title: Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for diabetic macular oedema.
abstract: BACKGROUND
  Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Although grid or focal laser photocoagulation has been shown to reduce the risk of visual loss in DMO or clinically significant macular oedema (CSMO), vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities has recently been proposed for improving vision in people with DMO.
  
  
  OBJECTIVE
  To assess the effectiveness, safety and cost-effectiveness of anti-VEGF therapy for preserving or improving vision in people with DMO.
  
  
  METHODS
  We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 6), MEDLINE (January 1946 to June 2012), EMBASE (January 1980 to June 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2012.
  
  
  METHODS
  We included randomised controlled trials (RCTs) comparing any antiangiogenic drugs with an anti-VEGF mechanism of action versus another treatment, sham treatment, or no treatment in patients with DMO. We also included economic evaluations to assess cost-effectiveness.
  
  
  METHODS
  Two review authors independently extracted the data. The risk ratio (RR) of visual loss and visual gain of three or more lines was estimated at least six months after treatment. Each economic analysis was described narratively using a structured format.
  
  
  RESULTS
  Eleven studies provided data on three comparisons of interest in this review. We based our conclusions on the RR of gain or loss of three or more lines of vision at about one year, which was more consistently reported as follow-up.Compared with sham treatment, there was evidence of moderate quality in three studies (497 participants, follow-up 8 to 12 months) that antiangiogenic therapy (pegaptanib: two studies, 246 participants; ranibizumab: one study, 151 participants) doubled and, respectively, halved, the chance of gaining or losing three or more lines of vision (RR: 2.19, 95% confidence interval (CI) 1.36 to 3.53; RR: 0.28, 95% CI: 0.13 to 0.59). In meta-analyses, the benefit was larger for ranibizumab compared to pegaptanib, but no significant subgroup difference could be demonstrated regarding our primary outcome.Compared with grid laser photocoagulation, there was evidence of moderate quality that antiangiogenic therapy (bevacizumab: two studies, 167 participants; ranibizumab: two studies, 300 participants; aflibercept: one study, 221 participants, 89 used for data extraction) more than doubled and, respectively, reduced by at least two thirds, the chance of gaining or losing three or more lines of vision (RR: 3.20, 95% CI 2.07 to 4.95 and RR: 0.13, 95% CI: 0.05 to 0.34, respectively). In meta-analyses, no significant subgroup difference could be demonstrated between bevacizumab, ranibizumab and aflibercept regarding our primary outcome, but, again, there was little power to detect a difference.Compared with grid laser photocoagulation alone, there was high quality evidence that ranibizumab plus photocoagulation (three studies, 783 participants) doubled and, respectively, at least halved, the chance of gaining or losing three or more lines of vision (RR: 2.11, 95% CI 1.67 to 2.67; RR: 0.29, 95% CI: 0.15 to 0.55).Systemic and ocular adverse events were rare in the included studies. Meta-analyses conducted for all antiangiogenic drugs compared with either sham or photocoagulation (nine studies, 104 events in 2159 participants) did not show a significant difference regarding arterial thromboembolic events (RR: 0.85 (0.56 to 1.28). Similarly, no difference was suggested regarding overall mortality (53 events, RR: 0.95 (0.52 to 1.74), but clinically significant differences could not be ruled out.
  
  
  CONCLUSIONS
  There is moderate quality evidence that antiangiogenic drugs provide a definite, but small, benefit compared to current therapeutic options for DMO, i.e. grid laser photocoagulation, or no treatment when laser is not an option. The quality and quantity of the evidence was larger for ranibizumab, but there was little power to investigate drug differences. Most data were obtained at one year, and a long-term confirmation is needed, since DMO is a chronic condition. Safety of both drug and the intravitreal injection procedure were good in the trials, but further long-term data are needed to exclude small, but clinically important differences regarding systemic adverse events.
authors.affiliation: Department of Specialised Surgical Sciences, University of Florence, Florence, Italy. gianni.virgili@unifi.it.
authors.forename: Gianni
authors.initials: G
authors.lastname: Virgili
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Parravano
authors.forename: Francesca
authors.initials: F
authors.lastname: Menchini
authors.forename: Massimo
authors.initials: M
authors.lastname: Brunetti
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D052157:Aptamers, Nucleotide / Q000627:therapeutic use; D000068258:Bevacizumab; D003930:Diabetic Retinopathy / Q000150:complications*; D006801:Humans; D017075:Laser Coagulation / Q000379:methods; D008269:Macular Edema / Q000188:drug therapy* / Q000601:surgery; D016032:Randomized Controlled Trials as Topic; D000069579:Ranibizumab; D014221:Triamcinolone / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide; D042461:Vascular Endothelial Growth Factor A; D014221:Triamcinolone; C495058:pegaptanib; D000068258:Bevacizumab; D000069579:Ranibizumab