Age-related macular degeneration

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Treatment is dependent on the category of disease at presentation, and is aimed at:[4][39]

reducing the rate of progression of intermediate age-related macular degeneration (AMD) to late AMD, and
treating macular neovascularisation (MNV) when present.

Specialist referral

Evaluation by an ophthalmologist specialising in diseases of the retina is recommended at any point in the disease process but may be particularly necessary for:

any patient who reaches Age-Related Eye Disease Study Group (AREDS) category 3 (unless the clinician is comfortable with diagnosis and staging of AMD) or AREDS category 4,
patients who experience subjective visual changes or abnormality on Amsler examination, or
when diagnosis is uncertain and/or atypical features are present.

Risk factor modification

All patients with AMD are encouraged to stop smoking; to eat a balanced diet that has a low glycaemic index and is rich in fruits, vegetables, and fish high in omega-3 fatty acids; and to modify cardiovascular risk factors (including lowering cholesterol and saturated fat intake, and controlling hypertension).[4][14][17][33][35]

Supplementation with omega-3 long-chain polyunsaturated fatty acids does not influence the risk of progressing to late AMD.[55][56] [ ]

Patients with early AMD (AREDS categories 1 and 2)

AREDS classifies AMD as category 1 in patients with no, or a few small (<63 micrometres in diameter), drusen; and category 2 in patients with many small drusen or a few intermediate-sized (63-124 micrometres in diameter) drusen, or mild abnormalities of the retinal pigment epithelium.[52]

There is no known effective treatment for these categories, and management is based on observation and risk factor modification (e.g., smoking cessation, dietary modification, atherosclerotic risk factor modification).[4][42]

These patients have a low risk of progression, therefore the potential benefits of antioxidant vitamin and mineral supplementation for slowing progression are minimal (around 4 fewer cases of progression to late AMD for every 1000 people taking supplements).[57]

Patients with intermediate AMD (AREDS category 3)

AREDS classifies AMD as category 3 in patients with extensive intermediate drusen, or at least one large (≥125 micrometres in diameter) druse, or geographic atrophy not involving the foveal centre.[52]

Management involves risk factor modification: smoking cessation, dietary modification, and atherosclerotic risk factor modification.[42]

Evidence from randomised controlled trials and one Cochrane review suggest that antioxidant vitamin and mineral supplementation may reduce the development of late AMD in patients with intermediate AMD in at least one eye.[4][52][56][57] The first AREDS study recommended replacement with vitamin C, vitamin E, beta‐carotene, zinc, and copper.[52] The AREDS2 study showed that lutein and zeaxanthin is a suitable replacement for beta‐carotene, especially among people with a history of smoking due to the potential increased risk of lung cancer with carotenoids.[56] The AREDS2 formula is typically recommended and widely available. Although systematic reviews indicate that antioxidant vitamin and mineral supplementation may delay progression to late AMD, they do not show that supplementation prevents or delays the onset of AMD.[57][58] [ ] [ ] A diet of fruits and vegetables rich in antioxidants may also be protective.[59][60][61][62]

Supplementation with omega-3 fatty acids does not appear to be beneficial in reducing risk of progression to late AMD.[55][56][63]

Patients with late AMD: atrophic (dry) (AREDS category 4)

AREDS classifies AMD as category 4 atrophic (dry) in patients with geographic atrophy involving the foveal centre.[52]

Evidence from randomised controlled trials and one Cochrane review suggest that in patients with late AMD in one eye, antioxidant vitamin and mineral supplementation may reduce the development of late AMD in the less involved eye.[4][52][56][57]

A repeat eye examination after 6-24 months may be considered for patients who remain asymptomatic, and these patients should be seen as soon as possible if they develop symptoms suggestive of MNV.[4]

Complement inhibitors may be considered for patients with geographic atrophy guided by consultant assessment. Two novel intravitreal complement inhibitors are approved in the US for the management of geographic atrophy: pegcetacoplan, a complement C3 inhibitor, and avacincaptad pegol, a complement C5 inhibitor.[4] Pegcetacoplan and avacincaptad pegol may not be available outside of the US (e.g., both drugs have not been approved in Europe).

Two randomised, double-masked, phase 3 studies of pegcetacoplan in patients with geographic atrophy have been carried out and published as a single paper. One trial found that treatment monthly or every other month slowed growth of geographic atrophy over 12 months by a difference of 21% and 16%, respectively, compared with sham treatment. The other trial did not find a significant difference in growth of geographic atrophy between pegcetacoplan and sham treatment at 12 months.[64]

In one randomised, double-masked, 24-month, phase 3 trial, monthly treatment with avacincaptad pegol slowed the growth of geographic atrophy over 12 months by a difference of 14% compared with sham treatment.[65]

Significant risks associated with intravitreal injection include endophthalmitis (rare), damage to the lens, and retinal detachment.[64][66][67][68][69][70][71] Risk of endophthalmitis can be reduced by using appropriate aseptic techniques.[72] Patients are made aware of signs indicative of endophthalmitis (pain, decreased vision, light sensitivity, and increasing redness) and retinal detachment (flashing lights, new floaters, and partially or completely obscured visual field).[4] If endophthalmitis develops, prompt referral for either vitreous tap followed by intravitreal antibiotics, or pars plana vitrectomy with injection of intravitreal antibiotics should be considered as an emergency.

Patients with late AMD: exudative (wet) (AREDS category 4)

AREDS classifies AMD as category 4 exudative (wet) in patients with neovascular maculopathy, including MNV, serous and/or haemorrhagic detachment of the retina or retinal pigment epithelium (RPE), retinal hard exudates, subretinal and sub-RPE fibrovascular proliferation, or disciform scar (subretinal fibrosis).[52] MNV is understood to be the root cause of the other abnormal findings listed, so treatment is targeted at the MNV.

Once a patient has developed MNV, treatment is based on the location and size of the neovascular disease.

Treatment for MNV is highly specialised and is best managed by an ophthalmologist who is an expert in diseases of the retina. Choice of treatment may be guided by factors such as treatment dose, cost, funding, and the experience and preference of the individual consultant.

Intravitreal injection of VEGF inhibitors

Intravitreal injection with VEGF inhibitors represents the first-line treatment for MNV.[4][43] Treatment is given as soon as possible after identification of MNV activity, to prevent irreversible retinal damage. VEGFs, including VEGF-A and VEGF-B, are required for blood vessel formation; VEGF inhibitors differ in the VEGF that they target and in their exact mechanism of action.[41][73]

The VEGF inhibitors ranibizumab, aflibercept, brolucizumab, and faricimab are approved in the US and Europe for the treatment of MNV.[74][75][76][77][78] Bevacizumab is also widely used around the world, but its use may be off-label in some countries.

Dosing regimens start with ‘loading’ doses at monthly intervals followed by as required dosing, a treat-and-extend dosing approach, or fixed dosing at extended intervals.

As required dosing involves giving loading doses (typically 3 or 4 loading doses at monthly intervals, depending on the drug and license), and then scheduling as required dosing based on visual and anatomical parameters on optical coherence tomography (OCT) scanning. Long-term, real-world data show a gradual loss of treatment effect in patients treated on an as required basis.[79]
The aim of the treat-and-extend dosing approach is to proactively continue treatment by sequentially increasing treatment interval or reducing it, as necessary, typically at 2-4 week intervals up to a maximum of 12-16 weeks, depending on the drug used. This may allow for patients to be treated at an individualised interval that maintains disease stability with fewer visits and fewer injections.[80][81]
Fixed dosing at extended intervals has been investigated for brolucizumab and faricimab.

Ranibizumab

Ranibizumab, a recombinant humanised monoclonal antibody fragment that binds to VEGF-A, resulted in significantly reduced vision acuity loss compared with sham injections or verteporfin photodynamic therapy when given monthly for 2 years in clinical trials.[41][70][82]

Aflibercept

Aflibercept, a recombinant fusion protein that binds to VEGF-A and VEGF-B, was non-inferior to monthly ranibizumab in maintaining vision when given in clinical trials in monthly or 2-monthly regimens.[41][71][83] In treat-and-extend trials of aflibercept over up to 2 years, treatment improved visual acuity.[84][85] Outcomes were similar between patients whose dose was adjusted every 2 and 4 weeks, and between patients who started the treat-and-extend regimen after 16 and 48 weeks of treatment. A higher dose of aflibercept, given up to every 16 weeks, has been approved for neovascular AMD based on the outcomes of a phase 3, randomised clinical trial in which a higher dose of aflibercept was found to be non-inferior to a lower dose in terms of change in best-corrected visual acuity from baseline to week 48.[86] However, the maximum dose intervals should follow local guidance.

Brolucizumab

Brolucizumab is a monoclonal antibody fragment that binds to VEGF-A.[41][87] In two phase 3, randomised trials in which brolucizumab was given in a fixed dosing regimen at extended intervals, brolucizumab was non-inferior to aflibercept in its effect on best-corrected visual acuity at 48 and 96 weeks.[67][88] Brolucizumab should not be given at intervals of less than 8 weeks due to the risk of intraocular inflammation, including retinal vasculitis and retinal vein occlusion.[89][90][91] One trial, in which brolucizumab was administered every 4 weeks, was terminated early because there were more intraocular inflammation adverse events in the 4-weekly brolucizumab arm compared with the 4-weekly aflibercept arm.[91] The UK Medicines and Healthcare products Regulatory Agency (MHRA) recommends that after three loading injections, doses of brolucizumab should be given at least 8 weeks apart to reduce adverse events.[92]

Faricimab

Faricimab, a recombinant bispecific monoclonal antibody that can simultaneously bind and neutralise VEGF-A and angiopoietin-2, is approved for the treatment of wet AMD based on the results of two phase 3 studies.[41][74] These trials found that faricimab was non-inferior for change in best-corrected visual acuity over a year when given at intervals of up to 4 months and compared with aflibercept given every 2 months.

Bevacizumab

Bevacizumab is a recombinant monoclonal antibody that binds to VEGF-A. In the US, the use of bevacizumab is off-label. It is only available as an intravenous formulation (which is approved for other indications), and an intravitreal formulation needs to be compounded from the available intravenous formulation. In Europe, bevacizumab (as bevacizumab gamma) is licensed for the treatment of wet AMD, and a proprietary intravitreal formulation is available.

Bevacizumab shows similar efficacy to ranibizumab in head-to-head studies.[41][66][93][94] One systematic review of randomised controlled trials comparing bevacizumab and ranibizumab did not detect a difference in systemic safety between the two drugs.[95] [ ]

In one phase 3, randomised controlled trial, monthly bevacizumab gamma was effective at improving or stabilising visual acuity when compared with ranibizumab dosed monthly for 3 months then quarterly.[96]

Switching between VEGF inhibitors

Clinical evidence suggests that switching between VEGF inhibitors can benefit patients with AMD who have incomplete response to initial therapy by improving retinal anatomy and stabilising vision. In one observational study of eyes switched from bevacizumab to ranibizumab or aflibercept, there was a significant reduction in central macular thickness and modest visual acuity gains that were not statistically significant at final follow-up (4 weeks after the last injection).[97] One real-world analysis of eyes switched from ranibizumab to aflibercept reported that at 12 months after switching, stable vision was maintained (mean visual acuity unchanged; 10% gained ≥10 letters) and median treatment interval increased from 42 to 56 days (P <0.001).[98] Switching to longer-acting agents such as faricimab may be of benefit in patients whose eyes respond to their initial therapy, but injection frequency remains high.[99]

Monitoring

Anatomical treatment response is monitored closely with OCT.[4][39]

Fluorescein +/- indocyanine green angiography is typically taken, when necessary, at baseline, and only intermittently thereafter depending on patient response. OCT angiography has reduced the need for fluorescein angiography.

Adverse events

Bevacizumab that has been compounded for intravitreal injection with inadequate aseptic technique has been associated with endophthalmitis.[72]

Patients are made aware of signs indicative of endophthalmitis (pain, decreased vision, light sensitivity, and increasing redness) and retinal detachment (flashing lights, new floaters, and partially or completely obscured visual field).[4] If endophthalmitis develops, prompt referral for either vitreous tap followed by intravitreal antibiotics, or pars plana vitrectomy with injection of intravitreal antibiotics should be considered as an emergency.

Biosimilars

Agents highly similar to the originator biological agent that can be prescribed at reduced cost (note that this is different to generic medicines, which are an exact copy).[100]

The American Academy of Ophthalmology has published a clinical statement about the use of biosimilars in ophthalmic practice, including the current status of ranibizumab, bevacizumab, and aflibercept biosimilars.[101] In the UK, guidance and supporting evidence has also been provided for the use of approved ranibizumab biosimilars.[102][103] An aflibercept biosimilar is also approved in the UK. Where available, follow local guidelines on the use of biosimilars.

Thermal laser photocoagulation

Thermal laser photocoagulation is a rarely used method of ablating MNV. This method is only suitable for small, well demarcated extrafoveal CNV (i.e., small areas of MNV outside the fovea).[104][105] A retinal specialist’s opinion is required to assess the risk of the laser causing scotoma in the visual field.

Photodynamic therapy (PDT) using verteporfin

PDT using verteporfin for subfoveal MNV lesions (that are predominantly type 2 on OCT) is inferior to VEGF inhibitors, and is no longer a commonly used treatment.

PDT, in combination with VEGF inhibitors, may be considered in the management of idiopathic polypoidal choroidal vasculopathy.[106]

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