Aplicación de la Fase 4: Evaluación ambiental

The questions for this review include:

1. Can treatment of early AMD prevent or slow progression to advanced forms (wet or dry)? 2. Can any treatments improve, or slow deterioration in, GA?

3. Can any treatments prevent GA progressing to wet AMD?

As our aim is to identify interventions that might have reached a stage where they could be assessed by the NIHR programmes [mainly Efficacy Mechanism and Evaluation (EME) and Health Technology Assessment (HTA)], we are not interested in–

l rehabilitation methods such as external low visual aids

l diagnostics

l research still at basic science stage, such as in vitro, including cell work, or methods of carriage of gene therapies into cells using viral carriers

l treatments with some evidence of efficacy in animal studies but not yet tested in humans. Such research might fall within the remit of the Medical Research Council (MRC) Translational Research Programme.

TABLE 1 Prevalences of dry AMD by age and stage

Age (years) Drusen Advanced dry AMD

65–69 M 9.7%, F 9.8% M 0.5%, F 0.1% 70_–74 M 12.5%, F 17.3% M 0.6%, F 1.0% 75–79 M 18.7%, F 18.1% M 1.9%, F 1.2% ≥80 M 23.3%, F 28.9% M 1.4%, F 5.8% All ages>65 15.4% 1.2% F, female; M, male.

Potential treatments might be divided into the following groups:

1. Treatments where proof of concept in humans has already been achieved but where research is needed to evaluate clinical efficacy, and which might be suitable for the EME programme.

2. Treatments where there is evidence that shows they can be effective, but where further research is needed to establish the clinical effectiveness and cost-effectiveness for the NHS in comparison with the current best alternative. Such research falls within the remit of the HTA programme.

3. Interventions where there is sufficient evidence of lack of benefit, so that no further research is justified. 4. Interventions where there is no good evidence of any benefit and on which no money should be spent.

Identifying these may help people who see unjustified claims or adverts. Outcomes

The most important outcomes are those that matter to patients: VA, contrast sensitivity, adverse effects of treatment, reading speed, ability to drive, health-related quality of life, progression of disease and patient preference.

However, VA loss is a late manifestation of AMD and not a good primary outcome in most trials, especially when the treatment is aiming at prevention of visual loss before it occurs. Early AMD may cause minimal or no symptoms. VA depends only on the centre of the fovea but this tends to go last in atrophic AMD and many patients have large areas of atrophy and experience considerable problems before the fovea goes. Reading and seeing faces of people can be extremely difficult and the ability to drive may be lost. Progression of dry AMD is slow, and so it could be years before a trial could show a decline in vision. Therefore, predictors or biomarkers of future decline can be accepted if there is good evidence that they are strong predictors of subsequent visual outcomes. These will include changes detectable by investigation, but not necessarily by people with AMD, including:

l Rod function, which may not correlate with VA as central VA acuity (as measured using VA charts) depends on foveal function, and the fovea is cone rich. But rod function is one of the earliest abnormalities detected in people who will later develop GA in AMD.

l Macular pigment density, because it appears to be protective.

l Integrity of the RPE layer, as determined by FAF and OCT.

l Drusen volume and number. Disappearance of drusen may be a sign of developing GA.

l Macular sensitivity, which can be measured by microperimetry.

l Dark adaptation.

Both photopic and scotopic vision need to be considered. Scotopic vision refers to low levels of light such as in near darkness.

One issue is the clinical significance of changes in VA. In past evaluations, for example of the anti-VEGF drugs, a clinically significant difference in VA has usually been considered as a change of≥10 letters. Changes of<5 letters are not regarded as clinically relevant as may indicate normal variability. Changes of 5–9 letters are not regarded as clinically useful but might be regarded a valuable outcome to investigate if seen in a short-term study, suggesting that a larger or longer trial is justified.

In dry AMD, no change (which could be lack of deterioration) could be regarded as clinically meaningful if observed over a long enough period.

Microperimetry

Microperimetry can detect changes in macular sensitivity in patients with early AMD and normal VA.79 Macular sensitivity measured using microperimetry focuses on the central macula instead of the entire visual field.80–83

Testing is performed either with a modified Humphrey Field Analyser or with a microperimeter.83

There is limited evidence of the reproducibility of microperimetry in patients with AMD, but current studies have suggested that it provides consistent and reproducible readings.84–86

Early AMD patients have rod sensitivity loss87_{and impaired rod-mediated parameters of dark adaptation,}88 which worsen as AMD progresses. The association between early AMD changes and macular sensitivity was further established by the observation that a correlation existed between altered AF signal and reduced macular sensitivity.79,89_{In GA, macular sensitivity was reduced in areas of increased fundus AF} signal at the junctional zone of areas of atrophy.90_{However, this observation has not yet been proven to} be a predictor of GA enlargement over time.90

Current evidence suggests that macular sensitivity is a valuable biomarker for early AMD and microperimetry has proven to be an easy and reliable test to measure it. It is not widely used in clinical practice, but has been used in clinical trials to evaluate the effects of treatments on macular sensitivity.91–96