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

What is the aim of this review?
The aim of this Cochrane Review was to find out if anti-vascular endothelial growth factor (anti-VEGF) works for the treatment of macular oedema (MO) secondary to branch retinal vein occlusion (BRVO). Cochrane researchers collected and analysed all relevant studies to answer this question and found eight studies.

Key messages
The review shows that people with MO due to BRVO benefit from treatment with anti-VEGF with an increased chance of improved vision at six and 12 months when compared with no treatment, laser or steroid injection.

What was studied in the review?
There are small blood vessels at the back of the eye (retina) known as arteries (when blood comes into the eye) and veins (when blood leaves the eye). BRVO occurs when a vein that drains part of the retina becomes blocked. This can lead to swelling (oedema) at the back of eye which may result in loss of vision, particularly if it occurs at the centre of the retina (macula).

One treatment option for MO due to BRVO is anti-VEGF injections. VEGF is a molecule found in the back of the eye associated with the inflammation. Anti-VEGF blocks the action of VEGF, which can help to reduce the amount of damage. Treating MO due to BRVO is important as it can prevent sight loss occurring.

The most commonly used anti-VEGF drugs are:

∙ ranibizumab (Lucentis)
∙ aflibercept (Eylea)
∙ bevacizumab (Avastin)

What are the main results of the review?
Cochrane researchers found eight relevant studies. These studies took place in Europe, North America, Eastern Mediterranean region and East Asia.

One study compared anti-VEGF to no treatment (sham injection); three studies compared anti-VEGF to another type of treatment (laser); and four studies compared anti-VEGF to steroids. The findings were as follows.

∙ People treated with anti-VEGF were more likely to have improved vision and less swelling at the back of the eye at six months after treatment compared to people who were not treated with anti-VEGF or who were treated with laser or steroids (moderate-certainty evidence).

∙ In general, there was only very low-certainty evidence on adverse events (harms) comparing anti-VEGF treatment to these other treatments. There were no cases of eye infection (endophthalmitis). There was evidence that people treated with steroids (injected into the eye) were more likely to develop cataract or raised pressure in the eye compared with anti-VEGF.

∙ Treatment with anti-VEGF was associated with a greater improvement in quality of life (moderate certainty).

How up to date is this review?
Cochrane researchers searched for studies that had been published up to June 2019.

Authors' conclusions: 

The available RCT evidence suggests that treatment of MO secondary to BRVO with anti-VEGF improves visual and anatomical outcomes at six and 12 months.

Read the full abstract...
Background: 

Branch retinal vein occlusion (BRVO) is one of the most commonly occurring retinal vascular abnormalities. The most common cause of visual loss in people with BRVO is macular oedema (MO). Grid or focal laser photocoagulation has been shown to reduce the risk of visual loss. Limitations to this treatment exist, however, and newer modalities may have equal or improved efficacy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) has recently been used successfully to treat MO resulting from a variety of causes.

Objectives: 

To investigate the efficacy and gather evidence from randomised controlled trials (RCTs) on the potential harms of anti-vascular endothelial growth factor (VEGF) agents for the treatment of macular oedema (MO) secondary to branch retinal vein occlusion (BRVO).

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 6); MEDLINE Ovid; Embase Ovid; the ISRCTN registry; ClinicalTrials.gov; and the WHO ICTRP. The date of the last search was 12 June 2019.

Selection criteria: 

We included randomised controlled trials (RCTs) investigating BRVO. Eligible trials had to have at least six months' follow-up 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 using standard methodological procedures expected by Cochrane. The primary outcome was the proportion of participants with an improvement from baseline in best-corrected visual acuity of greater than or equal to 15 letters (3 lines) on the Early Treatment in Diabetic Retinopathy Study (ETDRS) Chart at six months and 12 months of follow-up. The secondary outcomes were the proportion of participants who lost greater than or equal to 15 ETDRS letters (3 lines) and the mean visual acuity (VA) change at six and 12 months, as well as the change in central retinal thickness (CRT) on optical coherence tomography from baseline at six and 12 months. We also collected data on adverse events and quality of life (QoL).

Main results: 

We found eight RCTs of 1631 participants that met the inclusion criteria after independent and duplicate review of the search results. These studies took place in Europe, North America, Eastern Mediterranean region and East Asia. Included participants were adults aged 18 or over with VA of 20/40 or worse. Studies varied by duration of disease but permitted previously treated eyes as long as there was sufficient treatment-free interval. All anti-VEGF agents (bevacizumab, ranibizumab and aflibercept) and steroids (triamcinolone and dexamethasone) were included. Overall, we judged the studies to be at moderate or unclear risk of bias. Four of the eight studies did not mask participants or outcome assessors, or both.

One trial compared anti-VEGF to sham. At six months, eyes receiving anti-VEGF were significantly more likely to have a gain of 15 or more ETDRS letters (risk ratio (RR) 1.72, 95% confidence interval (CI) 1.19 to 2.49; 283 participants; moderate-certainty evidence). Mean VA was better in the anti-VEGF group at six months compared with control (mean difference (MD) 7.50 letters, 95% CI 5.29 to 9.71; 282 participants; moderate-certainty evidence). Anti-VEGF also proved more effective at reducing CRT at six months (MD −57.50 microns, 95% CI −108.63 to −6.37; 281 participants; lower CRT is better; moderate-certainty evidence). There was only very low-certainty evidence on adverse effects. There were no reports of endophthalmitis. Mean change in QoL (measured using the National Eye Institute Visual Functioning Questionnaire VFQ-25) was better in people treated with anti-VEGF compared with people treated with sham (MD 7.6 higher score, 95% CI 4.3 to 10.9; 281 participants; moderate-certainty evidence).

Three RCTs compared anti-VEGF with macular laser (total participants = 473). The proportion of eyes gaining 15 or more letters was greater in the anti-VEGF group at six months (RR 2.09, 95% CI 1.44 to 3.05; 2 studies, 201 participants; moderate-certainty evidence). Mean VA in the anti-VEGF groups was better than the laser groups at six months (MD 9.63 letters, 95% CI 7.23 to 12.03; 3 studies, 473 participants; moderate-certainty evidence). There was a greater reduction in CRT in the anti-VEGF group compared with the laser group at six months (MD −147.47 microns, 95% CI −200.19 to −94.75; 2 studies, 201 participants; moderate-certainty evidence). There was only very low-certainty evidence on adverse events. There were no reports of endophthalmitis. QoL outcomes were not reported.

Four studies compared anti-VEGF with intravitreal steroid (875 participants). The proportion of eyes gaining 15 or more ETDRS letters was greater in the anti-VEGF group at six months (RR 1.67, 95% CI 1.33 to 2.10; 2 studies, 330 participants; high-certainty evidence) and 12 months (RR 1.76, 95% CI 1.36 to 2.28; 1 study, 307 participants; high-certainty evidence). Mean VA was better in the anti-VEGF group at six months (MD 8.22 letters, 95% CI 5.69 to 10.76; 2 studies, 330 participants; high-certainty evidence) and 12 months (MD 9.15 letters, 95% CI 6.32 to 11.97; 2 studies, 343 participants; high-certainty evidence). Mean CRT also showed a greater reduction in the anti-VEGF arm at 12 months compared with intravitreal steroid (MD −26.92 microns, 95% CI −65.88 to 12.04; 2 studies, 343 participants; moderate-certainty evidence). People receiving anti-VEGF showed a greater improvement in QoL at 12 months compared to those receiving steroid (MD 3.10, 95% CI 0.22 to 5.98; 1 study, 307 participants; moderate-certainty evidence). Moderate-certainty evidence suggested increased risk of cataract and raised IOP with steroids. There was only very low-certainty evidence on APTC events. No cases of endophthalmitis were observed.

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