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Purpose: To evaluate efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with moderately severe to very severe nonproliferative diabetic retinopathy from the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study and Protein Kinase C β Inhibitor-Diabetic Retinopathy Study 2 ruboxistaurin (RBX) protein kinase C β inhibitor trials., Methods: Patients in these 3-year, randomized, placebo-controlled, double-masked, Phase 3 trials had best-corrected Early Treatment Diabetic Retinopathy Study visual acuity ≥45 letters (∼20/125 Snellen), Early Treatment Diabetic Retinopathy Study retinopathy level 47A/B-53E, and no previous panretinal photocoagulation in ≥1 eye. Patients received placebo (N = 401) or RBX 32 mg/day (N = 412). Data from the 2 studies were combined and masked evaluation of retinal photographs was performed for cause of visual decline in all patients experiencing sustained moderate visual loss (≥15-letter loss sustained for the last 6 months of study)., Results: In the studies combined, sustained moderate visual loss occurred in 10.2% of placebo-treated patients versus 6.1% of RBX-treated patients (P = 0.011). A ≥15-letter gain occurred in 2.4% of placebo versus 4.7% of RBX eyes (P = 0.021) and a ≥15-letter loss occurred in 11.4% versus 7.4%, respectively (P = 0.012). Diabetic macular edema was the probable primary cause of vision loss. Among eyes without focal/grid photocoagulation at baseline, fewer RBX group eyes (26.7%) required initial focal/grid photocoagulation versus placebo (35.6%; P = 0.008). No safety concerns were identified., Conclusion: Analysis of data combined from two similar studies adds further statistical significance to RBX's beneficial effects on visual loss, need for focal laser, and vision gain, most likely through effects on macular edema.

Purpose: To compare relationships between severity and duration of diabetic macular edema (DME) and visual acuity (VA) observed in the PKC-DRS2 with those from the Early Treatment Diabetic Retinopathy Study (ETDRS) and to assess the effect of the orally administered PKC beta inhibitor ruboxistaurin (RBX) on these parameters., Methods: In the PKC-DRS2, patients with moderately severe to very severe nonproliferative diabetic retinopathy (n = 685) were randomly assigned to 32 mg/d RBX or placebo and followed up for 36 months with ETDRS VA measurements and fundus photographs (FP) every 3 to 6 months. Mean VA was calculated across all FP visits for eyes in each level of the ETDRS DME severity scale at those visits. For eyes with baseline VA > or = 20/40, relationships between change in VA from baseline to last visit and duration of severe DME were analyzed with linear regression., Results: Mean VA decreased by approximately 22 letters between the mildest and most severe levels of the DME scale in the PKC-DRS2, compared with 27 letters in the ETDRS. In the placebo group, the rate of decrease in VA over time associated with duration of severe DME was 0.67 letters per month (24 letters over 36 months, compared with 20 letters over 28-36 months in the ETDRS). This rate was 30% less in the RBX group (0.47 letter per month, P = 0.022)., Conclusions: The VA decrease in the PKC-DRS2 associated with long-standing DME agrees well with estimates from the ETDRS. RBX appears to ameliorate this decrease, an effect that could be important clinically. (ClinicalTrials.gov number, NCT00604383.).

Objective: To evaluate the effect of ruboxistaurin, an orally administered protein kinase C beta (PKC beta) isozyme-selective inhibitor, on vision loss in patients with diabetes., Design: Thirty-six-month, randomized, double-masked, placebo-controlled, parallel, multicenter trial., Participants: Six hundred eighty-five patients randomized at 70 clinical sites., Methods: Ophthalmologic examination was performed at screening and at each 3-month visit. Retinopathy status was assessed every 6 months with Early Treatment Diabetic Retinopathy Study (ETDRS) standard 7-field 30 degrees color stereoscopic fundus photography. Levels of diabetic retinopathy and diabetic macular edema were determined by 2 independent graders masked to site and treatment assignment, with additional independent adjudication as required. Eligible patients had a best-corrected visual acuity (VA) score of > or =45 letters, retinopathy level > or = 47A and < or = 53E, and no prior panretinal photocoagulation in at least one eye., Main Outcome Measure: Effect of oral ruboxistaurin (32 mg/day) on reduction of sustained moderate visual loss (> or =15-letter decrease in ETDRS VA score maintained > or = 6 months) in patients with moderately severe to very severe nonproliferative diabetic retinopathy., Results: Sustained moderate visual loss occurred in 9.1% of placebo-treated patients versus 5.5% of ruboxistaurin-treated patients (40% risk reduction, P = 0.034). Mean VA was better in the ruboxistaurin-treated patients after 12 months. Baseline-to-end point visual improvement of > or =15 letters was more frequent (4.9% vs. 2.4%) and > or =15-letter worsening was less frequent (6.7% vs. 9.9%) in ruboxistaurin-treated patients relative to placebo (P = 0.005). When clinically significant macular edema was >100 microm from the center of the macula at baseline, ruboxistaurin treatment was associated with less frequent progression of edema to within 100 microm (68% vs. 50%, P = 0.003). Initial laser treatment for macular edema was 26% less frequent in eyes of ruboxistaurin-treated patients (P = 0.008)., Conclusion: Oral ruboxistaurin treatment reduced vision loss, need for laser treatment, and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy.

Ten Sloan letters were used in the visual acuity charts developed for use in the Early Treatment Diabetic Retinopathy Study. We used the data from the 3,710 Early Treatment Diabetic Retinopathy Study subjects to investigate the relative difficulty of the ten Sloan letters and to evaluate whether the position of a letter on a line affected its relative difficulty. In general, our findings were consistent with those of the previous study. The four letters with curved contours (C, O, S, and D) were more difficult to discern at threshold than the six letters (Z, N, H, V, R, and K) composed of straight lines. Our data demonstrate that under these test conditions, letters at the end of a line are more likely to be read incorrectly than letters at the beginning of the line. This finding indicates that these data are probably not useful for evaluating possible crowding phenomena.

Ophthalmologic examinations for cataract, glaucoma, diabetic retinopathy, macular degeneration and visual acuity were performed on 2631 of the 3977 members of the Framingham (Massachusetts) Heart Study population still living in 1973-1975. The subjects ranged in age from 52 to 85 years. This monograph presents the detailed protocols and record forms for screening and diagnostic examinations, definitions of the specific abnormalities and characteristics used to screen for each disease, criteria for suspicion and diagnosis of diseases, detailed tables of the basic data from the study, evaluation of quality of the data, and discussion of selected findings. The tables provide data on the number and proportion of persons and of eyes with each type of abnormality and each disease, by age and sex. Where appropriate, the data are further classified by location of abnormality, severity, bilaterality and associated visual acuity limitation. The study was sponsored by the National Eye Institute.

We studied 29 diabetic patients (eight without and 21 with retinopathy) and 29 matched control subjects for hemoglobins Ala-c and plasma levels of fibrinogen, von Willebrand factor, and factor VIII/von Willebrand factor antigen. Hemoglobins Ala-c were elevated in all diabetic patients, regardless of retinopathy (P less than 0.001); fibrinogen was elevated only in those with retinopathy (P less than 0.001); and plasma von Willebrand factor was clearly elevated in those with proliferative retinopathy and minimally, if at all, elevated in those with background or no retinopathy. Plasma from five diabetic patients with proliferative retinopathy and five control subjects was tested for its ability to enhance the ADP-induced platelet aggregation of normal or von Willebrand platelet-rich plasma; no differences were found. We conclude that elevated levels of fibrinogen and von Willebrand factor, both recognized plasma cofactors of platelet function, are associated with proliferative diabetic retinopathy. A plasma factor that enhances ADP-induced platelet aggregation could not be found in diabetic plasma, and we doubt that increased von Willebrand factor is responsible for its finding by others.

This article briefly summarizes the monography, The Framingham Eye Study Monograph: an Ophthalmological and Epidemiological Study of Cataract, Glaucoma, Diabetic Retinopathy, Macular Degeneration, and Visual Acuity in a General Population of 2631 Adults, 1973-1975. This 275-page monograph, authored by H. Liebowitz, D. Krueger, C. Maunder et al, has recently been published by Survey of Ophthalmology (Surv Ophthalmol 24 (suppl):335-610, 1980). The purpose of the study, undertaken by the National Eye Institute, was to provide a description of the prevalence and severity of four diseases that are believed to be the major causes of severe visual handicap among adults in the United States. The monography presents the detailed protocols and record forms, definitions of the specific abnormalities and characteristics, criteria for suspicion and diagnosis of disease, detailed tables of the basic data, evaluation of quality of the data, and discussion of selected findings.

Two physicians and two lay readers were trained according to a detailed protocol in the grading of 17 lesions found in diabetic retinopathy by evaluation of stereo fundus photographs according to a modified Airlie House classification. Intraobserver and interobserver variability of these readers was assessed by two methods: weighted kappa, and frequency of agreement within one grade. In general, physician readers were found to be less variable on replicate readings than were lay leaders, and had slightly better agreement with each other than with the lay readers. The physiological significance of the direction and magnitude of the difference between physician and lay reader variability for individual lesions was often uncertain. Assessment of contribution to disagreement by individual readers was possible and permits future training directed at reducing disagreement to acceptable values.