Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema

Jane Oh, Mercer University College of Pharmacy 2015

Diabetes may result in diabetic retinopathy, which is damage to the blood vessels in the retina, and can lead to blindness. Damaged blood vessels may cause vision loss by two ways: proliferative retinopathy and macular edema. Proliferative retinopathy is when fragile, abnormal blood vessels develop and leak blood into the eye center causing blurred vision. Macular edema is when fluid leaks to the center of the macula causing it to swell and blurs the vision.1

Vascular endothelial growth factor (VEGF) is considered an important mediator of physiologic processes including development and permeability of the vasculature. Anti-VEGF agents have been a preferred therapy to manage diabetic macular edema.2 Aflibercept, bevacizumab, and ranibizumab are anti-VEGF agents that work to reduce fluid leakage and interfere with new blood vessel growth in the retina.1

Title: Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema
Design Multicenter (89 United States clinical centers), randomized, intent-to-treat


To compare intravitreous aflibercept, bevacizumab, and ranibizumab for diabetic macular edema treatment involving the center of the macula and causing vision impairment in terms of efficacy and safety data
Study Groups Intravitreous aflibercept 2.0 mg (n= 224), intravitreous bevacizumab 1.25 mg (n= 218), or intravitreous ranibizumab 0.3 mg (n= 218) in one eye of each participant at an injection volume of 0.05 ml
Methods The study drugs were injected at baseline and every four weeks unless visual acuity was 20/ 20 or better with a central subfield thickness below the eligibility threshold and there was neither improvement nor worsening in response to the past two injections. Laser photocoagulation therapy was initiated at or after the 24-week visit for persistent diabetic macular edema.
Duration Three years
Primary outcome measure Mean change in visual acuity at one year
Baseline Characteristics Mean age 61+ 10 years, 47% women, 65% Caucasian, 90% type two diabetes, mean diabetes duration 17+ 11 years, mean baseline visual acuity score 64.8+ 11.3 (Snellen equivalent, 20/50), mean central subfield thickness 412+ 130 μm.
Results Mean improvement in the visual-acuity letter score after one year: aflibercept 13.3 vs. bevacizumab 9.7 vs. ranibizumab 11.2; P< 0.001 for aflibercept vs. bevacizumab; P= 0.03 for aflibercept vs. ranibizumab. Relative effect varied according to initial visual acuity (P< 0.001 for interaction with visual acuity as a continuous variable and P= 0.002 for interaction with visual acuity as a categorical variable).
Adverse Events Common Adverse Effects: Elevation in intraocular pressure (aflibercept 12%, bevacizumab 9%, ranibizumab 9%), vitreous hemorrhage (aflibercept 4%, bevacizumab 7%, ranibizumab 2%), inflammation (aflibercept 2%, bevacizumab 1%, ranibizumab 0%), injection-related cataract (aflibercept 1%, bevacizumab 0%, ranibizumab 0%), endophthalmitis (aflibercept 1%, bevacizumab 0%, ranibizumab 1%)
Serious Adverse Events: aflibercept 59 (n= 224), bevacizumab 46 (n= 218), ranibizumab 55 (n= 218), P= 0.40
Percentage that Discontinued due to Adverse Events: None reported
Study Author Conclusions Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision.

Although this study showed that the comparative-effectiveness of aflibercept was greater than that of bevacizumab or ranibizumab to increase mean visual acuity in center-involved diabetic macular edema, the magnitude of the greater effect of aflibercept lacked clinical applicability because it depended on the initial visual acuity.3 Mild vision loss (20/ 32 to 20/ 40) had little difference in mean visual acuity at one year among three agents.3 Worse initial vision levels showed that aflibercept had an advantage in improving visual-acuity letter scores of at least 15 (three Snellen lines).3


  1. Facts about diabetic eye disease. National Eye Institute. Accessed March 27, 2015.
  2. Boyer DS, Hopkins JJ, Sorof J, Ehrlich JS. Anti-vascular endothelial growth factor therapy for diabetic macular edema. Ther Adv Endocrinol Metab. 2013;4(6):151-69. Accessed March 27, 2014.
  3. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema. N Engl J Med. 2015; 372:1193-1203. doi: 10.1056/NEJMoa1414264. Accessed March 26, 2015.

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