title: Anti-vascular endothelial growth factor 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 is used to try to improve vision in people with DMO.
  
  
  OBJECTIVE
  To investigate the effects in preserving and improving vision and acceptability, including the safety, compliance with therapy and quality of life, of antiangiogenic therapy with anti-VEGF modalities for the treatment of DMO.
  
  
  METHODS
  We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2014), EMBASE (January 1980 to April 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to April 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (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 28 April 2014.
  
  
  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 people with DMO.
  
  
  METHODS
  We used standard methodological procedures expected by The Cochrane Collaboration. The risk ratios (RR) for visual loss and visual gain of three or more lines of logMAR visual acuity were estimated at one year of follow-up (plus or minus six months) after treatment initiation.
  
  
  RESULTS
  Eighteen studies provided data on four comparisons of interest in this review. Participants in the trials had central DMO and moderate vision loss.Compared with grid laser photocoagulation, people treated with antiangiogenic therapy were more likely to gain 3 or more lines of vision at one year (RR 3.6, 95% confidence interval (CI) 2.7 to 4.8, 10 studies, 1333 cases, high quality evidence) and less likely to lose 3 or more lines of vision (RR 0.11, 95% CI 0.05 to 0.24, 7 studies, 1086 cases, high quality evidence). In meta-analyses, no significant subgroup difference was demonstrated between bevacizumab, ranibizumab and aflibercept for the two primary outcomes, but there was little power to detect a difference. The quality of the evidence was judged to be high, because the effect was large, precisely measured and did not vary across studies, although some studies were at high or unclear risk of bias for one or more domains. Regarding absolute benefit, we estimated that 8 out of 100 participants with DMO may gain 3 or more lines of visual acuity using photocoagulation whereas 28 would do so with antiangiogenic therapy, meaning that 100 participants need to be treated with antiangiogenic therapy to allow 20 more people (95% CI 13 to 29) to markedly improve their vision after one year. People treated with anti-VEGF on average had 1.6 lines better vision (95% CI 1.4 to 1.8) after one year compared to laser photocoagulation (9 studies, 1292 cases, high quality evidence). To achieve this result, seven to nine injections were delivered in the first year and three or four in the second, in larger studies adopting either as needed regimens with monthly monitoring or fixed regimens.In other analyses antiangiogenic therapy was more effective than sham (3 studies on 497 analysed participants, high quality evidence) and ranibizumab associated with laser was more effective than laser alone (4 studies on 919 participants, high quality evidence).Ocular severe adverse events, such as endophthalmitis, were rare in the included studies. Meta-analyses conducted for all antiangiogenic drugs compared with either sham or photocoagulation did not show a significant difference regarding serious systemic adverse events (15 studies, 441 events in 2985 participants, RR 0.98, 95% CI 0.83 to 1.17), arterial thromboembolic events (14 studies, 129 events in 3034 participants, RR 0.89, 95% CI 0.63 to 1.25) and overall mortality (63 events in 3562 participants, RR 0.88, 95% CI 0.52 to 1.47). We judged the quality of the evidence on adverse effects as moderate due to partial reporting of safety data and the exclusion of participants with previous cardiovascular events in some studies.
  
  
  CONCLUSIONS
  There is high quality evidence that antiangiogenic drugs provide a benefit compared to current therapeutic options for DMO, that is grid laser photocoagulation, in clinical trial populations at one or two years. Future research should investigate differences between drugs, effectiveness under real-world monitoring and treatment conditions, and safety in high-risk populations, particularly regarding cardiovascular risk.
authors.affiliation: Department of Translational Surgery and Medicine, Eye Clinic, University of Florence, Largo Brambilla, 3, Florence, Italy, 50134.
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: Jennifer R
authors.initials: JR
authors.lastname: Evans
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; D040262:Receptors, Vascular Endothelial Growth Factor / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; 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; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D014221:Triamcinolone; C495058:pegaptanib; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab