Evaluation of a self-imaging SD-OCT system designed for remote home monitoring.

PURPOSE: To compare identification rates of retinal fluid of the Notal Vision Home Optical Coherence Tomography (OCT) device (NVHO) when used by people with age-related macular degeneration (AMD) to those captured by a commercial OCT. METHODS: Prospective, cross-sectional study where patients underwent commercial OCT imaging followed by self-imaging with either the NVHO 2.5 or the NVHO 3 in clinic setting. Outcomes included patients' ability to acquire analyzable OCT images with the NVHO and to compare those with commercial images. RESULTS: Successful images were acquired with the NVHO 2.5 in 469/531 eyes (88%) in 264/290 subjects (91%) with the mean (SD) age of 78.8 (8.8); 153 (58%) were female with median visual acuity (VA) of 20/40. In the NVHO 3 cohort, 69 eyes of 45 subjects (93%) completed the self-imaging. Higher rates of successful imaging were found in eyes with VA ≥ 20/320. Positive percent agreement/negative percent agreement for detecting the presence of subretinal and/or intraretinal fluid when reviewing for fluid in three repeated volume scans were 97%/95%, respectively for the NVHO v3. CONCLUSION: Self-testing with the NVHO can produce high quality images suitable for fluid identification by human graders, suggesting the device may be able to complement standard-of-care clinical assessments and treatments.

Analysis of the Long-term Visual Outcomes of ForeseeHome Remote Telemonitoring: The ALOFT Study.

PURPOSE: To evaluate long-term visual acuity (VA) and performance of a monitoring strategy with a self-operated artificial-intelligence-enabled home monitoring system in conjunction with standard care for early detection of neovascular age-related macular degeneration (nAMD). DESIGN: Retrospective review. SUBJECTS: Patients with dry-age-related macular degeneration from 5 referral clinics. METHODS: Clinical data of patients monitored with ForeseeHome (FSH) device from August 2010 to July 2020 were reviewed. MAIN OUTCOME MEASURES: Visual acuity at baseline, VA at diagnosis of nAMD for eyes that converted while monitored, and VA from the final study follow-up, weekly frequency of use, duration of monitoring, modality of conversion diagnosis (system alert vs. detection by other standard care means), and duration and number of treatments since conversion to final study follow-up were collected. RESULTS: We reviewed 3334 eyes of 2123 patients with a mean (standard deviation [SD]) age of 74(8) years, monitored for a mean (SD) duration of 3.1 (2.4) years, with a total of 1 706 433 tests in 10 474 eye-monitoring years. The mean (SD) weekly use per patient was 5.2 (3.4), and it was persistent over the usage period. Two hundred eighty-five eyes converted while monitored at an annual rate of 2.72% and were treated with a mean (SD) 17.3 (16.5) injections over a mean (SD) 2.7 (2.0) years, with 6.4 (3.1) injections per year for eyes treated for > 1 year. The median VAs at baseline and at final follow-up for eyes that did not convert were 20/27 and 20/34 with a median change of 0.0 letters. The median VAs at baseline, conversion, and final follow-up for eyes that converted during the monitoring period were 20/30, 20/39, and 20/32 with a median change from baseline to conversion, baseline to recent, and conversion to recent of -4, -4, and 0 letters, respectively. Fifty-two percent of conversions detected had a system alert before conversion. Forty-eight percent of patients were detected by symptoms or routine visit. Patients experienced a non-nAMD alert on average every 4.6 years. At conversion and at final follow-up, the proportion (95% CI) of eyes that maintained ≥ 20/40 was 84% (78% to 88%) and 82% (76% to 86%), respectively. CONCLUSIONS: Patients in the FSH monitoring program showed excellent long-term VA years after conversion to nAMD.

Visual Acuity, Vitreous Hemorrhage, and Other Ocular Outcomes After Vitrectomy vs Aflibercept for Vitreous Hemorrhage Due to Diabetic Retinopathy: A Secondary Analysis of a Randomized Clinical Trial.

IMPORTANCE: Although there were no differences in mean visual acuity (VA) over 24 weeks after vitrectomy with panretinal photocoagulation (PRP) vs aflibercept in a randomized clinical trial among eyes with vitreous hemorrhage due to proliferative diabetic retinopathy (PDR), post hoc analyses may influence treatment choices. OBJECTIVE: To compare exploratory outcomes between treatment groups that may affect treatment choices for patients with vitreous hemorrhage due to PDR. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of a randomized clinical trial conducted at 39 DRCR Retina Network sites included adults with vision loss due to PDR-related vitreous hemorrhage for whom vitrectomy was considered. Data were collected from November 2016 to January 2020. INTERVENTIONS: Random assignment to 4 monthly injections of aflibercept vs vitrectomy with PRP. Both groups could receive aflibercept or vitrectomy during follow-up based on protocol-specific criteria. MAIN OUTCOMES AND MEASURES: Visual acuity area under the curve (adjusted for baseline VA) and clearance of vitreous hemorrhage. RESULTS: A total of 205 eyes were included in the analysis (115 male [56%] and 90 [44%] female participants; mean [SD] age, 57 [11] years). Among 89 eyes with a baseline VA of 20/32 to 20/160 (47 receiving aflibercept, including 4 [9%] that had undergone vitrectomy; 42 undergoing vitrectomy, including 3 [7%] that had received aflibercept), the adjusted mean difference in VA letter score over 24 weeks between the aflibercept and vitrectomy groups was -4.3 (95% CI, -10.6 to 1.9) compared with -16.7 (95% CI, -24.4 to -9.1) among 59 eyes with baseline VA worse than 20/800 (P = .02 for interaction; 26 in the aflibercept group, including 6 [23%] that had undergone vitrectomy; 33 in the vitrectomy group, including 8 [24%] that had received aflibercept). In the full cohort, the median time to clearance of the initial vitreous hemorrhage was 36 (interquartile range [IQR], 24-52) weeks in the aflibercept group vs 4 (IQR, 4-4) weeks in the vitrectomy group (difference, 32 [95% CI, 20-32] weeks; P < .001). CONCLUSIONS AND RELEVANCE: Both initial aflibercept and vitrectomy with PRP are viable treatment approaches for PDR-related vitreous hemorrhage. Although this study did not find a significant difference between groups in the primary outcome of mean VA over 24 weeks of follow-up, eyes receiving initial vitrectomy with PRP had faster recovery of vision over 24 weeks when baseline VA was worse than 20/800 and faster vitreous hemorrhage clearance. Approximately one-third of the eyes in each group received the alternative treatment (aflibercept or vitrectomy with PRP). These factors may influence treatment decisions for patients initiating therapy for PDR-related vitreous hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02858076.

Real-World Performance of a Self-Operated Home Monitoring System for Early Detection of Neovascular Age-Related Macular Degeneration.

The real-world performance of a home telemonitoring strategy (ForeseeHome AMD Monitoring System®, Notal Vision, Inc.,Manassas VA, USA) was evaluated and compared to the device arm of the AREDS2-HOME study among patients with intermediate AMD (iAMD) who converted to neovascular AMD (nAMD). All patients with confirmed conversion to nAMD who used the home monitoring system from 10/2009 through 9/2018 were identified by Notal Vision Diagnostic Clinic's medical records. Selected outcome variables were evaluated, including visual acuity (VA) at baseline and at conversion, and change in visual acuity (VA) from baseline to time of conversion. In total, 8991 patients performed 3,200,999 tests at a frequency of 5.6 ± 3.2 times/week. The 306 eyes that converted from iAMD to nAMD over the study period (a 2.7% annual rate) were included in the analyses. There was a median (interquartile range) change of -3.0 (0.0-(-10.0)) letters among converted eyes, 81% [95% confidence interval (72-88%)] maintained a VA ≥ 20/40 at the time of conversion, while 69% of the conversion detections were triggered by system alerts. The real-world performance of an at-home testing strategy was similar to that reported for the device arm of the AREDS2-HOME study. The home telemonitoring system can markedly increase early detection of conversion to nAMD.

Retinal Specialist versus Artificial Intelligence Detection of Retinal Fluid from OCT: Age-Related Eye Disease Study 2: 10-Year Follow-On Study.

PURPOSE: To evaluate the performance of retinal specialists in detecting retinal fluid presence in spectral domain OCT (SD-OCT) scans from eyes with age-related macular degeneration (AMD) and compare performance with an artificial intelligence algorithm. DESIGN: Prospective comparison of retinal fluid grades from human retinal specialists and the Notal OCT Analyzer (NOA) on SD-OCT scans from 2 common devices. PARTICIPANTS: A total of 1127 eyes of 651 Age-Related Eye Disease Study 2 10-year Follow-On Study (AREDS2-10Y) participants with SD-OCT scans graded by reading center graders (as the ground truth). METHODS: The AREDS2-10Y investigators graded each SD-OCT scan for the presence/absence of intraretinal and subretinal fluid. Separately, the same scans were graded by the NOA. MAIN OUTCOME MEASURES: Accuracy (primary), sensitivity, specificity, precision, and F1-score. RESULTS: Of the 1127 eyes, retinal fluid was present in 32.8%. For detecting retinal fluid, the investigators had an accuracy of 0.805 (95% confidence interval [CI], 0.780-0.828), a sensitivity of 0.468 (95% CI, 0.416-0.520), a specificity of 0.970 (95% CI, 0.955-0.981). The NOA metrics were 0.851 (95% CI, 0.829-0.871), 0.822 (95% CI, 0.779-0.859), 0.865 (95% CI, 0.839-0.889), respectively. For detecting intraretinal fluid, the investigator metrics were 0.815 (95% CI, 0.792-0.837), 0.403 (95% CI, 0.349-0.459), and 0.978 (95% CI, 0.966-0.987); the NOA metrics were 0.877 (95% CI, 0.857-0.896), 0.763 (95% CI, 0.713-0.808), and 0.922 (95% CI, 0.902-0.940), respectively. For detecting subretinal fluid, the investigator metrics were 0.946 (95% CI, 0.931-0.958), 0.583 (95% CI, 0.471-0.690), and 0.973 (95% CI, 0.962-0.982); the NOA metrics were 0.863 (95% CI, 0.842-0.882), 0.940 (95% CI, 0.867-0.980), and 0.857 (95% CI, 0.835-0.877), respectively. CONCLUSIONS: In this large and challenging sample of SD-OCT scans obtained with 2 common devices, retinal specialists had imperfect accuracy and low sensitivity in detecting retinal fluid. This was particularly true for intraretinal fluid and difficult cases (with lower fluid volumes appearing on fewer B-scans). Artificial intelligence-based detection achieved a higher level of accuracy. This software tool could assist physicians in detecting retinal fluid, which is important for diagnostic, re-treatment, and prognostic tasks.

Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study).

PURPOSE: Assess follow-up treatment and clinical outcomes at 5 years in eyes initially treated with anti-VEGF therapy for center-involved diabetic macular edema (CI-DME) in a 2-year randomized clinical trial. DESIGN: Multicenter cohort study. PARTICIPANTS: Participants with diabetic macular edema (DME) and visual acuity (VA) 20/32 to 20/320 enrolled in DRCR.net Protocol T with visits 5 years after randomization (3 years after Protocol T completion). METHODS: Participants were assigned randomly to aflibercept, bevacizumab, or ranibizumab with protocol-defined follow-up and re-treatment for 2 years. Thereafter, participants were managed at clinician discretion and recalled for a 5-year visit. MAIN OUTCOME MEASURES: Anti-vascular endothelial growth factor (VEGF) treatment, VA letter score, and central subfield thickness (CST). RESULTS: Sixty-eight percent (317/463) of eligible participants completed the 5-year visit. Between years 2 and 5, 68% (217/317) of study eyes received at least 1 anti-VEGF treatment (median, 4; interquartile range [IQR], 0-12). At 5 years, mean VA improved from baseline by 7.4 letters (95% confidence interval [CI], 5.9-9.0) but decreased by 4.7 letters (95% CI, 3.3-6.0) between 2 and 5 years. When baseline VA was 20/50 to 20/320, mean 5-year VA was 11.9 letters (95% CI, 9.3-14.5) better than baseline but 4.8 letters (95% CI, 2.5-7.0) worse than 2 years. When baseline VA was 20/32 to 20/40, mean 5-year VA was 3.2 letters (95% CI, 1.4-5.0) better than baseline but 4.6 letters (95% CI, 3.1-6.1) worse than 2 years. Mean CST decreased from baseline to 5 years by 154 µm (95% CI, 142-166) and was stable between 2 and 5 years (-1 µm; 95% CI, -12 to 9). CONCLUSIONS: Among the two-thirds of eligible Protocol T participants who completed a 5-year visit, mean VA improved from baseline to 5 years without protocol-defined treatment after follow-up ended at 2 years. Although mean retinal thickness was similar at 2 and 5 years, mean VA worsened during this period. Additional investigation into strategies to improve long-term outcomes in eyes with DME seems warranted to determine if VA can be better maintained with different management approaches.

Visual Acuity Outcomes after Anti-Vascular Endothelial Growth Factor Treatment for Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report Number 19.

PURPOSE: To analyze best-corrected visual acuity (BCVA) outcomes after anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD). DESIGN: Prospective cohort study of participants enrolled in a clinical trial of oral supplements and receiving anti-VEGF therapy in routine clinical practice. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants (50-85 years of age) whose eyes met AREDS2 inclusion criteria at baseline (no late AMD, BCVA ≥20/100, no previous anti-VEGF injections) but received at least 1 anti-VEGF injection for incident neovascular AMD during follow-up. METHODS: Participants underwent refracted BCVA testing, ophthalmoscopic examination, and stereoscopic color fundus photography at baseline and annual study visits over 5 years. Self-reports of anti-VEGF injections (numbers, dates, and names of drug) were collected at baseline and annual study visits and during telephone calls every 6 months. MAIN OUTCOME MEASURES: Primary outcome measures were mean refracted BCVA and proportions of eyes with BCVA of 20/40 or better and 20/200 or worse. An exploratory outcome measure was the mean number of self-reported anti-VEGF injections. RESULTS: One thousand one hundred five eyes of 986 AREDS2 participants met the inclusion criteria; of these, 977 participants (99.1%) underwent at least 1 posttreatment visit. At the first and subsequent annual examinations after the first injection, mean refracted BCVAs were 68.0 letters (Snellen equivalent, 20/40), 66.1 letters, 64.7 letters, 63.2 letters, and 61.5 letters (Snellen equivalent, 20/60). Proportions of eyes with BCVA of 20/40 or better were 59.3%, 55.1%, 53.5%, 50.6%, and 49.7%, and those with BCVA of 20/200 or worse were 5.5%, 8.6%, 9.4%, 12.4%, and 14.4%. Mean annual numbers of self-reported anti-VEGF injections per eye were 2.9, 3.9, 3.3, 3.1, and 3.0. CONCLUSIONS: Refracted BCVA data were obtained in a clinical trial environment but were related to anti-VEGF treatment administered in normal clinical practice. Visual outcomes declined slowly with increased follow-up time: mean BCVA decreased by approximately 1.5 to 2 letters per year. At 5 years, half of eyes achieved BCVA of 20/40 or better, but approximately one sixth showed BCVA of 20/200 or worse. These data may be useful in assessing the long-term effects of anti-VEGF therapy.

Advances in the treatment of diabetic retinopathy.

As the diabetes epidemic in the United States continues to worsen, so too does the prevalence of diabetic retinopathy (DR). DR is divided broadly into nonproliferative and proliferative stages, with or without vision-threatening macular edema. Progression to proliferative DR is associated with vision loss that is often irreparable, and a rapid decline in health-related quality of life. Vascular endothelial growth factor (VEGF)-A is upregulated in the diabetic eye, and has been identified as a key driver of DR pathogenesis. With this perspective, we review the published phase III clinical trial data of anti-VEGF therapies approved for the treatment of DR in the United States. Using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale, in which an improvement of ≥2 steps is considered clinically significant, approximately one-third of patients with DR and macular edema experience this level of improvement after 1 year of treatment with either ranibizumab or aflibercept. The rates of clinically significant DR improvement with ranibizumab could be twice that in the subgroup of patients with moderately severe or severe nonproliferative DR and macular edema. These clinical trial data indicate that intraocular inhibition of VEGF is a rational approach for the management of DR.

Fellow Eye Anti-VEGF 'Crunch' Effect in Retinopathy of Prematurity.

BACKGROUND AND OBJECTIVE: Anti-vascular endothelial growth factor (VEGF) therapy is increasing in popularity for treatment of retinopathy of prematurity (ROP). Despite many technical benefits, issues remain prompting further investigation. PATIENTS AND METHODS: Retrospective case report and literature review. RESULTS: A 42-week-old postmenstrual age female with gestational age of 28 weeks and birth weight of 990 g presented with prominent progression of peripapillary purely tractional atypical stage 4A ROP in both eyes following intravitreal bevacizumab therapy in the right eye only. CONCLUSION: The authors present the first reported case, to their knowledge, of a "crunch" phenomenon tractional retinal detachment from fellow eye administration of bevacizumab. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e102-e104.].

Five-Year Outcomes of Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial.

Importance: Ranibizumab is a viable treatment option for eyes with proliferative diabetic retinopathy (PDR) through 2 years. However, longer-term results are needed. Objective: To evaluate efficacy and safety of 0.5-mg intravitreous ranibizumab vs panretinal photocoagulation (PRP) over 5 years for PDR. Design, Setting, and Participants: Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial evaluated 394 study eyes with PDR enrolled February through December 2012. Analysis began in January 2018. Interventions: Eyes were randomly assigned to receive intravitreous ranibizumab (n = 191) or PRP (n = 203). Frequency of ranibizumab was based on a protocol-specified retreatment algorithm. Diabetic macular edema could be managed with ranibizumab in either group. Main Outcomes and Measures: Mean change in visual acuity (intention-to-treat analysis) was the main outcome. Secondary outcomes included peripheral visual field loss, development of vision-impairing diabetic macular edema, and ocular and systemic safety. Results: The 5-year visit was completed by 184 of 277 participants (66% excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years, 135 (44%) were women, and 160 (52%) were white. For the ranibizumab and PRP groups, the mean (SD) number of injections over 5 years was 19.2 (10.9) and 5.4 (7.9), respectively; the mean (SD) change in visual acuity letter score was 3.1 (14.3) and 3.0 (10.5) letters, respectively (adjusted difference, 0.6; 95% CI, -2.3 to 3.5; P = .68); the mean visual acuity was 20/25 (approximate Snellen equivalent) in both groups at 5 years. The mean (SD) change in cumulative visual field total point score was -330 (645) vs -527 (635) dB in the ranibizumab (n = 41) and PRP (n = 38) groups, respectively (adjusted difference, 208 dB; 95% CI, 9-408). Vision-impairing diabetic macular edema developed in 27 and 53 eyes in the ranibizumab and PRP groups, respectively (cumulative probabilities: 22% vs 38%; hazard ratio, 0.4; 95% CI, 0.3-0.7). No statistically significant differences between groups in major systemic adverse event rates were identified. Conclusions and Relevance: Although loss to follow-up was relatively high, visual acuity in most study eyes that completed follow-up was very good at 5 years and was similar in both groups. Severe vision loss or serious PDR complications were uncommon with PRP or ranibizumab; however, the ranibizumab group had lower rates of developing vision-impairing diabetic macular edema and less visual field loss. Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for patients with PDR. These findings support either anti-vascular endothelial growth factor therapy or PRP as viable treatments for patients with PDR. Trial Registration: ClinicalTrials.gov Identifier: NCT01489189.

Treatment of Geographic Atrophy with Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study.

OBJECTIVE/PURPOSE: To evaluate efficacy and safety of monthly intravitreal injections of sirolimus, an immunosuppressive drug, for the treatment of age-related macular degeneration associated geographic atrophy (GA). DESIGN: Randomized, controlled, single-masked multi-center phase 2 clinical trial of intravitreal sirolimus vs. sham therapy in AREDS2 clinical centers. SUBJECTS: Participants with GA. METHODS: Participants eligible in one eye were randomly assigned to a monthly intravitreal injection of sirolimus (20 µL [440 µg]) or sham treatment while participants with two study eyes were assigned to a monthly intravitreal injection in a randomly-selected eye. Best-corrected visual acuities (BVCA), spectral domain optical coherence tomography (OCT), fundus color photography and fundus autofluorescence (FAF) images were obtained at baseline and every 6 months until visit month 24. MAIN OUTCOME MEASURES: Rate of progression of GA (mm2/year) measured on color fundus photograph from baseline to 24 months. Secondary outcome measures include change in BVCA, worsening of vision by ≥3 lines, and changes in area of GA measured on FAF and OCT. RESULTS: 52 participants (mean age 79 years) were enrolled with 27 study eyes assigned to sirolimus from May 2012 to March 2014. The baseline median area of GA was 4.73 DA (12.01 mm2). The mean (standard deviation) growth rates of GA detected on color fundus photographs were 2.27 (2.17) mm2 and 1.91 (2.27) mm2 at month 12, and 4.94 (2.96) mm2 and 5.72 (3.97) mm2 at month 24, for the sirolimus and sham groups, respectively. There was no statistically significant difference in the GA growth rates between the two treatment groups (P=0.33). Median visual acuity changes and incidence of 15-letter loss from baseline were not different between the 2 treatment groups (p=0.19). The intervention was stopped early because of sterile endophthalmitis that occurred in 3 participants in the sirolimus group. Participants were followed for safety until the study was closed in May 2015 due to lack of efficacy. CONCLUSION: Sirolimus did not result in different rates of GA growth in this phase 2 study. Immunosuppression may be important for some stages of the AMD process but may not necessarily be the main pathway for the development of GA.

EFFECTIVENESS OF DIFFERENT MONITORING MODALITIES IN THE DETECTION OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: The Home Study, Report Number 3.

PURPOSE: To determine the effectiveness of different monitoring modalities to detect incident neovascularization associated with age-related macular degeneration (AMD). METHODS: Secondary analyses compared the rates of detecting incident neovascular AMD in prescheduled office visits versus office visits triggered by monitoring device or by symptom realization in a randomized trial evaluating home telemonitoring device plus standard care (device arm) versus standard care alone. RESULTS: At prescheduled office visits, neovascular AMD was detected in 14/1927 visits (0.7%, 95% confidence interval [CI]: 0.4%-1.1%) and 14/1949 visits (0.7%, 95% CI: 0.3%-1.1%) in the device and standard care alone arms, respectively. Thirty-seven participants with neovascular AMD were detected in 318 office visits (11.6%, 95% CI: 8.1%-15.2%) triggered by device or symptom realization and 17 neovascular AMD in 65 office visits (26%, 95% CI: 15.5%-36.8%) triggered by symptom realization in the device and standard care alone arms, respectively. The home device strategy had a higher neovascular-AMD detection rate than prescheduled office visits (relative risk = 16.0 [95% CI: 8.8-29.3]). Neovascular AMD detected at triggered visits were associated with less vision loss from baseline in the device arm versus standard care alone arm (-3 letters vs. -11.5 letters, respectively, P = 0.03). CONCLUSION: Telemonitoring may alter the management of patients with AMD and improve vision outcomes.

Predictors of Diabetic Macular Edema Treatment Frequency with Ranibizumab During the Open-Label Extension of the RIDE and RISE Trials.

PURPOSE: To investigate the role of baseline demographics, disease characteristics, and treatment responses to ranibizumab during RIDE/RISE in predicting long-term treatment frequency with a criteria-based pro re nata (PRN) regimen during the open-label extension (OLE). DESIGN: Pooled, retrospective, post hoc analysis from the phase III, randomized RIDE/RISE studies and subsequent OLE. PARTICIPANTS: Five hundred patients enrolled in the OLE after completion of the 36-month RIDE/RISE studies. METHODS: Summary statistics of RIDE/RISE baseline characteristics and treatment responses were generated by PRN ranibizumab 0.5 mg annualized injection frequency in the OLE (0 and >7 annualized injections). Univariable regression and analysis of variance, and multivariable analysis of covariance were performed on the annualized number of ranibizumab injections administered during the OLE versus baseline characteristics and response to treatment during the RIDE/RISE studies. MAIN OUTCOME MEASURES: Association of patient characteristics and responses to treatment during RIDE/RISE with the observed ranibizumab treatment burden during the OLE. RESULTS: During the OLE, 121 patients required no treatment, 132 required >0 to ≤3 annualized injections, 159 required >3 to ≤7 annualized injections, and 88 required >7 annualized injections. Parameters identified in the multivariable analysis as related to the annualized number of injections included the total number of rescue focal macular lasers received during the core studies (P = 0.0203), central foveal thickness at baseline (P = 0.0002) and month 36 (P < 0.0001), fluorescein leakage area at month 36 (P = 0.0137), and glycated hemoglobin (HbA1c) levels at month 36 (P = 0.0054). Patients receiving 0 versus >7 annualized injections during the OLE had, on average, a shorter duration of diabetes and diabetic macular edema (DME) at baseline, were less likely to have proliferative diabetic retinopathy at baseline, received fewer rescue focal macular laser treatments, and were more likely to experience diabetic retinopathy severity scale improvement of ≥2 steps. CONCLUSIONS: Patients who received less frequent injections during the RIDE/RISE OLE tended to have less advanced disease at baseline and responded better to initial ranibizumab treatment, suggesting that earlier anti-vascular endothelial growth factor treatment of center-involving DME with visual acuity loss may decrease long-term treatment burden.

Association of Baseline Visual Acuity and Retinal Thickness With 1-Year Efficacy of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema.

IMPORTANCE: Comparisons of the relative effect of 3 anti-vascular endothelial growth factor agents to treat diabetic macular edema warrant further assessment. OBJECTIVE: To provide additional outcomes from a randomized trial evaluating 3 anti-vascular endothelial growth factor agents for diabetic macular edema within subgroups based on baseline visual acuity (VA) and central subfield thickness (CST) as evaluated on optical coherence tomography. DESIGN, SETTING, AND PARTICIPANTS: Post hoc exploratory analyses were conducted of randomized trial data on 660 adults with diabetic macular edema and decreased VA (Snellen equivalent, approximately 20/32 to 20/320). The original study was conducted between August 22, 2012, and August 28, 2013. Analysis was conducted from January 7 to June 2, 2015. INTERVENTIONS: Repeated 0.05-mL intravitreous injections of 2.0 mg of aflibercept (224 eyes), 1.25 mg of bevacizumab (218 eyes), or 0.3 mg of ranibizumab (218 eyes) as needed per protocol. MAIN OUTCOMES AND MEASURES: One-year VA and CST outcomes within prespecified subgroups based on both baseline VA and CST thresholds, defined as worse (20/50 or worse) or better (20/32 to 20/40) VA and thicker (≥400 µm) or thinner (250 to 399 µm) CST. RESULTS: In the subgroup with worse baseline VA (n = 305), irrespective of baseline CST, aflibercept showed greater improvement than bevacizumab or ranibizumab for several VA outcomes. In the subgroup with better VA and thinner CST at baseline (61-73 eyes across 3 treatment groups), VA outcomes showed little difference between groups; mean change was +7.2, +8.4, and +7.6 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively. However, in the subgroup with better VA and thicker CST at baseline (31-43 eyes), there was a suggestion of worse VA outcomes in the bevacizumab group; mean change from baseline to 1 year was +9.5, +5.4, and +9.5 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively, and VA letter score was greater than 84 (approximately 20/20) in 21 of 33 (64%), 7 of 31 (23%), and 21 of 43 (49%) eyes, respectively. The adjusted differences and 95% CIs were 39% (17% to 60%) for aflibercept vs bevacizumab, 25% (5% to 46%) for ranibizumab vs bevacizumab, and 13% (-8% to 35%) for aflibercept vs ranibizumab. CONCLUSIONS AND RELEVANCE: These post hoc secondary findings suggest that for eyes with better initial VA and thicker CST, some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups. Given the exploratory nature of these analyses and the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01627249.

Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial.

IMPORTANCE: Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME). OBJECTIVE: To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. INTERVENTIONS: Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME. MAIN OUTCOMES AND MEASURES: The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization. RESULTS: Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified. CONCLUSIONS AND RELEVANCE: Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01489189.

Assessing the Effect of Personalized Diabetes Risk Assessments During Ophthalmologic Visits on Glycemic Control: A Randomized Clinical Trial.

IMPORTANCE: Optimization of glycemic control is critical to reduce the number of diabetes mellitus-related complications, but long-term success is challenging. Although vision loss is among the greatest fears of individuals with diabetes, comprehensive personalized diabetes education and risk assessments are not consistently used in ophthalmologic settings. OBJECTIVE: To determine whether the point-of-care measurement of hemoglobin A(1c) (HbA(1c)) and personalized diabetes risk assessments performed during retinal ophthalmologic visits improve glycemic control as assessed by HbA(1c) level. DESIGN, SETTING, AND PARTICIPANTS: Ophthalmologist office-based randomized, multicenter clinical trial in which investigators from 42 sites were randomly assigned to provide either a study-prescribed augmented diabetes assessment and education or the usual care. Adults with type 1 or 2 diabetes enrolled into 2 cohorts: those with a more-frequent-than-annual follow-up (502 control participants and 488 intervention participants) and those with an annual follow-up (368 control participants and 388 intervention participants). Enrollment was from April 2011 through January 2013. INTERVENTIONS: Point-of-care measurements of HbA1c, blood pressure, and retinopathy severity; an individualized estimate of the risk of retinopathy progression derived from the findings from ophthalmologic visits; structured comparison and review of past and current clinical findings; and structured education with immediate assessment and feedback regarding participant's understanding. These interventions were performed at enrollment and at routine ophthalmic follow-up visits scheduled at least 12 weeks apart. MAIN OUTCOMES AND MEASURES: Mean change in HbA(1c) level from baseline to 1-year follow-up. Secondary outcomes included body mass index, blood pressure, and responses to diabetes self-management practices and attitudes surveys. RESULTS: In the cohort with more-frequent-than-annual follow-ups, the mean (SD) change in HbA(1c) level at 1 year was -0.1% (1.5%) in the control group and -0.3% (1.4%) in the intervention group (adjusted mean difference, -0.09% [95% CI, -0.29% to 0.12%]; P = .35). In the cohort with annual follow-ups, the mean (SD) change in HbA(1c) level was 0.0% (1.1%) in the control group and -0.1% (1.6%) in the intervention group (mean difference, -0.05% [95% CI, -0.27% to 0.18%]; P = .63). Results were similar for all secondary outcomes. CONCLUSIONS AND RELEVANCE: Long-term optimization of glycemic control is not achieved by a majority of individuals with diabetes. The addition of personalized education and risk assessment during retinal ophthalmologic visits did not result in a reduction in HbA(1c) level compared with usual care over 1 year. These data suggest that optimizing glycemic control remains a substantive challenge requiring interventional paradigms other than those examined in our study. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01323348.

Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.

BACKGROUND: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown. METHODS: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year. RESULTS: From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56). CONCLUSIONS: Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).