Study Finds Aflibercept Noninferior to Ranibizumab in Macular Edema, Results With Bevacizumab Inconclusive

Treating macular edema associated with central retinal vein occlusion (CRVO) with aflibercept was noninferior to ranibizumab treatment at 100 weeks, while the results for bevacizumab versus ranibizumab were inconclusive.

Earlier this year, a trial examining anti—vascular endothelial growth factor (anti-VEGF) therapy, the standard of care for the first-line treatment of macular edema associated with central retinal vein occlusion (CRVO), found that patient-reported visual function after treatment with bevacizumab was noninferior to that reported after treatment with aflibercept at 6 months.

The latest study on this topic, published Thursday in JAMA Ophthalmology, found that treating CRVO-related macular edema with aflibercept was noninferior to ranibizumab treatment at 100 weeks, while the results for bevacizumab versus ranibizumab were inconclusive.

This study showed that repeated intravitreal injection of 3 anti-VEGF agents—ranibizumab, bevacizumab, and aflibercept—improved and sustained visual function. It also found that aflibercept was noninferior to (or no worse than) ranibizumab at 100 weeks; however, at 100 weeks, bevacizumab was not noninferior to ranibizumab, meaning that vision changes using bevacizumab compared with ranibizumab (ie, the change in visual acuity from baseline), may or may not be worse when using bevacizumab compared with ranibizumab.

In addition, it is somewhat possible that bevacizumab was not noninferior to aflibercept, although the researchers said those results should be interpreted cautiously.

The noninferiority trial (Lucentis, Eylea, Avastin in Vein Occlusion [LEAVO] Study) took place from December 2014, through December 2016 in adults aged 18 or above. The prospective, 3-arm, double-masked, randomized clinical trial included 463 patients selected from 44 UK National Health Service ophthalmology departments.

Patients were included if their visual impairment due to CRVO-related macular edema of less than 12 months with best-corrected visual acuity (BCVA) letter score in the study eye was between 19 (20/400) and 78 (20/32), and had spectral domain optical coherence tomography (OCT) imaging central subfield thickness (CST) of 320 μm or greater.

Participants were randomized to receive repeated intravitreal injections of ranibizumab (0.5mg/0.05 mL) (n = 155), aflibercept (2.0mg/0.05 mL) (n = 154), or bevacizumab (1.25mg/0.05 mL) (n = 154) for 100 weeks. Mandated injections were given at baseline and 4, 8, and 12 weeks.

From week 16 through 96, patients were retreated if 1 or more of certain criteria were met.

Visits at weeks 16 and 20 were mandated, and from week 24, the visit interval could be increased from 4 weeks to 8 weeks if retreatment criteria were not met at 3 consecutive visits. Noninferiority was determined if the adjusted mean change in BCVA in the study eye at 100 weeks was statistically significant, with both the intention-to-treat and the per protocol analyses above —5 letters.

Results showed that the mean gain in BCVA letter score was 12.5 for ranibizumab, 15.1 for aflibercept, and 9.8 for bevacizumab at 100 weeks. Aflibercept was noninferior to ranibizumab (intention-to-treat—adjusted mean BCVA difference, 2.23 letters; 95% CI, –2.17 to 6.63 letters; P <.001).

Bevacizumab was not noninferior to ranibizumab (intention-to-treat—adjusted mean BCVA difference, –1.73 letters; 95% CI, –6.12 to 2.67 letters; P = .07). The per protocol analysis conclusions were similar.

Fewer mean injections were given in the aflibercept group (10.0) than in the ranibizumab (11.8) group (mean difference at 100 weeks, —1.9; 95%CI, –2.9 to –0.8). That observation was evident as early as 24 weeks, and the number of injections increased by 100 weeks. This difference has not been previously reported in macular edema due to CRVO; the authors said that could be a potential advantage to aflibercept use.

Mean changes in vision after treatment of macular edema due to CRVO were no worse using aflibercept compared with ranibizumab. Mean changes in vision using bevacizumab compared with ranibizumab were inconclusive regarding vision outcomes.

Off-label reference bevacizumab is becoming a treatment of choice in European nations due to its favorable cost effectiveness, and other developers are working on other bevacizumab products as well. The first biosimilar for bevacizumab, Amgen’s Mvasi, recently launched in the United States.


Hykin P, Prevost AT, Vasconcelos AC, et al. Clinical effectiveness of intravitreal therapy with ranibizumab vs aflibercept vs bevacizumab for macular edema secondary to central retinal vein occlusion: A randomized clinical trial [published online August 29, 2019]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2019.3305