Table 1.
Main findings of the studies included in the review.
| Design | Number of Eyes | Treatment | Follow-Up | Main Outcomes | |
|---|---|---|---|---|---|
| Gross et al. (2015) [30] |
Randomized clinical trial (PROTOCOL S) | 394 eyes with PDR with/without DME | Panretinal photocoagulation or Ranibizumab 0.5 mg eyes with DME have received ranibizumab | 2 years | Among eyes with PDR, treatment with ranibizumab resulted in visual acuity that was noninferior to PRP treatment at 2 years (visual acuity change was +2.8 in the ranibizumab group vs. +0.2 in the PRP group, p < 0.001). Mean peripheral visual field sensitivity loss was worse (p < 0.001), vitrectomy was more frequent (p < 0.001), and DME development was more frequent (28% vs. 9%; p < 0.001) in the PRP group vs. the ranibizumab group, respectively. |
| Bressler et al. (2017) [31] |
Secondary analysis of PROTOCOL T | 650 eyes with DME | Aflibercept 2.0 mg or ranibizumab 0.3 mg or bevacizumab 1.25 mg (every 4 weeks through 2 years following a re-treatment protocol) | 2 years | At 1 and 2 years, eyes with NPDR receiving anti-VEGF treatment for DME may experience improvement in DR severity. Aflibercept was associated with more improvement at 1 and 2 years in the smaller subgroup of participants with PDR at baseline. All three anti-VEGF treatments were associated with low rates of DR worsening. Specifically, at 1 year, among 423 NPDR eyes, 44 of 141 (31.2%) treated with aflibercept, 29 of 131 (22.1%) with bevacizumab, and 57 of 151 (37.7%) with ranibizumab had improvement of DR severity (p = 0.004 for aflibercept vs. bevacizumab; p = 0.01 for ranibizumab vs. bevacizumab; and p = 0.51 for aflibercept vs. ranibizumab). At 2 years, 33 eyes (24.8%) in the aflibercept group, 25 eyes (22.1%) in the bevacizumab group, and 40 eyes (31.0%) in the ranibizumab group had DR improvement; no treatment group differences were identified. For 93 eyes with PDR at baseline, 1-year improvement rates were 75.9% for aflibercept, 31.4% for bevacizumab, and 55.2% for ranibizumab (p < 0.001 for aflibercept vs. bevacizumab; p = 0.09 for ranibizumab vs. bevacizumab; and p = 0.02 for aflibercept vs. ranibizumab). These rates and treatment group differences appeared to be maintained at 2 years. |
| Sivaprasad et al. (2017) [23] |
Phase 2b, non-inferiority trial CLARITY study |
232 eyes with PDR | Aflibercept 2.0 mg or PRP | 1 year | Aflibercept was non-inferior and superior to PRP in both the modified intention-to-treat population mean best corrected visual acuity difference 3.9 letters (p < 0·0001) and the per-protocol population (4·0 letters, p < 0·0001). New-onset center involved DME (29% vs. 11%), vitreous hemorrhage (18% vs. 9%), need for vitrectomy (6% vs. 1%), and visual loss (10% vs. 5%) were more likely to occur in eyes treated with PRP than with aflibercept. |
| Wykoff et al. (2018) [19] |
Post hoc analysis of RISE and RIDE | 746 eyes with DME |
Ranibizumab 0.3 mg or ranibizumab 0.5 mg or sham | 36 months | Ranibizumab treatment resulted in DR improvements in all 3 baseline DR severity subsets examined. The greatest benefits in DR improvement occurred in patients with baseline moderately severe to severe NPDR (DR levels 47/53). Specifically, in patients with baseline DR levels 47/53, ranibizumab treatment reduced the probability of patients experiencing a new proliferative event at month 36 by 3 times compared with sham treatment (12.4% and 11.9% vs. 35.2% for ranibizumab 0.3 mg, ranibizumab 0.5 mg, and sham, respectively). |
| Bressler et al. (2018) [32] |
Sub-analysis of PROTOCOL I | 346 eyes with DME | Ranibizumab 0.5 mg | 5 years | Individuals receiving ranibizumab therapy for DME may have favorable changes in DR severity throughout a 5-year period concomitant with sequential reduction in anti-VEGF therapy. Among 235 participants with NPDR at baseline, there were 29%, 28%, and 32% eyes with retinopathy improvement at 1, 3, and 5 years, respectively. Among 111 participants with PDR, corresponding improvement percentages were 38%, 35%, and 23%. |
| Mitchell et al. (2018) [20] |
Secondary and exploratory analysis of VIVID and VISTA | 403 eyes (VIVID) and 459 eyes (VISTA) with DME | Aflibercept 2.0 mg every 4 weeks (2q4) or every 8 weeks (2q8) after a loading phase of 5 monthly injections or laser and sham injections | 2 years | The proportions of patients treated with 2q4, 2q8, and laser with a 2-step or more improvement in DRSS score at week 100 were 29.3%, 32.6%, and 8.2%, respectively, in VIVID-DME and 37.0%, 37.1%, and 15.6%, respectively, in VISTA-DME. The proportions with a 3-step or more improvement in DRSS score were 7.3%, 2.3%, and 0%, respectively, and 22.7%, 19.9%, and 5.2%, respectively. Fewer patients in aflibercept groups versus the laser group progressed to PDR at week 100. |
| Figueira et al. (2018) [24] |
Prospective, randomized, open-label PROTEUS study |
87 eyes with high-risk PDR | Ranibizumab 0.5 mg plus PRP or PRP alone | 12 months | The number of participants with neovascularization of the disc or elsewhere reductions was higher in combination group (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively). Complete neovascularization total regression was observed in 43.9% in the combination group versus 25.0% in the PRP monotherapy group (p = 0.066). |
| Lang et al. (2019) [33] |
PRIDE study | 106 eyes with PDR without DME | Ranibizumab 0.5 mg or PRP or Ranibizumab 0.5 mg plus PRP | 12 months | At Month 12, there was a statistically significant difference of −2.83 mm² in the least square mean change in neovascularization area between the ranibizumab monotherapy and PRP group, favoring ranibizumab (p = 0.0344). Visual acuity change was greater in the ranibizumab group compared with the PRP monotherapy group at Month 12 (p = 0.0495). |
| Lim (2021) [34] |
PANORAMA study | Moderately severe to severe NPDR without DME | Aflibercept 2.0 mg or sham | 2 years | At week 52, 65%, and 80% of eyes treated with 16-week and 8-week aflibercept, respectively, versus 15% of sham eyes had a ≥2-step improvement in DRSS score. At week 100, the same level was achieved by 62% and 50% of 16-week and 8-week aflibercept eyes respectively, versus 13% of sham eyes. At week 100, patients treated with intravitreal aflibercept had a 75% to 79% reduction in likelihood of developing a vision-threatening complication or DME as compared with patients in the sham arm. |
| Alagorie et al. (2021) [35] |
Prospective, multicenter trial RECOVERY study |
40 eyes with PDR and no DME | Aflibercept 2.0 mg monthly or quarterly | 12 months | Both monthly and quarterly groups demonstrated a statistically significant regression in DRSS from baseline to month 12 (p < 0.001). The monthly group demonstrated a statistically significant greater regression of DRSS score at the month 6 visit compared with the quarterly group (p = 0.019). However, the difference between the two groups became statistically insignificant at month 12 (p = 0.309). |
| Maturi et al. (2021) [36] | Randomized clinical trial (PROTOCOL W) | 399 eyes with moderate-to-severe NPDR without DME | Aflibercept 2.0 mg or sham (baseline;1,2,4 months; every 4 months through year 2) | 24 months | The 2-year cumulative probability of developing PDR was 13.5% in the aflibercept group versus 33.2% in the sham group (p < 0.001), and the 2-year cumulative probability of developing DME with vision loss was 4.1% in the aflibercept group versus 14.8% in the sham group (p < 0.001). The mean change in visual acuity from baseline to 2 years was −0.9 letters with aflibercept and −2.0 letters with sham, not reaching statistical significance. |
DME: diabetic macular edema; DRSS: diabetic retinopathy severity score; NPDR: non-proliferative diabetic retinopathy; PDR: proliferative diabetic retinopathy; PRP: panretinal photocoagulation.