NIHR Signal Regular monthly and “as needed” injections for wet age-related macular degeneration are similar in effect

Published on 19 January 2016

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.

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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.

Bibliography

NHS Choices. Macular degeneration. London: NHS Choices; 2015.

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.

RNIB. Key information and statistics. London: Royal National Institute of Blind People; 2015.

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.

Bibliography

NHS Choices. Macular degeneration. London: NHS Choices; 2015.

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.

RNIB. Key information and statistics. London: Royal National Institute of Blind People; 2015.

Treatment as Required versus Regular Monthly Treatment in the Management of Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis

Published on 15 September 2015

Schmucker, C. M.,Rucker, G.,Sommer, H.,Virgili, G.,Loke, Y. K.,Oeller, P.,Agostini, H.,Ehlken, C.

PLoS One Volume 10 , 2015

BACKGROUND: To investigate whether treatment as required 'pro re nata' (PRN) versus regular monthly treatment regimens lead to differences in outcomes in neovascular age-related macular degeneration (nAMD). Regular monthly administration of vascular endothelial growth factor (VEGF) inhibitors is an established gold standard treatment, but this approach is costly. Replacement of monthly by PRN treatment can only be justified if there is no difference in patient relevant outcomes. METHODS: Systematic review and meta-analysis. The intervention was PRN treatment and the comparator was monthly treatment with VEGF-inhibitors. Four bibliographic databases were searched for randomised controlled trials comparing both treatment regimens directly (head-to-head studies). The last literature search was conducted in December 2014. Risk of bias assessment was performed after the Cochrane Handbook for Systematic Reviews of Interventions. FINDINGS: We included 3 head-to-head studies (6 reports) involving more than 2000 patients. After 2 years, the weighted mean difference in best corrected visual acuity (BCVA) was 1.9 (95% CI 0.5 to 3.3) ETDRS letters in favour of monthly treatment. Systemic adverse events were higher in PRN treated patients, but these differences were not statistically significant. After 2 years, the total number of intravitreal injections required by the patients in the PRN arms were 8.4 (95% CI 7.9 to 8.9) fewer than those having monthly treatment. The studies were considered to have a moderate risk of bias. CONCLUSIONS: PRN treatment resulted in minor but statistically significant decrease in mean BCVA which may not be clinically meaningful. There is a small increase in risk of systemic adverse events for PRN treated patients. Overall, the results indicate that an individualized treatment approach with anti-VEGF using visual acuity and OCT-guided re-treatment criteria may be appropriate for most patients with nAMD.

“Wet” age-related macular degeneration (AMD) is so called because new blood vessels start growing underneath the macular - the part of the retina at the back of the eye responsible for central vision. However, these new blood vessels are fragile and bleed easily causing further damage to the macular. Vascular endothelial growth factor inhibitors (anti-VEGF treatment) are injected directly into the eye and act to prevent new blood vessel growth, so reducing this damage. Anti-VEGF is also used to treat some forms of cancer by reducing blood supply to tumours.

Expert commentary

This meta-analysis will not alter UK clinical practice as the majority of NHS retina clinics currently use the injections as needed approach. The authors rightly point out that the slightly superior visual acuity outcome in the continuous treatment arms compared to the outcomes in the as needed arms are unlikely to be clinically meaningful.

Professor Usha Chakravarthy, Professor of Ophthalmology and Vision Sciences, Royal Victoria Hospital (The Belfast Trust) and Queens University of Belfast, Northern Ireland