Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy

Abstract

Importance: Anti-vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown.

Objective: To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported.

Design, setting, and participants: Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME.

Interventions: Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss.

Main outcomes and measures: Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years.

Results: Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P < .001). The mean (SD) change in visual acuity from baseline to 4 years was -2.7 (6.5) letters with aflibercept and -2.4 (5.8) letters with sham (adjusted mean difference, -0.5 letters [97.5% CI, -2.3 to 1.3]; P = .52). Antiplatelet Trialists' Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants.

Conclusions and relevance: Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME.

Trial registration: ClinicalTrials.gov Identifier: NCT02634333.

Figure 1.. Study Selection, Randomization, and Flow of Participants’ Eyes

Protocol-specified visits occurred at baseline (randomization) and at target periods of 1 month (± 2-wk range), 2 months (± 1-wk range), 4 months (± 8-wk range); then every 4 months (± 12-wk range for annual visits; ± 8-wk range otherwise) through 4 years (range, −12 weeks to +24 weeks). ^aOf the 328 participants who were randomized, 71 bilateral participants (30 females and 41 males) had 1 eye randomized to receive afibercept and 1 eye randomized to receive sham. ^bThe 137 patients’ eyes that completed the 4-year visit indicates 68.5% of the 200 randomized (74.9% excluding 17 patients who died). ^cThe 134 patients’ eyes that completed the 4-year visit indicates 67.3% of the 199 randomized (73.2% excluding 16 patients who died). ^dDeaths exclude 1 participant (1 study eye) in the aflibercept group who completed a visit in the 4-year visit window but died before completing the designated 4-year study visit. ^eThe primary analysis of the key outcomes included all randomized participants using all available follow-up time for the anatomical outcome (time to development of proliferative diabetic retinopathy or center-involved diabetic macula edema) and multiple imputation for missing data of the visual acuity outcome (change in visual acuity from baseline to 4 years). ^fThe per-protocol analysis included eyes that were at least 80% adherent with protocol injections (aflibercept or sham) prior to the event or censoring time (for the primary anatomical outcome) and prior to the 4-year visit (for the primary visual acuity outcome). The compete-case analysis for the primary visual acuity outcome included all eyes that completed the 4-year visit.

Figure 2.. Distribution of Visual Acuity Change From Baseline Through 4 Years

The horizontal line in the box plots indicates the median, the top of the box indicates the 75th percentile, the bottom of the box indicates the 25th percentile, the whiskers indicate the nearest quartile to the most extreme data point within 1.5 times the IQR, and circles indicate values beyond these limits.

Figure 3.. Cumulative Percentages for Time From Baseline to Development of PDR or CI-DME With Vision Loss, PDR, and CI-DME With Vision Loss

Cumulative percentages were estimated using Kaplan-Meier (product-limit) method. Shading indicates 97.5% CIs. Median time from baseline to event or censoring time: for panel A, 1370 (IQR, 698 to 1465) days in the aflibercept group and 783 (IQR, 378 to 1428) days in the sham group; for panel B, 1411 (IQR, 740 to 1465) days in the aflibercept group and 1040 (IQR, 413 to 1457) days in the sham group; and for panel C, 1421 (IQR, 859 to 1474) days in the aflibercept group and 1408 (IQR, 707 to 1463) days in the sham group. ^aIndicates proliferative diabetic retinopathy (PDR) or center-involved diabetic macular edema (CI-DME), whichever develops first.