Anti-vascular endothelial growth factor for macular oedema secondary to branch retinal vein occlusion

Branch retinal vein occlusion (BRVO) occurs when a retinal vein that drains part of the retina becomes blocked. BRVO can affect approximately four to five people per 1,000 of the population. Known risk factors for BRVO include hypertension, atherosclerosis, high cholesterol, diabetes mellitus, and other inflammatory or autoimmune conditions. In a BRVO the severity of vision loss is related to the extent of macular involvement by haemorrhage, swelling (oedema), and poor blood supply (ischaemia). The most common cause of visual loss in patients with BRVO is macular oedema (MO). Patients with BRVO in one eye are at risk of a venous occlusion in the fellow eye. Untreated, approximately one third of affected eyes will achieve a high level of vision (20/40 or better). Current "gold" standard treatment is laser photocoagulation which has been shown to reduce the risk of visual loss and improve the vision in up to two thirds of individuals with macular oedema secondary to BRVO, however, limitations to this treatment exist and newer modalities have suggested equal or improved efficacy. Recent studies have suggested that an injection of anti-vascular endothelial growth factor (anti-VEGF) in the eye may be of benefit to patients with BRVO. In this review, we appraise and present the level of current evidence for the use of anti-VEGF injections in the treatment of macular oedema after BRVO. In total, we found one randomised controlled trial and one quasi-randomised controlled trial. One study from the USA. had 397 participants and compared anti-VEGF injections with sham injections. It demonstrated a potential benefit of repeated anti-VEGF injections to improve vision (at least 15 letters) at one year. A second study with 30 participants, conducted in Italy, compared anti-VEGF injections with laser photocoagulation and did not demonstrate an improvement in vision (of at least 15 letters) of anti-VEGF injections over laser photocoagulation at one year. Antiangiogenic treatment was well tolerated in these studies, but since the studies were only of one year duration, we were unable to discuss long-term effects. There are several ongoing studies which undoubtedly will add to the evidence available.

Authors' conclusions: 

The available RCT evidence suggests that repeated treatment of non-ischaemic MO secondary to BRVO with the anti-VEGF agent ranibizumab may improve clinical and visual outcomes at six and 12 months. However, the frequency of re-treatment has not yet been determined and the impact of prior or combined treatment with laser photocoagulation on the primary outcome is unclear. Results from ongoing studies should assess not only treatment efficacy but also, the number of injections needed for maintenance and long-term safety and the effect of any prior treatment.

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Background: 

Branch retinal vein occlusion (BRVO) is one of the most common occurring retinal vascular abnormalities. The pathogenesis of BRVO is thought to involve both retinal vein compression and damage to the vessel wall, possibly leading to thrombus formation at sites where retinal arterioles cross retinal veins. The most common cause of visual loss in patients with BRVO is macular oedema (MO). Grid or focal laser photocoagulation has been shown to reduce the risk of visual loss and improve visual acuity (VA) in up to two thirds of individuals with MO secondary to BRVO, however, limitations to this treatment exist and newer modalities have suggested equal or improved efficacy. Recently, antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) has been used successfully to treat MO resulting from a variety of causes. As elevated intraocular levels of VEGF have been demonstrated in patients with retinal vein occlusions there is a strong basis for the hypothesis that anti-VEGF agents may be beneficial in the treatment of vascular leakage and MO.

Objectives: 

To investigate the efficacy and safety of intravitreal anti-VEGF agents for preserving or improving vision in the treatment of MO secondary to BRVO.

Search strategy: 

We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2012), EMBASE (January 1980 to August 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to August 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 7 August 2012 and the clinical trials registers on 10 September 2012.

Selection criteria: 

We included randomised controlled trials (RCTs) and quasi-RCTS of at least six months duration where anti-VEGF treatment was compared with another treatment, no treatment, or placebo. We excluded trials where combination treatments (anti-VEGF plus other treatments) were used and trials that investigated the dose and duration of treatment without a comparison group (other treatment/no treatment/sham).

Data collection and analysis: 

Two review authors independently extracted the data. The primary outcome was the proportion of participants with an improvement from baseline in best-corrected visual acuity (BCVA) of greater than or equal to 15 letters (3 lines) on the Early Treatment in Diabetic Retinopathy Study (ETDRS) Chart at six months and at 12 months of follow-up. The secondary outcomes we report are the proportion of participants who lost greater than or equal to 15 ETDRS letters (3 lines) and the mean VA change at six months and any additional follow-up intervals as well as the change in central retinal thickness on optical coherence tomography (OCT) from baseline and final reported follow-up, the number and type of complications, the number of additional interventions administered and any adverse outcomes. Where available, the cost benefit and quality of life data reported in the primary studies is presented.

Main results: 

We found one RCT and one quasi-RCT that met the inclusion criteria after independent and duplicate review of the search results. The studies used different anti-VEGF agents and different study groups which were not directly comparable.

One multi-centre RCT (BRAVO) conducted in the USA randomised 397 individuals and compared monthly intravitreal ranibizumab (0.3 mg and 0.5 mg) injections with sham injection. The study only included individuals with non-ischaemic BRVO. Although repeated injections of ranibizumab appeared to have a favourable effect on the primary outcome, approximately 50% of the ranibizumab 0.3 mg group and 45% of the ranibizumab 0.5 mg group received rescue laser treatment which may have an important effect on the primary outcome. In addition, during the six-month observation period 93.5% of individuals in the sham group received intravitreal ranibizumab (0.5 mg). This cross-over design limits the ability to compare the long-term impact of ranibizumab versus a pure control group.

The second trial was a small study (n = 30) from Italy with limitations in study design that reported a benefit of as-required intravitreal bevacizumab (1.25 mg) over laser photocoagulation in MO secondary to BRVO. We present the evidence from these trials and other interventional case series.

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