Diabetic Macular Edema: Ranibizumab May Offer Good Outcomes

Norra MacReady

September 05, 2013

In a detailed analysis of patient-reported visual function data, ranibizumab alone or in conjunction with laser therapy was associated with better visual outcomes among patients with diabetic macular edema (DME) than laser monotherapy, in a phase 3, double-masked study.

Ranibizumab is a monoclonal antibody derived from the same mouse antibody as bevacizumab. Both work by blocking the action of vascular endothelial growth factor (VEGF).

Visual improvement associated with ranibizumab, as measured by change in National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) composite score from baseline to month 12, was especially good among patients with a baseline best corrected visual acuity of 68 or higher, which is approximately equal to a Snellen score of 20/50 or better, compared with the benefit among patients with lower visual acuity scores.

This suggests that "the better the level of visual acuity before you start treating, among eyes in this study, all of which had visual impairment at the start of the study, the better the visual acuity will likely be at 1 year," study coauthor Neil M. Bressler, MD, professor of ophthalmology and chief, Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine and Hospital, Baltimore, Maryland, told Medscape Medical News.

The findings, from the Ranibizumab Monotherapy or Combined with Laser vs Laser Monotherapy for Diabetic Macular Edema (RESTORE) trial, are reported in an article published online August 22 in JAMA Ophthalmology.

"[T]his study provides some of the first evidence, to our knowledge, that ranibizumab therapy increases the likelihood of clinically relevant improvements in patient-reported visual functioning, compared with laser alone, for eyes with vision impairment due to DME during a 12-month follow-up period using NEI VFQ-25 composite scores," write Paul Mitchell, MD, PhD, from the Department of Ophthalmology, University of Sydney, Australia, and colleagues.

RESTORE was a 12-month randomized, active-controlled trial that enrolled 345 patients at 73 outpatient retina clinics across Australia, Canada, and Europe. Eligible patients had type 1 or 2 diabetes, DME-related visual impairment in 1 or both eyes, and an Early Treatment Diabetic Retinopathy Study best corrected visual acuity letter score between 78 and 39 (approximate Snellen equivalent, 20/32 - 20/160). The researchers randomly assigned participants to receive ranibizumab monotherapy, consisting of 0.5 mg ranibizumab administered via intravitreal injection, plus sham laser therapy (n = 116); ranibizumab plus laser (n = 118); or laser plus sham injections (n = 111). The ranibizumab and sham injections were administered at baseline, month 1, and month 2 and then according to protocol-defined retreatment criteria up to month 12. The laser treatments were administered on day 1, with subsequent treatments provided according to the investigator's judgment.

In an earlier analysis, the RESTORE investigators found that ranibizumab alone or in combination with laser therapy produced significant improvements from baseline to 12 months in patients' NEI VFQ-25 composite scores compared with laser treatment alone. The new article includes NEI VFQ-25 subscale scores and subgroup analyses according to better-seeing eye or worse-seeing eye, baseline visual acuity, central retinal (subfield) thickness measures on optical coherence tomography, and baseline NEI VFQ-25 composite scores.

Longer Follow-Up Needed

At baseline, the mean NEI VFQ-25 composite scores in the patients assigned to treatment with ranibizumab, laser, or both were 72.8, 73.5, and 74.1, respectively. By 12 months, the mean scores among the patients receiving only ranibizumab had improved by 5 points (95% confidence interval [CI], 2.6 - 7.4) compared with 0.6 points for patients treated with the laser alone (95% CI, −1.8 to 3.0; P = .01). Scores improved by a mean of 5.4 points among patients treated with ranibizumab plus the laser (95% CI, 3.3 - 7.4), which was a statistically significant improvement relative to laser monotherapy (P = .004).

Similarly, for near activities, ranibizumab monotherapy was associated with a 9.0-point improvement (95% CI, 5.0 - 13.0) compared with laser monotherapy, which improved vision by 1.1 points (95% CI, −3.0 to 5.2; P = .01). Combination therapy produced a mean improvement of 9.1 points (95% CI, 5.6 - 12.6; P = .006 compared with laser monotherapy). Distance activities scores among patients receiving ranibizumab monotherapy improved by a mean of 5.3 points (95% CI, 1.8 - 8.9 points) vs a change of only 0.4 points with laser monotherapy (95% CI, −3.1 to 3.8; P = .04), whereas the combination of ranibizumab plus laser improved scores by 5.6 points (95% CI, 2.3 - 9.0) compared with the laser alone (P = .03).

In general, better visual acuity or lower central retinal thickness at baseline were associated with greater improvements with ranibizumab.

By itself, "laser therapy is an effective treatment for DME and has been demonstrated in multiple clinical trials to be helpful in reducing vision loss and in improving vision over several years," Abdhish R. Bhavsar, MD, senior managing partner, Retina Center of Minnesota, Minneapolis, and a clinical spokesperson for the American Academy of Ophthalmology, told Medscape Medical News. However, "recently the Diabetic Retinopathy Clinical Research Network (DRCR.net) trial found that anti-VEGF treatment for DME is superior to laser alone." Dr. Bhavsar was not involved in the RESTORE study.

"Neither the RESTORE nor the DRCR.net protocol showed that laser photocoagulation incrementally improves vision when performed in eyes receiving ranibizumab or as monotherapy in a typical DME study population," said Michael W. Stewart, MD, associate professor and chairman of ophthalmology, Mayo Clinic Florida, Jacksonville. "However, most investigators agree that laser monotherapy is indicated for eyes with localized areas of capillary leakage and fovea-threatening or fovea-involving DME with normal visual acuity," continued Dr. Stewart, who was not involved in RESTORE but has conducted research on ranibizumab.

These findings come from a controlled clinical trial, so their relevance to a real-world population remains to be seen, the authors write. Longer-term follow-up data also are needed to confirm that the benefits of ranibizumab persist, a cautionary note that Dr. Stewart seemed to endorse.

"Generally, the findings of the RESTORE trial are consistent with my own experiences," he said. "Anecdotally, I have not found that DME resolves as quickly with ranibizumab as reported in the RESTORE and other trials."

Dr. Mitchell has reported receiving consultancy fees, lecture fees, and travel support from Novartis Pharma AG, Pfizer, Solvay (Abbott), Bayer, Alcon, and Allergan. Novartis Pharma AG also funds a retina fellowship at Westmead Hospital, Sydney, for which Dr. Mitchell reported serving as supervisor. Dr. Bressler has reported serving as principal investigator of grants at the Johns Hopkins University sponsored by the following entities and the National Institutes of Health: Bayer, Genentech Inc, Lumenis Inc, National Eye Institute, Notal Vision, Novartis Pharma AG, Optovue, Regeneron Pharmaceuticals Inc, and the EMMES Corporation. Other authors have reported receiving funding from or being an employee of Novartis Pharma AG, Sanofi, Alcon Inc, Alimera Sciences Inc, Allergan Inc, Bausch and Lomb, Bayer Schering Pharma, Farmila-Thea, Genentech Inc, Hoffmann-LaRoche Ltd, Pfizer Inc, Novartis Pharmaceuticals Corporation, sanofi-aventis, and Thrombogenics Inc. Dr. Stewart is on the advisory boards of Allergan and Regeneron and is a consultant to Boehringer-Ingelheim. Dr. Bhavsar has disclosed no relevant financial relationships.

JAMA Ophthalmol. Published online August 22, 2013. Abstract


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