Anti-VEGF injections for diabetic retinopathy Lucentis, Avastin, & Eyelea ...a leaflet for patients
- VEGF = vascular endothelial growth factor
- IVA = Intravitreal Avastin
Anti-VEGF drugs: introduction
Macular oedema shown in green by the arrow. Macular oedema affects the centre
of the retina which is responsible for sharp vision, see
The front of the eye is on the
left, and the retina
is shown in red
Lucentis, Avastin and Eyelea are anti-growth
factor drugs (anti-VEGF). The drugs are given as injections into the
vitreous cavity of your eye. Lucentis, Avastin, & Eyelea= Ranibizumab, Bevacizumab, Aflibercept
The drugs are used to reduce
- macular oedema, that is fluid at the back of the eye, occurs
in diabetes, retinal vein occlusion.
- reduce retinal new vessel growth in these conditions
- to reduce new vessel growth on the iris (rubeotic glaucoma)
- The drugs are also used to treat ARMD, but that is not discussed here.
injection in a very clean room.
The drugs are given as an injection usually in a clean minor surgery room. The injection procedure
itself takes seconds and is usually feels like a tiny prick. You can
go home later that day...this is a 'day case' procedure. Repeated injections are
safe. VEGF levels drop
after the injection.
In the US
the term 'IVT' means intravitreal 'treatment', which might be triamcinolone,
Lucentis, Avastin, or Eylea. This page refers to Lucentis, Avastin, or Eylea, anti-VEGF drugs.
In the UK Avastin is not licenced, which means that
has not yet been approved by the NHS, but it is the commonest drug used round the world.
If the macular oedema is greater than 400µ, the NHS pays for treatment NICE. Avastin is much, much cheaper, is rarely funded by the NHS, but should be approved by NICE. NICE have refused to consider Avastin, as the drug company has not carried out much research etc. Avastin is marginally less powerful Jama 16 .
Diabetes and the other conditions damage blood vessels
in the retina, and the damaged blood vessels then start to leak.
The leakage makes the retina waterlogged, a bit like a sponge,
as in the diagram above. This is part of 'diabetic maculopathy'
(DME) or 'macular oedema' in retinal vein occlusion. animation. Text
The macula is the central area of the retina, responsible for
your central or 'sharp' vision used for reading & watching
TV.... our sharp & detailed vision. When the macula is swollen
(oedema) the sight is reduced, and people cannot see details
like faces and writing on TV, and bus numbers.
The retinal damage releases a chemical, VEGF (VEGF= vascular
endothelial growth factor). The VEGF then causes adjacent retina
to leak or grow 'new blood vessels' as below.
Anti-VEGFs block the effect of VEGF by binding to the VEGF receptors
on the cells in the retina. This then reduces the leakage, and
the sight may improve. See the evidence, also, DRRN, Byeon, India
Macular oedema (DME) and response to Anti-VEGF treatment
- DME = diabetic macular oedema
- will reduce macular oedema Anti-VEGF
- It is unlikely to improve sight if there is no oedema.
- Occasional patients will notice a deterioration in vision,
and such eyes are more likely to have more macular ischaemia
than the eyes that benefit.
- Eyes with vitreous traction may develop more traction on the retina.
- Intraretinal cysts are predictive at week 4, so examine after 1 injection to determine prognosis.
- Disrupted retinal inner layers (DRIL areas) indicate a worse prognosis see.
- Observing retinal thickness after 3 injections: if there is no improvement there will be no benefit no benefit of continuing anti-VEGF.
- The effectiveness is Eylea>Lucentis>Avastin, but the difference is not that great.
- Treatment needs to be OCT monitored: treatment should be
offered if there in increase in oedema. In June 2016 5 injections/eye are often arranged, with a monthly gap, but see response below.
- So if there is 400µ central macular thickness, anti-VEGF injections
are carried out monthly until there is no extra response. In
such a patient, oedema may reduce to 250µ. If a further
injection does not reduce the oedema, then 250µ would be
considered the best that can be achieved. After that injections
would be restarted if the thickness increases again. So if
the thickness increases, perhaps to 300µ, injections would
be restarted again so as to maintain 250µ.
- Even with injections vision may not improve. Vision improves
in 50% patients, but oedema reduces in most (?~80%). So vision
is NOT a good indicator of whether Anti-VEGF is needed.....macular
thickness on the OCT must be used.
- Generally 4 injections are effective in the first 6 m, 2 next 6 m, and occasional injections after that. However, monthly injections are still slightly more effective, but this would involve overtreating many patients.
- Ophthalmologists want to avoid oscillations of retina of retinal thickness, keeping it thin will give the best long term results.
- Resistant cases may respond to steroid
- The comments above relate to most cases of macular oedema, whether caused by diabetes (DME), retinal vein occlusion, or other causes.
A second effect of the VEGF is to make tiny blood vessels grow.
These are called 'new' blood vessels, and an ophthalmologists
calls these 'new vessels' see
animation . This is proliferative retinopathy.
These new vessels are very delicate and very easily bleed,
and this blood can damage your eye badly. This is 'proliferative
retinopathy'. If the blood spreads in front of the retina, scar
tissue can grow. The scar tissue can then shrink and pull the
retina off, causing blindness.
New blood vessel growth must be stopped. Laser is the main
treatment, but Lucentis and Avastin are new treatments that will generally
be used IN ADDITION to laser. See the evidence also . Minella. Tonella. May work instead of laser DRCRnet 16.
When the blood vessels grow in the 'drainage meshwork, the
aqueous humour produced in the eye cannot drain away. This leads
to a very high pressure in the eye, called rubeotic
glaucoma. Avastin is an excellent treatment for this, but
the effect may be temporary. Rubeotic glaucoma is described in
detail here with
an animation here.
See the evidence.
Laser is usually needed as soon as the pressure has
normal flow of aqueous
drain blocked by 'new' blood
vessels' aqueous trapped in eye, and this puts the pressure
- The eye is cleaned.
- Anaesthetic drops are instilled.
- In the injection room the eye is cleaned again, and a drape is placed around the eye
- a couple of minutes later the nearly painless injection is given
- (steroid implant insertion can be a little more painful)
- if triamcinolone is used
- Triamcinolone 40ml, 0.1ml=4mg
- So need 2mg = 0.05mls, same volume as Lucentis and Eyela, same size syringe
- Shake first just before draw up as there would otherwise be an uneven distrribution of the drug
- an alternative is Chlorhexidine, but in this area several infections have developed following Chlorhexidine use
- we are therefore recommending the continued use of iodine, but irrigation the out after 2 minutes after iodine installation
After the injection
By one month the drugs should be working. Many people will notice
some improvement in vision. Generally this improvement is temporary,
and the injection may be offered again months later. The macular
oedema reduces, with a maximum reduction at 2 weeks, and
starts to wear off after 3 months (see).
It gives a chance for laser treatment and lower blood pressure
etc to have their effect. Further injections are usually
needed, but as this treatment is new there is no definite
treatment plan available.
The injection will put the eye pressure up for
a few hours. It is therefore riskier is you have glaucoma, but this is
generally not a major problem. There should not be much pain. You may
see the drug floating around your eye for the next few hours.
- The cleaning solution can burn the surface of the eye, making it very sore during the night. There should be a full recovery over the next 1-2 days.
- There may be a small haemorrhage on the surface of the eye, and this should disappear over 1-2 weeks (subconjunctival haemorrhage).
- A bubble may appear in your vision, floating around: a bubble of gas may enter when the drug is injected. These disappears overnight.
About 1/1000 people
will develop a serious eye infection. The day after the injection your eye should be comfortable, there should
be very little pain. If your eye starts to get red, with misty vision
may be no pain), perhaps 2-5 days after the injection, you should
suspect an infection and attend your eye department urgently. In Birmingham
this is the Birmingham
and Midland Eye Centre Casualty at the
Birmingham & Midland
Eye Centre, City Hospital, Dudley Road, Birmingham B18 7QH
Tel: 0121-554 3801. Avastin, infection..preventing.
A scratchy after injentiosn is normal; a painful achy eye may be infected.
Check pressure 4, 8, & 16 weeks after injection EJO15 .
Symptoms of infection
These are the common symptoms that patients notice Eye 12
- blurred vision........96%
- redness ...............50%
- lid swelling ...........10%
- discharge .............10%
The drugs will reduce the retinopathy,
both the leakage and new vessel growth. Laser...if it has
not been carried out already will be needed, on many occasion. Rarely
the drugs will cause some loss of sight...there is no detailed information
as to the exact risk. Unlike a steroid, there should be
no long term pressure effects.
IVL or IVA may hasten cataract development or to vitreomacular traction Eye 17.
Please tell your doctor is you are pregnant,
and try and avoid getting pregnant for the 6 weeks following
the injection. This is a new drug and is probably UNWISE
IN PREGNANCY. In any respect, pregnancy makes active
diabetic retinopathy MUCH worse.Retina 2012
There is a 1% risk of a retinal tear
after this injection. Please seek attention (within 24 hours....the
next day is usually OK) from an ophthalmologist if you develop
the symptoms of a tear, that is (all of a sudden) a sudden
shower of floaters and flashes of light. These may happen in
the months after the injection.
Anticoagulants ...extra precautions
You should remind your ophthalmic team you use anticoagulants and ask for
specific advice. Treatment is safe continuing the anticoagulents (Retina
Remember the 'targets' for good control
By keeping to these levels as much as possible (or lower still) you will be
doing your best to stop your eyes getting worse. Occasionally by sticking to
these targets your retinopathy will improve, even without laser. Review BMJ17 Eye 17
minutes exercise a
- moderate alcohol consumption only,
obesity if possible,
- balanced diet including
- 9 portions of vegetables
or fruit a day (9 for men, 7 for women), Lowers BP
of animal or 'hard' vegetable fats,
salt, see the evidence
be limited to one drink or unit a day, six days a week
(Mukamal 2004). More than this leads to brain damage.
fish such as sardine, salmon,
tuna, trout, at least twice a week (small amounts are
fine...not a whole salmon!).
and healthy fats in the diet slows down retinopathy. No transfats
and minimal saturated fat.
- no (ultra) processed food
- generally 130/80 (see
graph) or preferably less BMJ 16. Even less if well <120 BMJ17
- (120/75 ..home monitoring)
- 125/75 or less if protein in urine present (115/70..
- ACE inhibitors
or Angiotensin Receptor Antagonists unless young/pregnant/very
low blood pressure/poorly tolerated
- The lower the better in macular oedema, as long as you feel well.
- An ideal pressure is below 115 (systolic, first number) for healthy people. <120 is is only suitable for new/well diabetes patients 2012. Otherwise slightly higher as above.
monitoring blood pressures should be 10mmHg (systolic) and 5mmHg (diastolic)
lower see than
these 'clinic' pressures.
- Depression & anxiety increase BP.
- 48-58 mmol/mol (6.5%-7.5%) or
less (see graph) with very few or preferably no hypos. These (or slightly
lower) levels are the best to prevent complications
- <58 mmol/mol (7.5%) for insulin users; <48 mmol/mol (6.5%) if not using insulin and have good
health. Problems with intensive control. Target should be adjusted according to health and age. If you are a type 1 patient and cannot achieve good control, you need to checked for other conditions such as coeliac disease (anti-TTG antibodies), addisons, and thyroid.
- If hypos develop, seek expert
advice from your diabetes nurse/doctor.
- if your HbA1c is high (say 97mmol/mol / 11%), then the next step may be to achieve
75 (9%)....in other words, and any improvement is helpful, gradually reaching
lower levels above.
- A sudden improvement in
control (HbA1c drop of 33 mmol/mol/3% ) will lead to a temporary rapid increase
in progression of retinopathy: laser may be needed.
- Good control is important
in the longer term, that is after about 2 years. When people who control
their diabetes well will be better off after this period. See
- A temporary increase in retinopathy is
most common when starting insulin for the first time, especially if
the diabetes is very badly controlled when you start the insulin.
- Individual targets Nice 16
- <4.0mmol/l, and statins recommended
for most adult patients with diabetes whatever the cholesterol.
- statins are recommended whatever the cholesterol,
if well tolerated age>40y
fibrate such as fenofibrate is advisable in
nearly every person with retinopathy. They reduce retinopathy
progression 40% (Fenofibrate 200mg od) Field
Study. We now recommend these for all adult patients, and
they can be used in addition to a statin.
- LDL <2
- Avoid if pregnant, GFR <15, pancreatitis
- If GFR low but still >15, need a lower dose.
- smoking 20
a day triples/quadruples retinopathy
- passive smoking may double
retinopathy: room-mates inhale at least 25%
- electronic cigarettes are much much safer and probably have a negligible effect on retinopathy debate BMJ 18
- even 'Just one cigarette a day seriously elevates cardiovascular risk
' BMJ18, so it is best to stop completely.
- everyone with diabetes should attend
an education course, such as DAFNE (insulin)
, DESMOND (type
2 at diagnosis), or XPERT (type
2). Primary Care Trusts are obliged to send you on such a course, but
very few patients have ever attended one. If you have not been on one,
discuss this with your diabetic team. Get a diabetes buddy.
- this contributes to macular oedema and loss of sight
(Schwartz, 2006), and many serious problems.
- It is common in
diabetes, particularly if you are overweight. Do you have sleep apnoea?
- see 15
- 5.0-7.2 mmol/l before meals
- <10.0 mmol/l after meals
- no serious hypos
- for patients who test their glucose levels and adjust insulin doses, the new glucose sensor is highly recommended and has transformed the lives of many patients. The cost is about £30/week).
- Rosiglitazone and pioglitazone should not be used
if there is significant retinopathy, and certainly not if macular oedema
is present, as they
increase macular oedema and fluid retention. Case
and Exenatide are drugs that can be used instead low also lower weight
(they are injections.)
- insulin users need to avoid serious hypoglycaemia.
Expert help is usually needed if episodes are severe/frequent. See
- many patients receive totally inadequate care BMJ 11. Some call this 'institutionalised neglect'.
- 10% compliance if multiple treatment,
? 60% one tablets
type 2 at diagnosis