This review did not find evidence for a meaningful difference in outcomes between monthly and as-needed injections of vascular endothelial growth factor inhibitors (anti-VEGF) for wet age-related macular degeneration (AMD). Patients may prefer the treatment-as-needed approach, because it generally leads to fewer injections. After two years, people receiving injections as needed had 8.4 fewer injections at the end of two years, compared with people receiving monthly injections.
AMD is the biggest cause of sight loss in the UK. Reducing the number of injections also reduces the cost to the NHS and healthcare providers.
The treatment-as-needed protocol reflects current UK practice where, after monthly injections for the first three months, further injections are only given if visual acuity (clarity of vision) deteriorates. Therefore, this review provides evidence for the effectiveness of the current treatment approach rather than requiring any change to practice.
Why was this study needed?
AMD causes sight loss in the central part of the eye, making it more difficult for people to read, recognise faces or drive. AMD is the leading cause of vision loss in the UK and it is estimated that one in ten people over 65 are affected to some extent. There are two types of AMD, “dry” – the more common type, which has a gradual onset and progression – and “wet” – which can come on suddenly and cause rapid deterioration in sight.
There are roughly 26,000 new cases of wet AMD a year. In the UK, wet AMD is normally treated with one injection per month for three months of an anti-VEGF drug (see Definitions tab), followed by monthly vision assessments with further injections given if vision deteriorates further (but no more than one a month). Aflibercept is an alternative drug that may be used and bevacizumab is available in an unlicensed use. Frequent appointments for assessment and treatment may be inconvenient for patients and caregivers.
This systematic review compared monthly anti-VEGF treatment with monthly assessments and injections only as needed.
What did this study do?
This systematic review included three randomised controlled trials that directly compared monthly injections versus monthly assessment with injections as needed. The trials included a total of 1844 participants, who were followed-up for two years. One of the trials treated people using 0.5 mg of ranibizumab (in line with UK guidelines), the other trials treated participants either with 0.5 mg of ranibizumab or 1.25 mg of bevacizumab. Bevacizumab is currently an unlicensed treatment, but known to be effective. The authors pooled data from the trials in a meta-analysis, comparing monthly treatment monthly with treatment as needed.
The trials included in the review were generally of a high quality, but all three were scored at high risk of bias due to a lack of blinding of participants and assessors as to which treatment participants had received. This may have affected any perception of the effectiveness of the treatment, but is likely to have increased the difference between groups. Also, the use of an objective measure of vision means that we can still have confidence in the results of this review. One of the trials, HARBOR, was industry sponsored.
What did it find?
- Visual acuity improved less with treatment-as-needed compared with monthly injections. At one year people receiving monthly treatment could see 1.7 more letters on an eye test (95% confidence interval [CI] 0.6 to 2.8), which increased to 1.9 letters (95% CI 0.5 to 3.3) at two years. This difference was statistically significant but unlikely to be an important difference for the individual.
- People receiving monthly injections had a retinal thickness of 28 µm (95% CI 11 to 45) less than those receiving treatment-as-needed at one year and 32 µm less (95% CI 11 to 52) at two years.
- At two years, people receiving treatment-as-needed had received 8.4 fewer injections compared with those receiving monthly injections (95% CI 7.9 to 8.9).
- There was a no difference in risk of death between the groups at one or two years. There was a trend for reduced risk of serious adverse events in the monthly treatment group but this just fell short of statistical significance.
What does current guidance say on this issue?
NICE guidelines recommend that wet AMD is treated using the VEGF-inhibitors ranibizumab (2008) or aflibercept (2013). Bevacizumab is not currently licensed for treating wet AMD, but may be used as an “unlicensed” treatment. Research commissioned by NICE indicated that bevacizumab is not widely used by clinicians in the UK to treat wet AMD. However, in 2015 the Royal College of Ophthalmologists called for bevacizumab to be assessed as a treatment for wet AMD, based on the same studies as included in this systematic review.
What are the implications?
The treatment-as-needed approach used in the included studies reflects recommended UK practice after the first three consecutive months of treatment. Although the review found that monthly anti-VEGF injections were associated with slightly better visual acuity compared with injections as needed, the difference was small and may not represent a meaningful difference for the patient.
There was also a suggestion that that monthly injections may cause fewer serious adverse events than as-needed injections, though this just fell short of statistical significance. This small measurable difference between the groups of 1.7 more letters on an eye test should be seen in the context of the typical visual acuity gains from either treatment of up to 7.9 letters over 2 years. The authors of the included trials set 3.5 to 5 letter improvements as the clinically important difference they were looking for to allow them to say that one treatment was different to the other.
Treatment-as-needed in the included studies also involved a similar number of injections per year as those costed in NICE guidelines. Although treatment-as-needed reduces drug costs by reducing the number of injections, there is still a cost involved in people visiting clinics for monthly assessment, so it may not represent a significant reduction in cost. The Royal College of Ophthalmologists renewed their call for UK regulatory bodies to appraise the use of bevacizumab for this indication, saying that using bevacizumab could save NHS England £102 million each year.
Overall, this review used objective measures of vision and was not prone to major problems with blinding, providing confidence in its results. These reinforce that current UK practice as safe and clinically effective.
Schmucker CM, Rücker G, Sommer H, et al. Treatment as required versus regular monthly treatment in the management of neovascular age-related macular degeneration: a systematic review and meta-analysis. PLoS One. 2015;10(9):e0137866.
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NICE. Aflibercept solution for injection for treating wet age‑related macular degeneration. TA294. London: National Institute for Health and Care Excellence; 2013.
NICE. Bevacizumab in eye conditions: Issues related to quality, use, efficacy and safety. Report by the Decision Support Unit. London: National Institute for Health and Care Excellence; 2012.
NICE. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration. TA155. London: National Institute for Health and Care Excellence; 2008.
RCOPHTH. NHS Clinical Commissioners co-ordinate support from CCGs to review use of Avastin to treat wet AMD. London: The Royal College of Ophthalmologists; 2015.
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