The evidence on using anti-VEGF for treating ROP

Vascular endothelial growth factor (VEGF) is, as the name suggests, a growth factor which plays an important physiological role in the development of blood vessels, including in the retina. Vascular endothelial growth factor is also important in ROP, as over-production of VEGF (along with other growth factors) stimulates the development of the abnormal blood vessels seen in ROP. However, VEGF also plays an important role in the development of the lungs, kidneys and brain during fetal and postnatal life.

Agents which block VEGF, known as anti-VEGF agents, were first developed as a treatment for cancer, and several different agents are now available. Anti-VEGF agents are now widely used for a range of eye conditions including age related macular degeneration and diabetic retinopathy. Their use in ROP is more recent, and there are still many unanswered questions.

In ROP, as in other eye conditions, anti-VEGF agents need to be injected into the eye. Although this increases the risk of infection, the procedure is much shorter than laser treatment, which makes it attractive.

When considering whether to use anti-VEGF agents for ROP it is important to consider the following:

1. Their effectiveness in comparison to laser treatment

2. Ocular complications in comparison to laser treatment

3. Other ocular effects

4. Possible systemic effects on the development of other organs

1. Effectiveness in relation to laser treatment

Several trials have been undertaken which show that anti-VEGF agents can lead to regression of ROP, but there has only been one reasonably large trial which compared anti-VEGF with laser.

A recent Cochrane systematic review and meta-analysis of three trials (Sankar et al. 2018) concluded that, compared to laser for Type I ROP, anti-VEGF agents do not reduce the risk of retinal detachment or recurrence of ROP and do not reduce the risk recurrence of ROP requiring re-treatment. Compared to laser outcomes for ROP in zone 1 and zone 2, anti-VEGF agents had better outcomes for zone 1, but worse outcomes for zone 2. The authors of the review state that the level of evidence is very low quality due to small sample sizes and other problems with the trials.

Many studies report late recurrence of new vessels after anti-VEGF agents, often many months after treatment. This means that babies need to be followed up closely after anti-VEGF treatment throughout infancy, unlike laser treatment in which recurrence occurs more quickly if laser treatment was not adequate. Careful examination of the retina in older infants can be challenging, and sometimes needs to be done under general anaesthesia.

2. Ocular benefits and complications in comparison to laser treatment.

Injection of anti-VEGF agents seems to be associated with less high myopia than laser. In some eyes anti-VEGF agents can lead to worsening of scar tissue inside the eye and the rapid development of retinal detachment.

3. Other ocular effects

Studies show that after treatment with anti-VEGF agents at the doses which have been used to date, retinal blood vessels can fail to grow normally to the ora serrata, leaving areas of peripheral retina without blood vessels, at least in the medium term. The retinal vessels can also be abnormal in other ways. Whether these findings are important in the long-term is not known.

4. Possible systemic effects

Of major concern are the effects anti-VEGF agents may have on the development of other organs. After injection into the eye, the agents pass into the blood stream where they block the VEGF which normally circulates in the blood. There are concerns that the resulting lack of VEGF at a critical time when the kidneys, lungs and brain are developing may lead to long-term, irreversible changes. This is a difficult area to study, and clinical trials are needed which recruit a large enough number of babies who are followed up into early childhood when their motor, cognitive and other functions can be assessed.

The treatment of ROP with anti-VEGF agents is a very active area of research, with studies exploring different agents, doses and dosing regimens. Indeed, evidence is emerging that far lower doses than have been used previously can also be effective, and possibly less harmful. More clinical trials are also needed to assess the effectiveness of these agents, with long enough follow up to assess safety for the eyes and other organs, particularly the brain.

In conclusion

Until such time as the evidence of benefits and harms are clearer it is wise to err on the side of caution and only use anti-VEGF agents when laser treatment is not possible. That is as ‘rescue’ treatment when the pupils do not dilate or the infant is too sick for laser or where maximum laser treatment has failed to control the condition.

Parents must be carefully counselled about the use of anti-VEGF agents, including the need for frequent, long-term follow up. Written, informed consent must be obtained before treatment.

Table: Pros and cons of intravitreal injections for ROP

What is the practice and guidance in your setting on the use of anti-VEGF agents for ROP management? Share your thoughts and concerns in the Comments.

If you have additional questions on anti-VEGF treatment, please add them to the Comments in the next step 3.15 for our experts to address during the live Q&A session this week.