-
1.
NEW BIOMARKER QUANTIFYING THE EFFECT OF ANTI-VEGF THERAPY IN EYES WITH PROLIFERATIVE DIABETIC RETINOPATHY ON ULTRAWIDE FIELD FLUORESCEIN ANGIOGRAPHY: RECOVERY Study.
Fan, W, Nittala, MG, Wykoff, CC, Brown, DM, Uji, A, Hemert, JV, Fleming, A, Robertson, G, Sadda, SR, Ip, M
Retina (Philadelphia, Pa.). 2022;(3):426-433
Abstract
PURPOSE To quantify changes of the retinal vascular bed area (RVBA) in mm2 on stereographically projected ultrawide field fluorescein angiography images in eyes with proliferative diabetic retinopathy after antivascular endothelial growth factor injection. METHODS This is a prospective, observational study. The early-phase ultrawide field fluorescein angiography images (Optos 200Tx) of 40 eyes with proliferative diabetic retinopathy and significant nonperfusion obtained at baseline and after six months (NCT02863354) were stereographically projected by correcting peripheral distortion. The global retinal vasculature on ultrawide field fluorescein angiography was extracted for calculating RVBA by summing the real size (mm2) of all the pixels automatically. RESULTS For the entire cohort, the global RVBA for the entire retina decreased from 67.1 ± 15.5 to 43.6 ± 18.8 mm2 after anti-VEGF treatment at six months (P < 0.001). In the subgroup receiving monthly anti-VEGF injections, the global RVBA decreased from 68.7 ± 16.2 to 33.9 ± 13.3 mm2 (P < 0.001). In the subgroup receiving anti-VEGF every three months, the global RVBA decreased from 65.6 ± 15.1 to 50.8 ± 19.3 mm2 (P = 0.004). CONCLUSION RVBA seems to be a new biomarker to indicate efficiency of retinal vascular changes after anti-VEGF injection. Eyes with proliferative diabetic retinopathy and significant nonperfusion demonstrate reduced RVBA after anti-VEGF treatment.
-
2.
Real-Time Photographic- and Fluorescein Angiographic-Guided Management of Diabetic Retinopathy: Randomized PRIME Trial Outcomes.
Yu, HJ, Ehlers, JP, Sevgi, DD, Hach, J, O'Connell, M, Reese, JL, Srivastava, SK, Wykoff, CC
American journal of ophthalmology. 2021;:126-136
Abstract
PURPOSE To assess the safety and efficacy of as-needed (PRN) intravitreal aflibercept injections (IAI) in managing diabetic retinopathy (DR) guided by the real-time DR severity scale (DRSS) level or panretinal leakage index (PLI) assessment among eyes without diabetic macular edema (DME). DESIGN Prospective, randomized phase 2 trial (PRIME). METHODS A total of 40 eyes with nonproliferative (NPDR) or proliferative DR (PDR) received monthly IAIs until a DRSS improvement of ≥2 steps was achieved and eyes were randomized (1:1) to DRSS-guided or PLI-guided management strategies graded by a central reading center. Main outcome measurements included safety and changes in DRSS and PLI. RESULTS Through week 52, 95% of eyes achieved a DRSS improvement of ≥2 steps. Following DRSS improvement, 97% of eyes required at least 1 PRN IAI. In eyes requiring PRN IAI and completing week 52, 100% and 59% experienced DRSS worsening (P = .01) in the DRSS- and PLI-guided arms, respectively. Through week 52, mean PLI decreased 18.2% (P = .49) and 54.6% (P <.0001), respectively, in the DRSS- and PLI-guided arms. NPDR versus PDR eyes at baseline achieved a DRSS improvement of ≥2 steps after a mean 4.9 and 3.6 IAIs (P = .03). Two eyes developed a PDR event at week 52 following 5 months of quiescence. CONCLUSIONS The randomized PRIME study analyzed 2 imaging-based biomarkers to guide PRN management with IAI of DR without DME: DRSS level and PLI. Within the context of this study with limitations, most patients required IAI re-treatment every 3-4 months, and deterioration of PLI appeared to precede DRSS level worsening. Finally, these findings reaffirm the fact that close clinical follow-up is important even among eyes that achieve substantial DRSS improvements with apparently quiescent disease.
-
3.
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.
-
4.
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
-
-
Free full text
-
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).
-
5.
Longitudinal panretinal microaneurysm dynamics on ultra-widefield fluorescein angiography in eyes treated with intravitreal aflibercept for proliferative diabetic retinopathy in the recovery study.
Babiuch, A, Wykoff, CC, Hach, J, Srivastava, S, Talcott, KE, Yu, HJ, Nittala, M, Sadda, S, Ip, MS, Le, T, et al
The British journal of ophthalmology. 2021;(8):1111-1115
Abstract
BACKGROUND/AIMS: Quantifying microaneurysms (MAs) turnover may be an objective measure for therapeutic response in diabetic retinopathy. This study assesses changes in MA counts on ultra-widefield fluorescein angiography (UWFA) in subjects undergoing treatment with intravitreal aflibercept injection (IAI) for proliferative diabetic retinopathy (PDR) in the Intravitreal Aflibercept for Retinal Non-Perfusion in Proliferative Diabetic Retinopathy(RECOVERY) study using an automated MA detection platform. METHODS RECOVERY is a prospective study that enrolled 40 subjects with PDR randomised 1:1 to receive 2 mg IAI every 4 weeks(q4wk) or every 12 weeks (q12wk). UWFA images were obtained at baseline, 6 months and 1 year. Images were analysed using an automated segmentation platform to detect and quantify MAs. Zones 1, 2 and 3 correspond to the macula, mid-periphery and far-periphery, respectively. RESULTS The q4wk cohort demonstrated a significant decline in MAs in all zones and panretinally at baseline versus month 6, baseline versus year 1, and month 6 versus year 1 (-20.0% to -61.8%; all p<0.001). In the q12wk cohort, baseline versus month 6 showed a significant decline panretinally (mean: -34.2%; p<0.001) and in zone 3 (mean -44.18%; p<0.001). Addiitonally, baseline to year 1 in the q12wk group demonstrated significant decline panretinally (mean: -47.7%; p<0.001) and in zone 3 (mean: -59.8%; p<0.001). All zones demonstrated significantly decline from month 6 to year 1 in the q12wk group. CONCLUSION Therapy with IAI demonstrates significantly reduced panretinal MA counts in PDR at 1 year in both treatment groups. The use of automated platforms to detect and quantify MAs may provide a novel imaging marker for evaluating disease activity and therapeutic impact. TRIAL REGISTRATION NUMBER NCT02863354.
-
6.
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.
-
7.
Retinal Fluid Volatility Associated With Interval Tolerance and Visual Outcomes in Diabetic Macular Edema in the VISTA Phase III Trial.
Ehlers, JP, Uchida, A, Sevgi, DD, Hu, M, Reed, K, Berliner, A, Vitti, R, Chu, K, Srivastava, SK
American journal of ophthalmology. 2021;:217-227
-
-
Free full text
-
Abstract
PURPOSE To describe longitudinal retinal fluid dynamics on spectral domain OCT and to identify imaging biomarkers that predict the worsening of DME with interval extension during anti-vascular endothelial growth factor (VEGF) therapy. DESIGN A post hoc sub-analysis of phase III, VISTA-DME study. METHODS Eyes received either intravitreal aflibercept injection 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly injections (2q8), and eyes imaged with the Cirrus HD-OCT system were included. The macular cube was analyzed for 10 time-points from baseline through week 100. Retinal OCT images were evaluated using a novel software platform to extract retinal fluid features for calculation of volumetric fluid parameters, including the retinal fluid index (RFI): the percentage of retinal volume that was occupied by intraretinal fluid. RESULTS Fifty-five eyes were included in the 2q4 group, and 58 eyes were included in the 2q8 group. Early RFI volatility with a central macular RFI increase by ≥5 points from week 4 to 8 (P = .004, odds ratio [OR] 31.3, 95% confidence interval [CI] 3.0 to 329) and cumulative RFI volatility with an aggregate increase in macular RFI by ≥10 points from those timepoints with increased RFI between baseline to week 20, P = .005, OR 10.2, 95% CI 2.1 to 51.3) were both significant predictors for the worsening of DME and visual acuity when the treatment interval was extended to 8 weeks in the 2q8 group. CONCLUSIONS Early fluid dynamics as measured by (1) early RFI volatility and (2) cumulative RFI instability with aggregate increased RFI were associated with intolerance of interval extension.
-
8.
Predictors of Visual Acuity Outcomes after Anti-Vascular Endothelial Growth Factor Treatment for Macular Edema Secondary to Central Retinal Vein Occlusion.
Sen, P, Gurudas, S, Ramu, J, Patrao, N, Chandra, S, Rasheed, R, Nicholson, L, Peto, T, Sivaprasad, S, Hykin, P
Ophthalmology. Retina. 2021;(11):1115-1124
Abstract
PURPOSE To evaluate whether baseline demographic, clinical, and OCT characteristics predict visual acuity (VA) outcomes in patients receiving anti-vascular endothelial growth factor (VEGF) therapy for macular edema (ME) due to central retinal vein occlusion (CRVO). DESIGN Post hoc analysis of the randomized noninferiority trial (Lucentis, Eylea, Avastin in CRVO) LEAVO Study from December 12, 2014, to December 16, 2016, carried out across 44 UK National Health Service ophthalmology departments. PARTICIPANTS Data on 267 participants with a baseline best-corrected mean visual acuity (BCVA) range of 19 to 78 Early Treatment Diabetic Retinopathy Study letter score (approximate Snellen equivalent, 20/32 to 20/320) who had central subfield thickness (CST) ≥ 320 μm on Spectralis OCT (Heidelberg Engineering) were analyzed. METHODS Study participants were randomized to receive repeated intravitreal injections of ranibizumab (0.5 mg/50 μl), aflibercept (2.0 mg/50 μl), or bevacizumab (1.25 mg/50 μl), and a protocol-driven pro re nata re-treatment regimen at 4 to 8 weekly visits was followed up to week 100 after 4 mandated 4-weekly loading injections. MAIN OUTCOME MEASURES Change in BCVA and percentage of patients gaining ≥ 10 letters and achieving BCVA letter score > 70 letters at 52 and 100 weeks. RESULTS The analysis was adjusted for treatment effects and confirmed by sensitivity analysis. Age ≥ 75 years is a poor predictor for all 3 visual outcomes. Lower baseline BCVA predicted 10-letter gainers and higher gains in BCVA, although it is a poor predictor of achieving > 70 Early Treatment Diabetic Retinopathy Study letters. None of the baseline OCT morphologic characteristics except ellipsoid zone (EZ) integrity influenced any visual outcomes. Both baseline CST and total macular volume showed a nonlinear relation to 10-letter gainers, with CST > 900 μm being a poor prognostic indicator. Baseline CST and macular volume did not predict mean change in BCVA or BCVA > 70 letters at 52 and 100 weeks. The sensitivity analysis conclusions after removing iCRVO were similar. CONCLUSIONS At presentation, younger age, higher baseline BCVA, and a definitely intact subfoveal EZ are predictors of BCVA score > 70 letters at 100 weeks.
-
9.
Outcomes in Patients with Diabetic Macular Edema Requiring Cataract Surgery in VISTA and VIVID Studies.
Moshfeghi, AA, Thompson, D, Berliner, AJ, Saroj, N
Ophthalmology. Retina. 2020;(5):481-485
Abstract
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.
-
10.
Longitudinal Panretinal Leakage and Ischemic Indices in Retinal Vascular Disease after Aflibercept Therapy: The PERMEATE Study.
Figueiredo, N, Srivastava, SK, Singh, RP, Babiuch, A, Sharma, S, Rachitskaya, A, Talcott, K, Reese, J, Hu, M, Ehlers, JP
Ophthalmology. Retina. 2020;(2):154-163
-
-
Free full text
-
Abstract
PURPOSE To characterize the longitudinal panretinal retinal vascular dynamics in diabetic macular edema (DME) and retinal vein occlusion (RVO) over a 12-month period while being treated with intravitreal aflibercept injections (IAIs). DESIGN Prospective open-label study (clinicaltrials.gov identifier, NCT02503540). PARTICIPANTS Thirty-one treatment-naive eyes with foveal-involving retinal edema secondary to DME and RVO. METHODS Participants received 2 mg IAI every 4 weeks for the first 6 months, followed by 2 mg every 8 weeks. Ultra-widefield fluorescein angiography (UWFA; California Optos [Optos, Dunfermline, United Kingdom]) and spectral-domain OCT (Cirrus; Zeiss, Oberkochen, Germany) scans were obtained and analyzed using a novel quantitative assessment platform. Visual acuity, central subfield thickness, and adverse events also were collected. MAIN OUTCOME MEASURES The primary end point was the mean change in panretinal leakage index at month 12 from baseline as measured by UWFA. RESULTS Mean age was 67.1 years. At month 12, visual acuity significantly improved by a mean of 18.4±21.4 letters (P < 0.0001), and central subfield thickness also improved significantly, with a mean reduction of 301.3±250.3 μm (P < 0.0001). Mean panretinal leakage index improved significantly, decreasing from 3.4% at baseline to 0.5% at month 6 (P <0.0001) and 0.4% at month 12 (P < 0.0001). Panretinal ischemic index did not demonstrate any significant change but showed a nonsignificant increase from 5.5% at baseline to 6.1% at month 6 (P = 0.315) and 8.7% at month 12 (P = 0.193). Eyes with DME showed a decrease in leakage index from 3.5±2.7% at baseline to 1.6±0.8% at month 12 (P = 0.018) and overall stability in ischemic index from 5.0±4.1% at baseline to 4.7±3.5% at month 12 (P = 0.689). Participants with RVO showed a decrease in leakage index from 3.3±1.1% at baseline to 0.02±0.03% at 12 months (P < 0.0001) and a nonsignificant increase in ischemic index from 5.9±4.5% at baseline to 12.6±9.8% at month 12 (P = 0.172). CONCLUSIONS Intravitreal aflibercept injections resulted in a dramatic reduction in panretinal leakage index. Panretinal ischemic index did not improve and trended toward worsening.