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. Objectives: To assess the effectiveness, safety and cost-effectiveness of anti-VEGF therapy for preserving or improving vision in people with DMO. Search 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. Selection criteria: 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. Data collection and analysis: 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. Main results: Eleven studies provided data on three comparisons of interest in this review. 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 3 or more lines of vision (RR: 3.20, 95% confidence interval (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. The quality of the evidence was moderate since the overall size was suboptimal for investigating between study, as well as between drug, heterogeneity. Regarding absolute benefit, eight out of 100 patients with DMO would gain 3 or more lines of visual acuity using photocoagulation, whereas 26 would do so with antiangiogenic therapy, meaning that 100 patients need to be treated with antiangiogenic therapy to allow 18 more people (95% CI from 9 to 32) to markedly improve their vision after one year. Using mean visual acuity outcome, the meta-analytic difference between antiangiogenic therapy and photocoagulation was 1.3 lines (1 to 1.6) after one year, favouring drug therapy. In other analyses, ranibizumab was more effective than sham (three studies on 497 participants) and ranibizumab associated with laser was more effective than laser alone (three studies on 783 participants). 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. Authors' 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.