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Effect of Aflibercept on Diabetic Retinopathy Severity and Visual Function in the RECOVERY Study for Proliferative Diabetic Retinopathy.
Alagorie, AR, Velaga, S, Nittala, MG, Yu, HJ, Wykoff, CC, Sadda, SR
Ophthalmology. Retina. 2021;(5):409-419
Abstract
PURPOSE To evaluate the effect of intravitreal aflibercept on diabetic retinopathy (DR) severity and visual function in patients with proliferative DR (PDR) without diabetic macular edema (DME). DESIGN Prospective, longitudinal, multicenter clinical trial. PARTICIPANTS Forty eyes of 40 patients with PDR and no DME were enrolled in this study. Patients were randomized into monthly and quarterly 2-mg aflibercept injection cohorts and were treated over a period of 12 months. METHODS All patients underwent ultra-widefield fundus imaging including pseudocolor and fluorescein angiography using an Optos 200Tx device. MAIN OUTCOME MEASURES Severity of DR at baseline, month 6, and month 12 was evaluated using the DR severity scale (DRSS). The DRSS scores were correlated with the 25-item Visual Function Questionnaire (VFQ-25) and 39-item Visual Function Questionnaire (VFQ-39) scores at baseline and month 12. RESULTS Mean age of the patients was 48.2 years (range, 25-75 years), mean duration of diabetes mellitus was 16.1 years (range, 2-36 years), and median glycated hemoglobin level was 8.8% (IQR, 7.4%-10%). Both monthly and quarterly groups demonstrated a statistically significant regression in DRSS from baseline to month 12 (P < 0.001). The monthly group demonstrated a statistically significant greater regression of DRSS score at the month 6 visit compared with the quarterly group (P = 0.019). However, the difference between the two groups became statistically insignificant at month 12 visit (P = 0.309). Also no difference was found in mean VFQ-25 and VFQ-39 composite scores between the monthly and quarterly groups at month 12 (P = 0.947 and P = 0.921, respectively). The improvement in mean VFQ-25 and VFQ-39 composite scores at month 12 was correlated significantly with improvement in DRSS score (r = 0.384 and P = 0.039, and r = 0.361 and P = 0.046, respectively). CONCLUSIONS In this study of eyes with PDR without DME, both monthly and quarterly aflibercept injection groups showed significant improvement in DR severity at month 12 compared with baseline. The improvement in DRSS score was associated with an improvement in VFQ-25 and VFQ-39 composite score.
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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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Prospective evaluation of aflibercept in pigment epithelial detachments secondary to neovascular age related macular degeneration.
Diaconita, V, Li, B, Pal, L, Bahnacy, F, Gonder, JR
Canadian journal of ophthalmology. Journal canadien d'ophtalmologie. 2019;(5):626-634
Abstract
OBJECTIVE To assess the efficacy of intravitreal aflibercept in treating visual loss and structural changes in patients with pigment epithelial detachments (PED) secondary to neovascular age-related macular degeneration (nAMD). METHODS Prospective, exploratory, open-label study (ClinicalTrials.gov Identifier: NCT02142296). Participants with PED secondary to nAMD were enrolled and received intravitreal aflibercept injection on a monthly basis for 3 months, followed by injections on a bimonthly basis for another 9 months. Best-corrected visual acuity (BCVA), ophthalmic examinations, optical coherence tomography (OCT) imaging, and fluorescein angiography were performed based on a predetermined schedule. RESULTS Thirty-six participants (37 eyes) were enrolled. At the end of study, 74.3% eyes demonstrated PED height reduction of 25% or more and 34.3% demonstrated complete resolution. The average reduction in retinal thickness was 128.4 μm. Participant eyes who had at least a 25% reduction in PED height at month 4 were labelled as "responders" (73.0%, n = 27), and those who had less than 25% reduction in PED height were labelled as "partial-responders" (27.0%, n = 10). Responders demonstrated more significant reduction in PED height than partial-responders (p <0.0001). The average gain in BCVA was 10.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Responders demonstrated more gain in BCVA than partial-responders (p = 0.0018). Among the responders, 57.7% demonstrated disease recurrences with increase in PED height during bimonthly dosing. CONCLUSIONS Intravitreal aflibercept injection for patients with PEDs secondary to nAMD has high response rate with few adverse events. Responders demonstrated BCVA gains, as well as structural improvements. However, high recurrence rate was found on bimonthly maintenance dosing.
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Retinal Nonperfusion Characteristics on Ultra-Widefield Angiography in Eyes With Severe Nonproliferative Diabetic Retinopathy and Proliferative Diabetic Retinopathy.
Nicholson, L, Ramu, J, Chan, EW, Bainbridge, JW, Hykin, PG, Talks, SJ, Sivaprasad, S
JAMA ophthalmology. 2019;(6):626-631
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Abstract
IMPORTANCE Threshold of retinal nonperfusion for the development of proliferative diabetic retinopathy (PDR) is unclear. OBJECTIVES To identify a threshold of retinal nonperfusion for the presence of retinal neovascularization and the distribution and area of retinal nonperfusion in eyes with severe nonproliferative diabetic retinopathy (NPDR), PDR, neovascularization of the optic disc (NVD), and retinal neovascularization elsewhere (NVE). DESIGN, SETTING, AND PARTICIPANTS This cross-sectional image analysis study was performed between September 24, 2018, and October 24, 2018, at a multicenter national study in the United Kingdom. Baseline images were obtained from 2 completed randomized clinical trials (Ranibizumab for Diabetic Macular Edema Panretinal Photocoagulation [RDP] study and Clinical Efficacy of Intravitreal Aflibercept vs Panretinal Photocoagulation for Best Corrected Visual Acuity in Patients With Proliferative Diabetic Retinopathy at 52 Weeks [CLARITY] study). The RDP study recruited eyes with severe NPDR between April 1, 2014, and December 31, 2015, and the CLARITY study recruited eyes with PDR between August 22, 2014, and November 20, 2015. Ultra-widefield angiography images of eyes with no prior panretinal photocoagulation treatment were included. MAIN OUTCOMES AND MEASURES The total area of retinal nonperfusion, the area of posterior pole retinal nonperfusion, and the area of peripheral retinal nonperfusion were measured. RESULTS A total of 92 patients (92 eyes) were included in the study: 59 in the PDR group (mean [SD] age, 42 [15] years; 20 female [33.9%]) and 33 in the NPDR group (mean [SD] age, 63 [10] years; 3 female [9.1%]). Forty eyes had NVE and 19 had NVD with or without NVE. We identified a retinal nonperfusion threshold of 118.3 disc areas (DA) with a specificity of 84.9% (95% CI, 68.1% to 94.9%) for PDR. The median area of retinal nonperfusion was 67.8 DA (95% CI, 44.2 to 107.3 DA) in the NPDR eyes and 147.9 DA (95% CI, 127.4 to 173.5 DA) for eyes with proliferative changes, with a difference of 69.0 DA (95% CI, 42.2 to 97.7 DA; P < .001). No difference was found in the median area of posterior nonperfusion between NPDR and PDR, with a difference of 0 DA (95% CI, -6.7 to 5.2 DA; P = .56). As for peripheral nonperfusion, NPDR eyes measured 64.1 DA and PDR eyes measured 130.6 DA, with a difference of 70.8 DA (95% CI, 48.4 to 94.9 DA; P < .001). Eyes with NVD had the largest total area of retinal nonperfusion, with a difference of 65.1 DA (95% CI, 28.6 to 95.8 DA; P < .001) compared with eyes with only NVE. CONCLUSIONS AND RELEVANCE These findings suggest eyes with at least 107.3 DA of nonperfusion are at risk of proliferative disease, and eyes with NVD have the largest area of retinal nonperfusion.
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Phase II/III Clinical Trial of Sub-Tenon Injection of Triamcinolone Acetonide (WP-0508ST) for Diabetic Macular Edema.
Ogura, Y, Shimura, M, Iida, T, Sakamoto, T, Yoshimura, N, Yamada, M, Ishibashi, T
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2019;(3):161-169
Abstract
PURPOSE To assess the efficacy and safety of sub-Tenon injection of triamcinolone acetonide (WP-0508ST) for the patients with diabetic macular edema (DME). METHODS This multicenter, randomized, double-masked, comparative, controlled study was performed in 95 patients with DME. The patients were randomly divided into 20 mg WP-0508ST, 40 mg WP-0508ST, and control groups. RESULTS A significant improvement in central macular thickness (CMT) was observed (p < 0.001) at 12 weeks after a single sub-Tenon injection of 20 mg WP-0508ST. The 40 mg group also demonstrated improvement in CMT, but the difference was not significant. In addition, the best-corrected visual acuity was improved in both the 20 mg and 40 mg groups at 12 weeks. The major side effects were increased intraocular pressure (9.4% in the 20 mg group and 13.3% in the 40 mg group) and lenticular opacity (6.3% in the 20 mg group and 10.0% in the 40 mg group). However, none of the patients with increased intraocular pressure required surgery. CONCLUSION The efficacy and tolerability of WP-0508ST in the treatment of DME were confirmed, and 20 mg was determined to be the optimal dose.
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EFFICACY AND FREQUENCY OF INTRAVITREAL AFLIBERCEPT VERSUS BEVACIZUMAB FOR MACULAR EDEMA SECONDARY TO CENTRAL RETINAL VEIN OCCLUSION.
Lotfy, A, Solaiman, KAM, Abdelrahman, A, Samir, A
Retina (Philadelphia, Pa.). 2018;(9):1795-1800
Abstract
PURPOSE To compare the safety, efficacy, and frequency of intravitreal injection of aflibercept and bevacizumab for treatment of macular edema secondary to central retinal vein occlusion. DESIGN Prospective, comparative, randomized, interventional study. PATIENTS AND METHODS Eyes with macular edema secondary to central retinal vein occlusion were randomized between two groups according to the intravitreal injection used. Group A included eyes treated with intravitreal aflibercept, and Group B included eyes treated with intravitreal bevacizumab injections. The inclusion criteria were macular edema secondary to central retinal vein occlusion and follow-up duration of at least 12 months after the first injection. Exclusion criteria were macular ischemia, associated diabetes, hypertensive or renal retinopathy, other retinal disease, and previous anti-vascular endothelial growth factor injection. The main outcome measures are central foveal thickness, best-corrected visual acuity, time intervals between injections, improved retinal nonperfusion, and any reported complication. RESULTS Group A included 39 patients with a mean age of 57.4 ± 8.2 years. Group B included 40 eyes with a mean age of 56.5 ± 9.1 years. Twelve months after the first injection, central foveal thickness significantly improved from 475.45 ± 71.05 m to 259.11 ± 20.67 m in Group A and from 460.22 ± 89.38 m to 264.29 ± 32.05 m in Group B; best-corrected visual acuity significantly improved from 0.81 ± 0.16 logarithm of the minimum angle of resolution (20/125) to 0.34 ± 0.14 logarithm of the minimum angle of resolution (20/40) in Group A and from 0.73 ± 0.15 logarithm of the minimum angle of resolution (20/100) to 0.33 ± 0.17 logarithm of the minimum angle of resolution (20/40) in Group B; the mean number of injections was 3.72 ± 2.93 in Group A and was 5.44 ± 2.85 in Group B (P < 0.05); and the mean interval between injections was 54.23 ± 8.47 days in Group A and was 35.12 ± 7.76 days in Group B (P < 0.05). Retinal nonperfusion improved in 9/12 eyes in Group A and in 3/8 eyes in Group B (P < 0.05). CONCLUSION Both aflibercept and bevacizumab are comparably effective for treatment of macular edema secondary to central retinal vein occlusion without significant complications. However, the burden of frequent intravitreal injections could be significantly reduced when using aflibercept.
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Efficacy of Ranibizumab in Eyes with Diabetic Macular Edema and Macular Nonperfusion in RIDE and RISE.
Reddy, RK, Pieramici, DJ, Gune, S, Ghanekar, A, Lu, N, Quezada-Ruiz, C, Baumal, CR
Ophthalmology. 2018;(10):1568-1574
Abstract
PURPOSE To determine whether there are baseline characteristics that distinguish patients with diabetic macular edema (DME) with coexisting macular nonperfusion (MNP) at baseline and assess these patients' potential to achieve favorable visual acuity (VA), anatomic, and diabetic retinopathy (DR) outcomes over 24 months. DESIGN Post hoc analysis of RIDE/RISE, 2 phase 3, parallel, randomized, multicenter, double-masked trials (ClinicalTrials.gov: NCT00473382; NCT00473330). PARTICIPANTS Study eyes with best-corrected VA (BCVA)/fluorescein angiogram (FA) data at baseline. METHODS To measure MNP, the Early Treatment for Diabetic Retinopathy Study (ETDRS) grid was overlaid on FAs of the macula. The MNP area was calculated by estimating the percentage of capillary loss in the central, inner, and outer subfields and converting into disc areas (DAs) using a software algorithm. Summary statistics and P values, respectively, were provided for all outcomes and comparisons of interest. MAIN OUTCOME MEASURES Baseline characteristics; MNP area, BCVA, and central subfield thickness (CST) at months 12 and 24; and incidence of study eyes with ≥2-step DR improvement at months 3, 6, 12, 18, and 24. RESULTS Baseline MNP was detected in 28.2%, 25.8%, and 26.3% of study eyes in the ranibizumab 0.3 mg (n = 213), ranibizumab 0.5 mg (n = 225), and sham (n = 228) arms, respectively. At baseline, patients with MNP were younger and had shorter diabetes duration, worse vision, increased CST, and worse DR severity (P values < 0.01 vs. those without MNP). In the ranibizumab 0.3 mg arm, eyes with baseline MNP had lower mean baseline BCVA (53.4 vs. 57.2 ETDRS letters for those without baseline MNP; P = 0.05), but mean BCVA gain at month 24 was comparable (+15.6 vs. +13.4 ETDRS letters, respectively; P = 0.2). Eyes with baseline MNP had increased CST at baseline, but experienced a greater decrease in CST by month 24. The proportion of eyes with ≥2-step DR improvement was greater for eyes with versus without baseline MNP in each ranibizumab arm. CONCLUSIONS Despite having worse vision/increased CST versus those without baseline MNP, eyes with concurrent DME and baseline MNP entering RIDE/RISE experienced robust VA and anatomic improvement with ranibizumab and therefore should not be excluded from therapy.
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Macular peeling-induced retinal damage: clinical and histopathological evaluation after using different dyes.
Romano, MR, Ilardi, G, Ferrara, M, Cennamo, G, Parolini, B, Mariotti, C, Staibano, S, Cennamo, G
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2018;(9):1573-1580
Abstract
PURPOSE To describe functional and histopathological findings after macular peeling using different dyes. METHODS Prospective, randomized, comparative, interventional, and immunohistochemical study. Forty-five eyes from 45 patients with idiopathic epiretinal membrane (ERM) underwent pars plana chromovitrectomy with ERM and inner limiting membrane (ILM) using trypan blue 0.15% + brilliant blue 0.05% + lutein 2% in group 1 (15 eyes), trypan blue 0.15% + brilliant blue 0.025% + polyethylene glycol 3350 4% in group 2 (15 eyes), and indocyanine green 0.05% in group 3 (15 eyes). We evaluated visual acuity (VA) and macular sensitivity (MS) preoperatively, 1, 3, and 6 months after surgery. The expression of glial fibrillary acidic protein (GFAP) and neurofilament protein (NF) was assessed immunohistochemically on the ILMs peeled as markers of glial and neuronal cells. RESULTS In group 1, both mean VA and MS were significantly better at 1 and 3 months after surgery (P < 0.05), whereas no significant difference was found after 6 months. GFAP and NF expression was significantly lower in group 1 (P < 0.05). CONCLUSIONS The ERM/ILM peeling is thought to rip off the intraretinal tissue, based on the amounts of GFAP and NF in the specimens. The use of lutein dyes reduces iatrogenic stress to the retinal tissue and allows a faster functional recovery in the first 3 months after surgery, suggesting a less iatrogenic adhesion to the retinal tissue.
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Extended targeted retinal photocoagulation versus conventional pan-retinal photocoagulation for proliferative diabetic retinopathy in a randomized clinical trial.
Nikkhah, H, Ghazi, H, Razzaghi, MR, Karimi, S, Ramezani, A, Soheilian, M
International ophthalmology. 2018;(1):313-321
Abstract
PURPOSE To determine the clinical efficacy of extended targeted retinal photocoagulation (ETRP) compared to conventional panretinal photocoagulation (CPRP) in proliferative diabetic retinopathy (PDR). METHODS In a single-masked randomized clinical trial, 270 eyes of 234 patients with naïve early or high-risk PDR were randomly assigned to receive either CPRP or ETRP (135 eyes, each treatment arm). Best-corrected visual acuity (BCVA) measurement, fundus examination, wide-field fluorescein angiography (WFFA) and optical coherence tomography were carried out before and 3 months after retinal photocoagulation. Primary outcome was early PDR regression, specified as reduction in retinal neovascularization based on WFFA at 3 months. Secondary outcomes were BCVA and central macular thickness (CMT) changes. RESULTS There were significantly more high-risk PDR eyes in ETRP group compared to CPRP (109 and 94 eyes, respectively, P = 0.04). Early PDR regression occurred in 71.9 and 64.4% of eyes in the ETRP and CPRP groups, respectively (P = 0.19). The mean number of applied laser spots in the ETRP was significantly fewer than CPRP (1202 vs. 1360, respectively, P < 0.001). Mean BCVA at baseline and 3 months post-laser were 0.37 ± 0.26 and 0.47 ± 0.19 logMAR in the ETRP arm, respectively. In the CPRP arm these values were 0.40 ± 0.27 and 0.47 ± 0.24 logMAR, respectively. Although mean BCVA decreased significantly in both treatment arms (ETRP P < 0.001, CPRP P = 0.009), the difference was not significant between arms (P = 0.68). CMT increased significantly in both groups (ETRP 41.08 μm, P < 0.001, CPRP 33.31 μm, P < 0.001). Nevertheless, the difference between the groups was not significant (P = 0.26). CONCLUSIONS ETRP with fewer number of laser spots may be an appropriate alternative to CPRP in PDR regression at least through 3 months. GOV REGISTRATION NUMBER NCT01232179.
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The Clinical Importance of Changes in Diabetic Retinopathy Severity Score.
Ip, MS, Zhang, J, Ehrlich, JS
Ophthalmology. 2017;(5):596-603
Abstract
PURPOSE To investigate the clinical importance of changes in diabetic retinopathy severity score (DRSS) in patients with diabetic macular edema (DME) treated with intravitreal ranibizumab. DESIGN Post hoc analysis of the phase III RIDE and RISE studies of ranibizumab for treatment of DME. PARTICIPANTS Four hundred sixty-eight eyes treated with ranibizumab from randomization with gradable DRSS on baseline fundus photographs. METHODS Visual and anatomic outcomes were examined in eyes grouped according to DRSS change from baseline to month 24. MAIN OUTCOME MEASURES Mean best-corrected visual acuity (BCVA) letter score change, proportion of patients with 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letter score change, mean contrast sensitivity change, proportion of patients with resolved macular edema, and leakage on fluorescein angiography. RESULTS Most (56.8%) patients treated with ranibizumab experienced 1-step or more improvement in DRSS from baseline to month 24; 40.0% had no change, and 3.2% experienced DRSS worsening. Patients with DRSS stability or improvement had greater mean BCVA letter score changes (+15.1, +14.2, +11.3, and +11.2 letters for ≥3-step improvement, ≥2-step improvement, 1-step improvement, and no DRSS change, respectively) compared with +5.0 letters in patients who had any DRSS worsening. Best-corrected visual acuity letter score gain of 15 letters or more was more common in patients with 2-step or 3-step or more DRSS improvement (51.9% and 44.6%, respectively) compared with those with a 1-step DRSS improvement, no change, or worsening (37.9%, 39.6%, and 26.7%, respectively). A loss of 15 letters or more in BCVA was more common in patients with any DRSS worsening (13.3%) compared with patients who had stable or improved DRSS (0%-2.8%). Resolution of macular edema was more common in patients with DRSS improvement: 84.2%, 87.7%, and 92.3% of patients with 1-step, 2-step or more, and 3-step or more improvement in DRSS achieved central foveal thickness of 250 μm or less, compared with 65.2% and 53.3% of patients who had no DRSS change or any DRSS worsening. CONCLUSIONS These findings provide further support that improvement in DRSS is a clinically important outcome that should be evaluated as a measure of treatment effectiveness in future studies of diabetic eye disease.