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Outcomes by Baseline Choroidal Neovascularization Features in Age-Related Macular Degeneration: A Post Hoc Analysis of the VIEW Studies.
Steinle, NC, Du, W, Gibson, A, Saroj, N
Ophthalmology. Retina. 2021;(2):141-150
Abstract
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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Two-year interim safety results of the 0.2 µg/day fluocinolone acetonide intravitreal implant for the treatment of diabetic macular oedema: the observational PALADIN study.
Mansour, SE, Kiernan, DF, Roth, DB, Eichenbaum, D, Holekamp, NM, Kaba, S, Werts, E
The British journal of ophthalmology. 2021;(3):414-419
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Abstract
BACKGROUND The 0.2 µg/day fluocinolone acetonide (FAc) implant delivers continuous, low-dose, intravitreal corticosteroid for the treatment of diabetic macular oedema (DMO). This ongoing, 3-year, observational clinical trial provides long-term, 'real-world' safety results for the FAc implant in DMO. METHODS This 24-month interim analysis of a prospective, observational study investigated patients with DMO receiving the commercially available intravitreal 0.2 µg/day FAc implant. The primary outcome was incidence of intraocular pressure (IOP)-lowering procedures. Other IOP-related signals and their relationship to previous corticosteroid exposure, best-corrected visual acuity, central subfield thickness (CST), ocular adverse events and frequency of other treatments were also measured. RESULTS Data were collected from 95 previously steroid-challenged patients (115 study eyes) for up to 36 months pre-FAc and 24 months post-FAc implant. Mean IOP for the overall population remained stable post-FAc compared with pre-FAc implant. IOP-related procedures remained infrequent (two IOP-lowering surgeries pre-FAc; two trabeculoplasties and four IOP-lowering surgeries post-FAc). Mean visual acuity was stable post-FAc (mean improvement of 1-3 letters) and fewer DMO treatments were required per year following FAc implant. Mean CST was significantly reduced at 24 months post-FAc implant (p<0.001) and the percentage of patients with CST ≤300 µm was significantly increased (p=0.041). CONCLUSION Few IOP-related procedures were reported during the 24 months post-FAc implant. Positive efficacy outcomes were noted after treatment, with stabilisation of vision and reduction in inflammation, demonstrated by CST. The FAc implant has a favourable benefit-risk profile in the management of DMO, especially when administered after a prior steroid challenge. TRIAL REGISTRATION NUMBER NCT02424019.
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Relationship of Topographic Distribution of Geographic Atrophy to Visual Acuity in Nonexudative Age-Related Macular Degeneration.
Shen, LL, Sun, M, Ahluwalia, A, Young, BK, Park, MM, Toth, CA, Lad, EM, Del Priore, LV
Ophthalmology. Retina. 2021;(8):761-774
Abstract
PURPOSE To investigate the topographic distribution of geographic atrophy (GA) and to identify an anatomic endpoint that correlates with visual acuity (VA) in eyes with GA. DESIGN Retrospective analysis of a multicenter, prospective, randomized controlled trial. PARTICIPANTS The Age-Related Eye Disease Study participants with GA secondary to nonexudative age-related macular degeneration. METHODS We manually delineated GA on 1654 fundus photographs of 365 eyes. We measured GA areas in 9 subfields on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid and correlated them with VA via a mixed-effects model. We determined the optimal diameter for the central zone by varying the diameter from 0 to 10 mm until the highest r2 between GA area in the central zone and VA was achieved. We estimated the VA decline rate over 8 years using a linear mixed model. MAIN OUTCOME MEASURES Geographic atrophy area in macular subfields and VA. RESULTS The percentage of area affected by GA declined as a function of retinal eccentricity. GA area was higher in the temporal than the nasal region (1.30 ± 1.75 mm2 vs. 1.10 ± 1.62 mm2; P = 0.005) and in the superior than the inferior region (1.26 ± 1.73 mm2 vs. 1.03 ± 1.53 mm2; P < 0.001). Total GA area correlated poorly with VA (r2 = 0.07). Among GA areas in 9 subfields, only GA area in the central zone was associated independently with VA (P < 0.001). We determined 1 mm as the optimal diameter for the central zone in which GA area correlated best with VA (r2 = 0.45). On average, full GA coverage of the central 1-mm diameter zone corresponded to 34.8 letters' decline in VA. The VA decline rate was comparable between eyes with initial noncentral and central GA before GA covered the entire central 1-mm diameter zone (2.7 letters/year vs. 2.8 letters/year; P = 0.94). CONCLUSIONS The prevalence of GA varies significantly across different macular regions. Although total GA area was associated poorly with VA, GA area in the central 1-mm diameter zone was correlated significantly with VA and may serve as a surrogate endpoint in clinical trials.
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Visual Acuity in Retinal Vein Occlusion, Diabetic, and Uveitic Macular Edema: Central Subfield Thickness and Ellipsoid Zone Analysis.
Ciulla, TA, Kapik, B, Grewal, DS, Ip, MS
Ophthalmology. Retina. 2021;(7):633-647
Abstract
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.
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Two-Year Results of the Phase 3 Randomized Controlled Study of Abicipar in Neovascular Age-Related Macular Degeneration.
Khurana, RN, Kunimoto, D, Yoon, YH, Wykoff, CC, Chang, A, Maturi, RK, Agostini, H, Souied, E, Chow, DR, Lotery, AJ, et al
Ophthalmology. 2021;(7):1027-1038
Abstract
PURPOSE To report the 2-year efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) compared with monthly ranibizumab in patients with treatment-naïve neovascular age-related macular degeneration (nAMD). DESIGN Two multicenter, randomized, phase 3 clinical trials with identical protocols (CEDAR and SEQUOIA). Analyses used pooled trial data. PARTICIPANTS The trials enrolled 1888 patients (1 eye/patient) with active choroidal neovascularization secondary to age-related macular degeneration and best-corrected visual acuity (BCVA) of 24 to 73 Early Treatment Diabetic Retinopathy Study letters. METHODS At enrollment, patients were assigned to study eye treatment with abicipar 2 mg every 8 weeks after initial doses at baseline and weeks 4 and 8 (abicipar Q8, n = 630), abicipar 2 mg every 12 weeks after initial doses at baseline and weeks 4 and 12 (abicipar Q12, n = 628), or ranibizumab 0.5 mg every 4 weeks (ranibizumab Q4, n = 630). MAIN OUTCOME MEASURES Efficacy measures included stable vision (<15-letter loss in BCVA from baseline) and change from baseline in BCVA and central retinal thickness (CRT). Safety measures included adverse events (AEs). RESULTS For patients who completed the study, efficacy of abicipar after initial doses was maintained through week 104. At week 104, the proportion of patients with stable vision was 93.0% (396/426), 89.8% (379/422), and 94.4% (470/498); mean change in BCVA from baseline was +7.8 letters, +6.1 letters, and +8.5 letters, and mean change in CRT from baseline was -147 μm, -146 μm, and -142 μm in the abicipar Q8 (14 injections), abicipar Q12 (10 injections), and ranibizumab Q4 (25 injections) groups, respectively. The overall incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3% from baseline through week 52 and 16.2%, 17.6%, and 1.3% from baseline through week 104 in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively. CONCLUSIONS Two-year results show efficacy of abicipar Q8 and Q12 in nAMD. First onset of IOI events with abicipar was much reduced in the second year and comparable with ranibizumab (0.8% and 2.3% vs. 1.0%). The extended duration of effect of abicipar allows for quarterly dosing and reduced treatment burden.
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Suprachoroidal CLS-TA plus Intravitreal Aflibercept for Diabetic Macular Edema: A Randomized, Double-Masked, Parallel-Design, Controlled Study.
Barakat, MR, Wykoff, CC, Gonzalez, V, Hu, A, Marcus, D, Zavaleta, E, Ciulla, TA
Ophthalmology. Retina. 2021;(1):60-70
Abstract
PURPOSE This study evaluated the potential safety, efficacy, and durability advantages of investigational triamcinolone acetonide suspension (CLS-TA; Clearside Biomedical, Alpharetta, GA) administered suprachoroidally in conjunction with intravitreal aflibercept compared with aflibercept monotherapy for treatment of diabetic macular edema (DME). DESIGN TYBEE was a prospective, controlled, double-masked study. Patients were randomized 1:1 to CLS-TA and aflibercept (active) or aflibercept monotherapy (control), and assessed over 24 weeks. PARTICIPANTS Treatment-naive DME patients with best-corrected visual acuity (BCVA) of 20 to 70 letters and central subfield retinal thickness (CST) of more than 300 μm. METHODS Patients in the active group (n = 36) received CLS-TA and aflibercept at baseline and week 12. Patients in the control group (n = 35) received aflibercept at baseline, week 4, week 8, and week 12. To mask both groups, sham suprachoroidal and intravitreal injections were utilized. All patients were eligible to receive aflibercept as needed at weeks 4, 8, 16, and 20 per prespecified criteria. MAIN OUTCOME MEASURE Mean change in BCVA from baseline. Treatment differences were assessed with a 2-sided significance level of 0.10. RESULTS Mean BCVA changes from baseline to week 24 were not statistically different in the active and control groups (intention-to-treat [ITT] population: +11.4 letters and +13.8 letters [P = 0.288]; per protocol [PP] population: +12.3 letters and +13.5 letters [P = 0.664]; respectively). Greater improvement in CST was seen in the active versus control group (ITT population: -212.1 μm and -178.6 μm [P = 0.089]; PP population: -226.5 μm and -176.1 μm [P = 0.035]; respectively). Compared with the control group, eyes in the active group received fewer treatments (scheduled plus as-needed treatments averaging 4.6 versus 2.6, respectively). No treatment-related serious adverse events were observed. Ocular adverse events were low for both arms. Cataract events, all assessed as unrelated to treatment, and events of elevated intraocular pressure trended higher in the active group. CONCLUSIONS CLS-TA administered suprachoroidally in conjunction with intravitreal aflibercept for treatment of DME provides simliar visual benefit at 24 weeks' follow-up compared with aflibercept monotherapy, is well tolerated and shows modest anatomic benefit with potential to reduce treatment burden.
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EFFICACY AND SAFETY OF INTRAVITREAL AFLIBERCEPT USING A TREAT-AND-EXTEND REGIMEN FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: The ARIES Study: A Randomized Clinical Trial.
Mitchell, P, Holz, FG, Hykin, P, Midena, E, Souied, E, Allmeier, H, Lambrou, G, Schmelter, T, Wolf, S, ,
Retina (Philadelphia, Pa.). 2021;(9):1911-1920
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Abstract
BACKGROUND/PURPOSE Treating neovascular age-related macular degeneration with intravitreal aflibercept treat-and-extend (T&E) can reduce treatment burden. ARIES assessed whether intravitreal aflibercept early-start T&E was noninferior to late-start T&E. METHODS A randomized, open-label, Phase 3b/4 study that included treatment-naïve patients aged ≥50 years with the best-corrected visual acuity 73-25 Early Treatment Diabetic Retinopathy Study letters and active choroidal neovascularization secondary to AMD. Patients received 2 mg intravitreal aflibercept at Week (W) 0, W4, W8, and W16. At W16, patients were randomized 1:1 to early-start (2W interval adjustments) or late-start T&E (8W intervals until W48 then 2W interval adjustments). Primary endpoint: the best-corrected visual acuity change from randomization to W104. RESULTS Two-hundred seventy-one patients were randomized. The mean (SD) best-corrected visual acuity at baseline was 60.2 (12.1; early-T&E) and 61.3 (10.8; late-T&E) letters. The mean (SD) best-corrected visual acuity change (W16-104) was -2.1 (11.4) versus -0.4 (8.4) letters (early-T&E vs. late-T&E; least-squares mean difference: -2.0; 95% confidence interval: -4.75 to 0.71; P = 0.0162 for noninferior); +4.3 (13.4) versus +7.9 (11.9) letters (W0-104). The mean (SD) number of injections was 12.0 (2.3) versus 13.0 (1.8). From baseline to W104, 93.4% and 96.2% maintained best-corrected visual acuity; the mean (SD) central retinal thickness change was -161.6 (135.6) µm and -158.6 (125.1) µm. The last injection interval (W104) was ≥12W for 47.2% and 51.9% of patients. CONCLUSION Outcomes were similar between patients with neovascular age-related macular degeneration treated with an intravitreal aflibercept early-T&E or late-T&E regimen after initial dosing, with one injection difference over 2 years. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02581891 https://clinicaltrials.gov/ct2/show/NCT02581891. Supplemental Digital Contents (files 1 http://links.lww.com/IAE/B419).
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PRAGMATISM OF RANDOMIZED CLINICAL TRIALS ON RANIBIZUMAB FOR THE TREATMENT OF DIABETIC MACULAR EDEMA: Impact on Clinical Outcomes.
Stewart, S, Yeong, JL, Virgili, G, Azuara-Blanco, A, Lois, N
Retina (Philadelphia, Pa.). 2020;(5):919-927
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PURPOSE To evaluate the pragmatism and generalizability of randomized clinical trials (RCTs) on ranibizumab for diabetic macular edema and determine whether clinical outcomes would differ based on whether or not patients fulfill the eligibility criteria of these RCTs. METHODS Pragmatism and generalizability of three RCTs on ranibizumab for diabetic macular edema (DRCRnet Protocols I and T, and RESTORE) were rated using the PRECIS-2 tool. A cohort of consecutive patients with diabetic macular edema was assessed to determine whether clinical outcomes differed based on whether or not patients met the RCT eligibility criteria. Univariable and multivariable regression analyses, adjusted for baseline best-corrected visual acuity, central retinal thickness and number of injections received, were used. RESULTS All RCTs were rated as being more pragmatic than explanatory, with DRCRnet trials being the most pragmatic. Of the 216 eyes (176 patients) included in the cohort, 63% would have met eligibility criteria for Protocol T, 61% for Protocol I, and 56% for RESTORE. When adjusted for best-corrected visual acuity, central retinal thickness, and number of ranibizumab injections received, there were no statistically significant differences in best-corrected visual acuity or central retinal thickness found between "eligible" and "ineligible" patients. CONCLUSION Randomized clinical trials evaluating ranibizumab for diabetic macular edema were more pragmatic than explanatory. "Ineligible" patients still benefited from ranibizumab therapy.
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Comparison of Retinal Layer Thickness in Eyes with Resolved Diabetic Macular Edema Receiving Ranibizumab with Normal Eyes.
Rentiya, ZS, Kherani, S, Usmani, B, Qazi, MA, Sadiq, MA, Iftikhar, M, Nguyen, QD, Shah, SM, Sepah, YJ, ,
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2020;(1):27-36
Abstract
PURPOSE To evaluate the thickness of individual retinal layers in eyes with resolved diabetic macular edema (DME) after treatment with ranibizumab (RBZ). METHODS Spectral-domain optical coherence tomography (OCT) scans of 25 eyes (25 patients) with DME that had been treated with RBZ (and shown resolution of edema as evident by the absence of fluid in a high-resolution grid placed on the fovea) were acquired using Spectralis HRA + OCTTM. Thickness measurements of individual layers were calculated using papillomacular bundle (PMB), central subfield, and inner- and outer-ring Early Treatment Diabetic Retinopathy Study (ETDRS) grids. Measurements were compared to 45 normal eyes with no known retinal disease. A post-hoc analysis was done correlating visual acuity (VA) with individual retinal layer thickness. RESULTS Full retinal thickness (FRT) was thinner than normal individuals across all 4 grids. There were similarities and differences among the 4 grids; however, PMB and inner-ring ETDRS grids displayed the most resemblance. The VA significantly correlated with the FRT measured in PMB (p = 0.004), central subfield (p = 0.02), and inner-ring (p = 0.006) ETDRS. CONCLUSIONS Segmentation of OCT scans revealed significant differences in the overall thickness of the retina and of individual retinal layers in patients with resolved DME. PMB grid showed a stronger correlation between affected retinal layers and VA compared to ETDRS. PMB also showed significance with VA in layers that were shown to be not significant in ETDRS grid.
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Are Dilated Fundus Examinations Needed for OCT-Guided Retreatment of Exudative Age-Related Macular Degeneration?
Patel, Y, Miller, DM, Fung, AE, Hill, LF, Rosenfeld, PJ
Ophthalmology. Retina. 2020;(2):141-147
Abstract
PURPOSE To determine whether presence of macular hemorrhage on dilated fundus examination (DFE) or fundus photography influences vision outcomes with OCT-guided pro re nata (PRN) ranibizumab retreatment in patients with neovascular age-related macular degeneration (nAMD), we investigated whether hemorrhage without OCT-detectable fluid impacted vision outcomes. DESIGN Post hoc analysis of prospectively collected data from the 24-month pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvascular age-related macular degeneration (HARBOR) trial (ClinicalTrials.gov identifier, NCT00891735). PARTICIPANTS This post hoc analysis examined 1097 patients from the intention-to-treat population of HARBOR. METHODS Dilated fundus examination and fundus photography were evaluated for hemorrhage, and spectral-domain (SD) OCT images from HARBOR participants were analyzed for macular fluid secondary to macular neovascularization. Agreement between methods was determined for each time point. Visual outcomes were evaluated for 82 patients with evidence of hemorrhage on DFE or fundus photography at 3 months and no evidence of SD-exudative activity requiring retreatment at month 3. MAIN OUTCOME MEASURES Pooled data from the intention-to-treat population of HARBOR were analyzed for hemorrhage on DFE or fundus photography and exudative activity on SD OCT. A subgroup of PRN patients were analyzed for best-corrected visual acuity gains at 24 months. RESULTS Most study eyes (89% [973/1095]) showed macular hemorrhages at baseline, declining to 31% (319/1042) at month 3 and stabilizing at 11% (111/989) by month 6 of follow-up. After baseline, exudative activity was detected on SD-OCT in more than 89% of eyes when hemorrhage was present on DFE or fundus photography. Patients not requiring a month 3 PRN ranibizumab injection achieved similar visual gains over 24 months, regardless of month 3 hemorrhage presence versus absence: 9.4 and 8.7 Early Treatment Diabetic Retinopathy Study letter scores, respectively (P = 0.74). CONCLUSIONS After 3 initial ranibizumab injections, SD-OCT detected nAMD activity in 89% of eyes when hemorrhage was present on fundus photography. Ranibizumab retreatment guided by monthly SD-OCT achieved similar vision gains with or without injection when hemorrhage was present without OCT-detectable fluid. This suggests that macular hemorrhages without OCT-detectable macular fluid may not require treatment and DFE may not be needed at every visit. These conclusions should be confirmed in a prospective randomized trial before firm recommendations regarding clinical practice can be made.