Intravitreal Ranibizumab for Diabetic Macular Edema: 3-Year Trial Results
The Diabetic Retinopathy Clinical Research Network conducted a randomized trial comparing intravitreal ranibizumab with prompt or deferred laser treatment for Diabetic Macular Edema (DME) over a 3-year period. The completion rate, baseline characteristics, visits, and injections prior to the 3-year visit were analyzed. The study aimed to provide insights into the long-term efficacy of ranibizumab in treating DME.
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The Diabetic Retinopathy Clinical Research Network Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt vs Deferred Laser Treatment: 3-year Randomized Trial Results 1
Background As previously reported, intravitreal ranibizumab with either prompt or deferred laser was more effective for DME through at least 2 years as compared with prompt laser alone The study was extended from the planned 3 years to 5 years to provide insight into the long- term course of DME treated with ranibizumab This report presents comparison data through 3 years for eyes randomized to the two ranibizumab groups 2
Completion of 3 Year Visit Completed: N = 291 (81%) Not Completed: N = 70 (19%) Death: N = 26 Withdrawals from the study: N = 27 Lost to follow-up: N = 14 Missed: N = 3 Completion rate (excluding deaths): 87% Baseline characteristics similar among completers and non-completers 3
Visits Prior to 3 Years* Ranibizumab + Prompt Laser N=144 Ranibizumab + Deferred Laser N=147 Median number of visits in year one Median number of visits in year two Median number of visits in year three Median number of visits prior to 3 year visit 13 13 8 10 7 8 28 30 * Only eyes that completed 3 year visit 4
Injections Prior to 3 Year* Ranibizumab + Prompt Laser N=144 Ranibizumab + Deferred Laser N=147 Maximal number of injections prior to 3- year visit 39 39 *Only eyes that completed 3 year visit 6
Injections Prior to 3 Year* Ranibizumab + Prompt Laser N=144 Ranibizumab + Deferred Laser N=147 Maximal number of injections prior to 3- year visit Median number of injections in year one (1st / 2nd 6 months) 39 39 8 (6/3) 9 (6/3) *Only eyes that completed 3 year visit 7
Injections Prior to 3 Year* Ranibizumab + Prompt Laser N=144 Ranibizumab + Deferred Laser N=147 Maximal number of injections prior to 3- year visit Median number of injections in year one (1st / 2nd 6 months) Median number of injections in year two 39 39 8 (6/3) 9 (6/3) 2 3 *Only eyes that completed 3 year visit 8
Injections Prior to 3 Year* Ranibizumab + Prompt Laser N=144 Ranibizumab + Deferred Laser N=147 Maximal number of injections prior to 3- year visit Median number of injections in year one (1st / 2nd 6 months) Median number of injections in year two Median number of injections in year three Median number of injections prior to 3 year visit 39 39 8 (6/3) 9 (6/3) 2 3 1 2 12 15 *Only eyes that completed 3 year visit 9
Injections Prior to 3 Year (continued)* Ranibizumab + Prompt Laser N=144 Ranibizumab + Deferred Laser N=147 Number (%) of eyes that met success** at 16 weeks and then received injection by 1-year visit Number (%) of eyes that met success at 1-year visit and then received injection by 2-year visit Number (%) of eyes that met success at 2-year visit and then received injection by 3-year visit 58 (88%) of 66 47 (82%) of 57 52 (60%) of 86 46 (67%) of 69 43 (47%) of 92 46 (53%) of 87 *Only eyes that completed 3 year visit **VA letter score 84 (~20/20) or OCT CSF < 250 m 10
Focal/Grid Laser Prior to 3 Years* Ranibizumab + Prompt Laser N = 144 Ranibizumab + Deferred Laser N = 147 Maximal possible number of focal/grid laser treatments prior to 3-year visit 12 10 Median number of focal/grid laser treatments prior to 3-year visit (from baseline) 3 0 % of eyes that did not receive focal/grid laser treatments prior to 3-year visit (from baseline) 0 54% * Only eyes that completed 3 year visit 11
Focal/Grid Laser Prior to 3 Years* Ranibizumab + Prompt Laser N = 144 Ranibizumab + Deferred Laser N = 147 Maximal possible number of focal/grid laser treatments prior to 3-year visit 12 10 Median number of focal/grid laser treatments from baseline to (prior to) 3-year visit 3 0 % of eyes that received focal/grid laser treatments from baseline to (prior to) 3- year visit * Only eyes that completed 3-year visit 100% 46% 12
Focal/Grid Laser Prior to 3 Years (Continued)* Ranibizumab + Prompt Laser N = 144 Ranibizumab + Deferred Laser N = 147 % of eyes that did not receive focal/grid laser treatments from 1-year to (prior to) 2-year visit % of eyes that did not receive focal/grid laser treatments from 2-year to (prior to) 3-year visit 58% 73% 75% 86% * Only eyes that completed 3 year visit 13
Mean Change in Visual Acuity* at Follow-up Visits 12 Change in Visual Acuity from Baseline 10 8 (Letter Score) Ranibizumab + Prompt Laser 6 Ranibizumab + Deferred Laser 4 N = 338 (52 weeks) N = 317 (104 weeks) N = 291 (156 weeks) 2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 68 84 104120136156 Visit Week 15 *Truncated to 30 letters
Mean Change in Visual Acuity* at Follow-up Visits 12 Ranibizumab + Prompt Laser Change in Visual Acuity from Baseline (Letter N = 338 (52 weeks) N = 317 (104 weeks) N = 291 (156 weeks) 10 Ranibizumab + Deferred Laser 8 Score) 6 4 2 0 52 104 156 Visit Week 16 *Truncated to 30 letters
Change in Visual Acuity* Estimated Difference (B vs. C) (95% CI) [P-Value] Ranibizumab + Prompt Laser N = 144 Ranibizumab + Deferred Laser N = 147 Change in Visual Acuity (letters)** 2-years (Estimated Means) -1.8 (-3.6 to +0.1) [P = 0.06] +7.2 +9.0 3- Years (Estimated Means) -2.9 (-5.4 to -0.4) [P = 0.02] +6.8 +9.7 *Visits occurring between 980 and 1204 days from randomization were included as 3 year visits **truncated to 30 letters, based on longitudinal analyses adjusting for baseline VA 17
Visual Acuity Gain at 3 Years 100% 90% Proportion of Visual Acuity Change 80% 70% 15 letter loss 10-14 letter loss 5-9 letter loss within 4 9-5 letter gain 14-10 letter gain 15 letter gain 60% 50% 40% 30% 20% 10% 0% Ranibizumab + Immediate Laser Ranibizumab + Deferred Laser N = 147 N = 144 18
Visual Acuity Gain at 3 Years 100% 90% Proportion of Visual Acuity Change 80% 15 letter loss 10-14 letter loss 5-9 letter loss within 4 9-5 letter gain 14-10 letter gain 15 letter gain 70% 60% 50% 40% 30% 20% 10% 0% Ranibizumab + Deferred Laser N = 147 Ranibizumab + Prompt Laser N = 144 19
Visual Acuity Subgroup Analyses 20
Change in Visual Acuity at 3 Years Stratified by Prior Laser Treatment 15 14 Mean Change in Visual Acuity 13 (letter score) from Baseline 12 11 N=85 N=62 10 Ranibizumab + Prompt Laser 9 N=61 8 N=83 Ranibizumab + Deferred Laser 7 6 5 4 3 2 1 0 No Yes Prior Laser for Diabetic Macular Edema 21
Change in Visual Acuity at 3 Year Stratified by Baseline Visual Acuity 17 16 Mean Change in Visual Acuity 15 N=75 (letter score) from Baseline 14 13 Ranibizumab + Prompt Laser 12 11 10 N=72 Ranibizumab + Deferred Laser 9 8 7 N=73 6 N=71 5 4 3 2 1 0 66 ( 20/50) Baseline Visual Acuity Letter Score (~Snellen Equivalent) 65 (<20/50) 22
Change in Visual Acuity at 3 Year Stratified by Eyes with Diffuse vs. Focal Edema at Baseline as Graded by Study Ophthalmologist 14 Mean Change in Visual Acuity (Letter Ranibizumab + Prompt Laser Ranibizumab + Deferred Laser N=63 12 Score) from Baseline N=36 N=49 10 8 N=67 N=35 6 N=41 4 2 0 Typical/predominantly focal Neither focal or diffuse Typical/predominantly diffuse 23 DME Type on Clinical Exam
Mean Change in CSF Thickening at Follow-up Visits 0 Mean Change in OCT Central Subfield -20 Thickness from Baseline (Microns) Ranibizumab + Prompt Laser Ranibizumab + Deferred Laser N = 334 (52 weeks) N = 305 (104 weeks) N = 259 (156 weeks) -40 -60 -80 -100 -120 -140 -160 -180 -200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Visit Week 25
Mean Change in CSF Thickening at Follow-up Visits 0 Ranibizumab + Prompt Laser Ranibizumab + Deferred Laser N = 334 (52 weeks) N = 305 (104 weeks) N = 259 (156 weeks) Mean Change in OCT Central Subfield -20 Thickness from Baseline (Microns) -40 -60 -80 -100 -120 -140 -160 -180 -200 52 104 156 Visit Week 26
Change in Retinal Thickening at 2 Years* Ranibizumab + Immediate Laser N = 152 Ranibizumab + Deferred Laser N = 153 Change in OCT CSF Median change from baseline ( m) Mean change from baseline ( m) -118 -135 -145 -154 Thickness <250 m with at least a 25 m decrease from baseline 61% 60% *Visits occurring between 616 and 840 days from randomization were included as 2 year visits 27
Change in Retinal Thickening at 3 Years* Ranibizumab + Prompt Laser N = 136 Ranibizumab + Deferred Laser N = 132 Change in OCT CSF Median change from baseline ( m) Mean change from baseline ( m) -142 -155 -152 -174 Thickness <250 m with at least a 25 m decrease from baseline 61% 63% *Visits occurring between 980 and 1204 days from randomization were included as 3 year visits 28
Conclusions Results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea and with vision impairment. Some of the observed differences in visual acuity at 3 years may be related to the fewer number of ranibizumab injections during follow-up in the prompt laser treatment group. Despite the decreasing number of injections given in the 2nd and 3rd year of management, the ranibizumab + deferred laser treatment group showed no decline in visual acuity, and the ranibizumab + prompt laser treatment group showed only a slight decline from the 1-year to 3-year visit. 29
Conclusions Focal/grid laser performed at the initiation of intravitreal ranibizumab is no better, and possibly worse, than deferring laser for at least 24 weeks in eyes with DME involving the fovea and vision impairment. Fewer injections were needed in years 2 and 3 to sustain VA gains observed in year 1. However, more were needed in the ranibizumab+deferred laser group. 26 possible injections between week 52 and week 156 ranibizumab + prompt laser group: o median 3 injections, average decline of ~1 letter ranibziumab + deferred laser group: o median 6 injections, average increase of ~1 letter 30
Conclusions Focal/grid laser at the initiation of intravitreal ranibizumab is no better, and possibly worse, than deferring laser for at least 24 weeks in eyes with DME involving the fovea with vision impairment Few injections in years 2 and 3 to sustain VA gains in year 1 More (3 more) injections, on average, in ranibizumab + deferred laser group compared with ranibizumab + prompt laser Of 26 possible injections from week 52 to week 156, 3 given in ranibizumab + prompt laser group with an average decline of ~1 letter from week 52 compared with 6 given in ranibziumab + deferred laser group with an average increase of ~1 letter from week 52 31
