Table 3. Development of PDR and CI-DME Outcomes Through 4 Years.
| PDR and CI-DME outcomesa | No. (4-y %) | Aflibercept vs sham, hazard ratio (97.5% CI)b | |||
|---|---|---|---|---|---|
| Aflibercept (n = 200) | Sham (n = 199) | Primary (n = 399)c | P value | Per-protocol (n = 327)d | |
| Development of PDR or CI-DME with vision loss (whichever came first, primary outcome)e | |||||
| Any PDR or CI-DME outcome | 54 (33.9) | 97 (56.9) | 0.40 (0.28 to 0.57) | <.001 | 0.37 (0.25 to 0.55) |
| Development of PDRe,f | |||||
| Any PDR outcome | 44 (27.9) | 82 (49.0) | 0.42 (0.29 to 0.61) | <.001 | |
| Neovascularization of the disc or elsewhere | 42 (26.9) | 74 (44.0) | |||
| Vitreous hemorrhage due to PDR | 12 (7.4) | 26 (16.2) | |||
| Preretinal hemorrhage due to PDRg | 6 (3.9) | 19 (11.6) | |||
| Traction retinal detachment due to PDR | 0 | 2 (1.3) | |||
| Neovascularization of the irish | 2 (1.4) | 1 (<1) | |||
| Neovascularization of the angle | 0 | 1 (<1) | |||
| Neovascular glaucoma | 0 | 2 (1.5) | |||
| Anti-VEGF for PDRi | 16 (10.2) | 42 (25.5) | |||
| Panretinal photocoagulation | 2 (1.2) | 6 (3.8) | |||
| Vitrectomy | 1 (<1) | 1 (<1) | |||
| Development of CI-DME with vision losse,j | |||||
| Any CI-DME outcome | 18 (11.3) | 32 (19.1) | 0.51 (0.27 to 0.97) | .02 | |
| CI-DME with ≥10% increase in center subfield thickness and ≥10 letter decrease in visual acuity at a single visitk | 12 (7.5) | 20 (12.0) | |||
| CI-DME with ≥10% increase in center subfield thickness and ≥5 letter decrease in visual acuity at 2 consecutive visitsk,l | 0 | 5 (3.0) | |||
| Anti-VEGF for CI-DMEm | 16 (9.9) | 29 (17.1) | |||
| Focal/grid laser | 3 (2.0) | 11 (7.0) | |||
| Corticosteroid | 2 (1.2) | 0 | |||
| Development of secondary outcomese | |||||
| Any PDR or CI-DME with vision loss criteria based on objective components defined in composite outcomen | 48 (30.3) | 88 (51.7) | |||
| CI-DME with ≥10% and ≥25 um increase in center subfield thickness | 18 (11.5) | 20 (12.6) | |||
| High-risk PDR (level ≥71) | 9 (5.6) | 20 (12.1) | |||
| Anti-VEGF for PDR or CI-DME | 30 (18.7) | 68 (40.7) | |||
Types of assessment used: reading center only (for neovascularization of the disc or elsewhere, CI-DME, and change in CST); reading center or clinical examination (for traction retinal detachment, vitreous hemorrhage, and preretinal hemorrhage); and clinical examination only (for neovascularization of the angle, neovascular glaucoma, neovascularization of the iris, change in visual acuity, and any treatment for PDR or CI-DME).
Hazard ratios were estimated using a marginal Cox regression model that adjusted for study eye laterality and baseline diabetic retinopathy severity score. The correlation between eyes of participants having 2 eyes in the study were modeled with a robust sandwich estimate of the covariance matrix.
The as-randomized principle was used to analyze all participants by randomized treatment group, regardless of treatment received. See Results for difference in 4-year cumulative incidence.
Included 163 eyes in aflibercept and 164 eyes in the sham group (that received ≥80% of injections according to protocol before meeting the outcome through the first 2 y and through 4 y when applicable; P <.001 for the hazard ratio).
Cumulative 4-year percentages were estimated using Kaplan-Meier estimates at the end of the 4-year visit window (1629 days after baseline). Eyes were considered at risk for an outcome until the outcome developed. Eyes that did not meet the outcome were censored at the time of the last completed visit. Censoring times for eyes censored at the 4-year visit were set to the end of the 4-year visit window for all analyses to prevent small numbers at risk from artificially inflating the outcome percentages at the end of the window.
Outcomes developed if PDR developed at any time during the study (irrespective of if/when CI-DME developed).
Indicates preretinal hemorrhage greater than one-half of the disc area.
Indicates neovascularization of the iris for at least 2 cumulative clock hours.
Not given without meeting another PDR outcome first.
Outcomes developed if CI-DME with vision loss developed at any time during the study (irrespective of if/when PDR developed).
Vision loss presumed to be from diabetic macular edema.
Consecutive visits at least 21 days apart.
Anti-VEGF for CI-DME was given to 6 aflibercept and 5 sham eyes without meeting another diabetic macular edema outcome first.
Included outcomes with reading center assessments on optical coherence tomography (CI-DME with visual acuity loss) or on fundus photos or fluorescein angiography (neovascularization of the disc or elsewhere, traction retinal detachment, vitreous hemorrhage, preretinal hemorrhage); excluded those based on clinical examinations.