Person:

Aiello, Lloyd

Purpose: To explore the correlation between optical coherence tomography (OCT) and stereoscopic fundus photographs (FP) for the assessment of retinal thickening (RT) in diabetic macular edema (DME) within a clinical trial. Methods: OCT, FP, and best corrected visual acuity (VA) measurements were obtained in both eyes of 263 participants in a trial comparing two photocoagulation techniques for DME. Correlation coefficients (r) were calculated comparing RT measured by OCT, RT estimated from FP, and VA. Principal variables were central subfield retinal thickness (CSRT) obtained from the OCT fast macular map and DME severity assessed by a reading center using a seven-step photographic scale combining the area of thickened retina within 1 disc diameter of the foveal center and thickening at the center. Results: Medians (quartiles) for retinal thickness within the center subfield by OCT at baseline increased from 236 (214, 264) μm in the lowest level of the photographic scale to 517 (455, 598) μm in the highest level (r = 0.67). However, CSRT interquartile ranges were broad and overlapping between FP scale levels, and there were many outliers. Correlations between either modality and VA were weaker (r = 0.57 for CSRT, and r = 0.47 for the FP scale). OCT appeared to be more reproducible and more sensitive to change in RT between baseline and 1 year than was FP. Conclusions: There was a moderate correlation between OCT and FP assessments of RT in patients with DME and slightly less correlation of either measure with VA. OCT and FP provide complementary information but neither is a reliable surrogate for VA.

Objective: Describe the underlying principles used to develop a web-based algorithm that incorporated intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) in a Diabetic Retinopathy Clinical Research Network (DRCR.net) randomized clinical trial. Design: Discussion of treatment protocol for DME. Participants: Subjects with vision loss from DME involving the center of the macula. Methods: The DRCR.net created an algorithm incorporating anti-VEGF injections in a comparative effectiveness randomized clinical trial evaluating intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser in eyes with vision loss from center-involved DME. Results confirmed that intravitreal ranibizumab with prompt or deferred laser provides superior visual acuity outcomes, compared with prompt laser alone through at least 2 years. Duplication of this algorithm may not be practical for clinical practice. In order to share their opinion on how ophthalmologists might emulate the study protocol, participating DRCR.net investigators developed guidelines based on the algorithm's underlying rationale. Main Outcome Measures: Clinical guidelines based on a DRCR.net protocol. Results: The treatment protocol required real time feedback from a web-based data entry system for intravitreal injections, focal/grid laser, and follow-up intervals. Guidance from this system indicated whether treatment was required or given at investigator discretion and when follow-up should be scheduled. Clinical treatment guidelines, based on the underlying clinical rationale of the DRCR.net protocol, include repeating treatment monthly as long as there is improvement in edema compared with the previous month, or until the retina is no longer thickened. If thickening recurs or worsens after discontinuing treatment, treatment is resumed. Conclusions: Duplication of the approach used in the DRCR.net randomized clinical trial to treat DME involving the center of the macula with intravitreal ranibizumab may not be practical in clinical practice, but likely can be emulated based on an understanding of the underlying rationale for the study protocol. Inherent differences between a web-based treatment algorithm and a clinical approach may lead to differences in outcomes that are impossible to predict. The closer the clinical approach is to the algorithm used in the study, the more likely the outcomes will be similar to those published.

Purpose: Explore differences in green compared with yellow focal/grid laser treatment on functional and anatomic endpoints in eyes with diabetic macular edema. Methods: Data from two randomized clinical trials were evaluated for differences in visual acuity (VA) and optical coherence tomography (OCT) parameters, eyes were assigned to sham injection+prompt laser, ranibizumab+prompt laser, or prompt laser only; among subgroups of eyes treated exclusively and electively with either green or yellow laser. Results: In the sham injection+prompt laser group, the mean VA letter score change for eyes receiving green and yellow laser treatment, respectively, was +2.4±14 and +5.1±13 at the 52-week visit (P = 0.06), and +2.4±15 and +6.0±13 at the 104-week visit (P = 0.13), with no corresponding evidence of differences in OCT thickness. When comparing wavelength groups in the ranibizumab+prompt laser and prompt-laser only groups, meaningful differences in VA and OCT thickness were not detected at 1 or 2 years. Conclusion: A trend towards improved vision outcome with yellow laser observed in one trial was not corroborated by anatomic outcomes or by the other trial. Without random assignment to different wavelengths controlling for bias and confounding, it is not possible to determine whether one wavelength is better than the other.

Objectives: To evaluate the effect of pupillary dilation on electronic-ETDRS visual acuity (EVA) in diabetic subjects and to assess post-dilation EVA as a surrogate for pre-dilation visual acuity (VA). Methods and Design: DRCR.net-protocol refraction and EVA were measured pre- and post-dilation in diabetic subjects by independent, masked examiners. Results: In 129 eyes of 66 subjects, median [25th, 75th percentiles] pre-dilation EVA score was 69 [54, 86] (Snellen-equivalent 20/40-1 [20/80-1, 20/20+1]). Pre-dilation VA was ≥20/20, 20/25-20/40, 20/50-20/80, and <20/80 in 29%, 19%, 26%, and 26% of eyes, respectively. Median EVA change post-dilation was -3 letters [-7, 0]. EVA change was ≥15 letters (≥ 3 ETDRS lines) in 9% of eyes and ≥10 letters (≥ 2 ETDRS lines) in 19% of eyes. Extent of change (range +12 to -25 letters) was associated with baseline VA. No relationship was identified between EVA change and gender, race, lens status, refractive error, DR severity, or primary cause of vision loss. Conclusions: In an optimized clinical trial setting, there is a decline in best-corrected EVA after dilation in diabetic subjects. The large range and magnitude of VA change preclude using post-dilation EVA as a surrogate for undilated VA.

Objective: To report 3-year follow-up 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 and sixty one participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea. Methods: Ranibizumab every four weeks until no longer improving (with resumption if worsening) and random assignment to focal/grid laser treatment promptly or deferred (≥24 weeks). 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 greater (9.7 versus 6.8, mean difference = 2.9, 95% confidence interval 0.4 to 5.4, 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 was 42% and 56% (P = 0.02), while the percentage of eyes with a ≥10 letter 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, respectively, from the 2- up to the 3-year visit. At the 3-year visit, the percentages of eyes with central subfield thickness ≥250 μm 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 appeared similar in the two 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 in eyes with DME involving the fovea and with vision impairment. Some of the observed difference in visual acuity at three years may be related to fewer cumulative ranibizumab injections during follow-up in the prompt laser treatment group. Follow-up through five years continues.

OBJECTIVE: Evaluate 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 (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea. METHODS: Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (> or =24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system. MAIN OUTCOME MEASURES: Best-corrected visual acuity and safety at 1 year. RESULTS: The 1-year mean change (+/-standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9+/-11, P<0.001) and ranibizumab + deferred laser group (+9+/-12, P<0.001) but not in the triamcinolone + prompt laser group (+4+/-13, P=0.31) compared with the sham + prompt laser group (+3+/-13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes. CONCLUSIONS: Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.

Purpose: To compare visual acuity (VA) scores obtained after autorefraction or using a pinhole occluder to scores obtained after refraction according to a standard clinical research protocol. Design: Prospective, comparative case series Participants: One hundred and ten study participants (209 eyes) with diabetes mellitus and a broad range of diabetic retinopathy severity and visual acuity (VA). Methods: VA was measured after autorefraction by a Topcon KR-8000 autorefractor as well as after a Diabetic Retinopathy Clinical Research Network (DRCR.net) protocol manual refraction. The order of testing was randomized and examiners were masked to the source of each refraction. A second VA measurement, utilizing an identical DRCR.net manual refraction, was made in a subset of eyes (N = 144, 69%) in order to establish test-retest variability for comparison purposes. All eyes underwent VA testing using a pinhole occluder. Main Outcome Measures: Best corrected VA as measured by the Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Test© (E-ETDRS). Results: In all eyes, the median E-ETDRS VA letter score (EVA) obtained after manual refraction (MR-EVA) was 69 (Snellen equivalent 20/40), ranging from 4 to 93 (20/800 to 20/16). The median MR-EVA was slightly better than the median EVA obtained after autorefraction (AR-EVA), with a median difference (AR-EVA – MR-EVA) of −1 letter (25th, 75th percentiles: −4, 2 letters). The absolute difference between AR-EVA and MR-EVA was similar to the test-retest variability of MR-EVA alone. In contrast, MR-EVA was better than EVA obtained using a pinhole occluder (PH-EVA), (median PH-EVA – MR-EVA: −4 letters [−9, 0]), and had significantly less test-retest variability (P<0.001). Generally, the spherical equivalent of autorefraction was slightly more hyperopic (or less myopic) than the spherical equivalent of manual refraction (median difference: +0.25 Diopters [0, +0.63 Diopters]). Conclusions: Given the substantial time and effort required for training and certification of study protocol refractionists, and the similarity between AR-EVA and MR-EVA, further evaluation of autorefraction, but not pinhole occluder testing, as an alternative to the current clinical research gold standard of ETDRS protocol manual refraction in study participants with diabetic retinopathy is warranted.

Purpose: To identify factors associated with the visual acuity outcome following focal/grid photocoagulation for diabetic macular edema (DME) among eyes randomized to the focal/grid photocoagulation treatment group within the Diabetic Retinopathy Clinical Research Network (DRCR.net) trial comparing triamcinolone with focal/grid laser. Design: Multicenter, randomized clinical trial. Participants: Three hundred thirty eyes with DME assigned to the focal/grid photocoagulation group, visual acuity 20/40 to 20/320 and optical coherence tomography (OCT) central subfield thickness ≥250 microns. Methods: Eyes were treated with a protocol-defined photocoagulation technique, which was repeated at 4-month intervals for persistent or recurrent edema. Separate logistic regression models were used to evaluate the associations of demographic, clinical, OCT, and fundus photographic variables with visual acuity improvement or worsening of 10 or more letters from baseline to 2 years. The association of the initial visual acuity outcome after treatment with the subsequent visual acuity course also was evaluated. Main Outcome Measures: Visual acuity measured with the electronic Early Treatment Diabetic Retinopathy Study method. Results: Worse baseline visual acuity was the only factor found to be associated with more frequent visual acuity improvement (P<0.001), and both greater baseline OCT-measured retinal volume (P=0.001) and better baseline visual acuity (P=0.009) were found to be associated with more frequent visual acuity worsening. Visual acuity outcomes were similar in eyes with and without prior macular or panretinal photocoagulation. The initial visual acuity outcome at 4 months was not generally predictive of the subsequent course. Many eyes that worsened 10 or more letters from baseline to 4 months subsequently improved, and many eyes that initially improved, subsequently worsened. Conclusions: At this time, focal/grid photocoagulation remains the standard management for DME and these results do not alter this paradigm.

Importance: Optimization of glycemic control is critical to reduce diabetes 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 employed in ophthalmology settings. Objective: To determine whether point-of-care measurement of HbA1c and personalized diabetes complication risk assessments performed during retinal ophthalmology visits improve glycemic control as assessed by HA1c. Design/Setting: Ophthalmologist office based clinical trial where investigators from 42 sites were randomly assigned to provide either study-prescribed augmented diabetes assessment and education, or usual care. Participants: Adults with type 1 or 2 diabetes enrolled into two cohorts: “more frequent” than annual follow-up (502 control and 488 intervention participants) and “annual” follow-up (368 and 388 participants). Intervention(s): Point-of-care measurement of HbA1c, blood pressure, and retinopathy severity; individualized estimate of retinopathy progression risk derived from the visit findings; structured comparison and review of past and current clinical findings; and structured education with immediate assessment and feedback regarding participant understanding. Intervention was performed at enrollment and routine ophthalmic follow-up visits scheduled at least 12 weeks apart. Main Outcome Measure(s): Mean change in HbA1c from baseline to 1 year. Secondary outcomes included body mass index, blood pressure, and diabetes self-management practices and attitudes surveys. Results: In the “more frequent” cohort, mean (SD) change in HbA1c 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% confidence interval −0.29% to +0.12%, P=0.35). In the “annual” cohort, mean (SD) change in HBA1c was 0.0% (1.1%) and −0.1% (1.6%), respectively (mean difference −0.05%, 95% confidence interval −0.27% to +0.18% P=0.63). 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. Addition of personalized education and risk assessment during retinal ophthalmology visits, as provided in this study, did not result in HbA1c improvement 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 this study.