This phase 3 randomized clinical trial compared 1 mg and 4 mg doses of preservative-free triamcinolone with focal/grid photocoagulation as treatments for eyes with DME and visual acuity ranging from 20/40 to 20/320. At 4 months, a greater positive treatment response on visual acuity was seen in the 4 mg triamcinolone group compared with the other two groups. However, by 1 year, there was little difference in visual acuity between the groups, and at the time of the two-year primary outcome assessment, visual acuity and safety (with respect to intraocular pressure and cataract) were significantly better in the laser group than in either the 4 mg triamcinolone or 1 mg triamcinolone groups. There was no significant difference between the 1 mg triamcinolone and 4 mg triamcinolone groups in visual acuity at 2 years. Treatment group differences in the change in retinal thickening generally mirrored the effect on visual acuity, with initially a greater reduction in the 4 mg triamcinolone group, an eventual greater reduction in the laser group, and no difference between the two triamcinolone groups at 2 years.
The lesser efficacy of triamcinolone on visual acuity relative to focal/grid photocoagulation at two years is unlikely to be on the basis of corticosteroid-induced lens changes alone, in view of the OCT results and since an analysis limited to eyes that were pseudophakic or without lens changes judged clinically relevant did not demonstrate a benefit of triamcinolone compared with focal/grid photocoagulation. Likewise, a benefit of triamcinolone relative to photocoagulation was not seen in prespecified subgroups of sufficient size based on baseline visual acuity, retinal thickening, or a history of prior macular photocoagulation. Among the small number of eyes with the most severe visual acuity loss at baseline (20/200 to 20/320), most of the eyes in the 4 mg triamcinolone group had an improvement in visual acuity at 2 years. However, the number of such eyes was too small (N=13) for a meaningful assessment of the treatment effect relative to focal/grid photocoagulation.
With respect to the safety of the intravitreal injections, through two years of follow up, there were no cases of infectious or noninfectious endophthalmitis following an injection of the preservative-free triamcinolone preparation used in this study. A relatively high incidence of detection of silicone oil droplets in the vitreous following intravitreal injections (about a quarter of eyes treated with intravitreal triamcinolone) was noted. This is a recognized occurrence after intravitreal injection using siliconized syringes.48
Although some subjects were symptomatic from floaters due to the silicone oil droplets, we have not identified any adverse effects on the eye attributable to the silicone oil. Consistent with other reports,22, 49, 50
the 4 mg triamcinolone injections were associated with an increased incidence of both elevation of intraocular pressure and development of cataract requiring surgery. Most cases of elevated intraocular pressure were adequately controlled with ocular hypotensive medications, but in the 4 mg triamcinolone group, two cases required a filtering procedure, one case required a laser trabeculoplasty, and one case required a ciliary body destructive procedure.
The 4 mg triamcinolone dose was evaluated because it was the dose most commonly used in clinical practice at the time the trial was initiated. The 1 mg dose was included because this dose was likely to exceed the concentration necessary to saturate the glucocorticoid receptors in the cell cytoplasm completely.51, 52
Also, it was hoped that adverse effects on the lens and intraocular pressure might be less frequent. Indeed, the 1 mg triamcinolone group had fewer side effects with respect to glaucoma and cataract than the 4 mg triamcinolone group. Although the 4 mg group was superior to the 1 mg group with respect to vision at 4 months and superior to the 1 mg group with respect to retinal thickening up to 1 year, no difference in visual acuity or retinal thickening was detected after 2 years of follow up. The retreatment protocol encouraged frequent reinjection, with reinjection of triamcinolone at 4-month intervals as long as edema was present, visual acuity or retinal thickening had not improved substantially since the last injection, futility criteria were not met (see methods), or an adverse event such as increased intraocular pressure had not occurred that precluded retreatment at that visit. The occurrence of elevated intraocular pressure may have limited the number of reinjections in some subjects. The early treatment effect of triamcinolone relative to focal/grid photocoagulation found in the current study is consistent with many published case series50, 53, 54
and a small randomized trial showing such an effect.55
One other small randomized trial reported no significant difference comparing focal/grid photocoagulation and 4 mg intravitreal triamcinolone after 4 months or 12 months.49
The trial had a sample size that was sufficiently large so that it is highly unlikely that a true 2-year benefit of triamcinolone over focal/grid photocoagulation went undetected, particularly since the results favored the photocoagulation group. The treatment groups were well balanced with regard to baseline factors. Although investigators and subjects were not masked to treatment group with respect to photocoagulation versus triamcinolone, it is unlikely that this was a source of bias favoring the photocoagulation group, since the prestudy presumption was that intravitreal triamcinolone might be a better treatment than focal/grid photocoagulation. Visual acuity was measured using a computerized system and OCT scans were graded at a reading center masked to treatment group, reducing the potential for bias in these assessments. The consistency between the visual acuity and OCT results adds further credence to the validity of the findings. The study completion rate of 83% (88% if deaths are excluded) was lower than expected, but we have no indication that this significantly influenced the results. The completion rate was similar among the treatment groups and analyses using three different methods for handling missing data produced similar results.
Based on data from the ETDRS, it appears likely that the visual acuity outcome with each of the three treatment regimens is superior to the expected untreated course. The best estimate of the untreated course of visual acuity in eyes with DME for comparison with the treatment groups in the current study comes from the treatment group in the ETDRS in which focal/grid photocoagulation was deferred. Among 235 ETDRS eyes in that group that had definite center thickening on fundus photographs, a visual acuity letter score <74 [worse than 20/32], and mild to moderate nonproliferative retinopathy at baseline, the median visual acuity letter score at two years was decreased from baseline by -6, with 12% improving 10 or more letters and 43% worsening 10 or more letters (unpublished data, provided by Frederick L. Ferris, M.D.). This was a substantially worse outcome than observed in any of our three treatment groups. It is important to note that in the current study, some eyes had more severe retinopathy than those included in this analysis of ETDRS data. Further support for the positive long-term effect on visual acuity and retinal thickening of intravitreal triamcinolone comes from a randomized trial conducted by Gillies et al.50
These authors reported a beneficial effect on visual acuity and retinal thickening of 4 mg intravitreal triamcinolone compared with sham injections after 2 years of follow up in a randomized trial involving 69 eyes of 43 subjects previously treated with focal/grid photocoagulation with persistent DME and visual acuity 20/30 or worse. The conclusions from the Gillies study cannot be directly compared with the conclusions from the current study because only about half of the control group eyes in the Gillies study received focal/grid photocoagulation during the study, and collectively these eyes fared much worse than the laser group in the current study.
The results of the current study elevate the importance of focal/grid photocoagulation in managing DME, across a wide range of visual acuities and a wide range of retinal thicknesses, even in eyes with prior macular photocoagulation for DME. It is important to note that eyes with prior macular photocoagulation were enrolled in this trial only if judged by the investigator to have the potential to benefit from additional laser treatment. Although the ETDRS demonstrated that focal/grid photocoagulation improves the visual outcome of DME, it has been largely believed that the benefit was in reducing the frequency of vision loss and not in improving visual acuity. However, this general conclusion ignores the fact that the majority of eyes in the ETDRS had normal or near normal visual acuity and thus did not have the potential for substantial visual acuity improvement. In a subset of 114 ETDRS eyes meeting the aforementioned criteria that were treated with immediate focal/grid photocoagulation, the results were similar to the findings in the current study. This ETDRS subset of eyes had a median change in the visual acuity letter score from baseline to two years of +4, with 29% improving 10 or more letters and 16% worsening 10 or more letters (unpublished data, provided by Frederick L. Ferris, M.D.). A prior DRCR.net study evaluating macular photocoagulation regimens also demonstrated that visual acuity improvement is not uncommon after focal/grid photocoagulation for DME.43
In the 46 eyes in that study with a baseline visual acuity letter score ≤73 (20/40 or worse) and central subfield thickness ≥250 microns that were in the focal/grid photocoagulation group, the median change in the visual acuity letter score from baseline to one year was +6, with 37% of eyes improving 10 or more letters and 9% worsening 10 or more letters (unpublished data). With respect to any deleterious effects of focal/grid photocoagulation on visual acuity, there has been no indication of an attenuation of the beneficial effect of photocoagulation through 2 years of follow up. Results from the ETDRS8
focal/grid photocoagulation group showing no deterioration of visual acuity through 3 years support the expectation that deterioration of visual acuity will not be seen during the third year of follow up in the current study. The fact that photocoagulation was administered by a wide range of treating physicians in the DRCR Network based on a written protocol without grading of photographs to confirm adherence to protocol enhances the generalizability of the study results.
The photocoagulation treatment regimen utilized in the current study, which was a modification of the regimen used in the ETDRS, encouraged frequent retreatment at 4-month intervals whenever there was persistent or new edema that had not been previously treated and had not improved substantially since the last treatment. In view of the importance of focal/grid photocoagulation in treating DME, as re-affirmed by this study, additional studies are needed to develop a better understanding of when photocoagulation treatment is complete and the optimal time interval for repeating treatment. To this end, the DRCR.net is currently conducting a study evaluating whether a less intensive photocoagulation retreatment algorithm offers enough promise to warrant a clinical trial comparing such treatment to the more intensive retreatment criteria used in this study. Pending such a study, it is not known whether a less aggressive approach of deferring retreatment with focal/grid photocoagulation as long as there is evidence of improvement in visual acuity or retinal thickening might produce results similar to the current study.
Although the results of the current study confirm the ETDRS finding that focal/grid photocoagulation has a substantial beneficial effect on DME, there is certainly a role for better treatments in the future, since about half of the study eyes in the photocoagulation group still had central retinal thickening at two years, with about one in five having worsened 10 or more letters from baseline and only about one in three having improved by 10 or more letters. The fact that the 4 mg intravitreal triamcinolone group had a greater positive treatment response on visual acuity and retinal thickening at 4 months while the photocoagulation group had a greater positive response later raises the possibility that combining focal/grid photocoagulation with intravitreal triamcinolone might produce greater benefit for DME than either focal/grid photocoagulation or intravitreal triamcinolone alone. A DRCR.net study is currently evaluating a combination of intravitreal triamcinolone and focal/grid photocoagulation, a combination of ranibizumab and photocoagulation, and ranibizumab alone, in eyes with characteristics similar to those included in the current study (protocol available at www.drcr.net
, date accessed June 5, 2008).
In conclusion, although intravitreal triamcinolone likely improves visual acuity over two years compared with the expected untreated course, the results of our study demonstrate that focal/grid photocoagulation is not only more effective over at least 2 years than intravitreal triamcinolone with respect to both visual acuity and OCT-measured retinal thickening, but also is associated with far fewer adverse events, particularly elevation of intraocular pressure and lens changes. Based on these results, 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.