An Extension of the Early Treatment Diabetic Retinopathy Study (ETDRS) System for Grading of Diabetic Macular Edema in the Astemizole Retinopathy Trial

Purpose: To compare the effects of astemizole, an antihistamine, versus placebo on the 1-year course of diabetic macular edema (DME) and to illustrate use of a modified ETDRS system for grading areas of retinal thickening and hard exudates that may be useful in clinical trials of treatments for this disorder. Methods: Between June 1994 and September 1997, at 2 clinics, 63 patients who had, in at least one eye (the study eye), DME that had not previously been treated with macular photocoagulation, and for which photocoagulation was not currently recommended by the investigator, were enrolled and randomly assigned to astemizole or placebo. Fifty-four of the 63 patients (86%, 26 in Clinic 1 and 28 in Clinic 2) completed 1 year of followup and had adequate 7-field stereoscopic film-based color fundus photographs of the study eye at the baseline and 1-year visits. DME was > 0.33 disc diameters (DD) from the center of the macula in 48% of study eyes and involved the center in 13%. Photographs were graded using the ETDRS protocol modified to allow estimates of areas of retinal thickening (RT) and hard exudate (HE) to be made on continuous scales in disc area (DA) units. Principal outcome measures were mean change in the square root of RT area (the average diameter of the area in DD), mean change in area of HE, and change in the degree to which RT involved or threatened the center of the macula. Results: At baseline, RT area in the 54 study eyes ranged from 0.09 to 4.0 DA (median 1.1). At the 1-year visit the square root of RT area (RTdd) had decreased by ≥ 0.3 DD in 10 eyes, increased by ≥ 0.3 DD in 19 and was about the same in 25. Mean change at 1 year was +0.09 DD (SD 0.57) for astemizole versus +0.19 DD (SD 0.48) for placebo, for a difference of −0.10 DD (95% CI −0.38, +0.19; p = 0.51). Adjustments for baseline and time-dependent risk factors did not change this result appreciably, although there was a trend towards a difference in favor of astemizole in the subgroup of patients with more severe retinopathy. Other morphologic outcomes paralleled change in RTdd. Change in RTdd did vary by clinic: −0.03 DD in Clinic 2, versus + 0.32 DD in Clinic 1, for a difference of −0.35 DD (95% CI −0.62, −0.07; p = 0.014). Clinic 1 is a tertiary retinal referral center in Pennsylvania and Clinic 2 a retinal clinic closely affiliated with a large diabetes clinic in Copenhagen. The unexpected clinic difference in outcome provided an opportunity for further analyses using the modified ETDRS system. In comparison to Clinic 1, Clinic 2 patients were more often male, were younger at diagnosis of diabetes, and had less severe retinopathy and better visual acuity, but these differences did not appear to explain the trend for lesser increase in RTdd. Conclusion: No effect of astemizole was found, but the confidence interval for the principal outcome, mean change in RTdd, included both a modest beneficial effect and a small harmful effect. This outcome measure did demonstrate a small difference in outcome by clinic, which could not be explained by baseline characteristics but may reflect differences in access to and/or continuity of care or other unmeasured differences associated with different referral patterns. Although optical coherence tomography may supplant photography as a measure of central RT, photographic assessments of change in RT and HE areas analyzed with the methods described herein may be useful outcomes in trials assessing treatment of early stages of DME. Application of these methods to other data sets is needed to confirm this conclusion.