|Year : 2008 | Volume
| Issue : 1 | Page : 3-6
Vascular endothelial growth factor blocking agents in retinal vein occlusion
Moorfields Eye Hospital, Dubai, United Arab Emirates
Medical Director, Moorfields Eye Hospital, Dubai
United Arab Emirates
Source of Support: None, Conflict of Interest: None
| Abstract|| |
This paper summarises the current status of the use of vascular endothelial growth factor (VEGF) blocking agents in retinal vein occlusion. There have been no randomised controlled trials comparing this treatment with the current standard treatment (largely laser) so the lower grade evidence of single treatment case series and anecdotal reports are discussed. VEGF blockers are good at reducing macular oedema in the short term, do improve visual acuity in many cases, and do not seem to adversely affect the long term revascularisation that is necessary to overcome the vein occlusion. VEGF blocking agents are not used in isolation in this condition - they will remain an adjunct to systemic and other local treatments. The literature was reviewed in online searches of Embase and Ovid and the papers quoted are a representative sample of a larger body of publications.
Keywords: retinal vein occlusion, vascular endothelial growth factor, avastin, bevacizumab
|How to cite this article:|
Canning C. Vascular endothelial growth factor blocking agents in retinal vein occlusion. Oman J Ophthalmol 2008;1:3-6
| Introduction|| |
Retinal vein occlusion remains an important blinding eye condition for which wholly effective therapies do not exist. Over the years ophthalmologists have tried many different treatments and as each new advance in treatment is developed it is tried on retinal vein occlusion. There have been intensive attempts to understand the basic mechanisms of the conditions in order to devise better treatments and many hundreds of papers have been published on the subject.
Vein occlusions are divided into branch, central and hemispheric and it seems that the pathogenesis of each differs. There are certain common themes - predisposing factors like hypertension, hypercoagulability and hyperviscosity contribute to all three types of occlusions. There are many papers in the literature describing small case series, longitudinal observational studies - this discussion presents a sample of these.
Vascular endothelial growth factor (VEGF) blockers
Growth factors are known to be important in the development and maintenance of blood vessels throughout the body, including the retinal circulation. They are also important in the vascular diseases. Various molecules stimulate growth of blood vessels in the eye including VEGF, Protein kinase C (beta isoform) and insulin-like growth factor (IGF-1), fibroblast growth factor (FGF), angiopoietins and cytokines (especially interleukin-8). VEGF is the dominant molecule in retinal neovascularisation whilst its role in choroidal neovascularisation is less clear.
VEGF has a number of effects. It is an endothelial cell mitogen, it induces tissue plasminogen activator (tPA), it regulates endothelial cell fenestrations in choriocapillaris, and it increases expression of integrins that affect endothelial cell migration. VEGF is produced by inner retina (especially glia) in response to hypoxia from neuronal activity.
The structure of VEGF is a dimeric glycoprotein similar to platelet derived growth factor (PDGF) and it is highly conserved in nature. There are four isoforms of VEGF-A with molecular weights of 121, 165, 189, 206 amino acids. VEGF is present in normal tissues especially during wound healing and response to ischaemic events.
Blocking the action of VEGF might be expected to modulate blood vessel behaviour in a number of retinal vascular events including diabetes and vein occlusion. The first effective VEGF blocking agent was pegaptanib. Pegaptanib is a 28-base ribonucleic acid aptamer (from the Latin aptus, to fit; and the Greek meros, part or region) that binds and blocks the activity of extracellular VEGF, specifically the 165-amino-acid isoform (VEGF 165 ). The aptamer is covalently linked to two branched 20-kD polyethylene glycol moieties (pegylated) to increase its biological half life.
Later a humanised monoclonal antibody was developed that was able to block all isoforms of VEGF - bevacizumab. This was introduced first as an adjunctive treatment for metastatic colorectal cancer. Bevacizumab is a relatively large molecule and it was believed that it would not easily penetrate the retinal barrier. A smaller recombinant humanised Fab fragment (ranibizumab) was therefore developed. As it turns out, both seem effective in retinal vessel disorders when injected intravitreally.
Branch retinal vein occlusion (BRVO)
This is the second most common retinal vascular event after diabetes. It usually occurs between 60 and 70 years of age, has no sex predisposition, and is associated with hypertension, diabetes, hyperlipidaemia, smoking, glaucoma and arteriosclerosis. Visual loss occurs primarily through disturbance of macular circulation (ischaemia and oedema) and through vitreous haemorrhage. 
The only treatment that has been proven for BRVO is grid laser photocoagulation of the macula to address the macula oedema.  A variety of other treatment options exist including triamcinalone,  Intravitreal or orbital floor, tissue plasminogen activator inhibitors , and peeling of the internal limiting membrane. 
Steroids such as triamcinalone have a variety of potentially beneficial actions - they are anti-inflammatory and may reduce vascular permeability. However ocular hypertension occurs in about a third of cases after injection and in a proportion of these the pressure proves very difficult to control. In a few cases it is even necessary to perform filtering surgery.
Tissue plasminogen activators may be effective in increasing the absorption of haemorrhage in the retina. There is controversy as to the effectiveness of this treatment in the rabbit model and the evidence in humans is anecdotal. Indeed, the haemorrhage within the retina is not a major cause of the vision loss in any case.
More recently attempts have been made to address the mechanical obstruction by separating the adventitial sheath between the vein and the artery at the point of occlusion.  Again early reports show promise and it appears that there is a role for this treatment in selected cases - those with a clear point of obstruction particularly where the event is recent before structural changes in the retina have occurred. Many studies have shown the variability of the natural history of BRVO, however, and effectiveness can only be judged with contemporaneous controls.
VEGF in retinal vein occlusions
The accumulated evidence to date suggests that blocking VEGF can reduce central retinal thickness on OCT (evidence that the amount of retinal oedema has reduced) and can improve vision in some cases. A significant minority of cases do not improve, however, most likely because macular ischaemia is the causative mechanism. In addition, the effect of the treatment is always temporary. Repeated injections are therefore required where an effect is observed.
Many questions remain unanswered - when to start treatment, which agent to use, how often to inject, the best method of injecting.
VEGF blockers should be considered when it becomes clear that the blockage is not going to clear itself spontaneously yet before too much structural damage has occurred in the macula. In practice this often means waiting around three months from the onset of the symptoms. However, if the eye is clearly deteriorating then starting before three months is reasonable, and if the visual loss is not that bad and the macular oedema not that clinically obvious then it may be reasonable to wait for much longer than three months.
Studies in neovascular age related macular oedema demonstrated that pegaptanib was able to stabilise the vision whilst ranibizumab was the first agent to be able to improve vision significantly. It is always unwise to extrapolate from one condition to another. However, there is very little literature regarding the use of pegaptanib in retinal vein occlusions. All the interest has centred on ranibizumab and bevacizumab. There has been no clear evidence yet that one is superior to the other. Ranibizumab has been more extensively studied in phase three randomised clinical settings and its safety profile is well known. The massive price differential between the two has meant that bevacizumab has been used widely and its results reported in case series and non randomised trials. Clinically there does not appear to be much difference between these agents.
The pharmacodynamics of VEGF blockers predicts that the effect should last 4-6 weeks following injection. No consensus has yet developed as to the best injection regimen. One common method is to inject every month for three months then three monthly afterwards. There are many variants on this, however. Clinical evidence suggests that a treatment effect can occur with the second or third injection even if there has been no response to the first one. It seems reasonable therefore to plan to do three injections at monthly intervals before deciding that this treatment is not going to work.
The duration of treatment depends on the clinical course. The natural history of BRVO is variable, but revascularisation is the rule. Once the venous pressure has normalised macular oedema should resolve spontaneously. Treatment with VEGF blockers is therefore aimed at preserving the integrity of the retina during the period of blockage. There is at least a theoretical risk that VEGF blockers may delay the natural revascularisation process since VEGF is important in this process. A number of case studies have reported rebound increase in macular oedema after stopping the injections. 
Central retinal vein occlusion (CRVO)
CRVO has a population based prevalence of 0.1-0.4%, occurring equally in males and females. It is most common over the age of 65 years and is usually unilateral (the risk of involvement of the fellow eye is about 1% per year). The main associated conditions are systemic hypertension (in 50-70%) and glaucoma (40%) based on the Central Vein Occlusion Study (CVOS). 
The presenting visual acuity is variable but an important prognostic indicator of final acuity and it is tightly correlated with the degree of retinal perfusion.  Vision is lost from macular oedema, macular ischaemia or neovascular complications (especially glaucoma).
The natural history of CRVO is for collateral vessels to form at the optic disc over a period of 6 or more months. Treatment is aimed at minimizing complications (neovascularisation, glaucoma and structural damage to the retina) whilst waiting for the revascularization to occur.
Systemic medical treatments, including anticoagulants (aspirin, heparin, and warfarin), vasodilators (pentoxifylline), anti-inflammatory agents (steroids, immunosuppressives) and haemodilution have all had little effect. Early panretinal laser has been shown to reduce iris and angle neovascularisation in non-perfused CRVO (Group N CVOS) and grid laser for macular oedema was ineffective in improving vision, although the oedema might be reduced (Group M CVOS). 
The use of laser to establish a chorioretinal venous anastomosis in non-ischaemic CRVO has been demonstrated,  but widespread clinical replication of this technique has not occurred.
More invasive approaches have also been used. Intravitreal triamcinalone clearly can reduce macular oedema,  but the same profile of complications exists as mentioned above. Tissue plasminogen activator (r-tPA) is a fibrinolytic agent aimed specifically at dissolving the thrombus. It can be administered systemically,  intravitreally  or via endovascular cannulation of retinal veins.  Overall there does seem to be an effect particularly with non ischaemic vein occlusions.
Radial optic neurotomy aims to create a chorioretinal anastomosis as well perhaps as relieving the "constriction" in the lamina cribrosa.  Both the mechanism of action and the effectiveness are still hotly debated. 
It is clear that there is no uniformly effective treatment for CRVO. It is no surprise, therefore, that VEGF blocking agents have been tried. ,, The emerging consensus is that bevacizumab is useful in reducing macular oedema; that the effect is temporary and injections need to be repeated; and that the improvement in visual acuity is variable but is better in non ischaemic CRVO than ischemic. Whilst there is a theoretical risk that blocking VEGF might slow the development of a collateral circulation, this has not been observed clinically.
CRVO may be complicated by iris vessels and rubeotic glaucoma. Bevacizumab produces a dramatic reduction in the anterior segment congestion within 48 hours.  This allows subsequent treatment with panretinal laser to provide long term control.
A standard treatment regimen is not yet settled, although monthly injections for three months then three monthly thereafter is often used. Treatment is continued whilst an effect is noted and until collateral circulation develops naturally (which may be 6 months to a year).
Safety is a vital consideration in any treatment. Both ranibizumab and bevacizumab can cause systemic and local side effects. The PACORES study of 4303 injections noted systemic reactions in 1.5% and ocular reactions in 0.27%.  Systemically effects include acute raised BP, cerebrovascular accidents, myocardial infarction, iliac artery aneurysm, toe amputation and death. Locally endophthalmitis (0.16%), tractional retinal detachment (0.16%), uveitis (0.09%), rhegmatogenous detachment, and vitreous haemorrhage were all noted. The Retina Associates in Alabama reported on 5233 bevacizumab injections over two years and only had one case of endophthalmitis.  Apart from doing injections in a sterile environment using meticulous aseptic technique, the key for safe injection is sterilisation of the conjunctiva with povidone iodine and avoiding contact between the needle and the eye lashes. 
The technique for injection is also very important with regard to pain. This is likely to be a repeated treatment and patients will be averse to having many injections if the first is painful. The key here is to have a high concentration of local anaesthetic at the injection site (either by raising a subconjunctival bleb of local anaesthetic or by holding a spear/applicator soaked in local on the site for a few minutes), to insert the needle through the sclera slowly, and to inject slowly.
| Conclusion|| |
Retinal vein occlusion remains one of the great challenges in retinal practice. The clinician may have to watch a potentially blinding eye condition evolving over months without being able to intervene effectively. VEGF blocking agents are not the cure, but they can be applied usefully in conjunction with other treatments.
One of the great problems with using VEGF blockers is that they need to be injected repeatedly. A longer acting preparation might be more acceptable to patients. Such agents may, however, produce other side effects.
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