Aflibercept Best in Diabetics With Bad Baseline Vision?

Becky McCall

March 01, 2016

Two-year results from a study comparing three vascular endothelial growth factor (VEGF) inhibitors — aflibercept (Eylea, Regeneron), bevacizumab (Avastin, Genetech/Roche), and ranibizumab (Lucentis, Genentech/Roche) — in patients with diabetic macular edema (DME) confirm the earlier 1-year findings by continuing to demonstrate that all three worked well.

"In patients with relatively good vision [20/32 or 20/40] at baseline, there was equivalent improvement in vision with the three therapies at 1 and 2 years," Jack Wells, MD, lead author and retinal specialist at the Palmetto Retina Center, Columbia, South Carolina, told Medscape Medical News.

But outcomes differed by the level of visual acuity at baseline, and aflibercept is clearly the better therapy in those patients with center-involved DME and 20/50 or worse eyesight, he stressed.

At 2 years in this worse-vision subgroup, aflibercept "was superior to bevacizumab," he noted.

But at 2 years, there was no longer any significant difference in vision improvement between aflibercept and ranibizumab in those with the worst baseline vision, he said.

Yet he still maintains aflibercept is the superior therapy because it results in less edema, and "If you look at the totality over the course of the study, aflibercept is better most of the way. I would treat patients with aflibercept because they will have better vision more quickly than if treated with ranibizumab," Dr Wells emphasized.

Of the three agents, bevacizumab is by far the cheapest; it is a cancer drug used off-label for DME.

Bevacizumab Best Choice in Mild Loss of Visual Acuity

The 2-year results of the PROTOCOL-T trial, run by the Diabetic Retinopathy Clinical Research Network, are published online February 27 in Ophthalmology, the journal of the American Academy of Ophthalmology, and were also presented this past weekend at the Macula Society meeting in Miami.

Dr Wells remarked that the results will help doctors and their patients with DME choose the most appropriate therapy.

"The study suggests there is little advantage in choosing aflibercept or ranibizumab over bevacizumab when a patient's loss of visual acuity from macular edema is mild, meaning a visual acuity of 20/40 or better."

But "patients with 20/50 or worse vision loss may benefit from aflibercept, which over the course of the 2-year study outperformed ranibizumab and bevacizumab," he asserted.

Retina specialist Rahul N Khurana, MD, clinical associate professor of ophthalmology at University of California, San Francisco Medical Center, and a spokesperson for the American Academy of Ophthalmology, said: "The findings highlight the importance of having all three options available for patients, depending on their risk factors and visual acuity at the time of treatment."

Dr Khurana was not involved with this current study.

Two Years: Aflibercept Still Better Than Bevacizumab

The 1-year results of PROTOCOL-T were published in the March 26, 2015 issue of the New England Journal of Medicine, as reported by Medscape Medical News.

This final analysis of the trial aimed to determine whether differences in treatment effects seen at 1 year were sustained and whether there were any differences in laser frequency between the three intravitreous injection therapies.

The study was performed at 89 clinical sites and included 660 adults with DME involving the macular center. Mean age was 61 years, and approximately 50% of the cohort had 20/50 vision or worse.

Participants were randomly assigned to receive intravitreous injections of aflibercept (2.0 mg), bevacizumab (1.25 mg), or ranibizumab (0.3 mg) performed up to monthly using a protocol-specific follow-up and retreatment regimen.

At each visit, eyes were assessed for retreatment with the relevant anti-VEGF agent based on visual acuity and optical coherence tomography (OCT) criteria. The main end points included the change in visual acuity and macular edema as measured by OCT central subfield thickness, adverse events, and frequency of retreatment.

The 1-year visual acuity analysis found that eyes in the aflibercept group were 63% more likely to gain 15 letters or more than eyes in the bevacizumab group and 34% more likely than eyes in the ranibizumab group.

However, at 2 years, these relative differences had dropped to 12% and 5%, respectively.

Mean Visual Acuity Letter Scores: 1- and 2-Year Results

Mean change in visual-acuity letter score from baseline Aflibercept Bevacizumab Ranibizumab
20/50 or worse vision
1-y change 19.4 12.6 14.7
2-y change 18.1 13.3 16.1
20/32 or 20/40 vision
1-y change 7.9 7.3 8.4
2-y change 7.8 6.8 8.6

The researchers report that overall, visual acuity at 2 years improved from baseline, on average, by 12.8 letters with aflibercept, 10.0 letters with bevacizumab, and 12.3 letters with ranibizumab.

Unsurprisingly, the cumulative number of injections given over 2 years were similar across groups (15,16, and 15 for aflibercept, bevacizumab, and ranibizumab, respectively), reported Dr Wells, and approximately half the number were given in year 2 as in year 1.

Lasers Used Less Frequently With Aflibercept, Less Edema

Lasers were used less frequently across the 2 years in eyes treated with aflibercept compared with the other two therapies.

The protocol allowed for laser at any time after 6 months if persistent edema was present. "Eyes in the aflibercept group were less likely to have persistent edema and so less likely to have laser," Dr Wells pointed out.

Regarding edema, the OCT outcomes showed that overall aflibercept reduced the edema more than the other two therapies. The central subfield thickness decreased on average 171 μm with aflibercept, 126 μm with bevacizumab, and 149 μm with ranibizumab at the 2-year end point.

However, there were some concerning adverse events seen in the study that were unexpected, noted Dr Wells.

Anti-Platelet Trialists' Collaboration (APTC) events, that mainly include strokes and heart attacks, occurred at least once in 5% of patients receiving aflibercept, 8% of those getting bevacizumab, and 12% in the ranibizumab group (global P = .047).

"This finding [with ranibizumab] was unexpected. APTC event rates in other studies have not known shown such a big difference between ranibizumab and the other two drugs. We think this is a surprising chance result and can't draw any conclusions from it," Dr Wells commented.

Nevertheless, these higher APTC event rates with ranibizumab over 2 years warrant continued evaluation in future trials, he and his colleagues say.

Bevacizumab by Far the Cheaper Drug

Based on US Medicare allowable charges, the per-injection costs of each drug at the doses used in this study were about $1850 for aflibercept, $60 for bevacizumab, and $1200 for ranibizumab.

"All three drugs work, but there are a lot of considerations in terms of the insurance coverage or meeting out-of-pocket costs in the decision over which drug to use," said Dr Wells.

There have also been some suggestions that some of the differences seen were due to dosing levels, as reported by Medscape Medical News.

Asked to comment, Dr Wells explained that outside of the United State, the approved ranibizumab dose is 0.5 mg, but the US Food and Drug Administration approved 0.3 mg for diabetic macular edema.

"Genentech [the manufacturer of ranibizumab] conducted two studies to compare the two doses in diabetic macular edema and found no difference between them," asserted Dr Wells. "I can't see how 0.5 mg can be argued as better than 0.3 mg. In fact, Genentech asked the FDA to approve the 0.3-mg dose because it had fewer adverse events associated with it."

Worst Patients: Better Vision More Quickly With Aflibercept

Asked overall how the results might specifically influence clinical practice, Dr Wells said that personally, he would still prefer aflibercept in patients with 20/50 or worse vision even though visual acuity results with ranibizumab catch up by year 2.

Put simply, patients will get better vision more quickly with aflibercept than with ranibizumab, he emphasized.

"The results show that in worse vision, even by weeks 8 to 12, this drug [aflibercept] is better than the other two drugs, and this difference widens further until 12 months of treatment. I wouldn't deny this early benefit to the patient, even though at 2 years a similar improvement in vision is found with ranibizumab."

Dr Wells declares receiving grants from Allergan, Ampio, Kalvista, Emmes, Neurotech, LPath, the National Institutes of Health, and Ophthotech; grants and nonfinancial support from Genentech and Regeneron during the conduct of the study; grants, personal fees, and nonfinancial support from Iconic; and grants and personal fees from Panoptica outside the submitted work. Disclosures for the coauthors are listed in the article. Dr Khurana reports consulting for Allergan, Genentech, and Regeneron and has been involved in research for Allergan and Regeneron.

Ophthalmology. Published online February 27, 2016. Abstract

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