Evaluate association of retinal nonperfusion (NP) on ultrawide field (UWF) fluorescein angiography (FA) with diabetic retinopathy (DR) severity and predominantly peripheral lesions (PPL).
Multicenter ...observational study, 652 eyes (361 participants) having nonproliferative DR (NPDR) without center-involved diabetic macular edema in at least one eye. Baseline 200° UWF-color and UWF-FA images were graded by a central reading center for color-PPL and FA-PPL, respectively. UWF-FA was graded for NP index within concentric zones: posterior pole (<10 mm from fovea), midperiphery (10-15 mm), and far periphery (>15 mm).
Baseline Early Treatment Diabetic Retinopathy Study DR severity was 31.7% no DR/mild NPDR, 24.1% moderate NPDR, 14.0% moderately severe NPDR, 25.6% severe/very severe NPDR, and 4.6% proliferative DR. Worse DR severity was associated with increased NP index overall (P = 0.002), in the posterior pole (P < 0.001), midperiphery (P < 0.001), and far periphery (P = 0.03). On average, 29.6% of imaged retinal NP was in the posterior pole, 33.7% in midperiphery, and 36.7% in far periphery. Increased NP index was associated with FA-PPL (P < 0.001) but not with color-PPL (P = 0.65).
Approximately, 70% of NP in diabetic eyes is located outside the posterior pole. Increased NP is associated with the presence of FA-PPL, suggesting UWF-FA may better predict future DR worsening than UWF-color alone.
To identify baseline factors associated with change in visual acuity or development of vision-impairing central-involved diabetic macular edema (DME) over 2 years when treating proliferative diabetic ...retinopathy (PDR) with ranibizumab or panretinal photocoagulation (PRP).
Post hoc analyses of randomized, multicenter clinical trial data.
Eyes completing the 2-year visit (n = 328) or without vision-impairing central-involved DME at baseline (n = 302) in Diabetic Retinopathy Clinical Research Network Protocol S.
Intravitreous ranibizumab (0.5 mg/0.05 ml) or PRP.
Change in visual acuity (area under the curve) and development of vision-impairing (20/32 or worse) central-involved DME over 2 years.
After multivariable model selection with adjustment for baseline visual acuity and central subfield thickness, no factors were identified as associated with change in visual acuity or development of vision-impairing central-involved DME within the ranibizumab group. In the PRP group, worse change in visual acuity was more likely with higher hemoglobin A
level (-0.6 letters per 1% increase; 95% confidence interval CI, -1.2 to -0.1 letters; continuous P = 0.03), more severe diabetic retinopathy (difference between high-risk PDR or worse vs. moderate PDR or better, -2.8 letters 95% CI, -5.5 to -0.2 letters; continuous P = 0.003), and higher mean arterial pressure (difference between ≥100 mmHg vs. <100 mmHg, -2.0 letters 95% CI, -4.6 to 0.5 letters; continuous P = 0.009). Development of vision-impairing central-involved DME was more likely with higher hemoglobin A
level (hazard ratio HR per 1% increase, 1.31 95% CI, 1.13-1.52; continuous P < 0.001), more severe diabetic retinopathy (HR for high-risk PDR or worse vs. moderate PDR or better, 1.46 95% CI, 0.73-2.92; continuous P = 0.03), and the presence of cystoid abnormalities within 500 μm of the macula center (HR, 2.90 95% CI, 1.35-6.24; P = 0.006).
For eyes managed with PRP, higher hemoglobin A
level and more severe diabetic retinopathy were associated with less vision improvement and an increased risk of vision-impairing central-involved DME developing. When managing PDR with ranibizumab, eyes gained vision, on average, with no baseline characteristics identified as associated with visual acuity or central-involved DME outcomes.
IMPORTANCE: Among eyes with center-involved diabetic macular edema (CI-DME) and good visual acuity (VA), randomized clinical trial results showed no difference in VA loss between initial observation ...plus aflibercept only if VA decreased, initial focal/grid laser plus aflibercept only if VA decreased, or prompt aflibercept. Understanding the initial observation approach is relevant to patient management. OBJECTIVE: To assess the DRCR Retina Network protocol-defined approach and outcomes of initial observation with aflibercept only if VA worsened. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc secondary analyses of a randomized clinical trial of the DRCR Retina Network Protocol V that included 91 US and Canadian sites from November 2013 to September 2018. Participants were adults (n = 236) with type 1 or 2 diabetes, 1 study eye with CI-DME, and VA letter score at least 79 (Snellen equivalent, 20/25 or better) assigned to initial observation. Data were analyzed from March 2019 to November 2019. INTERVENTIONS: Initial observation and follow-up with aflibercept only for VA loss of at least 10 letters from baseline at 1 visit or 5 to 9 letters at 2 consecutive visits. Follow-up occurred at 8 weeks and then every 16 weeks unless VA or optical coherence tomography central subfield thickness worsened. MAIN OUTCOMES AND MEASURES: Whether individuals received aflibercept. RESULTS: Among 236 eyes in 236 individuals (149 63% male; median age, 60 years interquartile range, 53-67 years) randomly assigned to initial observation, 80 (34%) were treated with aflibercept during 2 years of follow-up. At 2 years, the median VA letter score was 86.0 (interquartile range, 89.0-81.0; median Snellen equivalent, 20/20 20/16-20/25). Receipt of aflibercept was more likely in eyes with baseline central subfield thickness at least 300 μm (Zeiss-Stratus equivalent) vs less than 300 μm (45% vs 26%; hazard ratio HR, 1.98 95% CI, 1.26-3.13, continuous P = .005), moderately severe nonproliferative diabetic retinopathy (Early Treatment Diabetic Retinopathy Study retinopathy severity level 47) and above vs moderate nonproliferative diabetic retinopathy (retinopathy severity level 43) and below (51% vs 27%; HR, 2.22 95% CI, 1.42-3.47, ordinal P < .001), and among participants whose nonstudy eye received DME treatment within 4 months of randomization vs not (52% vs 25%; HR, 2.55 95% CI, 1.64-3.99, P < .001). CONCLUSIONS AND RELEVANCE: Most eyes managed with initial observation plus aflibercept only if VA worsened maintained good vision at 2 years and did not require aflibercept for VA loss. However, the eyes in the trial were approximately twice as likely to receive aflibercept for VA loss if they had greater baseline central subfield thickness, worse diabetic retinopathy severity level, or a nonstudy eye receiving treatment for DME. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01909791
IMPORTANCE: When a patient with neovascular age-related macular degeneration or diabetic macular edema does not respond to an initial anti–vascular endothelial growth factor agent, usually after ...several injections, ophthalmologists may switch to another anti–vascular endothelial growth factor agent. Authors of case series have suggested beneficial effects from switching. However, to our knowledge, there are no studies with an appropriate control group to evaluate how such patients would do without switching agents. OBJECTIVE: To assess outcomes in patients who have a poor initial response but continue treatment without switching agents. DESIGN, SETTING, AND PARTICIPANTS: We obtained data from 2 multicenter clinical trials, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Diabetic Retinopathy Clinical Research Network (DRCR.net). Based on typical clinical reasons for switching agents, we developed “switching rules” at both 3 and 6 months after initiation of treatment. Using these switching rules, we identified a 3-month and a 6-month cohort of “treatment failures” from both CATT and DRCR.net studies. INTERVENTIONS: Although the cohorts from each study met criteria for switching, they were treated with the initial agent throughout the study (bevacizumab or ranibizumab in CATT and ranibizumab in DRCR.net). MAIN OUTCOMES AND MEASURES: Primary outcomes were change in visual acuity and change in central retinal thickness on optical coherence tomography from the 3- or 6-month visit at which switching rules were met. RESULTS: The 126 patients from CATT and the 59 patients from DRCR.net who were selected for the switching analysis were similar in age, sex and race/ethnicity to the overall study populations. Among the participants who met the criteria for switching, the CATT participants were a mean (SD) of 79.7 (7.8) years of age, 65.9% women, and 97.6% white, while the DRCR.net participants were a mean (SD) of 65.5 (9.3) years of age, 44.1% women, and 76.3% white In all 4 cohorts, there was a 3- to 5-letter improvement in mean visual acuity over the 3 months after the switching rules were met, although all patients continued on their originally assigned treatment. Mean central retinal thickness also improved by 40 to 70 μM. CONCLUSIONS AND RELEVANCE: These results demonstrate the importance of having a comparison group to evaluate the effect of switching anti–vascular endothelial growth factor agents for treatment of neovascular age-related macular degeneration or diabetic macular edema. Without a comparison group, it is impossible to know whether any improvement observed after switching was related to the new treatment or was related to regression to the mean and time effects as observed in the 4 cohorts presented here. Randomization to switching or not switching drugs would provide a basis for valid conclusions about the effects of switching.
IMPORTANCE: Post hoc analyses from the Diabetic Retinopathy Clinical Research Network randomized clinical trial comparing aflibercept, bevacizumab, and ranibizumab for diabetic macular edema (DME) ...might influence interpretation of study results. OBJECTIVE: To provide additional outcomes comparing 3 anti–vascular endothelial growth factor (VEGF) agents for DME. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analyses performed from May 3, 2016, to June 21, 2016, of a randomized clinical trial performed from August 22, 2012, to September 23, 2015, of 660 participants comparing 3 anti-VEGF treatments in eyes with center-involved DME causing vision impairment. EXPOSURES: Randomization to intravitreous aflibercept (2.0 mg), bevacizumab (1.25 mg), or ranibizumab (0.3 mg) administered up to monthly based on a structured retreatment regimen. Focal/grid laser treatment was added after 6 months for the treatment of persistent DME. MAIN OUTCOMES AND MEASURES: Change in visual acuity (VA) area under the curve and change in central subfield thickness (CST) within subgroups based on whether an eye received laser treatment for DME during the study. RESULTS: Post hoc analyses were performed for 660 participants (mean SD age, 61 10 years; 47% female, 65% white, 16% black or African American, 16% Hispanic, and 3% other). For eyes with an initial VA of 20/50 or worse, VA improvement was greater with aflibercept than the other agents at 1 year but superior only to bevacizumab at 2 years. Mean (SD) letter change in VA over 2 years (area under curve) was greater with aflibercept (+17.1 9.7) than with bevacizumab (+12.1 9.4; 95% CI, +1.6 to +7.3; P < .001) or ranibizumab (+13.6 8.5; 95% CI, +0.7 to +6.0; P = .009). When VA was 20/50 or worse at baseline, bevacizumab reduced CST less than the other agents at 1 year, but at 2 years the differences had diminished. In subgroups stratified by baseline VA, anti-VEGF agent, and whether focal/grid laser treatment was performed for DME, the only participants to have a substantial reduction in mean CST between 1 and 2 years were those with a baseline VA of 20/50 or worse receiving bevacizumab and laser treatment (mean SD, −55 108 µm; 95% CI, −82 to −28 µm; P < .001). CONCLUSIONS AND RELEVANCE: Although post hoc analyses should be viewed with caution given the potential for bias, in eyes with a VA of 20/50 or worse, aflibercept has the greatest improvement in VA over 2 years. Focal/grid laser treatment, ceiling and floor effects, or both may account for mean thickness reductions noted only in bevacizumab-treated eyes between 1 and 2 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01627249
To evaluate optical coherence tomography (OCT) measurements and methods of analysis of OCT data in studies of diabetic macular edema (DME).
Associations of pairs of OCT variables and results of 3 ...analysis methods using data from 2 studies of DME.
Two hundred sixty-three subjects from a study of modified Early Treatment of Diabetic Retinopathy Study (mETDRS) versus modified macular grid (MMG) photocoagulation for DME and 96 subjects from a study of diurnal variation of DME.
Correlations were calculated for pairs of OCT variables at baseline and for changes in the variables over time. Distribution of OCT measurement changes, predictive factors for OCT measurement changes, and treatment group outcomes were compared when 3 measures of change in macular thickness were analyzed: absolute change in retinal thickness, relative change in retinal thickness, and relative change in retinal thickening.
Concordance of results using different OCT variables and analysis methods.
Center point thickness correlated highly with central subfield mean thickness (CSMT) at baseline (0.98-0.99). The distributions of changes in CSMT were approximately normally distributed for absolute change in retinal thickness and relative change in retinal thickness, but not for relative change in retinal thickening. Macular thinning in the mETDRS group was significantly greater than in the MMG group when absolute change in retinal thickness was used, but not when relative change in thickness and relative change in thickening were used. Relative change in macular thickening provides unstable data in eyes with mild degrees of baseline thickening, unlike the situation with absolute or relative change in retinal thickness.
Central subfield mean thickness is the preferred OCT measurement for the central macula because of its higher reproducibility and correlation with other measurements of the central macula. Total macular volume may be preferred when the central macula is less important. Absolute change in retinal thickness is the preferred analysis method in studies involving eyes with mild macular thickening. Relative change in thickening may be preferable when retinal thickening is more severe.
Visual acuity (VA) is the primary outcome measure in many studies involving eye diseases. A standard statistical approach for comparing a continuous measurement such as a VA letter score between 2 ...treatment groups is to perform a t test comparing the means. However, frequently a binary variable is created from the continuous VA letter score based on whether or not there has been a worsening (or gain) of > or =15 letters (equivalent to > or =3 lines), and a chi square or similar statistical test is performed to compare the proportions of success (or failure) between groups. The purpose of this article is to contrast these 2 approaches.
Clinical trial reports of retinal disorders were used to compare results using mean change in the VA letter score versus binary proportions created from the VA letter score. Additionally, analyses were performed using generated data to gain a perspective on the magnitude of differences that might be expected between the 2 methods.
Studies from the literature showed that differences of 6% to 15% in > or =15-letter worsening corresponded to mean differences in letter scores between groups of 3.0 to 7.0 (approximately 0.6 to 1.4 lines). Analyses using generated data demonstrated that a mean improvement in the VA letter score of 5 corresponded to a doubling of the proportion of eyes with > or =15-letter improvement and a 28% relative reduction in the proportion of eyes with > or =15-letter worsening.
How VA data should be analyzed in a clinical trial depends to large extent on the research question. The frequently used outcome of > or =15-letter change has several drawbacks, including loss of efficiency (need for a larger sample), misclassification of the outcome, and potential for a ceiling or floor effect. Therefore, for most clinical trials we believe that the primary outcome analysis should be a comparison of changes in the VA letter score, and created binary variables should be reported as secondary outcomes. This approach maximizes the information gained from the data and accommodates both improvement and worsening of acuity.
The prevalence of diabetes mellitus worldwide is increasing, in part due to an obesity epidemic. Thus, prevention and treatment of vision loss from diabetic retinopathy, including proliferative ...diabetic retinopathy and diabetic macular edema (DME), has become more important. For other patients, the standard treatment for DME since the mid-1980s has been laser photocoagulation. In 2001, intravitreal injections of corticosteroids were tested as an alternative to laser photocoagulation because it was suspected that diabetic retinopathy involved an inflammatory component. Here, Jampol et al examine the efficacy of anti-vascular endothelial growth factor treatment compared with laser photocoagulation.
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