Review question
We reviewed the evidence about the effect of anti-vascular endothelial growth factor (anti-VEGF) agents in people with macular oedema secondary to central retinal vein occlusion (CRVO).
Background
CRVO affects approximately one person per 1000 at any one time, and is associated with increasing age, high blood pressure, diabetes, glaucoma and various disorders of the blood. It frequently causes sudden, painless vision loss in one eye, although sometimes the vision loss may be minimal. If the vein blockage leads to inadequate oxygen delivery to the sensitive retinal tissue, the CRVO is the 'non-perfused' or 'ischaemic' subtype. More commonly, blood flow and oxygen delivery are restored following the vein blockage and the CRVO is the 'perfused' or 'non-ischaemic' subtype, and has a better visual outcome. Various other complications may develop over hours, days, weeks or months. These include macular oedema, in which fluid collects within the retina and causes reduction in vision. Until relatively recently there has been no evidence-based treatment for this condition. Anti-VEGF agents have been used successfully to treat patients with other retinal vascular disorders, including several conditions associated with macular oedema.
Study characteristics
This systematic review identified six trials which included 937 participants with macular oedema secondary to CRVO (as of 29 October 2013). The trials compared sham injections with one of four types of anti-VEGF agents: aflibercept (VEGF Trap-Eye, Eylea), bevacizumab (Avastin), pegaptanib sodium (Macugen) and ranibizumab (Lucentis). All trials treated participants for at least six months. Three trials were multicentre, international trials and three were conducted in Norway, Sweden or the USA.
Key results
Overall, treatment with anti-VEGF agents increased the chance of a significant gain in vision (at least 3 lines on the vision chart) at six months by more than two and a half times, compared to no treatment. Furthermore, the risk of losing significant vision (at least 3 lines on the vision chart) was reduced by 80% in those receiving anti-VEGF therapy compared to those receiving no treatment. No significant safety concerns were identified at six or 12 months, but the available studies do not allow a conclusion about their long-term effectiveness and safety to be drawn. Nevertheless, the availability of anti-VEGF treatment for CRVO macular oedema represents an important advance in the clinical management options for this sight-threatening disease.
Quality of the evidence
The six trials included in this review were high quality and consistently demonstrated visual benefit from anti-VEGF injections.
Compared to no treatment, repeated intravitreal injection of anti-VEGF agents in eyes with CRVO macular oedema improved visual outcomes at six months. All agents were relatively well tolerated with a low incidence of adverse effects in the short term. Future trials should address the relative efficacy and safety of the anti-VEGF agents and other treatments, including intravitreal corticosteroids, for longer-term outcomes.
Central retinal vein occlusion (CRVO) is a relatively common retinal vascular disorder in which macular oedema may develop, with a consequent reduction in visual acuity. Until recently there has been no treatment of proven benefit, but growing evidence supports the use of anti-vascular endothelial growth factor (anti-VEGF) agents.
To investigate the effectiveness and safety of anti-VEGF therapies for the treatment of macular oedema secondary to CRVO.
We searched CENTRAL (which contains the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 10), Ovid MEDLINE (January 1950 to October 2013), EMBASE (January 1980 to October 2013), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2013), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to October 2013), OpenGrey, OpenSIGLE (January 1950 to October 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and Web of Science Conference Proceedings Citation Index-Science (CPCI-S). There were no language or date restrictions in the electronic search for trials. The electronic databases and clinical trials registers were last searched on 29th October 2013.
We considered randomised controlled trials (RCTs) that compared intravitreal anti-VEGF agents of any dose or duration to sham injection or no treatment. We focused on studies that included individuals of any age or gender and a minimum of six months follow-up.
Two review authors independently assessed trial quality and extracted data. The primary outcome was the proportion of participants with a gain in best-corrected visual acuity (BCVA) from baseline of greater than or equal to 15 letters (3 lines) on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Secondary outcomes included the proportion of participants with a loss of 15 letters or more of BCVA, the mean change from baseline BCVA, the mean change in central retinal thickness (CRT), the number and type of complications or adverse outcomes, and the number of additional interventions administered. Where available, we also presented quality of life and economic data.
We found six RCTs that met the inclusion criteria after independent and duplicate review of the search results. These RCTs included 937 participants and compared outcomes at six months to sham injection for four anti-VEGF agents: aflibercept (VEGF Trap-Eye, Eylea), bevacizumab (Avastin), pegaptanib sodium (Macugen) and ranibizumab (Lucentis). Three trials were conducted in Norway, Sweden and the USA, and three trials were multicentre, one including centres in the USA, Canada, India, Israel, Argentina and Columbia, a second including centres in the USA, Australia, France, Germany, Israel, and Spain, and a third including centres in Austria, France, Germany, Hungary, Italy, Latvia, Australia, Japan, Singapore and South Korea. We performed meta-analysis on three key visual outcomes, using data from up to six trials. High-quality evidence from six trials revealed that participants receiving intravitreal anti-VEGF treatment were 2.71 times more likely to gain at least 15 letters of visual acuity at six months compared to participants treated with sham injections (risk ratio (RR) 2.71; 95% confidence intervals (CI) 2.10 to 3.49). High-quality evidence from five trials suggested anti-VEGF treatment was associated with an 80% lower risk of losing at least 15 letters of visual acuity at six months compared to sham injection (RR 0.20; 95% CI 0.12 to 0.34). Moderate-quality evidence from three trials (481 participants) revealed that the mean reduction from baseline to six months in central retinal thickness was 267.4 µm (95% CI 211.4 µm to 323.4 µm) greater in participants treated with anti-VEGF than in participants treated with sham. The meta-analyses demonstrate that treatment with anti-VEGF is associated with a clinically meaningful gain in vision at six months. One trial demonstrated sustained benefit at 12 months compared to sham. No significant ocular or systemic safety concerns were identified in this time period.