Putting DRCRnet Findings Into Clinical Practice

Studies evaluate surgical and pharmaceutical therapies.

ALI A. ZAIDI, MD

For more than a decade, the Diabetic Retinopathy Clinical Research Network (DRCRnet) has researhed a number of protocols for the treatment of diabetic retinopathy and diabetic macular edema. Funded primarily by the National Eye Institute, but also with the support of other sponsors, including Genentech (South San Francisco, CA) and Allergan (Irvine, CA), the DRCRnet’s treatment protocols have focused largely on combination therapies, particularly since the introduction of anti-VEGF agents for AMD.

Three of the more recent protocols — I, J, and N — examined the safety and efficacy of anti-VEGF drugs compared to or in combination with steroid and laser treatment. I discuss these studies below, according to their protocol designations. Because not all of the trials have reported data, some of the letters in the alphabetic sequence are missing.

My previous article, published in the April 2010 issue of Retinal Physician, summarized DRCRnet protocols A through H. I report here on the most recent subsequent publications.

PROTOCOL I

This phase 3, randomized, controlled clinical trial of approximately 850 eyes evaluated three different treatments for DME: (1) intravitreal 0.5-mg ranibizumab (Lucentis, Genentech) combined with prompt or deferred (24 weeks or more) focal/grid laser; (2) 4-mg triamcinolone acetonide (Kenalog, Bristol-Myers Squibb, New York, NY) combined with prompt focal/grid laser; or (3) sham injections with prompt focal/grid laser alone.¹

At two years of follow-up, the ranibizumab and deferred laser group had the best outcomes, with a median gain of 9 letters of visual acuity, followed by the ranibizumab plus prompt laser group, with a gain of 8 letters, and then the triamcinolone plus prompt laser and sham plus prompt laser groups, which both gained 6 letters (Table, page 24).

In the ranibizumab groups, the patients required a median of 8-9 injections during the first year and 2-3 injections during the second year. While the patients gained vision, approximately 40% had central macular edema seen on OCT at the two-year visit.

No increase in systemic adverse events occurred in the ranibizumab vs laser groups.

Subgroup Analysis

In the pseudophakic subgroup, the triamcinolone plus prompt laser group experienced a median gain of 9 letters, which was similar to the ranibizumab groups.

A follow-up study compared the ranibizumab plus prompt laser vs ranibizumab plus deferred laser groups at three years.² The prompt laser group required fewer injections over three years (12 vs 15 injections).

However, visual outcomes were superior in the deferred laser group: the prompt laser group gained a median of 8 letters vs 11 letters in the deferred laser group (P=.02). More patients gained more than 10 letters of vision in the deferred laser group than in the prompt laser group (56% vs 42%, P=.02).

Exploratory Analysis

An exploratory analysis, based on data from this study, evaluated the effect of ranibizumab or triamcinolone on the worsening of diabetic retinopathy.³ This analysis found that ranibizumab and triamcinolone were associated with a reduced risk of worsening of DR. Given the exploratory nature of the study and the adverse effects of intravitreal injections, the authors could not recommend using these agents solely for the prevention of worsening of DR.

These studies established that treatment with ranibizumab was superior to laser alone for DME. The addition of focal laser at the initiation of ranibizumab therapy did not result in better outcomes. Ranibizumab and triamcinolone also appeared to be protective against worsening of the severity of DR.

PROTOCOL J

This randomized, controlled clinical trial of approximately 350 eyes evaluated the use of ranibizumab or triamcinolone as adjuvants to focal laser and panretinal photocoagulation in eyes with DME and PDR.⁴

The protocol divided the patients into three groups: (1) sham injection followed by focal laser and PRP; (2) ranibizumab injection followed by focal laser and PRP and then a second ranibizumab injection at four weeks; or (3) triamcinolone injection followed by focal laser and PRP.

At 14 weeks, the eyes in the sham injection followed by laser group lost a mean of 4 letters of vision, the ranibizumab group gained a mean of 1 letter of vision, and the triamcinolone group gained a mean of 2 letters of vision (with a statistically significant difference).

The results were not maintained at the final 56-week follow-up visit. The authors concluded intravitreal triamcinolone or ranibizumab might reduce the risk of exacerbation of DME and visual acuity loss at up to 14 weeks following PRP in eyes also receiving laser for DME.

PROTOCOL N

This phase 3, randomized, controlled clinical trial of approximately 260 eyes compared three monthly ranibizumab injections with three monthly saline injections in eyes with vitreous hemorrhage from PDR.⁵ The main outcome was the rate of vitrectomy in each group at 16 weeks.

The rate of vitrectomy in the ranibizumab group was 12%, compared to 17% in the saline injection group — a difference that was not statistically significant (P=.37). Both groups had low rates of vitrectomy, which limited the power of the study to detect a difference.

A difference in secondary outcomes emerged between the two groups. The rate of completion of PRP was 44% in the ranibizumab group vs 31% in the saline group (P=.05). Greater improvement in visual acuity also occurred in the ranibizumab group than in the saline group (22 vs 16 letters, P=.04). The study did not find an increased risk of tractional or rhegmatogenous retinal detachments in the ranibizumab group. The authors found little likelihood of a clinically important difference between intravitreal ranibizumab and saline on the rate of vitrectomy at 16 weeks in eyes with vitreous hemorrhage from PDR.

FUTURE STUDIES

The DRCRnet is currently conducting clinical trials to address other important questions on the management of diabetic retinopathy. Protocol R is evaluating the efficacy of the topical NSAID nepafenac (Ilevro, Alcon, Fort Worth, TX) compared to placebo in noncentral DME. The primary outcome is retinal volume, and a secondary outcome is progression to center-involving DME.

Protocol T is comparing the efficacy and safety of ranibizumab, bevacizumab (Avastin, Genentech), and aflibercept (Eylea, Regeneron, Tarrytown, NY) in the treatment of center-involving DME.

CONCLUSION

The clinical studies conducted by the DRCRnet have added greatly to our knowledge of the management of DR. Anti-VEGF therapy appears superior to laser alone for the treatment of DME. Ongoing studies may help to identify which anti-VEGF agent is the most safe and effective.

The research by the DRCRnet will continue to add to our understanding of DR and provide new ways of treating this major cause of visual impairment. RP

REFERENCES