Miss Stella Hornby discusses current guidance on diagnosis and management of wet age-related macular degeneration, the role of primary care, and specifications for eye services

Age-related macular degeneration (AMD) is the commonest cause of sight loss in people aged over 55 years in the UK.1 It causes loss of central (but not peripheral vision). Visual loss can be gradual or acute depending on the form and severity of AMD. There are two main types of the condition: ‘wet’ and ‘dry’. Wet AMD refers to the exudative form with a choroidal neovascular membrane causing haemorrhage and leakage of fluid into the retina. It is a more severe condition compared with dry AMD, but is also more amenable to treatment. Patients who have AMD present with central blurring of vision, distortion in vision (straight lines looking wavy), and difficulty reading. Sight loss resulting from AMD is commonly associated with depression, loss of independence, increased risk of falls, and social isolation.2,3

The arrival of effective therapy for wet AMD in recent years has been both revolutionary and very demanding in terms of service delivery and costs, and was thrust on commissioners by NICE guidance in 2009.4 In response to the rapidly changing clinical area of AMD and the availability of new therapeutic options, the Royal College of Ophthalmologists developed a guideline on this condition in 2009, which is due for review in summer 2012.2 This guidance is intended to act as a benchmark for service planning by providers and commissioners, and to set national standards for audit.2

Improving timely access to services for wet AMD is a health priority for the UK in terms of preventing avoidable sight loss. Even with new treatments becoming available, many patients will still experience some sight loss and most will require support from low-vision services and social services.3

Prevalence

Estimates from the Royal National Institute of Blind People (RNIB) indicate that there may be 26,000 people with wet AMD who are eligible for treatment in the UK each year (as of 2007).5 With the rise of an ageing population, the prevalence of AMD is expected to increase significantly over the next decade—estimated costs for the decade 2010 to 2020 are £16.4 billion.3 Even with 90% treatment coverage, the prevalence of sight loss as a result of wet AMD is expected to increase over the decade, resulting in 44,000 more people with sight loss in the year 2020 compared with 2010.3 This is because the beneficial effect of treatment is overwhelmed by the demographic ‘ageing’ trend over the 10-year period.3


Role of primary care

Although there is a strong genetic component in AMD, potentially modifiable risk factors have been identified (e.g. smoking, obesity, and hypertension), which could be incorporated into existing public health messages. Primary care could provide opportunistic advice on primary prevention of AMD.2

An important role for primary care is to recognise symptoms of suspected wet AMD and to refer patients rapidly (within 1 week) to secondary care for diagnosis and treatment, as delays in treatment can lead to permanent sight loss. Optometrists may be used for ‘screening’ of patients with suspected wet AMD. However, referrals from the optometrist should be sent directly to an ophthalmology department and should not pass through the GP or a specialist interest (super optometrist) as such pathways will introduce unnecessary delays and misdiagnoses.2 A referral and treatment pathway for wet AMD is included in The Royal College of Ophthalmologists guideline (see Figure 1, below).2

General practitioners also play an important role in supporting the patient with visual impairment. ‘Signposting’ to organisations that can provide information, support, and advice is vital as sight loss causes a bereavement reaction, which compounds other barriers to accessing support such as difficulty reading, mobility, and transport problems. The Macular Disease Society and the RNIB are particularly relevant here. People with sight loss have cited not knowing how to access information or help that is available as the biggest barrier to coming to terms with their sight loss.2 Additionally, GP surgeries and practice websites can be adapted to help patients with visual impairment.

General practitioners can also respond to adjustment reactions from acute deterioration in vision and react to the stress that this may put on carers. Visual hallucinations are commonly associated with sight loss from AMD and many patients are frightened to mention them. A greater awareness of this phenomenon—known as ‘Charles Bonnet syndrome’—enables GPs to reassure patients that this is part of their eye condition and not indicative of mental illness.2

Figure 1: Referral and treatment pathway for wet age-related macular degeneration2

graph

*Patients should be given a direct phone number for local AMD services in case new symptoms develop in their second eye
AMD=age-related macular degeneration; ETDRS=Early Treatment Diabetic Retinopathy Study; VEGF=vascular endothelial growth factor
Adapted from Royal College of Ophthalmologists. Age-related macular degeneration guidelines for management. London: Royal College of Ophthalmologists, 2009. Reproduced with permission. Available at: www.rcophth.ac.uk/page.asp?section=451§ionTitle=Clinical+Guidelines


Diagnosis

There are a number of retinal disorders that can result in macular symptoms similar to those resulting from AMD. These include diabetic maculopathy, choroidal neovascularisation associated with high myopia or inflammatory choroidal syndromes, central serous retinopathy, telangiectasias, and polypoidal choroidopathy.2

Diagnosis of AMD requires an ophthalmological examination and retinal imaging (colour fundus photography, optical coherence tomography [OCT], fundus fluorescein angiography [FFA], or indocyanine green angiography [ICGA]. An integrated clinic for patients with AMD is recommended. Colour and OCT imaging can be reviewed in virtual clinics (retinal imaging is taken by a technician but the patient is not examined by an ophthalmologist; images can then be reviewed at a different time and place), thereby identifying patients requiring treatment. Medical assessments and further investigations can be triggered from these clinics as appropriate. Treatments such as intravitreal injections can be booked as appropriate following imaging review.2

Management of wet AMD

Current treatments for wet AMD include:2

  • laser photocoagulation
  • photodynamic therapy
  • intravitreal injections of anti-vascular endothelial growth factor (VEGF) for acute active disease
  • submacular surgery for late disease
  • radiotherapy.

Patients with advanced disease can also benefit from optical aids such as magnifiers, eccentric viewing training, and implantation of miniature lens systems.2,6

Laser treatment

Until 3 years ago the only available licensed and NICE-approved treatment for wet AMD was verteporfin photodynamic therapy, but this has been superseded by anti-VEGF injections, which are more effective.7,8

Anti-VEGF therapy

Anti-VEGF therapy works by blocking VEGF—a substance that causes new blood vessels to grow in the eye—thereby stopping the bleeding at the back of the eye, which causes the wet form of AMD.2,4 Three such therapies are pegaptanib, ranibizumab, and bevacizumab.

Pegaptanib
Pegaptanib has not been approved by NICE for the treatment of wet AMD.4

Ranibizumab
Ranibizumab is recommended as a treatment option only if all of the following conditions apply:4

  • Best-corrected visual acuity is between 6/12 and 6/96
  • There is no permanent damage to the fovea
  • Lesion size is no larger than 12 disc areas in the greatest linear dimension (large lesions are unlikely to respond to treatment)
  • There is evidence of recent presumed disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes)

and

  • The cost of ranibizumab beyond 14 injections in the treated eye is met by the manufacturer.

The best outcomes for ranibizumab have been achieved with monthly intravitreal injections. Evidence from the HORIZON study suggests that neovascular AMD may remain active for a number of years. In this study, 61% of patients treated with monthly ranibizumab over a 2-year period required further treatment in the third year.9 Thus, careful monitoring of patients with neovascular AMD, for extended time periods, is mandatory. The majority of patients will maintain vision on therapy with ranibizumab and one-third of patients will have improved vision. Approximately 10% of patients will not respond to this treatment.2

Ranibizumab is an expensive drug, costing £761.20 each time an eye is treated, although the cost beyond 14 injections will be met by the manufacturer.4,10 There are also additional costs associated with delivering treatment and for monitoring patients between treatments.5

Bevacizumab
Bevacizumab is a monoconal antibody to VEGF that was designed originally for use in treating cancer and which is much cheaper than ranizibumab; however its use for the treatment of AMD is unlicensed. Current available evidence supports the view that both ranibizumab and bevacizumab are equally effective for neovascular AMD, although the rate of serious systemic adverse events may be higher for bevacizumab.11 However, ranizibumab is the only anti-VEGF drug that is licensed for AMD in the UK and which has been approved by NICE.4,12 Currently, ranibizumab is used by most clinicians in the UK as this is recommended by General Medical Council and Royal College of Ophthalmologists guidelines (i.e. off-label medications are not recommended if there is a licensed alternative).2,13

A major limitation of VEGF inhibition therapy is the need for repeated intravitreal injection with its attendant risks of endophthalmitis (intraocular infection), retinal detachment, and traumatic cataract.14 Patients should understand the risks associated with intravitreal injections and be instructed to report symptoms suggestive of endophthalmitis (loss of vision, pain, or redness) without delay.


Surgical interventions

Macular translocation surgery has been shown to improve vision in a proportion of AMD cases: 40%–60% of patients showed an improvement in best-corrected visual acuity of two or more lines in two non-randomised case series with a 12-month follow-up period.14 NICE has assessed both limited and 360° retinotomy macular translocation and recommends that these procedures should only be used ‘with special arrangements for clinical governance, consent, and audit or research’.15,16

There is evidence for the use of implantable miniature lens systems in the low-vision rehabilitation of patients with advanced AMD, which can improve both vision and quality of life in the short term.17 These devices are particularly suitable for patients who require surgery for a co-existing cataract, but they should only be implanted if special arrangements for clinical governance, consent, or research have been made.6

Treatments in development

Alternative treatments for wet AMD are developing rapidly, including:

  • other methods of VEGF inhibition, such as a recombinant VEGF-binding protein called VEGF-Trap, receptor tyrosine kinase inhibitors, and post-transcriptional silencing of gene expression
  • combination therapies and revisiting radiotherapy using a targeted focal-delivery system18
  • different modes of drug delivery.

Commissioning services for age-related macular degeneration

The direct healthcare cost per 100,000 of the population for AMD alone is currently around £514,000 and outpatient attendances are rising year on year.19 The burning issue is the running costs of services for AMD, particularly with the cost of ranibizumab, and the infrastructure and running costs of retinal imaging and staff costs. However, these costs need to be balanced against the likely cost savings. Age-related macular degeneration results in reduced quality of life and increased risks of illness, particularly in relation to accidents—especially falls—and psychological ill-health (depression). Studies have also demonstrated that patients with visual impairment tend to have longer hospitalisations and greater use of health and community care services and nursing homes.20,21

The pressure on AMD clinics in terms of resources and service delivery will inevitably become more intense since new individuals will be added to the list and patients will need long-term monitoring. There is a shortage of suitably trained medical manpower to deliver services. Suggested solutions to this capacity problem include the use of trained optometrists or nurses to perform clinical assessments and evaluation of images.22

Ensuring that patients receive frequent follow up is very demanding; initially patients should be reviewed every 4 weeks for the first 3 months and then as needed after that. Current models for follow up include nurse-led or optometry led OCT clinics and mobile OCT scanners. Follow up could be performed in a GP surgery but would require specialist equipment for the retinal imaging and subsequent interpretation.23

Service specifications for AMD include:2,24

  • rapid access (less than 1 week from referral to assessment)2
  • minimum clinical services required for effective management including appropriate facilities for:
  • intravitreal injection
  • retinal imaging by trained technical staff
  • appropriate capacity for follow up, monitoring, and re-treatment
  • availability of support from Eye Clinic Liaison Officers.19

The Royal College of Ophthalmologists has developed a self-assessment tool of 20 questions—20/20 Quality, innovation, productivity and prevention quality assurance self test 24—which it has proposed as an indicator of quality improvement for organisations providing care to patients with AMD. It is envisaged that high-level (over 75%) positive compliance is needed to declare a good or excellent quality standard for AMD patient care; and departments would be scored and given a traffic light code for good, acceptable/borderline, or poor/unacceptable status.24 The Commissioning for eye care website is a useful resource for commissioners (www.commissioningforeyecare.org.uk).


Summary

General practitioners need to be able to recognise the symptoms of possible wet AMD and to refer rapidly to secondary care as delays in treatment may lead to permanent sight loss. The management of AMD has been revolutionised by technology for retinal imaging, which is essential in diagnosis and follow up; and new therapeutic agents, particularly intravitreal injections of anti-VEGF agents (e.g. ranibizumab). A cheaper drug (bevacizumab) is as effective, but is not licensed for this indication and has yet to be reviewed by NICE.

Rapid access to specialist AMD services is key to their effectiveness, but the quality of such services is variable. Capacity problems arise from both the lack of an endpoint to treatment and population demographics. The condition of AMD has not yet been completely resolved as some patients with wet AMD do not respond to anti-VEGF agents and there is no treatment for the dry form of AMD at the moment. Additionally, patients with both wet and dry AMD require low-vision services and psychosocial support including that from their GP.

Healthcare professionals may find the following websites useful:

  1. Owen C, Fletcher A, Donoghue M, Rudnicka A. How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom? Br J Ophthalmol 2003; 87 (3): 312–317.
  2. The Royal College of Ophthalmologists. Age-related macular degeneration guidelines for management. London: The Royal College of Ophthalmologists, 2009. Available at: www.rcophth.ac.uk/page.asp?section=451&sectionTitle=Clinical+Guidelines
  3. Minassian D, Reidy A. Future sight loss UK (2): an epidemiological and economic model for sight loss in the decade 2010–2020. EpiVision and Royal National Institute of Blind People, 2009.
  4. National Institute for Health and Care Excellence. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. Technology Appraisal 155. London: NICE, 2008. Available at: www.nice.org.uk/TA155 nhs_accreditation
  5. The Royal College of Ophthalmologists. Commissioning contemporary AMD services: a guide for commissioners and clinicians. London: The Royal College of Ophthalmologists, 2007.
  6. National Institute for Health and Care Excellence. Implantation of lens systems for advanced macular degeneration. Interventional Procedure Guidance 272. London: NICE, 2008. Available at: www.nice.org.uk/IPG272 nhs_accreditation
  7. Bressler N, Chang T, Fine J et al; Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) Research Group. Improved vision-related function after ranibizumab vs photodynamic therapy: a randomized clinical trial. Arch Ophthalmol 2009; 127 (1): 13–21.
  8. National Institute for Clinical Excellence. Guidance on the use of photodynamic therapy for age-related macular degeneration. Technology Appraisal 68. London: NICE, 2003. Available at: www.nice.org.uk/TA68
  9. Keane P, Tufail A, Patel P. Management of neovascular age-related macular degeneration in clinical practice: initiation, maintenance, and discontinuation of therapy. J Ophthalmol 2011; 2011: 752543.
  10. Royle P, Cummins E, Henderson R et al. Evidence review: ranibizumab for the treatment of diabetic macular oedema: a single technology appraisal. Aberdeen HTA Group 2011, 2011.
  11. CATT Research Group, Martin D, Maguire M et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011; 364 (20): 1897–1908.
  12. Monthly Index of Medical Specialities. MIMS. February 2012. London, Haymarket Medical Media, 2011.
  13. General Medical Council. Good medical practice. GMC: 2006, updated 2009. Available at: www.gmc-uk.org/guidance/good_medical_practice.asp
  14. Jager R, Aiello L, Patel S, Cunningham E. Risks of intravitreous injection: a comprehensive review. Retina 2004; 24: 676–698.
  15. National Institute for Health and Care Excellence. Limited macular translocation for wet age related macular degeneration. Interventional Procedure Guidance 339. London: NICE, 2010. Available at: www.nice.org.uk/IPG339 nhs_accreditation
  16. National Institute for Health and Care Excellence. Macular translocation with 360 degree retinotomy for age-related macular degeneration. Interventional Procedure Guidance 340. London: NICE, 2010. Available at: www.nice.org.uk/IPG340 nhs_accreditation
  17. Hudson H, Stulting R, Heier J et al. Implantable telescope for end-stage age-related macular degeneration: long-term visual acuity and safety outcomes. Am J Ophthalmol 2008; 146 (5): 664–673.
  18. National Institute for Health and Care Excellence. Epiretinal brachytherapy for wet age-related macular degeneration. Interventional Procedure Guidance 415. London: NICE, 2011. Available at: www.nice.org.uk/IPG415 nhs_accreditation
  19. UK Vision Strategy website. Commissioning guide for eye care and sight loss services. www.commissioningforeyecare.org.uk/commhome.asp?section=160&sectionTitle=The+business+case+for+improved+quality+in+eye+care (accessed 22 February 2012).
  20. West S, Munoz B, Rubin G et al. Function and visual impairment in a population-based study of older adults. The SEE project. Salisbury Eye Evaluation. Invest Ophthalmol Vis Sci 1997; 38 (1): 72–82.
  21. Misajon R, Hawthorne G, Richardson J et al. Vision and quality of life: the development of a utility measure. Invest Ophthalmol Vis Sci 2005; 46 (11): 4007–4015.
  22. The Royal College of Ophthalmologists. Maximising capacity in AMD services. London: The Royal College of Ophthalmologists, 2009.
  23. Amoaku W, Blakeney S, Freeman M et al. Action on AMD. Optimising patient management: act now to ensure current and continual delivery of best possible patient care. Eye (Lond) 2012; 26 Suppl: S2–S21.
  24. The Royal College of Ophthalmologists Quality Standards Development Group. 20/20 QIPP quality assurance self test for AMD services. London: The Royal College of Ophthalmologists, 2011.G