Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema

Abstract

Background: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown.

Methods: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year.

Results: From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56).

Conclusions: Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).

Figure 1. Mean Change in Visual Acuity over Time

Shown are the changes in visual acuity overall (Panel A) and according to baseline visual acuity (Panel B). In Panel B, solid lines indicate baseline visual acuity of 20/50 or worse, and dashed lines indicate baseline visual acuity of 20/32 to 20/40. Outlying values were truncated to 3 SD from the mean. The number of eyes assessed at each 4-week interval ranged from 195 to 224 in the aflibercept group, 188 to 218 in the bevacizumab group, and 188 to 218 in the ranibizumab group (see Fig. S2 in the Supplementary Appendix for the exact number assessed at each 4-week interval). I bars indicate 95% confidence intervals.

Figure 2. Mean Change in Central Subfield Thickness over Time

Shown are the changes in central subfield thickness overall (Panel A) and according to baseline visual acuity (Panel B). In Panel B, solid lines indicate baseline visual acuity of 20/50 or worse, and dashed lines indicate baseline visual acuity of 20/32 to 20/40. Central subfield thickness was assessed with the use of optical coherence tomography. The number of eyes assessed at each 4-week interval ranged from 192 to 221 in the aflibercept group, 186 to 216 in the bevacizumab group, and 185 to 215 in the ranibizumab group. I bars indicate 95% confidence intervals.