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.

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.

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.).

The Risk of Acute Infection Following Intra-articular Corticosteroid Injection Into a Pre-existing Total Knee Arthroplasty.

BACKGROUND: No previous studies have investigated the risk of infection following intra-articular corticosteroid injection (IACI) into a pre-existing total knee arthroplasty (TKA). The aim of this study is to determine the risk of acute infection following IACI into a pre-existing TKA. METHODS: A retrospective chart review identified all patients at a single institution between October 2009 and May 2015 that had an ipsilateral knee injection subsequent to a TKA. The risk of acute infection, as defined by development of an infection within 3 months of IACI, was determined via review of clinic notes, operative reports, laboratory records, and telephone interviews. RESULTS: A total of 1845 injections in 736 patients met the inclusion criteria. In total, 101 (4.8%) patients were lost to follow-up. Three infections in 3 patients occurred within 3 months of IACI, yielding an infection rate of 0.16% per injection, or 1 infection in every 625 IACIs following TKA. CONCLUSION: This study is the first to investigate the risk of acute infection following injection of corticosteroid into a pre-existing TKA. Given the dire consequences of infection following TKA, the routine use of IACI into a pre-existing TKA should be avoided, and a thorough workup should be performed in any patient with a painful TKA prior to consideration of IACI.

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.

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.

Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results.

OBJECTIVE: To report 5-year results from a previously reported trial evaluating intravitreal 0.5 mg ranibizumab with prompt versus deferred (for ≥24 weeks) focal/grid laser treatment for diabetic macular edema (DME). DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: Among participants from the trial with 3 years of follow-up who subsequently consented to a 2-year extension and survived through 5 years, 124 (97%) and 111 (92%) completed the 5-year visit in the prompt and deferred groups, respectively. METHODS: Random assignment to ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and prompt or deferred (≥24 weeks) focal/grid laser treatment. MAIN OUTCOME MEASURES: Best-corrected visual acuity at the 5-year visit. RESULTS: The mean change in visual acuity letter score from baseline to the 5-year visit was +7.2 letters in the prompt laser group compared with +9.8 letters in the deferred laser group (mean difference, -2.6 letters; 95% confidence interval, -5.5 to +0.4 letters; P = 0.09). At the 5-year visit in the prompt versus deferred laser groups, there was vision loss of ≥10 letters in 9% versus 8%, an improvement of ≥10 letters in 46% versus 58%, and an improvement of ≥15 letters in 27% versus 38% of participants, respectively. From baseline to 5 years, 56% of participants in the deferred group did not receive laser. The median number of injections was 13 versus 17 in the prompt and deferral groups, including 54% and 45% receiving no injections during year 4 and 62% and 52% receiving no injections during year 5, respectively. CONCLUSIONS: Five-year results suggest focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better than deferring laser treatment for ≥24 weeks in eyes with DME involving the central macula with vision impairment. Although more than half of eyes in which laser treatment is deferred may avoid laser for at least 5 years, such eyes may require more injections to achieve these results when following this protocol. Most eyes treated with ranibizumab and either prompt or deferred laser maintain vision gains obtained by the first year through 5 years with little additional treatment after 3 years.

Topical nepafenec in eyes with noncentral diabetic macular edema.

PURPOSE: To evaluate the effect of a topical, nonsteroidal antiinflammatory drug, nepafenac 0.1%, in eyes with noncentral diabetic macular edema. METHODS: Multicenter, double-masked randomized trial. Individuals with good visual acuity and noncentral-involved diabetic macular edema were randomly assigned to nepafenac 0.1% (N = 61) or placebo (nepafenac vehicle, N = 64) 3 times a day for 12 months. The primary outcome was mean change in optical coherence tomography retinal volume at 12 months. RESULTS: Mean baseline retinal volume was 7.8 mm. At 12 months, in the nepafenac and placebo groups respectively, mean change in retinal volume was -0.03 mm and -0.02 mm (treatment group difference: -0.02, 95% confidence interval: -0.27 to 0.23, P = 0.89). Central-involved diabetic macular edema was present in 7 eyes (11%) and 9 eyes (14%) at the 12-month visit (P = 0.79), respectively. No differences in visual acuity outcomes were identified. One study participant developed a corneal melt after using nepafenac in the nonstudy eye, which had a history of severe dry eye. No additional safety concerns were evident. CONCLUSION: In eyes with noncentral diabetic macular edema and good visual acuity, topical nepafenac 0.1% 3 times daily for 1 year likely does not have a meaningful effect on optical coherence tomography-measured retinal thickness.

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.

Randomized trial of a home monitoring system for early detection of choroidal neovascularization home monitoring of the Eye (HOME) study.

OBJECTIVE: To determine whether home monitoring with the ForeseeHome device (Notal Vision Ltd, Tel Aviv, Israel), using macular visual field testing with hyperacuity techniques and telemonitoring, results in earlier detection of age-related macular degeneration-associated choroidal neovascularization (CNV), reflected in better visual acuity, when compared with standard care. The main predictor of treatment outcome from anti-vascular endothelial growth factor (VEGF) agents is the visual acuity at the time of CNV treatment. DESIGN: Unmasked, controlled, randomized clinical trial. PARTICIPANTS: One thousand nine hundred and seventy participants 53 to 90 years of age at high risk of CNV developing were screened. Of these, 1520 participants with a mean age of 72.5 years were enrolled in the Home Monitoring of the Eye study at 44 Age-Related Eye Disease Study 2 clinical centers. INTERVENTIONS: In the standard care and device arms arm, investigator-specific instructions were provided for self-monitoring vision at home followed by report of new symptoms to the clinic. In the device arm, the device was provided with recommendations for daily testing. The device monitoring center received test results and reported changes to the clinical centers, which contacted participants for examination. MAIN OUTCOME MEASURES: The main outcome measure was the difference in best-corrected visual acuity scores between baseline and detection of CNV. The event was determined by investigators based on clinical examination, color fundus photography, fluorescein angiography, and optical coherence tomography findings. Masked graders at a central reading center evaluated the images using standardized protocols. RESULTS: Seven hundred sixty-three participants were randomized to device monitoring and 757 participants were randomized to standard care and were followed up for a mean of 1.4 years between July 2010 and April 2013. At the prespecified interim analysis, 82 participants progressed to CNV, 51 in the device arm and 31 in the standard care arm. The primary analysis achieved statistical significance, with the participants in the device arm demonstrating a smaller decline in visual acuity with fewer letters lost from baseline to CNV detection (median, -4 letters; interquartile range [IQR], -11.0 to -1.0 letters) compared with standard care (median, -9 letters; IQR, -14.0 to -4.0 letters; P = 0.021), resulting in better visual acuity at CNV detection in the device arm. The Data and Safety Monitoring Committee recommended early study termination for efficacy. CONCLUSIONS: Persons at high risk for CNV developing benefit from the home monitoring strategy for earlier detection of CNV development, which increases the likelihood of better visual acuity results after intravitreal anti-VEGF therapy.

Dexamethasone implant anterior chamber migration: risk factors, complications, and management strategies.

OBJECTIVE: To describe the risk factors, clinical course, and complications of migration of a dexamethasone (DEX) intravitreal implant (OZURDEX; Allergan, Inc., Irvine, CA) into the anterior chamber and subsequent management strategies. DESIGN: Retrospective, observational case series. PARTICIPANTS: Fifteen patients had 18 episodes of migration of the DEX implant into the anterior chamber. METHODS: The medical records of 15 patients with spontaneous migration of a DEX implant were retrospectively reviewed. MAIN OUTCOME MEASURES: Migration of the DEX implant into the anterior chamber. RESULTS: Migration of a DEX intravitreal implant into the anterior chamber occurred in 6 patients who were aphakic, 4 patients with an anterior chamber intraocular lens, 2 patients with a scleral-fixated posterior chamber intraocular lens (PCIOL), 2 patients with a PCIOL, and 1 patient with an iris-fixated PCIOL. All 15 patients had prior pars plana vitrectomy, and 14 patients (93%) had no lens capsule. The average interval from DEX implant injection to detection of the implant migration into the anterior chamber was 13 days (range, 5-44 days). In 14 patients, corneal edema developed. Among those eyes undergoing surgical removal of the implant, earlier intervention reduced the likelihood of permanent corneal edema (0.5 days [from diagnosis of migration to surgical removal of the implant] vs. 5.5 days; P = 0.04). Aspiration was necessary to remove the implant in 6 patients. Among the 14 patients with corneal edema, the corneal edema did not resolve in 10 patients (71%), 6 (43%) of whom required corneal transplantation. CONCLUSIONS: Absence of lens capsule and prior vitrectomy are risk factors for migration of the DEX implant into the anterior chamber. Early removal of the implant may be necessary to minimize the risk of chronic corneal edema.

Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results.

OBJECTIVE: To report the 3-year follow-up results within a previously reported randomized trial evaluating prompt versus deferred (for ≥24 weeks) focal/grid laser treatment in eyes treated with intravitreal 0.5 mg ranibizumab for diabetic macular edema (DME). DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: Three hundred sixty-one participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea. METHODS: Ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and random assignment to prompt or deferred (≥24 weeks) focal/grid laser treatment. MAIN OUTCOME MEASURES: Best-corrected visual acuity and safety at the 156-week (3-year) visit. RESULTS: The estimated mean change in visual acuity letter score from baseline through the 3-year visit was 2.9 letters more (9.7 vs. 6.8 letters; mean difference, 2.9 letters; 95% confidence interval, 0.4-5.4 letters; P = 0.02) in the deferral group compared with the prompt laser treatment group. In the prompt laser treatment group and deferral group, respectively, the percentage of eyes with a ≥10-letter gain/loss was 42% and 56% (P = 0.02), whereas the respective percentage of eyes with a ≥10-letter gain/loss was 10% and 5% (P = 0.12). Up to the 3-year visit, the median numbers of injections were 12 and 15 in the prompt and deferral groups, respectively (P = 0.007), including 1 and 2 injections, respectively, from the 2-year up to the 3-year visit. At the 3-year visit, the percentages of eyes with central subfield thickness of 250 µm or more on time-domain optical coherence tomography were 36% in both groups (P = 0.90). In the deferral group, 54% did not receive laser treatment during the trial. Systemic adverse events seemed to be similar in the 2 groups. CONCLUSIONS: These 3-year results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea and with vision impairment. Some of the observed differences in visual acuity at 3 years may be related to fewer cumulative ranibizumab injections during follow-up in the prompt laser treatment group. Follow-up through 5 years continues.

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.

Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration in Vulnerable Fellow Eyes: A Randomized Clinical Trial.

PURPOSE: To determine whether prophylactic ranibizumab prevents the development of neovascular age-related macular degeneration (nAMD) in eyes with intermediate age-related macular degeneration (AMD) for patients with preexisting nAMD in their contralateral eye. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Adults aged 50 years and older with intermediate AMD (multiple intermediate drusen [≥63 µm and <125 µm] or ≥1 large drusen [≥125 µm] and pigmentary changes) in the study eye and nAMD in the contralateral eye. INTERVENTION: Intravitreal ranibizumab injection (0.5 mg) or sham injection every 3 months for 24 months. MAIN OUTCOME MEASURES: Conversion to nAMD over 24 months (primary). Change in best-corrected visual acuity from baseline to 24 months (secondary). RESULTS: Among 108 enrolled participants (54 [50%] in each group), all except 2 were non-Hispanic Whites, 61 participants (56%) were female, and the mean age was 78 years. The mean baseline visual acuity was 77.7 letters (Snellen equivalent 20/32). Conversion to nAMD over 24 months occurred among 7 of 54 eyes (13%) in both groups (ranibizumab vs. sham hazard ratio = 0.91 [95% confidence interval (CI), 0.32-2.59]; P = 0.86). At 24 months, the cumulative incidence of nAMD adjusted for loss to follow-up was 14% (95% CI, 4%-23%) in the ranibizumab group and 15% (95% CI, 4%-25%) in the sham group. At 24 months, the mean change in visual acuity from baseline was -2.1 letters (standard deviation, 5.4 letters) with ranibizumab and -1.4 letters (standard deviation, 7.7 letters) with sham (adjusted difference = -0.8 letters [95% CI, -3.7 to 2.2 letters]; P = 0.62). The proportion of eyes that lost at least 10 letters of visual acuity from baseline at 24 months was 2 of 39 (5%) with ranibizumab and 4 of 40 (10%) with sham. There were no serious ocular adverse events in either group. CONCLUSIONS: Quarterly dosing of 0.5 mg ranibizumab in eyes with intermediate AMD did not reduce the incidence of nAMD compared with sham injections; however, the study was likely underpowered given the 95% CI, and a clinically meaningful effect cannot be excluded. There also was no effect on visual acuity at 24 months. Other strategies to reduce neovascular conversion in these vulnerable eyes are needed.

Association of Predominantly Peripheral Lesions on Ultra-Widefield Imaging and the Risk of Diabetic Retinopathy Worsening Over Time.

Importance: Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions compared with standard imaging. Whether detection of predominantly peripheral lesions (PPLs) better predicts rates of disease worsening over time is unknown. Objective: To determine whether PPLs identified on UWF imaging are associated with increased disease worsening beyond the risk associated with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites with 388 participants enrolled between February and December 2015. At baseline and annually through 4 years, 200° UWF-color images were obtained and graded for DRSS at a reading center. Baseline UWF-color and UWF-fluorescein angiography (FA) images were evaluated for the presence of PPL. Data were analyzed from May 2020 to June 2022. Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Predominantly peripheral lesions were defined as DR lesions with a greater extent outside vs inside the 7 standard ETDRS fields. Primary outcome was disease worsening defined as worsening 2 steps or more on the DRSS or receipt of DR treatment. Analyses were adjusted for baseline DRSS score and correlation between 2 study eyes of the same participant. Results: Data for 544 study eyes with nonproliferative DR (NPDR) were analyzed (182 [50%] female participants; median age, 62 years; 68% White). The 4-year disease worsening rates were 45% for eyes with baseline mild NPDR, 40% for moderate NPDR, 26% for moderately severe NPDR, and 43% for severe NPDR. Disease worsening was not associated with color PPL at baseline (present vs absent: 38% vs 43%; HR, 0.78; 95% CI, 0.57-1.08; P = .13) but was associated with FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36; P < .001). Conclusions and Relevance: Although no association was identified with color PPL, presence of FA PPL was associated with greater risk of disease worsening over 4 years, independent of baseline DRSS score. These results suggest that use of UWF-FA to evaluate retinas peripheral to standard ETDRS fields may improve the ability to predict disease worsening in NPDR eyes. These findings support use of UWF-FA for future DR staging systems and clinical care to more accurately determine prognosis in NPDR eyes.

Association of Ultra-Widefield Fluorescein Angiography-Identified Retinal Nonperfusion and the Risk of Diabetic Retinopathy Worsening Over Time.

Importance: Presence of predominantly peripheral diabetic retinopathy (DR) lesions on ultra-widefield fluorescein angiography (UWF-FA) was associated with greater risk of DR worsening or treatment over 4 years. Whether baseline retinal nonperfusion assessment is additionally predictive of DR disease worsening is unclear. Objective: To assess whether the extent and location of retinal nonperfusion identified on UWF-FA are associated with worsening in Diabetic Retinopathy Severity Scale (DRSS) score or DR treatment over time. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study with data for 508 eyes with nonproliferative DR and gradable nonperfusion on UWF-FA at baseline. All images were graded at a centralized reading center; 200° ultra-widefield (UWF) color images were graded for DR at baseline and annually for 4 years. Baseline 200° UWF-FA images were graded for nonperfused area, nonperfusion index (NPI), and presence of predominantly peripheral lesions on UWF-FA (FA PPL). Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Association of baseline UWF-FA nonperfusion extent with disease worsening, defined as either 2 or more steps of DRSS worsening within Early Treatment Diabetic Retinopathy Study fields on UWF-color images or receipt of DR treatment. Results: After adjusting for baseline DRSS, the risk of disease worsening over 4 years was higher in eyes with greater overall NPI (hazard ratio [HR] for 0.1-unit increase, 1.11; 95% CI, 1.02-1.21; P = .02) and NPI within the posterior pole (HR for 0.1-unit increase, 1.35; 95% CI, 1.17-1.56; P < .001) and midperiphery (HR for 0.1-unit increase, 1.08; 95% CI, 1.00-1.16; P = .04). In a multivariable analysis adjusting for baseline DRSS score and baseline systemic risk factors, greater NPI (HR, 1.11; 95% CI, 1.02-1.22; P = .02) and presence of FA PPL (HR, 1.89; 95% CI, 1.35-2.65; P < .001) remained associated with disease worsening. Conclusions and Relevance: This 4-year longitudinal study has demonstrated that both greater baseline retinal nonperfusion and FA PPL on UWF-FA are associated with higher risk of disease worsening, even after adjusting for baseline DRSS score and known systemic risk. These associations between disease worsening and retinal nonperfusion and FA PPL support the increased use of UWF-FA to complement color fundus photography in future efforts for DR prognosis, clinical care, and research.

Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.

OBJECTIVE: To report expanded 2-year follow-up of a previously reported randomized trial evaluating intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME). DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: A total of 854 study eyes of 691 participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea. METHODS: Continuation of procedures previously reported for the randomized trial. MAIN OUTCOME MEASURES: Best-corrected visual acuity and safety at the 2-year visit. RESULTS: At the 2-year visit, compared with the sham + prompt laser group, the mean change in the visual acuity letter score from baseline was 3.7 letters greater in the ranibizumab + prompt laser group (95% confidence interval adjusted for multiple comparisons [aCI], -0.4 to +7.7), 5.8 letters greater in the ranibizumab + deferred laser group (95% aCI, +1.9 to +9.8), and 1.5 letters worse in the triamcinolone + prompt laser group (95% aCI, -5.5 to +2.4). After the 1- to 2-year visit in the ranibizumab + prompt or deferred laser groups, the median numbers of injections were 2 and 3 (potential maximum of 13), respectively. At the 2-year visit, the percentages of eyes with central subfield thickness ≥250 µm were 59% in the sham + prompt laser group, 43% in the ranibizumab + prompt laser group, 42% in the ranibizumab + deferred laser group, and 52% in the triamcinolone + prompt laser group. No systemic events attributable to study treatment were apparent. Three eyes in 3 (0.8%) of 375 participants had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. CONCLUSIONS: The expanded 2-year results reported are similar to results published previously and reinforce the conclusions originally reported: Ranibizumab should be considered for patients with DME and characteristics similar to those of the cohort in this clinical trial, including vision impairment with DME involving the center of the macula.

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.