Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial

Writing Committee for the Diabetic Retinopathy Clinical Research Network, Jeffrey G Gross, Adam R Glassman, Lee M Jampol, Seidu Inusah, Lloyd Paul Aiello, Andrew N Antoszyk, Carl W Baker, Brian B Berger, Neil M Bressler, David Browning, Michael J Elman, Frederick L Ferris 3rd, Scott M Friedman, Dennis M Marcus, Michele Melia, Cynthia R Stockdale, Jennifer K Sun, Roy W Beck, Writing Committee for the Diabetic Retinopathy Clinical Research Network, Jeffrey G Gross, Adam R Glassman, Lee M Jampol, Seidu Inusah, Lloyd Paul Aiello, Andrew N Antoszyk, Carl W Baker, Brian B Berger, Neil M Bressler, David Browning, Michael J Elman, Frederick L Ferris 3rd, Scott M Friedman, Dennis M Marcus, Michele Melia, Cynthia R Stockdale, Jennifer K Sun, Roy W Beck

Abstract

Importance: Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME).

Objective: To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy.

Design, setting, and participants: Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015.

Interventions: Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME.

Main outcomes and measures: The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization.

Results: Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified.

Conclusions and relevance: Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy.

Trial registration: clinicaltrials.gov Identifier: NCT01489189.

Figures

Figure 1. Completion of Follow-up for Study…
Figure 1. Completion of Follow-up for Study Eyes
*Two-year completed visits include those that occurred between 644 and 812 days (between 92 and 116 weeks). ** Participants are not formally screened prior to obtaining an informed consent ITT = Intention-to-treat
Figure 2
Figure 2
Shown are changes in visual acuity over time for the overall cohort (Panel A), for eyes with baseline DME (Panel B), and for eyes without baseline DME (Panel C). Outlying values were truncated to 3 SD from the mean. Bars represent 95% confidence interval on the mean
Figure 2
Figure 2
Shown are changes in visual acuity over time for the overall cohort (Panel A), for eyes with baseline DME (Panel B), and for eyes without baseline DME (Panel C). Outlying values were truncated to 3 SD from the mean. Bars represent 95% confidence interval on the mean
Figure 2
Figure 2
Shown are changes in visual acuity over time for the overall cohort (Panel A), for eyes with baseline DME (Panel B), and for eyes without baseline DME (Panel C). Outlying values were truncated to 3 SD from the mean. Bars represent 95% confidence interval on the mean

References

    1. Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 2012;366(13):1227–39.
    1. Aiello LP. Angiogenic pathways in diabetic retinopathy. N Engl J Med. 2005;353:839–41.
    1. Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States. 2007 . Accessed 10-13-09.
    1. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology. 1981;88(7):583–600.
    1. Silva PS, Cavallerano JD, JK S, et al. Proliferative Diabetic Retinopathy. In: Ryan SJ, editor. Retina. 5th. Elsevier; Philadelphia, PA: 2013.
    1. American Society of Retina Specialists (ASRS) Global Trends in Retina Survey Results. Accessed 2/18/2015.
    1. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103(12):1796–806.
    1. Diabetic Retinopathy Clinical Research Network. Observational study of the development of diabetic macular edema following panretinal (scatter) photocoagulation given in 1 or 4 sittings. Arch Ophthalmol. 2009;127(2):132–40.
    1. The Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema following focal/grid laser for diabetic macular edema in eyes also receiving panretinal photocoagulation. Retina. 2011;31(6):1009–27.
    1. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064–77 e35.
    1. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(6):2247–54.
    1. Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol. 2012;130(9):1145–52.
    1. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191–4.
    1. Beck RW, Moke PS, Turpin AH, et al. A computerized method of visual acuity testing: adaptation of the early treatment of diabetic retinopathy study testing protocol. Am J Ophthalmol. 2003;135(2):194–205.
    1. Aiello LP, Beck RW, Bressler NM, et al. Rationale for the diabetic retinopathy clinical research network treatment protocol for center-involved diabetic macular edema. Ophthalmology. 2011;118(12):e5–14.
    1. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908.
    1. Beck RW, Maguire MG, Bressler NM, Glassman AR, Lindblad AS, Ferris FL. Visual acuity as an outcome measure in clinical trials of retinal diseases. Ophthalmology. 2007;114(10):1804–9.
    1. Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol. 2005;162(3):199–200.
    1. SAS Institute Inc. SAS/STAT 9.3 User’s Guide. Cary, NC: SAS Institute Inc; 2011.
    1. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308(6921):81–106.
    1. Diabetic Retinopathy Clinical Research N. Googe J, Brucker AJ, et al. Randomized trial evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema after focal/grid laser for diabetic macular edema in eyes also receiving panretinal photocoagulation. Retina. 2011;31(6):1009–27.
    1. Diabetic Retinopathy Clincical Research Network. Randomized clinical trial evaluating intravitreal ranibizumab or saline for vitreous hemorrhage from proliferative diabetic retinopathy. JAMA Ophthalmol. 2013;131(3):283–93.
    1. Diabetic Retinopathy Clinical Research N. Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193–203.

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