Table 2. Visual Acuity Outcomes at 4 Years.
| Visual acuity (best-corrected Early Treatment Diabetic Retinopathy Study) outcomes | No. (%)a | Aflibercept vs sham | |||
|---|---|---|---|---|---|
| Aflibercept (n = 137) | Sham (n = 134) | Primary (n = 399)b | Complete case (n = 271)c | Per-protocol (n = 196)d | |
| At baseline, letter score, mean (SD) | 87.4 (4.5) | 87.8 (4.7) | |||
| At 4 y, letter score, mean (SD) | 84.1 (11.1) | 85.3 (7.8) | |||
| Change from baseline to 4 y (primary outcome), letters, mean (SD)e | −2.7 (6.5) | −2.4 (5.8) | Mean difference, −0.5 (97.5% CI, −2.3 to 1.3)f | Mean difference, 0.0 (97.5% CI, −1.4 to 1.4)f | Mean difference, 0.2 (97.5% CI, −1.5 to 2.0)f |
| P value | .52 | >.99 | .78 | ||
| Average change over 4 y (area under the curve), letters, mean (SD) | −1.0 (4.2) | −1.3 (3.6) | Mean difference, −0.2 (97.5% CI, −1.2 to 0.8)f | ||
| P value | .65 | ||||
| Worsened ≥10 letters from baseline to 4 y | 18 (13.1) | 17 (12.7) | Odds ratio, 1.11 (97.5% CI, 0.55 to 2.22)g | ||
| P value | .74 | ||||
| Worsened ≥15 letters from baseline to 4 y | 8 (5.8) | 6 (4.5) | |||
| Worsened ≥5 letters from baseline to 4 y and the previous study visit | 25 (18.2) | 23 (17.2) | |||
| Improved ≥5 letters from baseline to 4 y and the previous study visit | 7 (5.1) | 5 (3.7) | |||
| Visual acuity of 20/20 or better (≥84 letters) at 4 y | 89 (65.0) | 92 (68.7) | |||
| Visual acuity of 20/40 or better (≥69 letters) at 4 y | 131 (95.6) | 129 (96.3) | |||
| Visual acuity of 20/200 or worse (≤38 letters) at 4 y | 2 (1.5) | 0 | |||
Numeric values are reported as No. (%) unless otherwise indicated.
The primary analysis followed the as-randomized principle, analyzing all participants by randomized treatment group (n = 200 aflibercept; n = 199 sham) regardless of treatment received, with multiple imputation (100 imputations) for missing data in the analysis of visual acuity change, area under the curve, and loss of 10 or more letters. The imputation model included treatment group, study eye laterality, baseline diabetic retinopathy severity score, baseline visual acuity, and change in visual acuity from baseline to each protocol assessment visit up to and including 4 years. A tipping point analysis identified shift parameters of 4 letters for aflibercept to be superior and 3 letters for sham to be superior.
The complete case analysis included 137 aflibercept eyes and 134 sham eyes that completed the 4-year visit.
The per-protocol analysis included 106 aflibercept eyes and 90 sham eyes that completed the 4-year visit, received at least 80% of injections (aflibercept or sham) according to protocol through the first 2 years and through 4 years, and had no other treatment for proliferative diabetic retinopathy or diabetic macular edema before the 4-year visit.
Outliers in visual acuity change from baseline to 4 years were truncated to within the overall mean (SD) 3 (−1.6 [3] × 6.7) of visual acuity change from baseline to 2 years. Values of outliers for the aflibercept group were −80, −44, and −26, and there was 1 outlier for the sham group (−41).
Mean differences between treatment groups were estimated using linear mixed models with a random intercept for the correlation between eyes of participants having 2 study eyes and fixed effects for treatment group, study eye laterality, baseline diabetic retinopathy severity score, and baseline visual acuity.
This adjusted odds ratio was estimated using generalized estimating equations with an exchangeable correlation structure for the correlation between eyes of participants having 2 study eyes and regression terms for treatment group, study eye laterality, baseline diabetic retinopathy severity score, and baseline visual acuity.