Home » Protocol V, LEAVO Among Retina Highlights at ARVO 2019

Protocol V, LEAVO Among Retina Highlights at ARVO 2019

Protocol V, LEAVO Among Retina Highlights at ARVO 2019

VANCOUVER – Leave it to ARVO 2019 – the Association for Research in Vision and Ophthalmology – to keep attendees waiting until mid-evening to hear first-time results from two highly anticipated studies on diabetic macular edema (DME) and vein occlusion.

The much anticipated Protocol V results were made public at an evening symposium from the Diabetic Retinopathy Clinical Research (DRCR) Network, which concurrently renamed itself the DRCR Retina Network to reflect its expanding research focus into other retinal diseases beyond diabetic eye disease.

In the 10 years since anti-vascular endothelial growth factor (VEGF) agents have been found to be effective and superior to both laser and observation for DME in eyes with poor visual acuity, none of the trials evaluated eyes with good visual acuity (VA), the group noted. Protocol V hoped to determine what is the effect on vision loss of initial management with intravitreous injection of aflibercept 2 mg (Eylea, Regeneron, n = 226), laser photocoagulation (n = 240), or observation (n = 236), with aflibercept added to laser photocoagulation and observation if vision worsens (when or if VA decreased by 1 line on two consecutive visits or by 2 lines at one visit). In this study, the groups used targeted laser combined with grid laser to the thickened macula.

Long story short: There is no statistical or clinical difference in vision loss at two years in any of the arms. The study reported a primary outcome of ≥5 letter loss at two years. (Of the 702 eyes enrolled, by year 2 the group had a 98% retention rate).

The proportion of participants who lost at least 1 line of vision from baseline to two years was virtually identical among the three groups: aflibercept (16%), laser photocoagulation (17%), and observation (19%). Mean VA at two years was about 20/20 in all three treatment groups, and the proportion of eyes that had 20/20 visual acuity at year 2 was 77% in the aflibercept group, 71% in the laser group, and 66% in the observation group.

Plus, 74% of those in the laser group and 64% of those in the observation group did not need injections during the first two years, indicating that delaying treatment until VA worsens is a viable – that is, cost-effective – option.

Jennifer Sun, MD, chair of the diabetes initiatives for the group, said that previous studies evaluated anti-VEGF treatment to see “if there was any difference in eyes with predominantly focal edema versus intermediate mixed edema versus prominent diffused edema as judged by our investigators. We’ve never been able to see a difference in treatment outcomes based on those categories.” One of the reasons laser was a treatment arm in Protocol V was that “we suspect that perhaps there are eyes with very focal leaks that might be well treated with laser and that might not need subsequent anti-VEGF,” she said.

As with most DRCR.net publications, this has been simultaneously published in JAMA Ophthalmology (doi:10.1001/jama.2019.5790), along with editorials and comments from the National Eye Institute.

LEAVO Outcomes

Routine treatment for macular edema due to central retinal vein occlusion (CRVO) “does not support bevacizumab as being interchangeable with aflibercept or ranibizumab,” said Philip Hykin, FRCS, FRCOphth, of Moorfields Eye Hospital, London. He presented results of the LEAVO trial, the first randomized clinical trial to compare the clinical and cost effectiveness of the three widely used anti-VEGF agents – ranibizumab (Lucentis, Roche/Genentech), aflibercept, and bevacizumab (Avastin, Roche/Genentech) – for visual impairment caused by macular edema due to CRVO over a two-year period.

Professor Hykin cautioned that LEAVO was designed as a non-inferiority study to compare bevacizumab or aflibercept to ranibizumab, as that had been the only approved anti-VEGF at the time of the study design. The study randomized 463 patients with CRVO and center-involving macular edema 1:1:1: ranibizumab (n = 154), aflibercept (n = 155), and bevacizumab (n = 154). The primary outcome was change and BCVA letter score from baseline to 100 weeks.

“The mean gain in BCVA at 100 weeks was 12.5 letters for ranibizumab, 15.1 for aflibercept, and 9.8 for bevacizumab,” Professor Hykin stated. Although aflibercept was non-inferior to ranibizumab, he said, “It was not superior.”

Bevacizumab also produced the lowest percentage of patients with a 3-line gain at weeks 52 and 100, with aflibercept and ranibizumab about equal at week 52. LEAVO results were “consistent with the data in the COPERNICUS study,”1 at week 100 (52% in the aflibercept arm gained 3 or more lines). Across all arms, fewer than 5% of patients lost ≥30 letters.

“Optical coherence tomography central subfield thickness across study arms from baseline to 100 weeks showed a steep decrease in thickness initially during the mandated injection phase, small increase during the early PRN phase, but was consistent and mirrored well the VA data, and then slowly decreased again out to 100 weeks,” Professor Hykin said. “The differences at 100 weeks were not statistically significant.”

Also of interest, there were fewer aflibercept injections at week 100 (9.8) compared with ranibizumab (11.8) or bevacizumab (11.5), but data were not presented on statistical differences.

Imaging analyses showed no edema was common in both the aflibercept and ranibizumab arms, but not in the bevacizumab arm. Fundus imaging showed 50% of patients across all arms still had hemorrhages at week 100, however.

“VA can be maintained with monthly injections, but a loss of 3 letters is common once treatment is extended to quarterly,” according to Sobha Sivaprasad, MBBS, MS, DM, FRCS, FRCOphth, of Moorfields Biomedical Research Centre. “Over the long term, the maximum treatment extension should be to eight weeks.”

For questions about this article, please contact Michelle Dalton at mdalton@dalton-and-associates.com.


  1. Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS Study. Ophthalmology 2014;121:1414–20.e1.


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