes with neovascular age-related macular degeneration (NVAMD) and early persistent retinal fluid after 3 initial monthly injections.

Design: A post hoc analysis of eyes enrolled in VIEW 1 and VIEW 2, 2 similarly designed, randomized, phase 3 trials.

Participants: A total of 1815 eyes with NVAMD from VIEW 1 and VIEW 2.

Methods: Analyses included patients with known fluid status at baseline and weeks 4, 8, and 12 in 3 treatment groups: ranibizumab 0.5 mg every 4 weeks (Rq4) (n = 595), intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4) (n = 613), and IAI 2 mg every 8 weeks (2q8) after 3 monthly injections (n = 607).

Main Outcome Measures: Mean best-corrected visual acuity (BCVA) change from baseline over weeks 16 to 52 and the proportion of eyes that gained ≥15 letters or lost ≥5 letters were evaluated in eyes with and without persistent fluid (cystic intraretinal or subretinal fluid at all 4 initial visits). Visual outcomes also were assessed in eyes with persistent fluid by fluid type (intraretinal and subretinal fluid).

Results: The proportions of eyes with persistent fluid were 29.4%, 18.8%, and 20.3% in the Rq4, 2q4, and 2q8 groups, respectively. In these eyes, mean BCVA gain from baseline to week 52 was greater with 2q4 compared with Rq4 (P < 0.01) and 2q8 (P < 0.05), whereas it was similar with Rq4 and 2q8 (P = 0.294). At week 52, similar proportions of eyes gained ≥15 letters (31.5%-35.2%), whereas fewer eyes lost ≥5 letters with 2q4 compared with Rq4 and 2q8 (6.5% vs. 16.6% and 16.2%). The pattern of visual outcomes was similar regardless of fluid type. In eyes without persistent fluid, BCVA changes were similar across treatment groups.

Conclusions: In patients with early persistent fluid, 2q4 may provide additional clinical benefit over 2q8 or Rq4.
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http://dx.doi.org/10.1016/j.ophtha.2016.05.016DOI Listing
September 2016

Comprehensive Review of Ocular and Systemic Safety Events with Intravitreal Aflibercept Injection in Randomized Controlled Trials.

Ophthalmology 2016 07 12;123(7):1511-20. Epub 2016 Apr 12.

Cole Eye Institute, Cleveland, Ohio. Electronic address:

Purpose: To assess the ocular and systemic safety of intravitreal aflibercept injection (IAI) compared with controls in IAI trials in neovascular age-related macular degeneration (nAMD), macular edema following central retinal vein occlusion (MEfCRVO), macular edema following branch retinal vein occlusion (MEfBRVO), and diabetic macular edema (DME).

Design: Comprehensive review of 10 phase II and III trials of IAI in retinal diseases.

Participants: Patients were included from IAI trials in nAMD (CLEAR-IT 2 [52 weeks], VIEW 1 [96 weeks], VIEW 2 [96 weeks], VIEW 1 extension [208 weeks]); MEfCRVO (COPERNICUS [100 weeks], GALILEO [76 weeks]); MEfBRVO (VIBRANT [52 weeks]); and DME (DA VINCI [52 weeks], VIVID [100 weeks], VISTA [100 weeks]).

Methods: Rates were calculated as events/100 person-years at risk (PYR). When applicable, rate ratios (RRs) and 95% confidence intervals (CIs) were provided.

Main Outcome Measures: Outcomes included rates for intraocular inflammation, endophthalmitis, serious adverse events (SAEs), wound-healing complications, hypertension (HTN), adjudicated Anti-Platelet Trialists' Collaboration (APTC)-defined arterial thromboembolic events (ATEs) (nonfatal myocardial infarction, nonfatal stroke, and vascular death), and death from all causes.

Results: More than 4000 patients contributed >7000 PYR. For all outcomes, there were no meaningful differences between evaluated adverse event rates for IAI and controls. Overall intraocular inflammation rates were 2.37 (control) and 2.06 (IAI); overall RR was 0.87 (95% CI, 0.61-1.27). Overall endophthalmitis rates were 0.52 (control) and 0.22 (IAI); overall RR was 0.42 (95% CI, 0.18-1.03). Overall SAE rates were 23.09 (control) and 20.80 (IAI); overall RR was 0.90 (95% CI, 0.80-1.02). Overall rates of wound-healing complications were 0.17 (control) and 0.15 (IAI); overall RR was 0.85 (95% CI, 0.24-3.86). Overall HTN rates were 14.87 (control) and 11.27 (IAI), with an overall RR of 0.76 (95% CI, 0.65-0.89); HTN rates were highest in MEfBRVO and lowest in nAMD. For adjudicated APTC-defined ATEs, rates were 2.04 (control) and 2.19 (IAI), with an RR of 1.07 (95% CI, 0.73-1.61). Overall death rates were 1.16 (control) and 1.49 (IAI); overall RR was 1.28 (95% CI, 0.80-2.15).

Conclusions: Rates of selected ocular and systemic adverse events with IAI were similar to those of controls and similar across disease states in evaluated IAI trials. Intravitreal aflibercept injection was generally well tolerated in the patients evaluated.
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http://dx.doi.org/10.1016/j.ophtha.2016.02.046DOI Listing
July 2016

Effect of Fluid Status at Week 12 on Visual and Anatomic Outcomes at Week 52 in the VIEW 1 and 2 Trials.

Ophthalmic Surg Lasers Imaging Retina 2016 Mar;47(3):238-44

Background And Objective: To evaluate effect of retinal fluid status at week 12 on visual and anatomic outcomes at week 52 in patients with neovascular age-related macular degeneration from the VIEW studies.

Patients And Methods: Post-hoc analysis included 1,465 eyes treated with intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) 2 mg every 4 weeks (2q4) or every 8 weeks following three initial monthly injections (2q8) or ranibizumab (Lucentis; Genentech, South San Francisco, CA) 0.5 mg every 4 weeks (Rq4), which had known retinal fluid status at weeks 12 and 52.

Results: At 12 weeks, 512 (35%) eyes had fluid and 953 (65%) were fluid-free. Two hundred three (41.5%), 148 (29.8%), and 161 (33.5%) eyes had fluid in Rq4, 2q4, and 2q8, respectively. Best-corrected visual acuity (BCVA) change at week 52 from baseline was independent of retinal fluid status at week 12 or treatment assignment. Eyes were more likely to remain fluid-free at week 52 if absent of fluid at week 12.

Conclusion: At week 52, 2q4, 2q8, and Rq4 improved BCVA independent of fluid status at week 12.
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http://dx.doi.org/10.3928/23258160-20160229-06DOI Listing
March 2016

Intravitreal Aflibercept Injection in Diabetic Macular Edema Patients with and without Prior Anti-Vascular Endothelial Growth Factor Treatment: Outcomes from the Phase 3 Program.

Ophthalmology 2016 Apr 28;123(4):850-7. Epub 2016 Jan 28.

Retina-Vitreous Associates Medical Group, Beverly Hills, California.

Purpose: To evaluate visual and anatomic outcomes after intravitreal aflibercept injection (IAI) versus laser in diabetic macular edema (DME) patients with and without prior anti-vascular endothelial growth factor (VEGF) treatment for DME.

Design: Post hoc analysis of eyes from 2 similarly designed, phase 3 trials, VISTA and VIVID.

Participants: Patients (eyes) with DME with central involvement from VISTA (n = 461) and VIVID (n = 404).

Methods: Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or macular laser photocoagulation.

Main Outcome Measures: This study reports exploratory outcomes through week 100. Analyses focused on VISTA because more patients received prior anti-VEGF therapy in VISTA (42.9%) versus VIVID (8.9%).

Results: Of 42.9% of patients in VISTA who received prior anti-VEGF treatment, 83.3% to 92.6% received ≥ 1 prior injections of bevacizumab, and 71.4% to 82.4% received bevacizumab only as prior anti-VEGF treatment for a duration ranging from 28 days to 3.9 years. In patients with prior anti-VEGF treatment, mean best-corrected visual acuity (BCVA) changes from baseline in the IAI 2q4, IAI 2q8, and laser groups were +10.4 letters, +10.5 letters, and -0.7 letters at week 52 and +10.9 letters, +10.8 letters, and -0.8 letters at week 100, respectively. Corresponding changes in patients without prior anti-VEGF treatment were +14.1 letters, +11.0 letters, and +0.9 letters at week 52 and +12.0 letters, +11.3 letters, and +2.1 letters at week 100. In patients with prior anti-VEGF treatment, mean reductions in central retinal thickness were 180.2 μm, 192.2 μm, and 90.9 μm at week 52 and 180.1 μm, 196.4 μm, and 94.1 μm at week 100. Corresponding reductions in patients without prior anti-VEGF treatment were 190.3 μm, 175.7 μm, and 61.0 μm at week 52 and 200.0 μm, 186.7 μm, and 76.9 μm at week 100. The most frequent serious ocular adverse event was vitreous hemorrhage (1.3%, 0.7%, and 1.9%, respectively).

Conclusions: Visual and anatomic improvements over laser with both IAI regimens were significant and similar through week 100 in subgroups of patients in VISTA with and without prior anti-VEGF treatment for DME.
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http://dx.doi.org/10.1016/j.ophtha.2015.11.008DOI Listing
April 2016