Laser photocoagulation remains option for diabetic macular edema

Amidst a search for alternate treatments and despite incomplete response to therapy in some patients, laser photocoagulation is still a viable option in the treatment of diabetic macular edema.

Michael S. Ip

In an era when intravitreal injection has come to dominate the landscape of retinal practice, laser photocoagulation remains a feasible treatment for patients with diabetic macular edema.

Based on more than 2 decades of evidence from large clinical trials, laser photocoagulation is widely regarded as a standard of care for treatment of diabetic macular edema. However, incomplete response to therapy in some patients has prompted a search for alternatives that deliver higher success rates.

The nonresponder rate seen in early laser trials was a driving force behind recent efforts to identify alternate treatment modalities. Most recently, that effort has been led by the Diabetic Retinopathy Clinical Research Network (DRCR.net), which originally sought to compare laser with intravitreal triamcinolone injections.

“It was really designed to see if there was a new treatment that would be superior in visual acuity results to laser photocoagulation, which was the gold standard for many years,” Michael S. Ip, MD, a DRCR.net investigator, said.

In a more recent development, the collaborative research effort has designed and published the first results of a clinical trial to compare laser with an anti-VEGF and laser combination, again in an effort to achieve better treatment success. In two arms of the trial, laser therapy was combined with anti-VEGF therapy, with the hypothesis that the combination therapy might improve the odds for treatment success.

“Certainly, better treatments are always welcome, especially given the apparent consistent ability to improve visual acuity with laser photocoagulation,” Dr. Ip said.

ETDRS data

Starting in the early 1990s, with the publication of results from the Early Treatment Diabetic Retinopathy Study, laser photocoagulation became the predominant treatment paradigm for macular edema secondary to diabetes, albeit with a caveat. In that study, prompt focal laser photocoagulation, rather than scatter photocoagulation, was found to lower the risk of moderate vision loss compared with delayed laser treatment. Researchers recommended that laser treatment be considered when macular edema threatened the center of the macula.

The ETDRS showed that 17% of patients gained more than three lines of vision. However, characteristics of enrolled patients may have limited the extent to which the patient population benefited from early laser photocoagulation.

In a presentation at the Retina 2010 meeting, Andrew P. Schachat, MD, said that the ETDRS enrolled a large percentage of patients with better than 20/40 vision at baseline — patients incapable of gaining three lines of vision. In that study, risk of vision loss was halved in the laser group, 3% gained three lines and 17% had any vision improvement at 5 years.

But, according to Dr. Schachat, a large number of patients with visual acuity worse than 20/40 at baseline gained three lines of vision by the study’s end.

“The ETDRS was a setup to not be able to have improvement,” he said. “Of those who could gain three lines of vision, about 40% did so.”

The 40% finding is similar to the 47% of laser recipients with vision gain at 4 years reported in the recent DRCR.net protocol B study, which tested laser therapy against intravitreal triamcinolone injection. Other researchers have consistently noted that glycemic control is the most assured way of reducing the degenerative effects of diabetes on retinal health. Yet, in the controlled clinical trial setting, focal/grid photocoagulation achieved better long-term outcomes than any other available treatment.

In the DRCR.net protocol B study, results suggested that steroid did, in fact, improve vision while reducing central macular thickness more so than laser. However, after 4 months, the difference was no longer statistically significant, and by 16 months, laser had overtaken steroid. In addition, patients treated with laser had fewer adverse treatment effects, such as cataract or increased IOP.

In a 2008 report on their findings, the DRCR.net researchers wrote: “The strongest scientific evidence currently supports focal/grid photocoagulation as the most effective treatment for patients with DME who have similar characteristics to the cohort in this clinical trial. The results of this study also support that focal/grid photocoagulation currently should be the benchmark against which other treatments are compared in clinical trials of DME.”

To most, the findings translated directly to clinical practice. The manner in which the large, multicenter DRCR.net trial was conducted suggests that the results are generalizable to the clinical setting, in that it called for long-term follow-up of patients enrolled at clinics and academic centers representing a large swath of the U.S. demographic landscape.

“I do think the results from that clinical trial are generalizable as much as any results of a clinical trial can be generalizable, because it wasn’t a trial that was just university-based clinical sites,” Dr. Ip said. “To some extent, every clinical trial has to have some restrictions on who to enroll, but given the restrictions we had, I think it is fair to say that we can extrapolate the results from DRCR.net protocol B to the general population of patients with characteristics similar to those enrolled in the trial.”

Role of anti-VEGF

Despite the effectiveness of laser described in the protocol B study, there was still a high rate of nonresponders: About 50% of laser-treated patients still had significant central retinal thickness at 2 years, and 20% had worse vision than at the time of enrollment.

On the heels of the protocol B study, and in response to numerous case series touting the efficacy of anti-VEGF therapy for reducing macular edema secondary to diabetes, the DRCR.net researchers designed their protocol I study, comparing Lucentis (bevacizumab, Genentech) with prompt laser vs. ranibizumab with deferred laser vs. laser alone.

After 1 year of follow-up, both ranibizumab groups had significantly improved vision compared with the laser treated group. Two-year follow-up is planned and data are forthcoming.

“For the first time, we’ve shown that something other than laser alone is effective. The mean difference between the combination ranibizumab and laser group vs. the laser-alone group was a mean of nine letters, and that’s a fairly significant difference in visual acuity,” Dr. Ip said.

Yet, the results of this recent trial might take time to change the current standard of care. For one, patients in the protocol I study were followed using a fairly complex re-treatment algorithm. Additionally, patients often required multiple injections to achieve successful treatment, which is not an insignificant consideration, Dr. Ip said.

“On average, patients in the first year received nine ranibizumab injections, so it’s a relatively large number of ranibizumab injections, so that treatment does come with attendant costs in terms of patient convenience and physician time in the office,” he said.

Also, anti-VEGF treatment alone has not been compared in a large, multicenter trial with laser alone, although that is being done in the RISE and RIDE trials sponsored by Genentech. Additionally, ranibizumab has not been compared directly with Avastin (bevacizumab, Genentech), nor will the results from the CATT trial be directly applicable given the separate disease states and patient populations. Yet, questions about the efficacy of ranibizumab vs. bevacizumab may be important given the significantly higher cost of the former.

Finally, ranibizumab, like bevacizumab, is not yet approved by the U.S. Food and Drug Administration for use in diabetic macular edema. Ranibizumab may be superior to laser, but its use in the clinic may hinge on cost and insurance coverage considerations.

“Maybe right now, this is all hypothetical, because some patients may not have ready access to ranibizumab injections at present,” Dr. Ip said. “This, however, may change in the near future as some local carriers have made or will soon make decisions to cover ranibizumab for diabetic macular edema. If and when ranibizumab becomes widely available, I do think that ranibizumab will become a mainstay of therapy. Most likely, clinicians will follow a re-treatment algorithm similar to what was seen in protocol I.” – by Bryan Bechtel

References:

• Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmol. 2010;117(6):1064-1077.e35.
• Diabetic Retinopathy Clinical Research Network, Beck RW, Edwards AR, et al. Three-year follow up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127(3):245-251.
• Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmol. 2008;115(9):1447-1449.e1-e10.
• Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmol. 1991;98(5 Suppl):766-785.
• Schachat AP. A new approach to the management of diabetic macular edema. Ophthalmol. 2010;117(6):1059-1060.
• Schachat AP. A new look at an old treatment for diabetic macular edema. Ophthalmol. 2008;115(9):1445-1446.

• Michael S. Ip, MD, can be reached at University of Wisconsin, Fundus Photograph Reading Center, Park West One, 406 Science Dr., Suite 400, Madison, WI 53711-1068; 608-263-2853; fax: 608-262-1899; e-mail: msip@wisc.edu.
• Andrew P. Schachat, MD, can be reached at the Cole Eye Institute, i-30 Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; 216-444-7963; e-mail: schacha@ccf.org.