Clinical Effectiveness of Intravitreal Therapy With Ranibizumab vs. Aflibercept vs. Bevacizumab for Macular Edema Secondary to Central Retinal Vein Occlusion: A Randomized Clinical Trial by the LEAVO Study Group

Written by: Avni P. Finn, MD

October 2019

Hykin P, Prevost AT, Vasconcelos JC, 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. JAMA Ophthalmol. Published online August 29, 2019. doi:10.1001/jamaophthalmol.2019.3305

Visual impairment in central retinal vein occlusion (CRVO) due to associated macular edema is unlikely to improve spontaneously and is most often treated with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents. The Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO) trial evaluated the comparative clinical effectiveness of anti-VEGF monotherapies in CRVO-related macular edema. This was a multi-center, double-masked randomized non-inferiority trial that took place in the UK, randomizing 463 patients to one of the three anti-VEGF agents in 1:1:1 fashion – the primary outcome was change in and BCVA letter score from baseline to 100 weeks. It is important to note that LEAVO was designed as a non-inferiority study comparing bevacizumab or aflibercept to ranibizumab.

The mean gain in BCVA at 100 weeks was 9.8 letters for bevacizumab, 12.5 letters for ranibizumab, and 15.1 letters for aflibercept. Patients randomized to the bevacizumab group also had the lowest percentage of patients with a 3-line gain at both 52 and 100 weeks, while both ranibizumab and aflibercept were equal at 52 weeks in this regard. Of note, patients in the aflibercept group required fewer injections (9.8) at week 100 compared to 11.5 in the bevacizumab and 11.8 in the ranibizumab group, though this was not statistically significant. On OCT, central subfield thickness < 320 um at week 100 was achieved in 59% of the eyes in the bevacizumab group compared with 66% of those in the ranibizumab group and 81% in the aflibercept group.

Overall, this was a robust study given the size and design. Eyes in all three anti-VEGF agent subgroups saw improved BCVA and maintained these changes. However, bevacizumab may not be as interchangeable with aflibercept and ranibizumab for the treatment of macular edema due to CRVO, and further large studies are needed. Some limitations included the inclusion of patients with severe vision loss and ischemia, which may have had a ceiling effect on visual gains, though these eyes were equally distributed among the three groups.

As a retina specialist thinking about how best and how often to treat my patients, this study did provide some important insights about treatment interval. Compared to prior CRVO studies such as CRUISE and SCORE2 where 6 mandated injections were given, the initial BCVA improvement overall in this study was lower, perhaps due to only 4 mandated initial injections followed by PRN treatment. However, visual acuity gains at week 24 were maintained through 100 weeks in this study – a notable achievement compared to those seen in prior studies. A difference in the study design of re-treatment based on visual acuity coupled with OCT findings every 4 to 8 weeks rather than the quarterly dosing seen in prior studies may have led to this difference. These data suggest that monthly treatment for 6 months followed by retreatment at least every 4-8 weeks may lead to the best possible maintained visual acuity gains in patients with CRVO and macular edema, though this must be balanced with treatment and visit burden.