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THERAPY REVIEW ■

Age-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 endothe-lial 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, pre-vention, current treatments and manage-ment of visual loss.

What is AMD?AMD is a disease of metabolic dysfunc-tion 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

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 biochemistry leads to hypoxia and stimulation of new blood ves-sel 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.

Prevention and treatment of age-related macular degenerationSARAH 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.

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

a

b

Neurosensory retina

Retinal pigment epithelium

Bruch’s membrane

Fovea

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How is AMD classified?AMD is commonly described as ‘dry’ or ‘wet’ (neovascular). Wet AMD may be fur-ther subdivided based on fluorescein angio-gram and occasionally indocyanine green angiography appearances into classic, occult, retinal angiomatous proliferation and choroidal polyps. There are multiple classifi-cation 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

Which patient groups are most susceptible?Nonmodifiable risk factors for AMD are age and genetics, while the most consist-ent modifiable risk factor is smoking.3,4 Patients of increasing age, current smok-ers 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-sight-edness, iris colour, dietary carotenoids (which make up macular pigment), alco-hol intake, omega-3 and -6 fatty acid intake, obesity, hypertension, cardiovas-cular disease, diabetes, cataract surgery, sunlight exposure, gender and race.

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 read-ing 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 dis-torted vision (“straight lines look wavy”),

is suggestive of wet AMD. Charles Bonnet syndrome, in which patients report 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 pigmentary 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 techniquesOcular coherence tomography (OCT) scanning is a noninvasive imaging tech-nique that provides a cross-sectional 3D image of the retina and can detect intra-retinal 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 prolifera-tion, which are subtypes of wet AMD. OCT angiography is a new imaging technique that uses OCT technology to visualise the retinal and choroidal vascula-

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

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

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)

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ture and may be used to detect choroidal neovascular membranes. It is less inva-sive than FFA but not yet widely available.

The treatment optionsNICE has published technology appraisal guidance supporting the use of spe-cific 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 pub-lished guidelines on AMD management in 2013.7

Dry AMDTreatment of dry AMD remains limited. Specific vitamin supplementation is recommended in patients with interme-diate or advanced AMD based on the

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 par-ticipants 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 Beta-carotene 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 AMDNICE currently recommends the anti-VEGF agents ranibizumab (Lucentis) or aflibercept (Eylea) for use in subfoveal

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 dam-age 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 some-times 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-

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

a b

Macular haemorrhages

Subretinal fluid

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care professionals. Clinical trials admin-istered monthly injections for 24 months. In the NHS, injections are usually admin-istered 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 anti-VEGF 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 ranibi-zumab 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.

What is the GP’s role in management?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 optom-etry or hospital retina service, depending on local structuring of services. The Royal College of Ophthalmologists has devel-oped 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 supported 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.

Patients who present with reduced vision following an intravitreal injection should be referred to an eye casualty unit or dis-cussed with an on-call ophthalmologist. GPs can signpost relevant chari-ties 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 depres-sion.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.

ConclusionAMD is a common cause of visual loss in older people. Intravitreal anti-VEGF injec-tions 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 ena-bling 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.

500mg vitamin C400IU vitamin E80mg zinc oxide2mg copper± lutein and zeaxanthin

Box 1. Currently recommended dietary supplementation for patients with intermediate or advanced age-related macular degeneration

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

Macular Societywww.macularsociety.org0300 3030 111

Royal National Institute for the Blind (RNIB)www.rnib.org.uk0303 123 9999

DVLA https://www.gov.uk/guidance/visual-disorders-assessing-fitness-to-drive

NHS low vision supporthttp://www.nhs.uk/Livewell/Eyehealth/Pages/Livingwithlowvision.aspx

Box 2. Sources of information and support for patients with age-related macular degeneration

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2. Age-Related Eye Disease Study Research G. The Age-Related Eye Disease Study system for classifying age-related macular degener-ation from stereoscopic color fundus photo-graphs: 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 degener-ation: the Blue Mountains Eye Study. Arch Ophthalmol 2007;125(8):1089–95.4. Chakravarthy U, et al. Clinical risk fac-tors 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 degenera-tion. TA155. August 2008. Last updated: May 2012. www.nice.org.uk/guidance/ta1556. NICE. Aflibercept solution for injection for treating wet age-related macular degenera-tion. TA294. July 2013. www.nice.org.uk/guidance/ta2947. Royal College of Ophthalmologists. Age-related macular degeneration: guidelines for management. September 2013. www.rcophth.

ac.uk/standards-publications-research/ clinical-guidelines8. A randomized, placebo-controlled, clinical trial of high dose supplementation with vita-mins 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 degen-eration: the Age Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 2013;309(19):2005–15.10. Rosenfeld PJ, et al. Ranibizumab for neo-vascular 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 degenera-tion. Ophthalmology 2012;119(12):2537–48.13. Martin DF, et al. Ranibizumab and bevacizumab for neovascular age-related

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-AMD- Electronic-Referral-Form-edited.pdf16. Evans JR, et al. Depression and anxiety in visually impaired older people. Ophthalmology 2007;114(2):283–8.

Declaration of interestsNone to declare.

Dr Horton is a medical ophthalmology specialty registrar and Dr Guly is a consultant ophthalmic physician, University Hospitals Bristol NHS Foundation Trust

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 depart-ment, 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 con-trolled noninferiority trial of single dose

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 treat-ment 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 con-tacted (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 treat-ment (difference 2.3%; 95% CI -4.1% to 8.6%). This difference did not meet the researchers’ threshold for noninferior-ity of 8%, meaning that treatment with dexa methasone was slightly less effec-tive. The hospitalisation rate was low (3%) and did not differ between treat-ment groups. Side-effects were more common in the prednisone group.

POEMsSingle-dose dexamethasone an option for acute adult asthma

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