Recommendations for research
The guideline committee has made the following recommendations for research. The committee's full set of research recommendations is detailed in the full guideline.
What is the effectiveness of antioxidant and zinc supplements on AMD disease progression for people with early AMD at high risk of progression in the context of a randomised controlled trial?
Age-related eye disease study (AREDS 2001) examined the effect of antioxidant supplementation on AMD progression using the AREDS formation, which included beta carotene, vitamin E, vitamin C and zinc. Although the study showed some beneficial effects of the combined antioxidant supplementation in a subgroup of participants, the effects of each of the formula components on AMD progression were unclear. Additionally, 1 of the ingredients (beta carotene) in the AREDS 2001 formulation is associated with a possible risk of lung cancer among smokers. The AREDS research group introduced a new formulation that excluded beta carotene in the AREDS2 study, but the effect of AREDS2 formulation on AMD disease progression is unknown because of a complicated study design involving secondary randomisation and no placebo control. Therefore, a well-conducted randomised trial would provide an evidence base for the benefits and risks of individual components of the antioxidant supplements, and provide the ability to establish the treatment effect of antioxidant supplementation (the AREDS2 formula) on AMD progression by comparing AREDS2 formula with no treatment (for instance normal diet).
What is the long-term effectiveness, in terms of patient-relevant outcomes including visual acuity and quality of life, of different models of care that aim to reduce time from initial presentation to referral, diagnosis and treatment?
There is robust evidence showing that visual loss is linked with delays to diagnosis and/or treatment. However, there is a lack of evidence evaluating the impact of any particular model of care/services in reducing any of the time intervals throughout the referral and treatment process, or the subsequent influence of different models of care on peoples' visual acuity and quality of life. A well-conducted trial would, therefore, provide the evidence base to assess the long-term effectiveness of different organisational models on referral, diagnosis and treatment for people with late AMD (wet active).
When should anti-vascular endothelial growth factor (VEGF) treatment be suspended or stopped in people with late AMD (wet)?
Anti-VEGF treatment is associated with inconvenience, risk of adverse events and – especially when aflibercept or ranibizumab is used – substantial costs. People typically receive anti-VEGF for extended periods, and it is unclear whether it is always beneficial. After successful treatment, the disease can become sufficiently dormant that treatment could be safely suspended. After ineffective treatment, there may be no benefit in continuing to treat eyes with advanced damage. The committee agreed that this gap in evidence could be addressed by a 2‑stage research strategy. Observational research (for example, using registries recording administration of anti-VEGF and relevant outcomes) should be undertaken to establish the point at which the benefits of continuing treatment are unclear. This would involve eyes in which disease has responded well to treatment, and eyes in which pathological appearances or visual acuity suggest that disease is not responding to antiangiogenic treatment. This research should then be used to establish a protocol for suspending or stopping treatment. The protocol would be assessed in a non-inferiority randomised controlled trial (RCT) in which participants would be randomised to protocol-dependent stopping rules or usual care (continued treatment at clinician discretion). The committee agreed that the first step would be necessary to fulfil the ethical requirements of an RCT, as no consensus currently exists about the point(s) at which it may be safe to stop treatment.
What is the long-term cost effectiveness, in terms of patient-relevant outcomes including best-corrected visual acuity and quality of life, of different review frequencies/strategies for people at risk of progression to late AMD (wet active)?
There is currently no evidence on the different frequencies for monitoring people with AMD. This means that it is not possible to identify an optimum monitoring strategy for people at different stages of AMD, leading to uncertainty in how to correctly manage treatment for individuals or how to configure eye care services to support patients. A study of the needs of people at risk of progression to late AMD (wet active) to identify the optimum review arrangements would remove this uncertainty. Trials would need to measure visual outcomes and health service resource use to measure the trade-offs between the optimal management of people at risk of disease progression in relation to the use of resource.
Does earlier detection of the incidence of late AMD (wet active) by self-monitoring in people diagnosed with early AMD, indeterminate AMD or late AMD (dry) lead to earlier treatment and better long-term outcomes?
A review of the evidence demonstrated that self-monitoring interventions result in earlier diagnosis for people with late AMD (wet active). However, the evidence failed to demonstrate that earlier diagnosis would result in improvements in long-term outcomes such as visual acuity, and also failed to capture potential negative effects of self-monitoring (including the potential for increased anxiety). A study could be carried out to follow up a cohort of people diagnosed with early, indeterminate or late AMD (dry) to the time when the diagnosis of late AMD (wet active) is established. Comparisons would include time to diagnosis of late AMD (wet active), time to treatment, long-term visual acuity and participants' quality of life. This would help to establish the association between early detection and early treatment plus good long-term vision outcome. It would also help any such positive effects to be weighed against the potential for harm.