title: Comparison of Aflibercept, Bevacizumab, and Ranibizumab for Treatment of Diabetic Macular Edema: Extrapolation of Data to Clinical Practice.
abstract: OBJECTIVE
  The Diabetic Retinopathy Clinical Research Network (DRCR Network), sponsored by the National Eye Institute, reported the results of a comparative effectiveness randomized clinical trial (RCT) evaluating the 3 anti-vascular endothelial growth factor (anti-VEGF) agents aflibercept (2.0 mg), bevacizumab (1.25 mg), and ranibizumab (0.3 mg) for treatment of diabetic macular edema (DME) involving the center of the retina and associated with visual acuity loss. The many important findings of the RCT prompted the American Society of Retina Specialists to convene a group of experts to provide their perspective regarding clinically relevant findings of the study.
  
  
  OBJECTIVE
  To describe specific outcomes of the RCT judged worthy of highlighting, to discuss how these and other clinically relevant results should be considered by specialists treating DME, and to identify unanswered questions that merit consideration before treatment.
  
  
  METHODS
  The DRCR Network-authored publication on primary outcomes of the comparative effectiveness RCT at 89 sites in the United States. The study period of the RCT was August 22, 2012, to August 28, 2013.
  
  
  RESULTS
  On average, all 3 anti-VEGF agents led to improved visual acuity in eyes with DME involving the center of the retina and with visual acuity impairment, including mean (SD) improvements by +13.3 (11.1) letters with aflibercept vs +9.7 (10.1) letters with bevacizumab (P < .001) and +11.2 (9.4) letters with ranibizumab (P = .03). Worse visual acuity when initiating therapy was associated with greater visual acuity benefit of aflibercept (+18.9 [11.5]) over bevacizumab (+11.8 [12.0]) or ranibizumab (14.2 [10.6]) 1 year later (P < .001 for interaction with visual acuity as a continuous variable, and P = .002 for interaction with visual acuity as a categorical variable). It is unknown whether different visual acuity outcomes associated with the use of the 3 anti-VEGF agents would be noted with other treatment regimens or with adequately repackaged bevacizumab, as well as in patients with criteria that excluded them from the RCT, such as persistent DME despite recent anti-VEGF treatment.
  
  
  CONCLUSIONS
  On average, all 3 anti-VEGF agents led to improved visual acuity in eyes with DME involving the center of the retina and visual acuity impairment. Worse visual acuity when initiating therapy was associated with greater visual acuity benefit of aflibercept over bevacizumab or ranibizumab 1 year later. Care needs to be taken when attempting to extrapolate outcomes of this RCT to differing treatment regimens. With access to adequately repackaged bevacizumab, many specialists might initiate therapy with bevacizumab when visual acuity is good (ie, 20/32 to 20/40 as measured in the DRCR Network), recognizing that the cost-effectiveness of bevacizumab outweighs that of aflibercept or ranibizumab.
authors.affiliation: Ophthalmic Consultants of Boston, Boston, Massachusetts.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Heier
authors.affiliation: Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland3Editor, JAMA Ophthalmology.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Bressler
authors.affiliation: California Retina Consultants, Santa Barbara.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Avery
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Bakri
authors.affiliation: Retina Vitreous Associates Medical Group, Keck School of Medicine of University of Southern California, Los Angeles.
authors.forename: David S
authors.initials: DS
authors.lastname: Boyer
authors.affiliation: Retina Consultants of Houston, Baylor College of Medicine, Houston, Texas.
authors.forename: David M
authors.initials: DM
authors.lastname: Brown
authors.affiliation: Retinal Consultants of Arizona, Phoenix9University of Southern California Eye Institute, Keck School of Medicine of University of Southern California, Los Angeles.
authors.forename: Pravin U
authors.initials: PU
authors.lastname: Dugel
authors.affiliation: Vitreous-Retina-Macula Consultants of New York, New York University School of Medicine, New York.
authors.forename: K Bailey
authors.initials: KB
authors.lastname: Freund
authors.affiliation: Jaeb Center for Health Research, Tampa, Florida.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Glassman
authors.affiliation: Medical College of Wisconsin, Milwaukee.
authors.forename: Judy E
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Martin
authors.affiliation: Illinois Retina Associates, Chicago15Department of Ophthalmology, Rush University Medical Center, Chicago, Illinois.
authors.forename: John S
authors.initials: JS
authors.lastname: Pollack
authors.affiliation: Wills Eye Hospital Retina Service and Mid Atlantic Retina, Philadelphia, Pennsylvania17Department of Ophthalmology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Regillo
authors.affiliation: Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenfeld
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Schachat
authors.affiliation: Palmetto Retina Center, West Columbia, South Carolina.
authors.forename: John A
authors.initials: JA
authors.lastname: Wells
mesh_terms: D020533:Angiogenesis Inhibitors / Q000191:economics / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000191:economics / Q000627:therapeutic use*; D003362:Cost-Benefit Analysis; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000503:physiopathology; D004339:Drug Compounding; D016527:Drug Costs; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema / Q000188:drug therapy* / Q000503:physiopathology; D017410:Practice Guidelines as Topic; D010818:Practice Patterns, Physicians'; D016032:Randomized Controlled Trials as Topic; D000069579:Ranibizumab / Q000191:economics / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000191:economics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000191:economics / Q000627:therapeutic use*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014792:Visual Acuity / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab