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Management Brief No. 126

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Management eBriefs
Issue 126April 2017

The report is a product of the VA/HSR Evidence Synthesis Program.

Comparative Effectiveness of Anti-Vascular Endothelial Growth Factor Agents

Visual impairment is a common problem among Veterans and results in significant reduction in quality of life. Diseases commonly responsible for substantial vision loss include neovascular (“wet”) age-related macular degeneration (AMD), diabetic macular edema (DME), and central or branch retinal vein occlusion (CRVO or BRVO). While the etiologies of these diseases are complex, all are driven at least in part by vascular endothelial growth factors (VEGFs). This has led to the development of several drugs called anti-VEGF agents designed to block these factors and thus limit their damage to the eye. The most commonly used anti-VEGF agents—aflibercept, bevacizumab, and ranibizumab—have been shown to slow and even reverse the vision loss typically seen in patients with AMD, DME, BRVO, and CRVO. However, the comparative effectiveness, harms, and costs of these drugs are unclear.

This systematic review sought to compare both the clinical and economic effectiveness of anti-vascular endothelial growth factor agents, specifically aflibercept, bevacizumab, and ranibizumab. Investigators with VA’s Evidence-based Synthesis Program Center located in Portland, OR searched multiple data sources, including MEDLINE to December 11, 2015, in addition to PubMed, EMBASE, Elsevier, and Ovid EMB Reviews to February 2, 2016. Grey literature (i.e., trial registries, conference proceedings, etc.) also were examined for relevance. After reviewing more than 6,300 citations, they identified 16 trials that were relevant to their analysis. Patients with AMD were the best-studied population (11 trials), and the most commonly compared agents were bevacizumab and ranibizumab.

Summary of Review
This review found:

  • No clear, consistent, clinically meaningful differences between anti-VEGF drugs for most effectiveness outcomes and rates of systemic or ocular harms (including endophthalmitis). However, the studies were not powered to detect differences between drugs for harms.
  • Aflibercept may provide a greater visual acuity benefit than the other agents among patients with low baseline visual acuity over the short-term, but the longer-term findings are unclear and more trials assessing the effects of aflibercept are needed.
  • Bevacizumab appears to be significantly more cost-effective than the other drugs, although all trials evaluating its costs used compounded bevacizumab treatment (not currently available within the VA).
  • In choosing among these drugs, clinicians also may need to consider factors such as patient preference, individual treatment response, convenience, and distance to facility.

Within trials, potential reasons for variability in individual treatment response (indicated by large standard deviations) include factors such as age, time to treatment initiation, genetics, severity of disease, and baseline visual acuity. While few differences between agents were seen for most adverse events, some previous trials and systematic reviews have shown that patients treated with intravitreal (substance delivered into the eye) anti-VEGF agents are at a higher risk for some serious systemic adverse events – compared to patients receiving sham injections or other treatments.

Evidence gaps and ongoing research
More research is needed to determine the comparative effectiveness of aflibercept and its potential for less-frequent dosing schedules. Very limited evidence was found in patients with BRVO or CRVO; currently ongoing large clinical trials will help fill current research gaps for these conditions. Future studies should include quality of life and functional status outcomes, and follow patients for longer periods of time.

A cyberseminar session titled "Comparative Clinical and Economic Effectiveness of Anti-Vascular Endothelial Growth Factor Agents Report" will be held on Wednesday, May 10, 2017 from 1:00pm to 2:00pm (ET). To register, go to the HSR&D Cyberseminar web page.

Low A, Kansagara D, Freeman M, Fu R, Bhavsar K, Faridi A, Kondo K, Paynter R. Comparative Clinical and Economic Effectiveness of Anti-Vascular Endothelial Growth Factor Agents. VA ESP Project #05-225; 2017.

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ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.


This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers – and to disseminate these reports throughout VA.

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