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:[23][30]

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

Patients with early or intermediate-stage disease have few or no visual symptoms, whereas patients with late AMD (geographic atrophy or neovascular AMD) may have severe visual loss, especially if the condition involves the center of the fovea.

Treatment of patients with CNV is determined by the locations and size of the neovascular disease.

Specialist referral

Evaluation by an ophthalmologist specializing 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 in one eye,
patients who experience subjective visual changes or abnormality on Amsler exam, 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 glycemic 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).[9][23][24][25][26][27]

Supplementation with omega-3 long-chain polyunsaturated fatty acids does not influence the risk of progressing to advanced AMD.[41] [ ]

Patients with early AMD (AREDS 1 and 2)

AREDS classifies AMD as category 1 in patients with no, or a few small (<63 micrometers in diameter), drusen; and category 2 in patients with many small drusen or a few intermediate-sized (63-124 micrometers in diameter) drusen, or mild abnormalities of the retinal pigment epithelium.[34]

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, and atherosclerotic risk factor modification).

Patients with intermediate AMD (AREDS 3)

AREDS classifies AMD as category 3 in patients with extensive intermediate drusen, or at least one large (≥125 micrometers in diameter) druse, or geographic atrophy not involving the foveal center.[34]

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

Compared with placebo, oral supplementation with antioxidant vitamins plus zinc can significantly reduce the development of advanced AMD in patients with intermediate or advanced AMD in at least one eye.[9][23][34][42][43] Replacement is recommended with vitamin C, vitamin E, beta‐carotene, and zinc; lutein/zeaxanthin is also a suitable replacement for beta-carotene among people who smoke.[26][44] 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.[44][45] [ ] [ ] [ ] A diet of fruits and vegetables rich in antioxidants may also be protective.[46][47][48][49]

Supplementation with omega-3 fatty acids does not appear to be beneficial.[26][42][43]

Patients with advanced AMD: atrophic (dry) (AREDS 4)

AREDS classifies AMD as category 4 atrophic (dry) in patients with geographic atrophy involving the foveal center.[34]

No current treatment has been shown to be effective. One review of the investigational visual cycle modulators, emixustat and fenretinide, concluded that there was limited evidence to support their use. A possible reduction in the incidence of CNV was observed with fenretinide, and to a lesser extent, emixustat.[50]

Patients who have progressed to intermediate or advanced AMD in at least one eye can consider taking the AREDS2 formulation, which may decrease the risk of progression to advanced or late AMD in the less-involved eye.[23]

A repeat eye exam after 6 to 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 CNV.[23]

Patients with advanced AMD: exudative (wet) (AREDS 4)

AREDS classifies AMD as category 4 exudative (wet) in patients with neovascular maculopathy, including CNV, serous and/or hemorrhagic detachment of the retina or retinal pigment epithelium (RPE), retinal hard exudates, subretinal and sub-RPE fibrovascular proliferation, or disciform scar (subretinal fibrosis).[34] CNV is understood to be the root cause of the other abnormal findings listed, so treatment is targeted at the CNV.

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

Treatment for CNV is highly specialized and is carried out by an ophthalmologist who is an expert in diseases of the retina. Choice of treatment often depends on the preference of the individual specialist. Treatment options for CNV include intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors, thermal laser photocoagulation, and photodynamic therapy. Treatment also depends on where the CNV lesion is located: subfoveal (underneath the fovea), extrafoveal (outside the fovea), or juxtafoveal (near to the fovea).

Intravitreal injection with VEGF inhibitors

Intravitreal injection with VEGF inhibitors represents the first-line treatment for CNV.[23][51] Treatment is given as soon as possible after identification of CNV activity, to prevent irreversible retinal damage. Ranibizumab, aflibercept, brolucizumab, and faricimab are approved for the treatment of CNV.[52][53][54][55][56][57]

Bevacizumab is not licensed for intravitreal injection, but head-to-head studies indicate that its efficacy is similar to that of ranibizumab.[58][59][60] Bevacizumab that has been repackaged for intravitreal injection with inadequate aseptic technique has, however, been associated with endophthalmitis.[61] One systematic review of randomized controlled trials comparing bevacizumab and ranibizumab did not detect a difference in systemic safety between the two drugs.[62] [ ]

Commonly used administration protocols include loading doses (typically 3 or 4 loading doses at monthly intervals, depending on drug and license), and then scheduling as required based on visual and anatomic 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.[63]

Ranibizumab, aflibercept, brolucizumab, and faricimab have been approved for "treat-and-extend" or "personalized" dosing regimens, thereby reducing the number of patient visits and injections and lowering direct annual medical costs, compared with monthly injections.[64]

Treat-and-extend dosing

The treat-and-extend dosing approach has become increasingly popular. It aims 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. The aim is to treat at an individualized interval that maintains disease stability. One trial reported an equivalent effect on visual acuity (at 2 years) among patients with neovascular AMD who were randomized to receive either bevacizumab or ranibizumab administered using a treat-and-extend regimen.[65]

Real world outcome data from Australia also show long-term maintenance of vision for up to seven years when neovascular AMD is treated with a treat-and-extend regimen using ranibizumad and aflibercept.[66][67]

Treat-and-extend regimens with variable treatment intervals (2-week or 4-week adjustments), up to a maximum interval of 16 weeks, have been shown to be effective in clinical trials for aflibercept. However, maximum dose intervals should be follow local guidance.

In one treat-and-extend study of aflibercept, patients received one intravitreal dose of aflibercept each month for three doses. At week 16, patients were randomized to a treat-and-extend regimen of either 2- or 4-week adjustments. Outcomes were assessed after 52 and 96 weeks. By week 52, a large proportion of patients had an intended injection interval of 16 weeks, which was the maximum interval studied. Visual acuity outcomes were maintained at week 96, and noninferiority was shown between the 2- and 4-week extension of treatment intervals.[68] A higher dose of aflibercept, given up to every 16 weeks, approved in the US for neovascular AMD based on the outcomes of the PULSAR trial, shows potential for a greater proportion of patients to achieve longer treatment intervals.[69][70] This has the potential to enable more patients to be treated at longer intervals.

Fixed dosing at extended intervals

Fixed dosing at extended intervals has been reported in the HAWK and HARRIER studies of brolucizumab versus aflibercept. After three loading injections, the eyes treated with brolucizumab were injected every 12 weeks, but this interval could be adjusted to 8 weeks if disease activity was present. Just over 50% of patients were maintained on a 12 weekly dosing schedule after the loading injections, with approximately 80% predictability of remaining on this interval by the end of two years.[71] Adverse events of intraocular inflammation, vasculitis, and retinal occlusive vasculitis have been reported in relation to brolucizumab at slightly higher rates than with other VEGF inhibitors.[71][72][73]

In the MERLIN trial, when brolucizumab was given every 4 weeks, the rate of intraocular inflammation was 9.3% (compared with 4.5% in the aflibercept arm). The trial was terminated early, as were trials investigating brolucizumab given every 4 weeks in the context of retinal vein occlusion. Clinicians should not treat patients with brolucizumab at intervals of less than 8 weeks, following the first three doses; this includes individualized dosing under specialist guidance.[74] 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.[75]

Faricimab is a bispecific antibody that can simultaneously bind and neutralize VEGF-A and angiopoietin-2. The phase 2 STAIRWAY study assessed the extended durability of faricimab dosed up to every 16 weeks. A proportion of patients receiving 12-weekly and 16-weekly doses showed outcomes comparable to monthly ranibizumab. Faricimab is approved in the US and Europe for the treatment of wet AMD based on the results of two phase 3 studies (TENAYA, LUCERNE) that found faricimab was well tolerated and noninferior for visual gains over a year when given at intervals of up to 4 months and compared with aflibercept given every 2 months.[52][76] The main potential benefit over other treatments is a greater proportion of patients achieving longer interval between treatments; however, this was not conclusively proven in the clinical trials because the dosing regimes were not matched.

Anatomical treatment response is monitored closely with OCT.

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

Adverse events associated with intravitreal injection

Significant risks are endophthalmitis (rare), damage to the lens, and retinal detachment. Risk of endophthalmitis can be reduced by using appropriate aseptic techniques.[77][78][79][80][81][82]

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 obscured visual field). If endophthalmitis develops, prompt treatment with intravitreal antibiotics is recommended.

Biosimilars

Agents highly similar to the originator biologic agent that can be prescribed at reduced cost (note that this is different to generic medicines, which are an exact copy).[83]

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.[84] In the UK, guidance and supporting evidence has also been provided for the use of approved ranibizumab biosimilars.[85][86] Where available, follow local guidelines on the use of biosimilars.

Thermal laser photocoagulation

Thermal laser photocoagulation is a rarely used method of ablating CNV. This method is only suitable for small, well demarcated extrafoveal CNV (i.e., small areas of CNV outside the fovea).[87][88] A retinal specialist’s opinion is required to assess the risk of the laser causing scotoma in the visual field.

Treatment response is monitored closely with fluorescein angiography and OCT.

Recurrence may occur and retreatments may be necessary.[87][88][89]

Although thermal laser photocoagulation can be considered for small extrafoveal CNV, the first-choice treatment for extrafoveal CNV is intravitreal injection with VEGF inhibitors.

Photodynamic therapy (PDT) using verteporfin

PDT using verteporfin for subfoveal CNV lesions (that are predominantly classic on fluorescein angiography) is inferior to VEGF inhibitors, and is no longer recommended as a first-line treatment. Combinations of intravitreal VEGF inhibitors plus PDT have been studied, but there is a lack of evidence that they confer an advantage over intravitreal VEGF inhibitors alone.[23][90][91][92]

Patients receiving photodynamic therapy need to cover all skin surface areas when in sunlight following treatment, to avoid developing a burn-like photosensitivity reaction. Patients with porphyria should not receive photodynamic therapy.

PDT, in combination with VEGF inhibitors, may be considered in the management of idiopathic polypoidal choroidal vasculopathy.[93]

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