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January 2009 Supplement January 2009 Supplement

Laser Therapy's Role in Managing DME

Laser photocoagulation remains the most effective treatment for diabetic macular edema.

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Laser therapy has been part of our armamentarium for treating diabetic macular edema (DME) since the mid-1980s. Twenty-plus years later, the question is: Is this a procedure we still want to be doing and doing regularly, or are we ready to cast it aside in favor of pharmacologic means for treating macular edema?

FOCAL/GRID LASER IN THE ETDRS
I am using the term focal/grid laser photocoagulation to refer to the technique that was evaluated in the Early Treatment Diabetic Retinopathy Study (ETDRS), a two-part treatment performed at one sitting.1 For the focal component of the treatment, you first identify the focal leakage sites within the area of thickened retina, namely microaneurysms, and directly ablate them with light intensity and small spots of photocoagulation. For the grid component, you place a limited macular scatter pattern within the areas of edematous or thickened retina, being careful to place these spots between spots that have already addressed the focal leaks. The grid treatment generally corresponds to areas of leaking capillary beds on fluorescein angiography.

This is the treatment that we have been using for more than 20 years. We call it modified now because we use a lighter-intensity burn, and most clinicians use the 50-μm spot size.

LESSONS FROM THE ETDRS
From the ETDRS, we learned that performing focal/grid treatment reduced the risk of moderate vision loss—three or more lines of acuity—as compared with no treatment. We also learned that, when monitored for 3 years, only 15% of patients with clinically significant macular edema, center-involved or noncenter-involved, who received focal/grid treatment experienced moderate vision loss. This was half as frequently as the eyes assigned to observation. That summarizes the primary outcome of the ETDRS, which has led us to do focal/grid treatment for eyes with DME for the last 20 years.

We also learned in the ETDRS that eyes with less severe (not considered clinically significant) macular edema in the treatment group had reduced rates of moderate vision loss as compared with eyes with equivalent degrees of macular edema in the observation group. We concluded, however, that it was probably reasonable to monitor eyes with lesser degrees of macular edema, follow them until they developed clinically significant edema, and then perform the focal/grid treatment rather than intervene during earlier phases of macular edema.

At the end of the ETDRS, we were disappointed that, despite successful treatment and decreased retinal thickening, only 17% of patients recovered three or more lines of acuity relative to their entry levels of vision. That is why we have been searching for better treatments. In addition to being able to stop vision loss over time, we would like to be able to restore vision in a greater proportion of patients.

TWENTY YEARS LATER
At the beginning of this decade, some isolated cases and then small case series touted the benefits of intravitreal steroid administration.2,3 After putting steroids into the vitreous, several researchers observed that some eyes experienced a rapid reduction in retinal thickening, as confirmed by optical coherence tomography (OCT). Some of those patients also had an associated improvement in visual acuity as their edema improved. So with the presentation and publication of those short-term, small case series, the retina community began experimenting with intravitreal steroids.

In the 2005 Preferences and Trends survey conducted by the American Society of Retina Specialists, more than 90% of the 370 respondents reported they were using intravitreal steroids to manage patients with persistent DME. That set the stage for a randomized clinical trial to compare our gold standard treatment, focal/grid laser, with intravitreal steroids. The Diabetic Retinopathy Clinical Research Network (DRCR.net) recently completed and published results from such a study.4

STUDY DESIGN, OBJECTIVE, ELIGIBILITY
The recently completed DRCR.net trial was a multicenter, randomized clinical trial with three treatment arms: photo-coagulation and two dosages (1 mg or 4 mg) of preservative- free triamcinolone acetonide delivered intravitreally. The primary goal was to compare the efficacy and safety of the steroid vs laser therapy. We looked at two dosages of triamcinolone because we expected complications, such as glaucoma and cataract, and we wanted to find out if a lower dosage would reduce the frequency of complications while providing the same degree of efficacy. Follow-up visits were quarterly for 3 years, and all patients were eligible for retreatment with the treatment assigned at entry as often as every 4 months if edema persisted.

The primary outcome assessment was at the 2-year visit, and the major outcome variable was visual acuity, specifically the average change in vision over time. The scientific objective was mean change in visual acuity; the regulatory objective, as proposed by the US Food and Drug Administration, was the proportion of patients with a decrease of ≥15 letters. An important secondary measure was retinal thickening on OCT.

Patients were eligible to participate if they had type 1 or type 2 diabetes. Every patient had DME with center involvement, which was confirmed on OCT with a central subfield thickness reading of at least 250 μm. Best-corrected visual acuity could not be better than 20/40 or worse than 20/320. We studied 840 eyes (about 140 people had both eyes in the study) with about 250 people enrolled in each of the treatment arms. Follow up at the 2-year visit was nearly 90%.

KEY STUDY RESULTS
At 2 years, individuals who had been assigned to laser, on average, gained one letter of acuity on standardized eye charts; whereas, those receiving the lower dose steroid, on average, lost two letters, and those receiving the higher dose steroid, on average, lost three letters, which is equivalent to half a line of vision. When you compare the distribution of changes in vision over time, the differences in outcomes always favored laser treatment.

Looking at the median acuity, note that all three groups began balanced—somewhere between 20/50 and 20/60 (Snellen equivalent)—and 4 months into the study, the steroid group showed improvement. Relative to the laser group, on average, vision in both steroid groups was improving, particularly patients receiving the higher-dose steroid. A year later, however, visual acuity in the laser group was slowly improving, while visual acuity in the steroid groups was declining from their initial upturn. The difference between the groups became significant at month 16 in favor of laser, and that significant difference was maintained through month 24. The laser-treated eyes had a slight improvement overall relative to baseline, and the steroidtreated eyes had a slight diminution, so that there was a significant difference when comparing laser to either of the steroid groups.

Considering that vision in the steroid-treated groups improved initially and then declined, you might wonder if these patients were developing cataracts from the repeated intravitreal steroid injections. We took the presence of cataract off the table by analyzing the data and confining our review to people who were pseudophakic when they joined the study or who had undergone cataract surgery at some point before the 2-year visit, or people for whom the retina surgeon determined had minimal or no cataract at the 2- year visit. Even isolating the analysis to these individuals, the laser-managed eyes did better over time than those receiving steroids (Figure 1). Even if we look only at the relatively small number of people who were pseudophakic at baseline— maybe one-sixth of the participants—if anything, the 2-year outcomes favored laser. So we cannot blame cataract for interfering with the vision outcomes in the steroid group.

What about central subfield thickness on OCT? Note that the three groups started balanced with central subfield thickness measurements of about 400 μm. At 4 months, as anticipated, the steroid group rapidly acted like a reverse sponge, drying up. The laser-treated eyes slowly demonstrated further reductions in central subfield thickness, however, so that by month 16, they had the most edema resorption (Figure 2). This is a significant difference that persisted through 24 months, favoring the laser-treated eyes.

We saw few complications, such as retinal detachments or endophthalmitis, from intravitreal injections; however, four patients in the 4-mg dosage group needed filtration surgery to manage elevated IOPs. Roughly 30% of individuals in this treatment group had IOP increases of 10 mm Hg or more during the study.

Investigators were encouraged to remove visually significant cataracts that developed during the study, and some older patients in the laser group had cataract surgery during the 2 years. The rate of cataract surgery doubled in the lower-dose steroid group, and then doubled again with the higher dose relative to the laser-treated eyes. In the 4-mg triamcinolone group, one-half of the initially phakic eyes needed cataract surgery during the 2 years while receiving, on average, three intravitreal steroid injections.

STUDY RESULTS PROMPT NEW QUESTION
The visual acuity benefit at 4 months favored the higherdose steroid, which was consistent with results from the small case series reported earlier. By 1 year, however, there was no advantage for the steroids, and by 2 years, there was a clear-cut advantage for laser treatment in terms of visual outcome and fewer adverse effects. The OCT findings paralleled the visual acuity outcomes.

Twenty years after the ETDRS report, we have evidence that focal/grid photocoagulation is very much here to stay and in our patients’ best interests. It is the most effective means of managing DME, and looking forward, it must remain the benchmark for any further clinical trials. Given what we know now about the importance of photocoagulation in managing eyes with DME, we need to ask: Should we forego the focal component of laser treatment and the angiograms required to identify the focal sites of leakage and just grid the posterior pole? The DRCR.net addressed this question in a prospective randomized study.

DRCR.NET PILOT STUDY
This study of 263 patients compared the modified ETDRS (mETDRS) focal/grid laser technique with a mild macular grid (MMG), a technique in which burns were placed throughout a zone within 3,000 μm of the fovea, about one burn width apart, whether or not the retina was thickened.5 Figure 3 shows an eye that was treated with the mETDRS focal/grid treatment. You can barely see the light intensity burns. In contrast, Figure 4 shows the MMG grid treatment that we explored. Treatment spots began about 500 μm from the foveal center and extended almost to the arcade, about 2 disc diameters in every direction, utilizing a light intensity such that 6 weeks later, not much is visible in the fundus.

With 200 patients enrolled, we had excellent power to detect a minimum difference of 50 μm in central retinal thickening between these two laser modalities on OCT. There were 323 eyes randomized within this trial, about half in each laser technique group. Follow up at the 12-month visit was 88%.

As Figure 5 shows, the differences in central subfield thickness between groups are not statistically significant, but we see a trend toward thinner measurements in the mETDRS laser technique group.

What about vision improvement? At follow-up visits at 3, 8, and 12 months, a higher proportion of patients in the mETDRS group are achieving moderate vision improve-ment. Similarly, for vision loss of three or more lines of acuity at 3.5 months and again at 12 months, a smaller proportion of those who are receiving focal/grid treatment are losing vision compared to those in the grid group (Figure 6).

The bottom line is: The MMG treatment appears to be less effective in reducing retinal thickening than the mETDRS treatment, as confirmed by OCT. These results suggested that a much larger trial exploring grid photocoagulation is not necessary because it is unlikely we would find it superior to the more traditional focal/grid technique. We saw no data that suggested we should change the technique we have been using.

We did recognize, however, that by 1 year, edema had resolved in only 30% of subjects who had undergone mETDRS treatment. These outcomes support the need for us to continue to explore other treatments.

LASER PREVAILS AS SEARCH CONTINUES
Is focal/grid treatment still indicated to treat DME? My answer is an emphatic yes. By performing this procedure in eyes with clinically significant edema, particularly centerinvolved, we are reducing the risk of moderate vision loss over a 2-year period to about 20%. We now also recognize there is more vision improvement than we thought previously. Unfortunately, 20% of patients will decline, so we must continue to search for more ways to treat them.

In this trial, we evaluated eyes that started at 20/40 or worse, so that every eye had the potential to recover 3 or more lines of vision. In fact, one of three study eyes had two or more lines of acuity improvement with focal/grid laser treatment. That frequency of vision improvement is much better than we formerly thought. So the bar for improved outcomes with new treatment modalities is somewhat higher than we formerly thought. Although there are other potential therapies—intravitreal steroids, bevacizumab, ranibizumab—we need to remind ourselves that none of these agents has been shown to have a greater and more durable effect than laser therapy for eyes with DME. ■

1. Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report No. 1. Arch Ophthalmol. 1985;103:1796- 1806.
2. Jonas JB, Söfker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol. 2001;132:425-427.
3. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109:920-927.
4. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447-1449.
5. Fong DS, Strauber SF, Aiello LP, et al. Diabetic Retinopathy Clinical Research Network. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007;125:469-480.

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