Diabetic Macular Edema: Three VEGF Inhibitors Similar

Lara C. Pullen, PhD

February 20, 2015

Aflibercept, bevacizumab, and ranibizumab all improve vision in eyes with center-involved diabetic macular edema, according to a randomized clinical trial. The relative effect of the three drugs depended on baseline visual acuity, with aflibercept being more effective in patients with worse levels of initial visual acuity.

The Diabetic Retinopathy Clinical Research Network published the results of the trial online February 18 in the New England Journal of Medicine. The researchers performed the study at 89 clinical sites and included 660 adults with diabetic macular edema involving the macular center. They randomly assigned participants to receive intravitreous aflibercept (2.0 mg), bevacizumab (1.25 mg), or ranibizumab (0.3 mg).

Patients were treated on an as-needed basis as often as every 4 weeks, as opposed to on fixed dose intervals.

From baseline to 1 year, the mean visual-acuity letter score improved by 13.3 with aflibercept, 9.7 with bevacizumab, and 11.2 with ranibizumab. The improvements were greater with aflibercept than with the other drugs (aflibercept vs bevacizumab, P < .001; aflibercept vs ranibizumab, P = .03). A closer examination of the data, however, revealed that the difference between the drugs was driven by improvements in eyes with worse visual acuity at baseline (P < .001 for interaction).

The investigators found no difference between the three drugs when visual acuity loss was mild (initial visual acuity score, 78 - 69). In these patients, the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P > .50 for each pairwise comparison).

When the initial letter score was less than 69, however, the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P < .001 for aflibercept vs bevacizumab, P = .003 for aflibercept vs ranibizumab, and P = .21 for ranibizumab vs bevacizumab).

The three groups did not differ with regard to adverse events (serious adverse events, hospitalizations, death, or major cardiovascular events).

"There is something in the results for everybody," author Lee M. Jampol, MD, from Northwestern University in Chicago, Illinois, explained to Medscape Medical News. Although all drugs performed well, aflibercept appears to be the best choice for patients with more severe vision impairment.

"The results are somewhat surprising in this condition, since other head-to-head comparisons in age-related macular degeneration did not show differences in these drugs. This speaks more toward the disease state being treated, and that subtle differences in the drugs may be more impactful under these circumstances," Rishi Singh, MD, from the Cleveland Clinic in Ohio, told Medscape Medical News. Dr Singh was not affiliated with the study, but has served as a consultant and performs clinical research trials for Genentech/Roche and Regeneron/Bayer.

Treating Patients With Diabetic Macular Edema

Increases in diabetes and diabetic retinopathy have translated into an increased number of patients with diabetic macular edema being treated by ophthalmologists.

"The bottom line for physicians is that, in those patients with worse vision, 20/50 or worse, aflibercept improves vision to a greater extent than bevacizumab or ranibizumab. At vision levels better than this, all drugs perform equally well. This comparative effectiveness study, spurred on from studies like the [Comparison of Age-related Macular Degeneration Treatment Trials (CATT)] trial, evaluates cheaper agents in comparison to more expensive ones," explained Dr Singh.

The current study found that the more expensive agent (aflibercept) performs better in patients with worse vision.

The study results also underscore the possibility of effective as-needed treatment. Dr Singh explained that ophthalmologists had assumed that fixed-interval dosing would be superior to as-needed dosing. The visual gains seen in this study, however, are similar to those seen in the phase 3 fixed dosage trials of these agents.

Dr Jampol reiterated an acknowledged concern among ophthalmologists about repackaging bevacizumab: Although bevacizumab is widely used by ophthalmologists, its use is off-label.

Bevacizumab is sold as an anticancer drug (Avastin, Genentech, Inc) and must be repackaged by the pharmacist. "If Avastin continues to be used, and we expect that it will be, then this repackaging issue needs to be paid attention to," he elaborated.

Dr Jampol reports grant support from the National Eye Institute during the conduct of the study, personal fees from Quintiles/Stem Cell Organization, and nonfinancial support from Novartis outside the submitted work. Several co-authors report receiving fees or grants from one or more of the following companies: Alimera, Allergan, Genentech, Regeneron, Valeant, Bayer, Aerpio, Novartis, Pfizer, Ophthotec, DRCR Network, Optovue, Eisai, Kowa, Boston Micromachines, Kalvista, Abbott Laboratories. Full conflict-of-interest information is available on the journal's website. Dr Singh is a consultant and performs clinical research trials for Genentech/Roche and Regeneron/Bayer.

N Engl J Med. Published online February 18, 2015. Full text


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