Abstract
Introduction
Diabetic retinopathy is the most common microvascular complication of diabetes. It is also the most common cause of blindness in working-age adults in industrialised nations. Older people and those with worse diabetes control, hypertension, and hyperlipidaemia are most at risk. Diabetic macular oedema, which can occur at any stage of diabetic retinopathy, is related to increased vascular permeability and breakdown of the blood retinal barrier, in part related to increased vascular endothelial growth factor (VEGF) levels. About 1% to 3% of people with diabetes suffer vision loss because of diabetic macular oedema.
Methods and outcomes
We conducted a systematic overview, aiming to answer the following clinical questions: What are the effects of intravitreal VEGF inhibitors versus each other for diabetic macular oedema? What are the effects of intravitreal VEGF inhibitors plus laser therapy versus intravitreal VEGF inhibitors alone for diabetic macular oedema? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 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 240 studies. After deduplication and removal of conference abstracts, 149 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 90 studies and the further review of 59 full publications. Of the 59 full articles evaluated, eight systematic reviews and four RCTs were added at this update. We performed a GRADE evaluation for four PICO combinations.
Conclusions
In this systematic overview, we categorised the efficacy for six comparisons based on information about the effectiveness and safety of intravitreal VEGF inhibitors aflibercept, bevacizumab, and ranibizumab, and each of these intravitreal VEGF inhibitors plus laser therapy.
Key Points
Diabetic retinopathy is the most common microvascular complication of diabetes. It is also the most common cause of blindness in working-age adults in industrialised nations. Older people and those with worse diabetes control, hypertension, and hyperlipidaemia are most at risk.
Diabetic retinopathy can cause microaneurysms, haemorrhages, exudates, changes to blood vessels, and retinal thickening.
Diabetic macular oedema, which can occur at any stage of diabetic retinopathy, is related to increased vascular permeability and breakdown of the blood retinal barrier, in part related to increased vascular endothelial growth factor (VEGF) levels.
In addition to increased vascular permeability, it is characterised by central retinal thickening and the deposition of hard exudates.
Involvement of macular oedema in the central subfield, as identified on optical coherence tomography, is associated with a reduction in visual acuity.
Diabetic macular oedema is now the principal cause of vision loss in people with type 2 diabetes and affects 21 million people worldwide.
The previous version of this overview examined treatments for diabetic retinopathy. However, for this updated overview we have focused on selected interventions for diabetic macular oedema.
We searched for evidence from RCTs and systematic reviews of RCTs on the effects of ranibizumab, bevacizumab, pegaptanib, and aflibercept for our comparisons of interest. We found no evidence for pegaptanib. As it is not licensed for the treatment of diabetic macular oedema and not in general clinical use, this drug was not included in the overview for this update.
Several anti-VEGF agents are also currently used for the treatment of wet age-related macular degeneration (see the BMJ Clinical Evidence overview on Age-related macular degeneration: anti-vascular endothelial growth factor treatment ) and retinal vein occlusion. However, because the pathophysiology, response to treatment, and prognosis vary among the different indications, it is not sufficient to assume that if a treatment is more effective in one condition, this will be applicable to all. Therefore, head-to-head data are required for all conditions.
Considering only the evidence from RCTs and systematic reviews meeting our inclusion criteria for this overview, we don’t know whether intravitreal ranibizumab, bevacizumab, or aflibercept differ in effectiveness at improving visual acuity or central macular thickness in people with diabetic macular oedema.
Published after the search date of this overview, the DRCRN 2015 study is a large, multicentre RCT that directly compared intravitreal ranibizumab, aflibercept, and bevacizumab in people with centre-involved diabetic macular oedema. We have included this study in the Comment section of the overview.
This RCT found that: for patients with poor baseline visual acuity or significant central macular thickening, treatment with intravitreal aflibercept may be more effective than with other anti-VEGF agents. While in patients with good baseline visual acuities and lesser central retinal thickening there may be little difference in efficacy between intravitreal bevacizumab, ranibizumab, or aflibercept.
Further studies directly comparing these anti-VEGF agents are needed to validate the findings from this RCT.
In clinical practice, other factors such as cost, local availability, and individual response to treatment may play a role in deciding optimal treatment.
Anti-VEGF agents given intra-ocularly can enter the systemic circulation and may result in a small increase in the absolute risk of arteriothromboembolic events.
No significant differences appear to exist between ranibizumab, aflibercept, and bevacizumab in ocular or systemic adverse events, but studies were not powered to detect small changes and excluded patients with previous arteriothromboembolic events.
We found no RCT evidence on the effectiveness of intravitreal aflibercept plus laser therapy compared with intravitreal aflibercept alone in people with diabetic macular oedema.
We found no evidence of additional benefit in terms of visual outcomes in eyes with centre-involving diabetic macular oedema by combining macular laser therapy with either intravitreal ranibizumab or bevacizumab compared with intravitreal ranibizumab or bevacizumab alone.
Laser treatment close to fixation has potential to vision loss and paracentral scotomas. If required, can be deferred in order to maintain visual gains.
Clinical context
General background
Diabetic macular oedema (DMO) is a sight-threatening condition, treated until recently with focal or grid macular laser treatment. However, conventional laser treatment can cause scarring with a prolonged onset of response over a period of months. The aim of treatment is visual stability rather than gain. Anti-vascular endothelial growth factor (anti-VEGF) agents provide a rapid improvement in reduction of oedema and resultant improvement in the visual acuity without retinal scarring. However, the treatment is not sustained, and repeat treatments are required in order to maintain visual gain. Several anti-VEGF agents are in current use for the treatment of wet age-related macular degeneration (see the BMJ Clinical Evidence overview on Age-related macular degeneration: anti-vascular endothelial growth factor treatment) and retinal vein occlusion. As such, there are several head-to-head trials looking at the comparative effectiveness among these treatments for the different pathologies. The pathophysiology, response to treatment and prognosis vary among these indications, and it is not sufficient to assume that if a treatment is more effective in one condition, this will be applicable to all. Therefore, head-to-head data are required for all conditions.
Focus of the review
This overview focuses on the comparison of the three anti-VEGF treatments in use in current clinical practice. Knowledge of which agent is the most effective in eyes with diabetic macular oedema is of benefit in providing a tailored treatment to patients. There is increasing pressure and focus on cost effectiveness, which has led to the widespread use of unlicensed intra-ocular bevacizumab. Thus, we have also focused on the comparative efficacy and safety of bevacizumab compared to the licensed anti-VEGF agents. Comparison with aflibercept, which has a slightly different mode of action to ranibizumab and bevacizumab, is important to provide evidence of any improved efficacy. The gold standard of treatment was previously laser treatment and, therefore, this modality should be included in an overview of treatment for diabetic macular oedema. There are several intra-ocular corticosteroid treatments licensed for use in diabetic macular oedema (dexamethasone intravitreal implant and fucinolone acetonide intravitreal implant). These may have a particular role in chronic diabetic macular oedema unresponsive to anti-VEGF treatment, and so are not covered in this overview.
Comments on evidence
Although outside the scope of this overview, most studies and analyses that we found on individual VEGF inhibitors were comparing VEGF inhibitors to inactive control or laser. However, head-to-head RCTs between different VEGF inhibitors are now being reported. Much of the published data used eyes, rather than people, as the unit of analysis. We found many analyses that compared VEGF inhibitors plus laser with laser alone, rather than the comparison of VEGF inhibitors plus laser with VEGF inhibitor alone, which is the subject of this overview. For our pre-specified comparisons of interest, we found most evidence on ranibizumab and bevacizumab, and no evidence on the effects of pegaptanib. As pegaptinib is not routinely used for the treatment of diabetic macular oedema, it is not included any further in this overview.
Search and appraisal summary
The update literature search for this overview was carried out from the date of the last search, June 2010, to September 2014. 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 240 studies. After deduplication and removal of conference abstracts, 149 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 90 studies and the further review of 59 full publications. Of the 59 full articles evaluated, eight systematic reviews and four RCTs were added at this update.
About this condition
Definition
Diabetes mellitus is a major health problem estimated to affect 387 million people[1] or 9% of the world's population as of 2014[2] and 3.3 million people or about 6% of the population in the UK.[3] [4] [5] [6] [7] This is expected to rise to 592 million people worldwide by 2035.[1] Diabetic retinopathy is the most common microvascular complication of diabetes.[8] It is also the most common cause of blindness in working-age adults in industrialised nations.[9] [10] Almost half of those with diabetes will have some degree of retinopathy at any given time. Diabetic retinopathy can be classified into non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). The earliest visible signs in NPDR are micro-aneurysms and retinal haemorrhages. With increasing ischaemia, cotton wool spots, venous beading, and intraretinal microvascular abnormalities develop (moderate/severe NPDR). Vision loss is primarily from the development of abnormal new retinal vessels (PDR), which can lead to haemorrhage, fibrosis, traction, and retinal detachment. Diabetic macular oedema (DMO) is a sight-threatening condition that can occur at any stage of diabetic retinopathy. It is characterised by increased vascular permeability, central retinal thickening, and the deposition of hard exudates. Increased levels of vascular endothelial growth factor (VEGF) causes increased vascular permeability; increased levels are found in the vitreous of patients with diabetic macular oedema. When this is present close to or at the central macula, it is termed 'clinically significant macular oedema'. Anti-VEGF treatment for DMO For this overview, we have focused on the effects of the three most widely used intravitreal VEGF inhibitors compared with each other, and also the effects of intravitreal drugs alone compared with combination treatment with macular laser for treatment of DMO. Laser treatment has been shown to reduce risks of moderate vision loss from clinically significant macular oedema, but treatment can lead to retinal scarring with resultant reduced vision, especially in eyes with central involvement. Intravitreal treatment with anti-VEGF agents results in reduced central retinal thickness with associated improvements in the vision over and above treatment with laser. Re-classification of clinically significant macular oedema, which was based on biomicroscopic examination of centre-involving DMO defined by optical coherence tomography classification, identifies those who would most benefit from treatment with anti-VEGF agents. Unlike laser treatment, use of anti-VEGF agents results in a more rapid but less sustained effect, requiring repeated treatments to maintain effects.
Incidence/ Prevalence
Diabetic eye disease is responsible for 14% of registrable blindness in the UK[11] and for 2% of blindness worldwide.[12] [13] Diabetic retinopathy affects 93 million people worldwide.[8] DMO is now the principal cause of vision loss in people with type 2 diabetes[9] and affects 21 million people worldwide.[8] Of people living with diabetes, about 1% to 3% suffer vision loss because of DMO.[14] [15]
Aetiology/ Risk factors
Duration of diabetes is the strongest factor influencing the development of retinopathy, with more than 60% of those with type 2 diabetes having some form of diabetic retinopathy after 20 years. There are several modifiable systemic risk factors strongly associated with retinopathy, including glycaemic control, blood pressure, and dyslipidaemia. Evidence from several well-conducted RCTs and observational studies show that tight glycaemic control reduces the incidence and progression of retinopathy.[16] For type 1 diabetes, the Diabetes Control and Complications Trial (DCCT) showed that each 1% decrease in HbA1c (e.g., 75 mmol/mol to 64 mmol/mol [9% to 8%]) reduces the risk of retinopathy by 39%,[17] and this beneficial effect persisted long after the period of intensive control.[18] In type 2 diabetes, the UK Prospective Diabetes Study (UKPDS) showed that each 10% decrease in HbA1c reduces the risk of microvascular events, including retinopathy, by 25%.[19] A Cochrane review in 2015 demonstrated that there is good evidence that more intensive blood pressure control intervention protects patients with both diabetes and hypertension against developing new diabetic retinopathy.[20] There is also some evidence that intensive BP control is protective against progression of diabetic retinopathy. However, the review did not find that tight BP control reduced the risk of progression of vision loss from diabetic retinopathy. There is good evidence that treatment of dyslipidaemia with fenofibrate protects patients with diabetes against progression of diabetic retinopathy.[21] The ACCORD Eye Study showed that combination lipid therapy with fenofibrate and simvastatin reduced the progression of retinopathy by about one third, from 10.2% to 6.5%, over 4 years, compared with simvastatin treatment alone.[22] Other risk factors include pregnancy,[23] renal impairment,[24] race,[25] inflammation,[26] and genetic influences.[27]
Prognosis
Natural history studies from the 1960s found that at least half of people with proliferative diabetic retinopathy progressed to Snellen visual acuity of less than 6/60 (20/200) within 3 to 5 years.[28] [29] [30] After 4 years' follow-up, the rate of progression to less than 6/60 (20/200) visual acuity in the better eye was 1.5% in people with type 1 diabetes, 2.7% in people with non-insulin-dependent type 2 diabetes, and 3.2% in people with insulin-dependent type 2 diabetes.[31]
Aims of intervention
To prevent visual disability, partial sight, and blindness; to improve quality of life, with minimum adverse effects.
Outcomes
Visual acuity (measured using an ETDRS chart, unless otherwise stated); incidence of visual disability (visual acuity 6/24 [20/80] or worse in the better eye), partial sight registration (visual acuity 6/60 [20/200] or worse in the better eye), and registrable blindness (visual acuity 3/60 [10/200] or worse in the better eye); adverse effects. Clinically important loss of vision is often defined as loss of 15 ETDRS letters (2 or more Snellen lines) of acuity, roughly equivalent to doubling of the visual angle (visual angle is the angle subtended at the eye of the smallest letter visible by that eye) — a measure used extensively in research. Also, we have reported on central macular thickness, which is the retinal thickness within the area defined by the Early Treatment of Diabetic Retinopathy Study 9-sector layout.[32] The central macular thickness is used as a criterion for treatment eligibility by the National Institute for Health and Care Excellence.[33]
Methods
Search strategy BMJ Clinical Evidence search and appraisal date September 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to September 2014, Embase 1980 to September 2014, The Cochrane Database of Systematic Reviews issue 9, 2014 (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 for inclusion in this systematic overview were systematic reviews and RCTs published in English, at least single-blinded, and containing more than 20 individuals (or at least 10 per intervention if multiple-intervention studies), 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. We also included network meta-analyses from systematic reviews where these were reported. Where we have reported such analyses, we have clearly indicated that they are network, and may not include RCTs with direct head-to-head comparisons for our pre-specified comparisons of interest. 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 (see below). 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 questions: What are the effects of laser treatments in people with diabetic retinopathy? What are the effects of drug treatments for diabetic retinopathy? What are the effects of treatments for vitreous haemorrhage? We have added two new questions at this update: What are the effects of intravitreal vascular endothelial growth factor (VEGF) inhibitors versus each other for diabetic macular oedema? What are the effects of intravitreal vascular endothelial growth factor (VEGF) inhibitors plus laser therapy versus intravitreal VEGF inhibitors alone for diabetic macular oedema? 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 Diabetic retinopathy: intravitreal vascular endothelial growth factor inhibitors for diabetic macular oedema.
| Important outcomes | Visual acuity | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of intravitreal vascular endothelial growth factor (VEGF) inhibitors versus each other for diabetic macular oedema? | |||||||||
| 7 (at least 274) | Visual acuity | Intravitreal ranibizumab versus intravitreal bevacizumab | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for weak methods and incomplete reporting of results; directness point deducted for indirect comparison |
| 8 (number unclear) | Visual acuity | Intravitreal aflibercept versus intravitreal ranibizumab | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results; directness point deducted for indirect comparison |
| What are the effects of intravitreal vascular endothelial growth factor (VEGF) inhibitors plus laser therapy versus intravitreal VEGF inhibitors alone for diabetic macular oedema? | |||||||||
| 2 (number unclear; at least 311 eyes) | Visual acuity | Intravitreal ranibizumab plus laser therapy versus intravitreal ranibizumab alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for weak methods and incomplete reporting of results |
| 3 (132) | Visual acuity | Intravitreal bevacizumab plus laser therapy versus intravitreal bevacizumab alone | 4 | –3 | 0 | –2 | 0 | Very low | Quality points deducted for weak methods, sparse data, and incomplete reporting of results; directness points deducted for short follow-up, and for use of regimens not representative of clinical practice |
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.
- ETDRS score
A measure of visual acuity. The Early Treatment Diabetic Retinopathy Study (ETDRS) chart,[73] the gold standard tool for measuring visual acuity,[74] uses letters printed in lines of decreasing size, which are read from a fixed distance; usually 6 metres (20 feet) for distance acuity. The ETDRS visual acuity is written as a number – for example, 70 letters is equivalent to 6/24 Snellen.[75] ETDRS letter score is often represented as a Snellen equivalent for ease of comprehension.
- 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.
- Proliferative retinopathy
Characterised by new vessels at the disc or elsewhere.
- Snellen visual acuity
The Snellen chart usually includes letters, numbers, or pictures printed in lines of decreasing size, which are read or identified from a fixed distance; distance visual acuity is usually measured from a distance of 6 m (20 feet). The Snellen visual acuity is written as a fraction: 6/18 means that from 6 m away the best line that can be read is a line that could normally be read from a distance of 18 m away.
- Very low-quality evidence
Any estimate of effect is very uncertain.
- Visual angle
a measure used extensively in research, it describes the angle subtended at the eye of the smallest letter visible by that eye.
Age-related macular degeneration
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.
Contributor Information
Quresh Amir Mohamed, Ophthalmology Department, Gloucestershire NHS Foundation Trust, Gloucester, UK.
Emily C. Fletcher, Ophthalmology Department, Gloucestershire NHS Foundation Trust, Gloucester, UK.
Miranda Buckle, Ophthalmology Department, Bristol Eye Hospital, Bristol, UK.
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