Diabetic retinopathy: intravitreal vascular endothelial growth factor inhibitors for diabetic macular oedema
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.
Substantive changes at this update
Ranibizumab (intravitreal) versus other intravitreal VEGF inhibitors (bevacizumab, aflibercept) New option. Eight systematic reviews and two RCTs added. Categorised as 'beneficial'.
Bevacizumab (intravitreal) versus other intravitreal VEGF inhibitors (ranibizumab, aflibercept) New option. Six systematic reviews and two subsequent RCTs added. Categorised as 'beneficial'.
Intravitreal ranibizumab plus laser therapy versus intravitreal ranibizumab alone New option. Eight systematic reviews added. Categorised as 'unlikely to be beneficial'.
Intravitreal bevacizumab plus laser therapy versus intravitreal bevacizumab alone New option. Five systematic reviews and two RCTs added. Categorised as 'unlikely to be beneficial'.
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.
Mohamed QA, Fletcher EC, Buckle M. Diabetic retinopathy: intravitreal vascular endothelial growth factor inhibitors for diabetic macular oedema. Systematic review 702. BMJ Clinical Evidence. . 2016 March. Accessed [date].
Anti-vascular endothelial growth factor for diabetic macular oedema. ( 02 March 2016 )
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