Download Prevention and treatment of age‐related macular degeneration

THERAPY REVIEW ■
Prevention and treatment of agerelated macular degeneration
SARAH HORTON AND CATHERINE GULY
Age-related macular
degeneration (AMD) is a
common cause of visual
loss in older people and
GPs play a critical role in
identification and timely
referral. This article
discusses the features
of AMD, preventing
progression, treatment
options, and the GP’s role
in management.
a
Fovea
Neurosensory
retina
Retinal pigment
epithelium
Bruch’s membrane
b
A
ge-related macular degeneration
(AMD) is a degenerative change of
the central area of the retina (macula)
in people aged 55 years and above and
is the leading cause of irreversible sight
loss in the developed world.
The management of AMD has been
transformed over the last decade with
the introduction of anti-vascular endothelial growth factor (anti-VEGF) agents.
Early treatment of neovascular or ‘wet’
AMD results in better visual outcomes
and GPs play a critical role in the early
identification and prompt referral of
patients with this condition. This article
will describe clinical aspects of AMD, prevention, current treatments and management of visual loss.
What is AMD?
AMD is a disease of metabolic dysfunction within the aging retina. Lipid and
protein material accumulates beneath
the retinal pigment epithelium (RPE) and
within Bruch’s membrane (see Figure
1). Focal collections of lipid material are
seen as ‘drusen’ on examination of the
retina and morphological alteration of the
RPE causes hyper- and hypopigmentation
(see Figure 2). These changes form part
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Figure 1. Optical coherence tomography (OCT) scans demonstrating
the layers of the retina at the fovea in cross-section. The top image
[a] shows healthy retina. In the lower image [b], the usually smooth
profile of the retinal pigment epithelium and Bruch’s membrane is
irregular due to drusen
of ‘dry’ AMD. As AMD progresses, the
breakdown of light-sensitive cells leads
to one or more areas of well-demarcated
depigmented (atrophic) RPE, described
as ‘geographic atrophy’ (see Figure 3).
In some patients, disordered local
anatomy and biochemistr y leads to
hypoxia and stimulation of new blood vessel growth through the release of angio­
genic growth factors (including VEGF).
These abnormal blood vessels, known
as a choroidal neovascular membrane,
lie beneath and within the retina and can
easily bleed and leak blood constituents.
Prescriber January 2017 ❚ 37
■ THERAPY REVIEW l Age-related macular degeneration
Figure 2. Colour fundus photograph of a patient’s left
eye: dry age-related macular degeneration with large
drusen and hyperpigmentation of the retinal pigment
epithelium at the macula
Classification
AREDS
Category
Clinical signs
No AMD
1
None or a few small drusen (<63 microns)
Early AMD
2
Any or all of the following: multiple small
drusen, few intermediate drusen (63 to 124
microns in diameter), or retinal pigment
epithelium abnormalities
Intermediate AMD
3
Any or all of the following: extensive
intermediate drusen, at least one large
drusen (≥125 microns in diameter), or
geographic atrophy not involving the centre
of the fovea
Advanced AMD
4
Geographic atrophy involving the fovea and/
or any of the features of neovascular AMD
Table 1. The four-stage classification of (AMD) from the Age-Related Eye Disease Study (AREDS)
Which patient groups are most
susceptible?
Nonmodifiable risk factors for AMD are
age and genetics, while the most consistent modifiable risk factor is smoking.3,4
Patients of increasing age, current smokers and those with a family history of the
condition are therefore most susceptible
to the disease.
There is inconsistent evidence for an
association between AMD and long-sightedness, iris colour, dietary carotenoids
(which make up macular pigment), alcohol intake, omega-3 and -6 fatty acid
intake, obesity, hypertension, cardiovascular disease, diabetes, cataract surgery,
sunlight exposure, gender and race.
Figure 3. Colour fundus photograph of a patient’s right
eye: advanced dry age-related macular degeneration
(geographic atrophy). There is central well-demarcated
geographic atrophy of the retinal pigment epithelium
with visible choroidal vessels and surrounding drusen
How is AMD classified?
AMD is commonly described as ‘dry’ or
‘wet’ (neovascular). Wet AMD may be further subdivided based on fluorescein angiogram and occasionally indocyanine green
angiography appearances into classic,
occult, retinal angiomatous proliferation and
choroidal polyps. There are multiple classification systems of AMD, but the Age-Related
Eye Disease Study (AREDS) system has a
practical application in the prescription of
prophylactic vitamins (see Table 1).1,2
38 ❚ Prescriber January 2017
What are the signs and
symptoms of AMD?
AMD may be asymptomatic in the early
stages and is often identified incidentally
at a routine optometry review.
In dr y AMD, patients typically
describe gradual onset blurred central
vision, whereas in wet AMD the onset is
more rapid over days to weeks. Patients
with AMD may complain of difficulty reading or of missing letters in words. Subtler
symptoms include impaired light-dark
adaptation (the patient may describe
a central dark patch in the visual field
that clears within a few minutes as they
adapt) and loss of contrast sensitivity.
Metamorphopsia, the perception of distorted vision (“straight lines look wavy”),
is suggestive of wet AMD. Charles Bonnet
syndrome, in which patients repor t
formed visual hallucinations, may occur
in patients with severe loss of vision.
Visual acuity may be normal in early
dry and wet AMD, but deteriorates with
progression of the disease. Dilated
examination of the retina may reveal
drusen, retinal pigmentar y changes
and atrophy at the macula in dry AMD.
Retinal haemorrhage and subretinal
fluid are seen in addition to dry changes
in wet AMD.
Retinal imaging techniques
Ocular coherence tomography (OCT)
scanning is a noninvasive imaging technique that provides a cross-sectional 3D
image of the retina and can detect intraretinal and subretinal fluid in wet AMD
(see Figure 4).
Fundus fluorescein angiography (FFA)
is used to confirm the diagnosis and
establish the angiographic subtype of wet
AMD. To perform FFA, fluorescein dye is
injected into a peripheral vein and a series
of retinal images is taken. FFA may be
combined with indocyanine green angio­
graphy where more detailed images of the
choroidal vasculature are required. This is
particularly helpful for detecting choroidal
polyps and retinal angiomatous proliferation, which are subtypes of wet AMD.
OCT angiography is a new imaging
technique that uses OCT technology to
visualise the retinal and choroidal vasculaprescriber.co.uk
Age-related macular degeneration
ture and may be used to detect choroidal
neovascular membranes. It is less invasive than FFA but not yet widely available.
The treatment options
NICE has published technology appraisal
guidance supporting the use of specific anti-VEGF therapies in AMD and is
expected to publish full guidelines on
the condition in August 2017. 5,6 The
Royal College of Ophthalmologists published guidelines on AMD management
in 2013.7
Dry AMD
Treatment of dry AMD remains limited.
Specific vitamin supplementation is
recommended in patients with intermediate or advanced AMD based on the
a
AREDS trial. This randomised-controlled
trial showed that the risk of progression
from intermediate to advanced AMD was
reduced by around 25 per cent in participants who took zinc and antioxidant
supplements.8
AREDS was followed by the AREDS2
trial, which showed there was no detriment
when beta-carotene was omitted.9 Betacarotene was therefore removed from the
recommended formulation (see Box 1) as
it can increase the risk of lung cancer in
smokers. The benefit of supplementation
in early AMD remains unproven.
Wet AMD
NICE currently recommends the antiVEGF agents ranibizumab (Lucentis) or
aflibercept (Eylea) for use in subfoveal
l THERAPY REVIEW ■
choroidal neovascular membranes (see
Table 2). Patients may be treated if they
have a visual acuity of 6/12 to 6/96 and
there is no permanent structural damage to the fovea. These agents improve
vision in around a third of patients, the
majority will maintain their visual acuity
and around 10 per cent will not respond
to therapy.7 Bevacizumab (Avastin) is an
anti-VEGF agent that was developed for
use in colorectal carcinoma. It is cheaper
than the other anti-VEGF agents but is
unlicensed for use in AMD. It is sometimes used ‘off label’.
These drugs are administered as an
intravitreal injection under topical local
anaesthetic. This takes place as a day
case in a hospital or community unit,
often by nurses or trained allied health-
b
Macular haemorrhages
Subretinal fluid
Figure 4. Colour fundus photographs and ocular coherence tomography (OCT) scans of a right eye before anti-VEGF treatment [a]; and after
anti-VEGF treatment [b]. There is resolution of the macular haemorrhages and subretinal fluid
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Prescriber January 2017 ❚ 39
■ THERAPY REVIEW l Age-related macular degeneration
500mg vitamin C
400IU vitamin E
80mg zinc oxide
2mg copper
± lutein and zeaxanthin
Box 1. Currently recommended dietary
supplementation for patients with
intermediate or advanced age-related
macular degeneration
care professionals. Clinical trials administered monthly injections for 24 months.
In the NHS, injections are usually administered monthly for three months. After
this, treatments are either given each
month as a PRN (when required) regimen
or as part of a treat and extend regimen,
ie treat monthly until stable and then
extend the treatment interval each time
the patient is stable up to an injection
once every three months. Treatment is
then withdrawn after a period of stability
or treatment failure.
Potentially serious adverse events
occur in <0.1% of intravitreal injections
and include endophthalmitis, retinal
detachment and cataract. Systemic antiVEGF agents confer an increased risk
of events classified as arterial thrombo­
embolism (ATE), including myocardial
infarction and stroke. There may be a
small increased risk of these events in
patients who receive intravitreal anti-VEGF
agents. The MARINA trial demonstrated
an ATE rate of 4.6% in recipients of ranibizumab versus 3.8% in recipients of a
sham injection at 24 months; however,
this was not statistically significant.10
Photodynamic therapy is rarely used
but is an option in patients with choroidal
polyps.
Macular Society
www.macularsociety.org
0300 3030 111
What is the GP’s role in
management?
NHS low vision support
http://www.nhs.uk/Livewell/
Eyehealth/Pages/Livingwithlowvision.
aspx
The rapid onset of central distortion in
an older adult should be considered AMD
until proven otherwise. GPs ought to
make an urgent referral to a local optometry or hospital retina service, depending
on local structuring of services. The Royal
College of Ophthalmologists has developed a “Wet AMD rapid access referral”
form for optometrists and GPs.15
GPs may provide advice on how to
slow progression of the disease. Patients
who smoke should be suppor ted in
smoking cessation. Patients should be
advised to eat a diet rich in dark green
leafy vegetables and on the benefits of
vitamin supplementation in intermediate
and advanced AMD.
Complications of intravitreal injections
are rare but potentially sight threatening.
Drug name
Mode of action
Key relevant trials
NICE
approved?
Ranibizumab
(Lucentis)
Humanised Fab fragment of a
monoclonal antibody that binds
to and inhibits the action of all
isoforms of VEGF-A
MARINA10
ANCHOR11
(superiority studies
against sham
injection) Yes
Aflibercept (Eylea)
Fusion protein that inhibits all
isoforms of VEGF-A and placental
growth factor
VIEW1/VIEW212
(noninferiority
studies against
ranibizumab)
Yes
Bevacizumab
(Avastin)
Humanised full-length monoclonal
antibody derived from the same
antibody as ranibizumab. Likely to
bind to all the same isoforms of
VEGF-A as ranibizumab, but with a
different affinity
CATT13
IVAN14
(noninferiority
studies against
ranibizumab)
No
VEGF-A = vascular endothelial growth factor A
Table 2. Properties of antiangiogenic therapies for wet age-related macular degeneration
40 ❚ Prescriber January 2017
Royal National Institute for the Blind
(RNIB)
www.rnib.org.uk
0303 123 9999
DVLA
https://www.gov.uk/guidance/visualdisorders-assessing-fitness-to-drive
Box 2. Sources of information and support
for patients with age-related macular
degeneration
Patients who present with reduced vision
following an intravitreal injection should
be referred to an eye casualty unit or discussed with an on-call ophthalmologist.
GPs can signpost relevant charities or low vision services for practical
advice and emotional support (see Box
2). Clinicians must be vigilant to the
development of depression, as visual
impairment in older people is associated
with a higher than normal risk of depression.16 Referral to an ophthalmologist
for registration of visual impairment
should be considered for patients with
a visual acuity of 6/60 or worse in both
eyes. Drivers with a car or motorcycle
licence require visual acuity of 6/12 or
better with both eyes open and patients
should be advised to contact the DVLA if
their corrected visual acuity is below the
threshold for driving.
Conclusion
AMD is a common cause of visual loss in
older people. Intravitreal anti-VEGF injections are the mainstay of treatment for
wet AMD. In patients with intermediate
or advanced AMD, vitamin supplements
may slow progression. GPs play a critical
role in identification and timely referral,
facilitating smoking cessation and enabling patients to access support services
for the visually impaired.
References
1. Ferris FL, et al. Clinical classification
of age-related macular degeneration.
Ophthalmology 2013;120(4):844–51.
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Age-related macular degeneration
2. Age-Related Eye Disease Study Research
G. The Age-Related Eye Disease Study system
for classifying age-related macular degeneration from stereoscopic color fundus photographs: the Age-Related Eye Disease Study
report number 6. Am J Ophthalmol 2001;
132(5):668–81.
3. Tan JS, et al. Smoking and the long-term
incidence of age-related macular degeneration: the Blue Mountains Eye Study. Arch
Ophthalmol 2007;125(8):1089–95.
4. Chakravarthy U, et al. Clinical risk factors for age-related macular degeneration: a
systematic review and meta-analysis. BMC
Ophthalmol 2010;10:31.
5. NICE. Ranibizumab and pegaptanib for the
treatment of age-related macular degeneration. TA155. August 2008. Last updated: May
2012. www.nice.org.uk/guidance/ta155
6. NICE. Aflibercept solution for injection for
treating wet age-related macular degeneration. TA294. July 2013. www.nice.org.uk/
guidance/ta294
7. Royal College of Ophthalmologists. Agerelated macular degeneration: guidelines for
management. September 2013. www.rcophth.
ac.uk/standards-publications-research/
clinical-guidelines
8. A randomized, placebo-controlled, clinical
trial of high dose supplementation with vitamins C and E, beta carotene, and zinc for
age-related macular degeneration and vision
loss: AREDS report no. 8. Arch Ophthalmol
2001;119(10):1417–36.
9. Age-Related Eye Disease Study 2 Research
Group. Lutein + zeaxanthin and omega-3
fatty acids for age-related macular degeneration: the Age Related Eye Disease Study
2 (AREDS2) randomized clinical trial. JAMA
2013;309(19):2005–15.
10. Rosenfeld PJ, et al. Ranibizumab for neovascular age-related macular degeneration.
New Engl J Med 2006;355(14):1419–31.
11. Brown DM, et al. Ranibizumab versus
ver teporfin for neovascular age-related
macular degeneration. New Engl J Med
2006;355(14):1432–44.
12. Heier JS, et al. Intravitreal aflibercept (VEGF
trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119(12):2537–48.
13. Mar tin DF, et al. Ranibizumab and
bevacizumab for neovascular age-related
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macular degeneration. New Engl J Med
2011;364(20):1897–908.
14. Chakravarthy U, et al. Ranibizumab versus
bevacizumab to treat neovascular age-related
macular degeneration: one-year findings from
the IVAN randomized trial. Ophthalmology
2012;119(7):1399–411.
15. Royal College of Ophthalmologists.
Wet AMD rapid access referral form.
https://www.rcophth.ac.uk/wp-content/
uploads/2015/04/2010-SCI-048-AMDElectronic-Referral-Form-edited.pdf
16. Evans JR, et al. Depression and anxiety in
visually impaired older people. Ophthalmology
2007;114(2):283–8.
Declaration of interests
None to declare.
Dr Horton is a medical ophthalmology
specialty registrar and Dr Guly is a
consultant ophthalmic physician,
University Hospitals Bristol NHS
Foundation Trust
POEMs
Single-dose dexamethasone an option for acute adult asthma
Clinical question:
Is a single dose of dexamethasone as
effective as five days of prednisone for
acute exacerbations of asthma?
Bottom line:
A single dose of 12mg dexamethasone,
which has a longer duration of action
than prednisone, is almost as effective
as five days of 60mg prednisone for
the prevention of relapse in adults with
acute asthma treated in a emergency
department. It is a reasonable option
for treatment in the emergency department, given its fewer side-effects. In this
study, patients who received the single
dose also took placebo for four days;
further research is needed to determine
whether patients are comfortable with
taking just a single dose. (LOE = 2b)
Reference:
Rehrer MW, et al. A randomized controlled noninferiority trial of single dose
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of oral dexamethasone versus 5 days of
oral prednisone in acute adult asthma.
Ann Emerg Med 2016;68(5):608–13.
Study design: Randomised controlled
trial (double-blinded). Funding source:
Foundation. Allocation: Concealed.
Setting: Emergency department.
Synopsis:
These investigators enrolled 456 adults
younger than 56 years who presented
with acute asthma to an emergency
department and required at least one
treatment with a beta-agonist. The
patients were randomly assigned, using
concealed allocation, to receive treatment with prednisone 60mg daily for five
days or a single dose of dexamethasone
12mg followed by four days of placebo.
Treatment was started in the emergency
department.
Of the 456 people initially enrolled,
376 could be evaluated; 16 were
admitted before leaving the emergency
department and 73 could not be contacted (more in the dexamethasone
group). Over the subsequent two weeks,
12.1% of the dexamethasone group
and 9.8% of prednisone group had a
relapse that required additional treatment (difference 2.3%; 95% CI -4.1% to
8.6%). This difference did not meet the
researchers’ threshold for noninferiority of 8%, meaning that treatment with
dexa­methasone was slightly less effective. The hospitalisation rate was low
(3%) and did not differ between treatment groups. Side-effects were more
common in the prednisone group.
POEM (Patient Orientated Evidence
that Matters) editors review more
than 1200 studies monthly from over
100 medical journals, presenting
only the best as Daily POEMs. For
more information visit:
www.essentialevidenceplus.com
Prescriber January 2017 ❚ 41