Rationale and Application of the Protocol S Anti-Vascular Endothelial Growth Factor Algorithm for Proliferative Diabetic Retinopathy

Abstract

Purpose: To present the rationale, guidelines, and results of ranibizumab treatment for proliferative diabetic retinopathy (PDR) in Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S.

Design: Post hoc analyses from a randomized clinical trial.

Participants: Three hundred five participants (394 study eyes) having PDR without prior panretinal photocoagulation (PRP).

Methods: Intravitreous ranibizumab (0.5 mg) versus PRP for PDR. Ranbizumab-assigned eyes (n = 191) received monthly injections for 6 months unless resolution was achieved after 4 injections. After 6 months, injections could be deferred if neovascularization was stable over 3 consecutive visits (sustained stability). If neovascularization worsened, monthly treatment resumed. Panretinal photocoagulation could be initiated for failure or futility criteria.

Main outcome measures: Neovascularization status through 2 years.

Results: At 1 month, 19% (35 of 188) of ranibizumab-assigned eyes showed complete neovascularization resolution and an additional 60% (113) showed improvement. At 6 months, 52% (80 of 153) showed neovascularization resolution, 3% (4) were improved, 37% (56) were stable, and 8% (13) had worsened since the last visit. Among eyes with versus without resolved neovascularization at 6 months, the median (interquartile range) number of injections between 6 months and 2 years was 4 (1-7; n = 73) versus 7 (4-11; n = 67; P < 0.001). Injections were deferred in 68 of 73 eyes (93%) meeting sustained stability at least once during the study; 62% (42 of 68) resumed injections within 16 weeks after deferral. At 2 years, 43% (66 of 154) showed neovascularization resolution, 5% (7) showed improvement, 23% (36) were stable, and 27% (42) had worsened since the last visit. Only 3 eyes met criteria for failure or futility through 2 years.

Conclusions: The DRCR.net treatment algorithm for PDR can provide excellent clinical outcomes through 2 years for patients initiating anti-vascular endothelial growth factor (VEGF) therapy for PDR. When choosing between anti-VEGF and PRP as first-line therapy for PDR, treatment decisions should be guided by consideration of the relative advantages of each therapeutic method and anticipated patient compliance with follow-up and treatment recommendations.

Figure 1.

Principles of the Diabetic Retinopathy Clinical Research Network (DRCR.net) Anti-VEGF Treatment Algorithm for proliferative diabetic retinopathy. * 4-week, not 1-month, intervals were used. † 4 injections were required every 4 weeks initially; it is not known whether a different number of injections initially would have worked as well. DRCR.net also required 2 additional injections at months 5 and 6 unless there was complete absence of neovascularization (“resolved”). ‡ Relevant details: 1) deferral of injections due to stability occurred only when “sustained stability” criteria were met, defined as neovascularization clinically unchanged at the current visit and the and last 2 injection visits, 2) “resolved” was defined as absence of neovascularization of the iris, neovascularization of the disc, neovascularization elsewhere, and neovascularization of the angle (if the angle was assessed). § Injection was at investigator discretion if neovascularization status was sustained stability or resolved and was performed 15% and 23% of the time in these cases, respectively. ∥ Panretinal photocoagulation was permitted if failure criteria were met, namely, if neovascularization worsened substantially despite at least 4 monthly injections or iris neovascularization involving the angle developed. ¶ Follow-up continued every 4 weeks through the 52-week visit and did not permit extension of follow-up until after the 52-week visit. If injection was withheld due to no resolution or sustained stability at 3 consecutive visits following the week 52 visit, follow-up interval was doubled to 8 weeks and then again to 16 weeks if still no change.

Figure 2.

Paired baseline (A, C, E, G) and follow-up (B, D, F, H) fundus photographs of retinal neovascularization (NV) showing 4 types of NV change over time. Resolved: NV that fully resolved without any residual vessels or fibrosis 1 week after anti-VEGF treatment (A, B). Improved: NV decreased in extent and severity 1 week after anti-VEGF therapy but with some residual NV and fibrosis (C, D). Stable: NV that remained stable in extent and severity over a period of 1 year without treatment (E, F). Worsened: NV of the disc that worsened in extent and severity over 32 Weeks (G, H).

Figure 3.

Status of retinal neovascularization at each visit as determined by investigators (R = randomization visit at which injection was required).

Figure 4.

Percentage of eyes with stable neovascularization or sustained stability of neovascularization (stability at 3 consecutive visits) at each visit.

Figure 5:

Cumulative probability of resuming injections after deferral due to sustained stability of neovascularization (stability at 3 consecutive visits).