Purpose: Anti-vascular endothelial growth factor (VEGF) agents have been shown to decrease neovascularization and inflammation associated with diabetic macular edema (DME). Dosing, administration schedules, and costs vary among these agents, and to date, their effectiveness and safety have not been explicitly compared.
Method: We conducted a systematic review of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 2000 to December 22, 2011). Included reports were randomized controlled trials (RCTs) and observational studies published in English, with comparisons of at least one intravitreal anti-VEGF agent to laser photocoagulation, sham injection, or other control (single-arm observational studies and studies in other ocular conditions were eligible for safety evaluations). Identified agents included aflibercept, bevacizumab, pegaptanib, and ranibizumab. Outcomes of interest included improvement in best-corrected visual acuity (BCVA) and incidence of serious adverse events within and outside the eye. Direct meta-analyses were conducted for each agent using RevMan (v.5.1.6); pairwise indirect treatment comparisons between agents also were conducted, using software developed by the Canadian Agency for Drugs and Technologies in Health (CADTH).
Result: 15 RCTs and 8 observational studies met inclusion criteria. No RCT directly compared any of the anti-VEGF agents of interest. Study populations varied with respect to duration of diabetes, level of glycemic control, and baseline visual acuity. RCTs of bevacizumab tended to be small, investigator-initiated studies, in contrast to evidence for other agents. Substantial improvement in visual acuity relative to control was seen with all agents, ranging from a weighted mean difference of 5-12 letters over 6-24 months of follow-up. No consistent differences in effectiveness were observed between agents in indirect comparisons, either in primary analyses or sensitivity analyses incorporating poor-quality studies and multiple control populations. Ocular harms such as endophthalmitis were rare among all agents; rates of major non-ocular events and death did not materially differ between anti-VEGF therapy and control. However, comprehensive and rigorous reporting of adverse events was generally lacking in studies of bevacizumab.
Conclusion: Evidence suggests that all anti-VEGF agents improve visual acuity in patients with DME relative to macular laser treatment or sham injection; however, our analyses suggest no significant differences in clinical performance among available agents. The side effect profile of bevacizumab relative to other anti-VEGF agents remains the greatest element of uncertainty.
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