Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema

Abstract

Objective: Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).

Design: Multicenter, randomized clinical trial.

Participants: A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea.

Methods: Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (> or =24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.

Main outcome measures: Best-corrected visual acuity and safety at 1 year.

Results: The 1-year mean change (+/-standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9+/-11, P<0.001) and ranibizumab + deferred laser group (+9+/-12, P<0.001) but not in the triamcinolone + prompt laser group (+4+/-13, P=0.31) compared with the sham + prompt laser group (+3+/-13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes.

Conclusions: Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.

Figure 1

Completion of follow-up for study eyes. One-year completed visits include those that occurred between 308 and 420 days (between 44 and 60 weeks) from randomization. Two-year completed visits include those that occurred between 616 and 840 days (between 88 and 120 weeks) from randomization. Ranib = ranibizumab; Triam = triamcinolone.

Figure 2

Cumulative distribution of injections/sham with randomized assigned treatment before the 52-week study visit. Includes eyes that completed the 52-week study visit; 56 eyes in sham group with other eye in the ranibizumab + deferred laser group are not included in figure because they were unmasked and a sham injection was not required per protocol. There were 13 possible sham or study drug injections. Study drug injections and sham injections included a baseline treatment and monthly retreatments through 12 weeks. After 16 weeks, eyes assigned to one of the ranibizumab groups could receive ranibizumab as often as every 4 weeks; eyes assigned to intravitreal triamcinolone could receive triamcinolone as often as every 16 weeks with sham injections as often as every 4 weeks in between triamcinolone injections; eyes assigned to sham + prompt laser could receive sham injections as often as every 4 weeks. Of 503 injections given in triamcinolone group before 1 year, 36% were triamcinolone injections. Ranib = ranibizumab.

Figure 3

Mean change in visual acuity at follow-up visits. Values that were ±30 letters were assigned a value of 30. P values for difference in mean change in visual acuity from sham + prompt laser at 52 weeks: ranibizumab + prompt laser <0.001, ranibizumab + deferred laser <0.001, and triamcinolone + prompt laser groups = 0.31. Each visit week includes visits that are ±14 days, except the 52-week visit, which includes visits that occur between 308 and 420 days (between 44 and 60 weeks) from randomization, and the 104-week visit, which includes visits that occur between 616 and 840 days (between 88 and 120 weeks) from randomization.

Figure 4

A, Ten letter or greater improvement in visual acuity at follow-up visits. P values for difference in proportion of ≥10 letter improvement in visual acuity from sham + prompt laser at the 52-week visit: ranibizumab + prompt laser <0.001, ranibizumab + deferred laser <0.001, and triamcinolone + prompt laser = 0.16. Each visit week includes visits that are ±14 days, except the 52-week visit, which includes visits that occur between 308 and 420 days (between 44 and 60 weeks) from randomization, and the 104-week visit, which includes visits that occur between 616 and 840 days (between 88 and 120 weeks) from randomization. B, Ten letter or greater loss in visual acuity at follow-up visits. P values for difference in proportion of 10 letter loss in visual acuity from sham + prompt laser at the 52-week visit: ranibizumab + prompt laser <0.001, ranibizumab + deferred laser <0.001, and triamcinolone + prompt laser = 0.75. Each visit week includes visits that are ±14 days, except the 52-week visit, which includes visits that occur between 308 and 420 days (between 44 and 60 weeks) from randomization, and the 104-week visit, which includes visits that occur between 616 and 840 days (between 88 and 120 weeks) from randomization.

Figure 5

Mean change in visual acuity at follow-up visits among eyes that were pseudophakic at baseline. Values of ±30 or more letters were assigned a value of 30. Each visit week includes visits that are ±14 days, except the 52-week visit, which includes visits that occur between 308 and 420 days (between 44 and 60 weeks) from randomization, and the 104-week visit, which includes visits that occur between 616 and 840 days (between 88 and 120 weeks) from randomization.

Figure 6

Optical coherence tomography central subfield thickness <250 μm with at least a 25 μm decrease in thickness from baseline at follow-up visits. P values for difference in proportion in OCT central subfield thickness <250 μm with at least a 25 μm decrease in thickness from sham + prompt laser at the 52-week visit: ranibizumab + prompt laser <0.001, ranibizumab + deferred laser = 0.001, and triamcinolone + prompt laser <0.001. Each visit week includes visits that are ±14 days, except the 52-week visit, which includes visits that occur between 308 and 420 days (between 44 and 60 weeks) from randomization, and the 104-week visit, which includes visits that occur between 616 and 840 days (between 88 and 120 weeks) from randomization. OCT = optical coherence tomography.

Figure 7

Two or more step improvement in the logarithmic transformation of OCT central subfield thickness from baseline. Each visit week includes visits that are ±14 days, except the 52-week visit, which includes visits that occur between 308 and 420 days (between 88 and 120 weeks) from randomization, and the 104-week visit, which includes visits that occur between 616 and 840 days (between 88 and 120 weeks) from randomization. logOCT = logarithmic transformation of optical coherence tomography calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounded to the nearest hundredth. (Ferris FL III, Miller KM, Glassman AR, Beck RW. A proposed method of logarithmic transformation of optical coherence tomography data for use in clinical research. Ophthalmology. In Press.)

Figure 8

Mean change in OCT central subfield retinal thickening at follow-up visits. P values for difference in mean change in OCT central subfield retinal thickness from sham + prompt laser at the 52-week visit: ranibizumab + prompt laser <0.001, ranibizumab + deferred laser <0.001, and triamcinolone + prompt laser <0.001. Each visit week includes visits that are ±14 days, except the 52-week visit, which includes visits that occur between 308 and 420 days (between 44 and 60 weeks) from randomization, and the 104-week visit, which includes visits that occur between 616 and 840 days (between 88 and 120 weeks) from randomization. OCT = optical coherence tomography.

Figure 9

Cumulative probability of cataract surgery through 2 years of follow-up for all eyes phakic at baseline. Eyes pending a 2-year visit or that were lost to follow-up were censored at their last visit. N is the number of eyes phakic at baseline. *Number of eyes at the start of the interval without previous cataract surgery. **Number of eyes with cataract surgery during the subsequent 4-month period.