Age-related macular degeneration: anti-vascular endothelial growth factor treatment

Abstract

Introduction

Sight-threatening (late) age-related macular degeneration (AMD) is found in about 1.4% of people of European ancestry aged 70 years, with prevalence increasing with age. Early-stage disease is marked by normal vision but retinal changes (drusen and pigment changes). Disease progression leads to worsening central vision, but peripheral vision is generally preserved.

Methods and outcomes

We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments for exudative age-related macular degeneration? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).

Results

At this update, searching of electronic databases retrieved 901 studies. After deduplication and removal of conference abstracts, 597 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 423 studies and the further review of 174 full publications. Of the 174 full articles evaluated, two systematic reviews, 10 RCTs, and four further reports were added at this update. We performed a GRADE evaluation of the quality of evidence for nine PICO combinations.

Conclusions

In this systematic overview, we categorised the efficacy for four interventions, based on information relating to the effectiveness and safety of anti-angiogenesis (using aflibercept, bevazicumab, and ranibizumab) and ranibizumab plus photodynamic therapy with verteporfin.

Key Points

Sight-threatening (late) age-related macular degeneration (AMD) is found in about 1.4% of people of European ancestry aged 70 years, with prevalence increasing with age.

• Early-stage disease is marked by normal vision but retinal changes (drusen and pigment changes). Disease progression leads to worsening central vision, but peripheral vision is generally preserved.

• Late-stage disease is classified as atrophic (dry) AMD or exudative (wet) AMD marked by choroidal neovascularisation (CNV), which leads to a more rapid loss of sight.

• The main risk factor is age. Hypertension, smoking, and a family history of AMD are also risk factors.

Anti-angiogenesis treatment using the vascular endothelial growth factor (VEGF) inhibitor ranibizumab reduces the risk of moderate vision loss and may improve vision at 12 and 24 months in people with CNV and AMD compared with sham treatment.

• Fixed dosing schedules of monthly ranibizumab are efficacious, although similar effects were achieved in as-needed (PRN) dosing with monthly monitoring. However, fixed quarterly regimens may be less effective than monthly or PRN regimens.

Intravitreal injection of the VEGF inhibitors bevacizumab and ranibizumab may be equally effective at reducing the risk of moderate visual loss and improving vision in people with CNV and AMD.

• We don't know how PRN dosing of bevacizumab compares with monthly dosing of bevacizumab at reducing the risk of vision loss for people with CNV secondary to AMD at 1 to 2 years.

The VEGF inhibitor aflibercept has similar benefit to ranibizumab in preventing vision loss and improving vision in CNV due to AMD.

• In the first 12 months, 8-weekly dosing may give similar benefit as 4-weekly dosing.

Serious but rare ocular adverse events are associated with intravitreal injection procedures.

Combination therapy with ranibizumab plus photodynamic therapy (PDT) with verteporfin with either full or half fluence did not demonstrate benefit over ranibizumab monotherapy.

• The use of combination therapy did not result in decreased frequency of ranibizumab injections.

• The clinical use of PDT with verteporfin as a first-line treatment , either alone or in combination with an anti-VEGF agent, is now limited to people with polypoidal choroidal vasculopathy, a variant of wet AMD.

Clinical context

General background

Age-related macular degeneration (AMD) is common and has a major public health impact, with cost to both society and the individual through visual impairment and loss of quality of life. Loss of central vision occurs in the late stages of the disease, due to both atrophy (dry AMD) and exudation and scarring from choroidal neovascularisation (wet AMD). Management for dry AMD is limited to the provision of low vision aids and other disability services.

Focus of the review

Although visual loss in untreated wet AMD is generally rapid and more profound, the outlook for and management of people with choroidal neovascularisation (CNV) in AMD has been revolutionised following introduction of anti-vascular endothelial growth factor (VEGF) therapy into clinical practice. Previous therapies attempted showed only borderline benefit, chiefly limitation of visual loss, and were limited to a small subset of people with wet AMD. However anti-VEGF therapy has demonstrated that visual improvement over the first 1 to 2 years is possible.

Comments on evidence

We found RCT evidence for all our interventions of interest. They were all medium to large studies; however, there were weaknesses in the methods and/or analysis used. Most studies did not report quality of life as an outcome.

Search and appraisal summary

The update literature search for this overview was carried out from the date of the last search, March 2006, to January 2014. A back search from 1966 was performed for the new options added to the scope at this update. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 901 studies. After deduplication and removal of conference abstracts, 597 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 423 studies and the further review of 174 full publications. Of the 174 full articles evaluated, two systematic reviews, 10 RCTs, and four further reports were added at this update.

Additional information

Further phase I, II, and III RCTs of alternate therapies are under way, which may bring added benefit by targeting a broader range of growth factors and by less intense treatment regimens.

About this condition

Definition

Age-related macular degeneration (AMD) typically affects those aged 50 years and older. Early stages are usually asymptomatic and marked by drusen and pigmentary changes within 2 disc diameters of the fovea. It is distinguished from small drusen (<63 microns) without pigment change, which is considered normal ageing. Early stages are classified into early AMD, with medium-sized drusen, and intermediate AMD, marked by large drusen (>125 microns and/or drusen associated with pigmentary abnormalities). Late AMD is associated with a decrease in central vision and has two forms: atrophic (or dry) AMD, characterised by geographic atrophy; and exudative (or wet) AMD, characterised by choroidal neovascularisation (CNV), which eventually causes a disciform scar.[1] Anti-vascular endothelial growth factor inhibitors (VEGF) therapy in wet AMD Before the advent of anti-VEGF therapy by intravitreal injection, the standard management for CNV in AMD was provision of visual aids, with only a small percentage of people benefiting in terms of limitation of vision loss from previous therapies, such as photodynamic therapy (PDT) with verteporfin and laser photocoagulation. Ranibizumab given monthly was the first treatment for CNV in AMD that demonstrated stabilisation of vision in most people, and clinically meaningful improvement in up to 40% at 12 and 24 months. Anti-VEGF therapy rapidly became the standard of care for all people with CNV in AMD. PDT with verteporfin was previously standard of care for a subset of people with wet AMD with predominantly classic CNV, and ranibizumab monthly was compared with PDT with verteporfin in people with predominantly classic CNV in AMD in the ANCHOR trial. The inclusion of an untreated (sham or placebo) arm in later RCTs was no longer possible on ethical grounds, and aflibercept was studied in comparison to ranibizumab therapy. Bevacizumab, an anti-VEGF agent licensed for use in cancer therapy, became widely used off label to treat CNV in AMD as a cheap and available alternative.

Incidence/ Prevalence

AMD is a common cause of blindness registration in industrialised countries. Meta-analysis finds a pooled global prevalence in the adult population of any AMD at about 8.7% (95% CI 4.26 to 17.40), of early AMD 8.0% (95% CI 3.98 to 15.49), and late AMD 0.4% (95% CI 0.18 to 0.77), with a higher prevalence in Europeans than in Asians and Africans.[2] Among late AMD patients there is no systematic difference between the prevalence of atrophic and neovascular AMD.[3] [4] The prevalence of late AMD increases with age, approximately quadrupling per decade increase beyond 50 years. Among people of European ancestry, late (sight-threatening) AMD is found in about 1.4% (95% CI 1.0% to 2.0%) of people aged 70 years, rising to 5.6% (95% CI 3.9% to 7.7%) at age 80, and 20% (95% CI 14% to 27%) at at age 90.[4]

Aetiology/ Risk factors

Proposed hypotheses for the cause of atrophic and exudative AMD involve vascular factors and oxidative damage, coupled with genetic predisposition determined by racial ancestry.[5] Age is the strongest risk factor. Other risk factors with strong and consistent association with late AMD in a meta-analysis of available data are family history of AMD, current cigarette smoking (RR 1.86, 95% CI 1.27 to 2.73 for cohort studies and OR 3.58, 95% CI 2.68 to 4.79 for cross-sectional studies), and previous cataract surgery (RR 3.05, 95% CI 2.05 to 4.55). Body mass index, history of cardiovascular disease, hypertension, and higher plasma fibrinogen show moderate and consistent associations with AMD.[6] Complement factor H (CFH), a major inhibitor of the alternative complement pathway, seems to play a major role in the pathogenesis of AMD blindness. Meta-analysis reveals that polymorphism at the CFH Y4002H accounts for 59% of the population-attributable risk of AMD; people with CC and TC genotype are approximately six and two and a half times more likely to have AMD, respectively, than people with the protective TT haplotype.[7]

Prognosis

AMD impairs central vision, which is required for reading, driving, face recognition, and all fine visual tasks. Although early AMD may be asymptomatic, reading difficulties and distortion are common early symptoms. In late AMD, visual loss progresses to a central defect (scotoma) in the visual field. Peripheral vision is preserved, allowing the person to be mobile and independent. The ability to read with visual aids depends on the size and density of the central scotoma and the degree to which the person retains sensitivity to contrast. Atrophic AMD progresses slowly over many years, and time to legal blindness is highly variable (usually about 5–10 years).[8] [9] Exudative AMD is more often threatening to vision; vision loss in untreated cases is rapid, with severe vision loss in 21% of eyes at 6 months and 42% by 3 years, and the proportion of eyes with legal blindness rising from 20% at baseline to 76% by 3 years.[3] Five-year estimates of risk of progressing to late AMD range from 0.5% for normal ageing changes, to 50.0% for the highest intermediate AMD risk group.[1] Once exudative AMD has developed in one eye, the other eye is at high risk; one study showed that neovascular AMD developed in the fellow eye in 12% of people by 12 months, and in 27% by 4 years.[3]

Aims of intervention

To minimise loss of visual acuity and central vision; to preserve the ability to read with or without visual aids; to optimise quality of life; to minimise adverse effects of treatment.

Outcomes

Visual acuity (proportion of people with moderate or severe loss in visual acuity, legal blindness); quality of life (health-based quality-of-life scores); adverse effects (thrombotic events [myocardial infarction, stroke], infection, bleeding, and death; for ranibizumab plus verteporfin PDT: vision decrease, back pain, and sunburn). Visual acuity is measured using special eye charts (logMAR charts, usually the Early Treatment of Diabetic Retinopathy Study [ETDRS] chart), although many studies do not specify which chart was used. In this overview, it may be assumed that the logMAR chart has been used unless otherwise stated. Stable vision is usually defined as loss of two lines or less (<15 letters) on the ETDRS chart. Moderate visual loss is defined as a loss of greater than three lines (15 letters), and severe visual loss is defined as a loss of greater than six lines (30 letters). Loss of vision to legal blindness (<20/200) is also used as an outcome.

Methods

Search strategy BMJ Clinical Evidence search and appraisal January 2014. Databases used for the identification of studies include: Medline 1966 to January 2014, Embase 1980 to January 2014, The Cochrane Database of Systematic Reviews 2014, issue 1 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria included systematic reviews and RCTs in published in English, at least single blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported question: What are the effects of interventions to prevent progression of early- or late-stage age-related macular degeneration? Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Age-related macular degeneration: anti-vascular endothelial growth factor treatment.

Important outcomes	Quality of life, Visual acuity
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of treatments for exudative age-related macular degeneration?
2 (900)	Visual acuity	Ranibizumab versus sham treatment	4	–1	0	0	0	Moderate	Quality point deducted for weak methods (uncertain randomisation method)
2 (900)	Quality of life	Ranibizumab versus sham treatment	4	–2	0	0	0	Low	Quality points deducted for weak methods (uncertain randomisation method) and incomplete reporting of results
3 (at least 1980)	Visual acuity	Ranibizumab versus bevacizumab	4	–2	0	0	0	Low	Quality points deducted for incomplete reporting (absolute event rates) and lack of statistical analysis in some RCTs
3 (2617)	Visual acuity	Different regimens of ranibizumab versus each other	4	–2	0	0	0	Low	Quality points deducted for weak methods and incomplete reporting of results (absolute event rates) and for lack of statistical analysis in some RCTs
2 (598)	Quality of life	Different regimens of ranibizumab versus each other	4	–2	0	0	0	Low	Quality points deducted for weak methods and for incomplete reporting of results (absolute event rates) and lack of statistical analysis in RCTs
2 (at least 2108)	Visual acuity	Aflibercept versus ranibizumab	4	–1	0	0	0	Moderate	Quality point deducted for lack of statistical analysis for some assessments
3 (at least 1841)	Visual acuity	Different regimens of aflibercept versus each other	4	–2	0	0	0	Low	Quality points deducted for incomplete reporting of results and lack of statistical analysis in the largest RCT
1 (380)	Visual acuity	Different regimens of bevacizumab versus each other	4	–2	0	0	0	Low	Quality points deducted for incomplete reporting of results (absolute event rates) and for lack of statistical analysis
3 (615)	Visual acuity	Ranibizumab plus PDT with verteporfin versus ranibizumab monotherapy	4	–2	0	0	0	Low	Quality points deducted for incomplete reporting and weak methods (unclear randomisation and masking methods)

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Best corrected visual acuity (BCVA)

The best vision that can be achieved with correction (such as glasses), as measured on the standard eye chart.

Choroidal neovascularisation (CNV)

New vessels in the choroid, classified by fluorescein angiography and ocular coherence tomography in terms of their relation to retinal layers — sub-retinal pigment epithelium, sub-retinal, and intra-retinal; and in terms of their position in relation to the fovea — extrafoveal, juxtafoveal, or subfoveal. Associated with detachments of the retinal pigment epithelium, sub- and intra-retinal exudation and haemorrhage, sub-retinal fibrosis, and the formation of a disciform scar.

Drusen

Small, yellow, bright objects, often near the macula, seen by ophthalmoscopy. They are located under the basement membrane of the retinal pigment epithelium. Drusen <63 microns are considered part of normal ageing and are present in many older people with normal vision. Drusen >63 microns, especially with associated pigmentary changes, indicates higher risk of subsequent loss of acuity from age-related macular degeneration.

Early age-related macular degeneration (early AMD)

Presence of medium-sized drusen (>63 microns </= 125 microns) without pigmentary abnormalities within 2 disc diameters of the fovea.

Geographic atrophy (GA)

A feature of atrophic age-related macular degeneration, characterised by atrophy of the retinal pigment epithelium and inner choroidal layers of the macula, leaving only the deep choroidal vessels visible. Classified as foveal sparing or foveal-involving GA.

Health-related quality of life

Relates to a person's perception of the impact of their health on their quality of life, and is measured by various questionnaires and interviews, such as NEI-VFQ.

Intermediate age-related macular degeneration (intermediate AMD)

Presence of large drusen (>125 microns) and/or drusen-associated pigmentary abnormalities within 2 disc diameters of the fovea.

Intravitreal injection

An injection into the vitreous cavity within the centre of the eye.

Legal blindness

Visual acuity less than 20/200. A reading of 20/200 (or 6/60 in metric) on the Snellen chart means that a person can see at 20 feet (or 6 m) what a normally sighted person can see at 200 feet (or 60 m).

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate vision loss

Loss of three or more lines of distance vision measured on a special eye chart, corresponding to a doubling of the visual angle.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

NEI-VFQ

National Eye Institute Visual Function Questionnaire 25. The NEI VQF-25 is an interview-based questionnaire used to evaluate the impact of visual disability on a person’s perception of his or her quality of life. It consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question.

Photodynamic treatment

A two-step procedure of intravenous infusion of a photosensitive dye followed by application of a non-thermal laser that activates the dye. The treatment aims to cause selective closure of the choroidal new vessels.

Severe vision loss

Loss of six or more lines of distance vision measured on a special eye chart, corresponding to a quadrupling of the visual angle.

Vascular endothelial growth factor (VEGF)

A protein involved in the pathogenesis of choroidal neovascularisation in age-related macular degeneration.

Verteporfin

A photosensitive dye used in photodynamic treatment.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.