title: Systematic review and mixed treatment comparison of intravitreal aflibercept with other therapies for diabetic macular edema (DME).
abstract: BACKGROUND
  This was an indirect comparison of the effectiveness of intravitreal aflibercept (IVT-AFL) 2 mg every 8 weeks after 5 initial monthly doses (or if different periods, after an initial monthly dosing period) (2q8) and other diabetic macular edema (DME) therapies at doses licensed outside the USA.
  
  
  METHODS
  A comprehensive search was undertaken to source relevant studies. Feasibility networks were prepared to identify viable comparisons of 12-month outcomes between IVT-AFL 2q8 and therapies licensed outside the USA, which were assessed for clinical and statistical homogeneity. Pooled effect sizes (mean difference [MD] and relative risk/risk ratio [RR]) were calculated using fixed- and random-effects models. Indirect comparisons were performed using Bucher analysis. If at least one 'head-to-head' study was found then a mixed treatment comparison (MTC) was performed using Bayesian methods. Two 12-month comparisons could be undertaken based on indirect analyses: IVT-AFL 2q8 versus intravitreal ranibizumab (IVR) 0.5 mg as needed (PRN) (10 studies) and IVT-AFL 2q8 versus dexamethasone 0.7 mg implants (three studies).
  
  
  RESULTS
  There was an increase in mean best-corrected visual acuity (BCVA) with IVT-AFL 2q8 over IVR 0.5 mg PRN by 4.67 letters [95% credible interval (CrI): 2.45-6.87] in the fixed-effect MTC model (10 studies) and by 4.82 letters [95% confidence interval (CI): 2.52-7.11] in the Bucher indirect analysis (four studies). IVT-AFL 2q8 doubled the proportion of patients gaining ≥ 10 Early Treatment Diabetic Retinopathy Study letters at 12 months compared with dexamethasone 0.7 mg implants (RR = 2.10 [95% CI: 1.29-3.40]) in the fixed-effect model. There were no significant differences in safety outcomes between IVT-AFL 2q8 and IVR 0.5 mg PRN or dexamethasone 0.7 mg implants.
  
  
  CONCLUSIONS
  Studies of IVT-AFL 2q8 showed improved 12-month visual acuity measures compared with studies of IVR 0.5 mg PRN and dexamethasone 0.7 mg implants based on indirect comparisons. These analyses are subject to a number of limitations which are inherent in indirect data comparisons.
authors.affiliation: Université Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, F-33000 Bordeaux; Service d'Ophtalmologie, CHU de Bordeaux, Bordeaux, France. jean-francois.korobelnik@chu-bordeaux.fr.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Korobelnik
authors.affiliation: School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, Limburg, the Netherlands. jos@systematic-reviews.com.
authors.forename: Jos
authors.initials: J
authors.lastname: Kleijnen
authors.affiliation: Kleijnen Systematic Reviews Ltd., Escrick Business Park, Escrick, York, England, YO19 6FD, UK. shona@systematic-reviews.com.
authors.forename: Shona H
authors.initials: SH
authors.lastname: Lang
authors.affiliation: Kleijnen Systematic Reviews Ltd., Escrick Business Park, Escrick, York, England, YO19 6FD, UK. richard@systematic-reviews.com.
authors.forename: Richard
authors.initials: R
authors.lastname: Birnie
authors.affiliation: Kleijnen Systematic Reviews Ltd., Escrick Business Park, Escrick, York, England, YO19 6FD, UK. regina@systematic-reviews.com.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Leadley
authors.affiliation: Kleijnen Systematic Reviews Ltd., Escrick Business Park, Escrick, York, England, YO19 6FD, UK. kate@systematic-reviews.com.
authors.forename: Kate
authors.initials: K
authors.lastname: Misso
authors.affiliation: Kleijnen Systematic Reviews Ltd., Escrick Business Park, Escrick, York, England, YO19 6FD, UK. gill@systematic-reviews.com.
authors.forename: Gill
authors.initials: G
authors.lastname: Worthy
authors.affiliation: Global Health Economics and Outcomes Research, Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, Whippany, New Jersey, 07981, USA. dominic.muston@bayer.com.
authors.forename: Dominic
authors.initials: D
authors.lastname: Muston
authors.affiliation: Truhlsen Eye Institute, University of Nebraska Medical Center, 985540 Nebraska Medical Center, Omaha, Nebraska, 68198-5540, USA. diana.do@unmc.edu.
authors.forename: Diana V
authors.initials: DV
authors.lastname: Do
mesh_terms: D003907:Dexamethasone / Q000627:therapeutic use; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema / Q000188:drug therapy*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014792:Visual Acuity / Q000187:drug effects / Q000502:physiology
chemical_list: D005938:Glucocorticoids; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D003907:Dexamethasone; D040262:Receptors, Vascular Endothelial Growth Factor