Ranibizumab Deemed Major Advance for Diabetic Retinopathy

Caroline Helwick

November 14, 2015

LAS VEGAS — Ranibizumab, a vascular endothelial growth-factor (VEGF) inhibitor that is part of the existing armamentarium for retina specialists, may be the first major treatment advance in 40 years for proliferative diabetic retinopathy, new research suggests.

In the Protocol S study, injections of ranibizumab yielded superior vision over the course of 2 years, and reduced the incidence of diabetic macular edema and peripheral visual field loss compared with panretinal photocoagulation, the standard treatment for proliferative diabetic retinopathy.

"Panretinal photocoagulation has been effective for proliferative diabetic retinopathy over the last 4 decades," but ranibizumab is at least as good for visual acuity at 2 years, said Jeffrey G. Gross, MD, who chaired the study, sponsored by the Diabetic Retinopathy Clinical Research Network (DRCDnet).

Dr Gross, from the Carolina Retina Center in Columbia, South Carolina, added that ranibizumab may become "the preferred initial treatment approach for some patients."

The results of the study were presented here at the American Academy of Ophthalmology (AAO) 2015 Annual Meeting and were simultaneously published online November 13 in JAMA.

Photocoagulation "Inherently Destructive"

Proliferative diabetic retinopathy leads to blindness in between 12,000 and 24,000 persons a year in the United States, Dr Gross reported. Panretinal photocoagulation is the standard treatment for reducing severe visual loss, but it has its drawbacks.

"Panretinal photocoagulation substantially reduces the risk of severe vision loss, but it's inherently destructive. It can cause peripheral visual field loss and night vision loss, and can exacerbate preexisting diabetic macular edema," said Dr Gross during his presentation.

"It's also not perfect. Severe vision loss (worse than 5/200 at two consecutive visits) still occurs in 5% of patients," despite treatment, he added.

"Anti-VEGF, when given for diabetic macular edema, decreases the risk of diabetic retinopathy worsening and increases the chance of improved retinopathy level," he noted.

Study Details

To evaluate ranibizumab in patients with proliferative diabetic retinopathy, the researchers conducted a multicenter 55-site study to determine whether visual acuity using ranibizumab was noninferior to treatment with panretinal photocoagulation at 2 years. The noninferiority margin was 5 letters on the visual-acuity letter score; a difference exceeding 5 letters was judged to be a clinically important difference.

Secondary outcomes included the effect of ranibizumab on vision throughout follow-up, peripheral vision loss, the development of macular edema, and the incidence of vitrectomy.

The study included 305 adults (394 eyes) with proliferative diabetic retinopathy. Eyes with or without central-involved diabetic macular edema were eligible. Approximately one quarter of each treatment group had diabetic macular edema with visual acuity loss at baseline.

Individual eyes were randomly assigned to receive panretinal photocoagulation (n = 203) or ranibizumab 0.5 mg (n = 191). Photocoagulation was completed in one to three visits; ranibizumab was given by intravitreous injection at study entry, and as frequently as every 4 weeks thereafter based on a structured retreatment protocol.

If the size or amount of neovascularization increased after initial panretinal photocoagulation, then additional injections could be administered; this was done for 45% of this group.

Ranibizumab Effective on Multiple Endpoints

The mean improvement in the visual acuity letter score at 2 years was +2.8 in the ranibizumab group vs +0.2 in the photocoagulation group, for a difference of +2.2 (P < .001 for noninferiority). The mean change in the visual acuity letter score over the course of 2 years (area under the curve) was +4.5 for the ranibizumab group compared with −0.3 for the PRP group, for a mean difference of +4.2 (P < .001).

For eyes with diabetic macular edema at baseline, the mean change in visual acuity differed between the ranibizumab and photocoagulation groups by +3.0; for eyes without baseline macular edema, the mean differed by +1.4, with both differences favoring ranibizumab.

In addition to panretinal photocoagulation, 35% of the laser treatment group received ranibizumab for diabetic macular edema at baseline, and an additional 18% received it for macular edema within the 2 years of the study, the study authors report.

The findings suggest that ranibizumab may have been protective against new macular edema development, which was observed in 9% of the ranibizumab group and 28% of the laser group (P < .001). Furthermore, the laser group had more peripheral visual field loss (P < .001) and required more vitrectomies (P < .001).

Few patients (6%) in the ranibizumab group required panretinal photocoagulation during the study. It was "rarely given for futility or failure," said Dr Gross.

In addition, no systemic safety concerns with ranibizumab were identified, apart from one case of endophthalmitis in the ranibizumab cohort. The photocoagulation group experienced more inflammation, a greater need for cataract surgery, and elevation in intraocular pressure.

Whether the results would be similar with ranibizumab 0.3 mg or with bevacizumab or aflibercept remains unknown at this time, Dr Gross added.

Effect of Diabetic Macular Edema on Treatment

Dr Gross discussed the potential effect of diabetic macular edema when initiating treatment of diabetic retinopathy.

"When diabetic macular edema is present and treatment with an anti-VEGF agent is planned, panretinal photocoagulation may be unnecessary in most cases, provided that the patient is expected to be compliant with follow-up," he said. If macular edema is not present, ranibizumab is more effective in preserving visual function, but cost, compliance, and patient preference should be considered, he added.

Session participant Jennifer K. Sun, MD, associate professor of ophthalmology at Harvard Medical School in Boston, Massachusetts, said that for most patients with macular edema at baseline, "anti-VEGF is first-line treatment."

On the basis of the study results, she added, "I am very comfortable starting with ranibizumab as long as I have a fairly compliant patient who does not have lots of neovascularization. I would continue this until diabetic macular edema is resolved," and then evaluate whether to continue anti-VEGF treatment or initiate photocoagulation.

For the high-risk patient without macular edema at baseline, Neil M. Bressler, MD, said his greatest concern pertains to follow-up.

"It all depends on this. If I believe the patient will come in for follow-up, I will start with anti-VEGF. Before the results of Protocol S, I was not doing this," said Dr Bressler, the James P. Gills Professor of Ophthalmology and chief of the Retina Division at the Wilmer Eye Institute at Johns Hopkins, Baltimore.

"It is associated with less peripheral field loss and less chance of edema forming, so I think the patient will function better," he said. However, "if the patient is not going to come for follow-up, then panretinal photocoagulation is a great treatment."

In an accompanying editorial to the JAMA paper, Timothy W. Olsen, MD, from Emory University, Atlanta, Georgia, wrote that although short-term use of anti-VEGF agents seems to represent a viable alternative therapy for adherent patients with high-risk proliferative diabetic retinopathy, photocoagulation remains the standard of care and may be the best long-term treatment option.

The DRCRnet will continue to follow patients in this study for a total of 5 years.

This work was funded through the National Institutes of Health and the US Department of Health and Human Services. Genentech provided the ranibizumab and clinical site funding. Dr Gross has received grant support from Regeneron and Acucela. Dr Bressler and Dr Sun have received grant support from Genentech and numerous other companies. Dr Olsen reports that he serves as the site principal investigator for a lampalizumab study by Genentech-Roche and does not accept any consulting fees or direct salary support.

JAMA. Published online November 13, 2015. Article full text, Editorial full text

American Academy of Ophthalmology (AAO) 2015 Annual Meeting. Presented November 13, 2015.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: