Anti‐vascular endothelial growth factor for macular oedema secondary to branch retinal vein occlusion
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of this review is to investigate the effectiveness and safety of anti‐vascular endothelial growth factor (VEGF) agents for the treatment of macular oedema (MO) secondary to branch retinal vein occlusion (BRVO).
Background
Description of the condition
Branch retinal vein occlusion (BRVO) is the second most commonly occurring retinal vascular abnormality after diabetic retinopathy (Mitchell 1996). A BRVO is an occlusion of either a major branch retinal vein draining one quadrant of the retina, a macular branch vein draining the macula, or a peripheral branch vein draining a portion of the retinal periphery. The pathogenesis of BRVO is thought to involve both retinal vein compression and damage to the vessel wall, possibly leading to thrombus formation. BRVOs are thought to occur at sites where retinal arterioles cross retinal veins. Histopathological studies support the hypothesis that because of a common adventitial sheath, thickening of the arteriolar wall compresses the lumen of the vein which alters blood flow causing thrombosis and venous occlusion (Frangieh 1982). Once the occlusion occurs, vascular endothelial damage to the affected vein may induce low‐grade, chronic inflammation of the retinal microvasculature and upregulation of inflammatory mediators. These mediators include prostaglandins, leukotrienes, intercellular adhesion molecule‐1, integrins, tumour necrosis factor‐a, and vascular endothelial growth factor (VEGF) (Ehlers 2011; Funk 2009; Rehak 2008).
The 15 year incidence of BRVO in an elderly Caucasian population is 1.8% (Klein 2008) and most studies report a range of between 0.6% and 2% (Klein 2000; Mitchell 1996; Wong 2005; Xu 2007; Yasuda 2010). A recent pooled analysis of 68,751 individuals indicates an age and gender standardised prevalence for BRVO of 4.42 per 1,000 (confidence interval (CI) 3.65 to 5.19; Rogers 2010a). Second eye involvement by BRVO may occur in between 3.5% to 9% of cases over time (Glacet‐Bernard 1996; Rogers 2010b) and affected individuals have a loss in vision‐related quality of life despite having normal vision in the fellow eye (Awdeh 2010).
Known risk factors for BRVO include hypertension, atherosclerosis, hyperlipidaemia, diabetes mellitus, thrombophilia and other inflammatory and myeloproliferative disorders (Dodson 1982; Dodson 1992; EDCCS Group 1993). A systematic review of the natural history of BRVO suggests that although the baseline visual acuity is generally poor (less than 20/40), with time the visual acuity improves, and between one third and three quarters of eyes show at least a 2‐line improvement in visual acuity without intervention. However, clinically significant improvement beyond 20/40 is uncommon (Rogers 2010b).
The most common cause of visual loss in BRVO patients is macular oedema (MO), which occurs in between 5% to 15% of patients within the first year (Rogers 2010b). Other causes of visual loss include macular ischaemia, glaucoma and neovascularisation (Rogers 2010b). Macular oedema and neovascularisation of the retina or disc are the two major complications which require therapy (BVOS Group 1984; Shilling 1976).
The BVOS clinical trial in the laser treatment of macular oedema following BRVO demonstrated that a grid pattern of photocoagulation in the distribution of leaking capillaries resulted in a sustained and significant increase in visual acuity compared to no intervention. Since its publication in 1984, this has been the gold standard treatment. The ideal time to administer laser treatment has not been proven, however, treatment is recommended after a period of three to six months following the initial event, after the majority of retinal haemorrhage is absorbed thus minimising excessive laser damage (BVOS Group 1984). More recently based on the GENEVA study (Haller 2010), a dexamethasone implant (OZURDEX) has received Food and Drug Administration (FDA) and European Union (EU) approval and is licensed in the UK for the treatment of adult patients with MO following either BRVO or central retinal vein occlusion (CRVO). However, recent interventional and prospective case series have suggested a significant benefit and favourable side effect profile for the use of anti‐VEGF agents in BRVO (Garnock‐Jones 2011).
Description of the intervention
Monoclonal antibodies against VEGF administered intravitreally have been approved for the treatment of age‐related macular degeneration (Rosenfeld 2006) and recent evidence has demonstrated the clinical effectiveness of its use in MO secondary to retinal vein occlusions (Campochiaro 2010a; Prager 2009).
How the intervention might work
Elevated intraocular levels of VEGF have been demonstrated in patients with retinal vein occlusions (Noma 2006). Sustained release of VEGF in primate eyes causes vascular leakage and MO (Ozaki 1997) and several studies have demonstrated that anti‐VEGF antibodies inhibit VEGF mediated neovascularisation and permeability in both in vitro and in vivo studies (Aiello 1995a; Aiello 1995b; Boyd 2002). Thus there is a strong basis for the hypothesis that anti‐VEGF agents may be beneficial in the treatment of vascular leakage and MO (Campochiaro 2008).
Why it is important to do this review
BRVO is the most common retinal vascular occlusion and a significant cause of visual morbidity. Current treatment regimens licensed in the UK include macular photocoagulation and more recently intravitreal steroid implants. Intravitreal anti‐VEGF therapy has a good side effect profile (serious adverse ocular events less than 0.1%) (Kourlas 2007) and is not associated with side effects such as a sustained rise in intraocular pressure commonly seen with steroid preparations. Several recent reports suggest an important clinical efficacy for the use of anti‐VEGF in MO secondary to BRVO (Campochiaro 2010a; Campochiaro 2010b; Kriechbaum 2008; Moradian 2011; Prager 2009; Rabena 2007).
Objectives
The aim of this review is to investigate the effectiveness and safety of anti‐vascular endothelial growth factor (VEGF) agents for the treatment of macular oedema (MO) secondary to branch retinal vein occlusion (BRVO).
Methods
Criteria for considering studies for this review
Types of studies
We will include all randomised controlled trials (RCTs) in the review.
Types of participants
We will include RCTs with participants of all ages and both genders who have had unilateral or bilateral MO secondary to BRVO. We will exclude trials where participants had CRVOs and hemispheric retinal vein occlusions.
Types of interventions
We will include RCTs where anti‐VEGF treatment is compared to another treatment, no treatment, or placebo. We will exclude trials where combination treatments (anti‐VEGF plus other treatments) are used. We will also exclude trials that investigate the dose and duration of treatment.
Types of outcome measures
Primary outcomes
The primary outcome for this review is the proportion of participants with an improvement from baseline in best‐corrected visual acuity (BCVA) of greater than or equal to 15 letters (3 lines) on the Early Treatment in Diabetic Retinopathy Study (ETDRS) Chart after a minimum of six months of follow up and any additional follow up intervals.
Secondary outcomes
The following secondary outcomes will be examined as they represent important clinical and therapeutic indices of safety and effectiveness.
-
Mean visual acuity change at six months and any additional follow‐up intervals reported. We will report the method of visual acuity measured (e.g. Snellen or ETDRS).
-
The proportion of participants with a loss of 15 or more letters (ETDRS) compared to baseline, at six months and any additional follow‐up intervals.
-
Change in central retinal thickness on ocular coherence tomography (OCT) from baseline and final reported follow up.
-
The number and type of complications.
-
The number of additional interventions administered.
Adverse outcomes
We will report any ocular or systemic adverse outcomes reported in the trials. In particular, we will seek to report the following ocular adverse effects: subconjunctival haemorrhage or hyperaemia, worsening MO, retinal tears or detachment, ocular inflammation or endophthalmitis. We will seek to report the following systemic effects: thromboembolic events, hypertension.
Economic data
We will report any cost benefit data reported in the primary studies.
Quality of life data
We will report any quality of life data reported in the studies.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library), MEDLINE, EMBASE, Latin American and Caribbean Health Sciences Literature Database (LILACS), the metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov). There will be no date or language restrictions in the electronic searches for trials.
See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), mRCT (Appendix 5) and ClinicalTrials.gov (Appendix 6).
Searching other resources
We will manually search the references of identified studies to try and elucidate other relevant studies. If indicated, we will contact the corresponding authors of included studies to find further information of relevant published or unpublished work.
Data collection and analysis
Selection of studies
Two review authors will independently review all the titles and abstracts identified from the electronic and manual searches against the inclusion criteria. Each report will be classified as either: Include, possibly include, exclude and unclear. We will obtain the full‐text articles of all 'possibly include' articles and both review authors will independently assess and classify these articles. Disagreement will be handled by discussion between the review authors or by a third author review. We will contact authors of studies identified as unclear if needed for clarification and we will document all studies that are excluded.
Data extraction and management
We will extract the following participant and trial characteristics and report them in appropriate table format:
-
Participant characteristics (gender, age, type and location of BRVO, diagnostic criteria used, baseline visual acuity, fluorescein angiography features and OCT determined macular thickness). If available we will report the type of anti‐VEGF agent used.
-
Intervention (drug, dose, timing interval, time from diagnosis, frequency and length of treatment).
-
Methodology (group size, randomisation, masking).
-
Primary and secondary outcomes.
-
Additional data (quality of life).
-
Treatment compliance and dropout rate/ loss to follow up.
Two review authors will extract the data independently using forms developed by the Cochrane Eyes and Vision Group. The authors will compare the two sets of extracted data and any identified discrepancies will be resolved through discussion and consulting a third author if necessary. One author will then enter data in to Review Manager (RevMan 2011) and a second author will check that the data entered is correct.
Assessment of risk of bias in included studies
Two review authors will assess the methodological quality of the selected trials according to Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will consider the following main criteria:
-
Selection bias: sequence generation, allocation concealment.
-
Performance bias: masking of participants, researchers and outcome assessors.
-
Attrition bias: loss to follow‐up, rates of compliance.
-
Reporting bias: selective outcome reporting.
We will report each parameter as high risk of bias, low risk of bias or unclear. We will contact study authors to clarify any unclear studies. If there is no response from the authors, we will classify the trial based on available information. Magnitude and direction of bias estimation will also be assessed.
Measures of treatment effect
These will be defined according to the data types established in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011) which include:
Dichotomous data
Variables in this group will include the primary outcome, the proportion of participants experiencing a complication or adverse event during follow up and the proportion of participants given additional treatments during follow up. We will report dichotomous variables as risk ratios (RRs) with 95% confidence intervals (CIs).
Continuous data
These variables will include mean changes in visual acuity, macular thickness, area of MO and grade of MO. We will report continuous variables as a mean difference +/‐ standard deviation (normal distribution) or median and inter‐quartile range (not normally distributed).
Ordinal data
The types of adverse events, complications, interventions performed and the quality of life data will be ordinal data. This will be reported qualitatively.
Counts and rates data
The number of adverse events, number of complications and interventions performed will be measured as counts or rates data.
Unit of analysis issues
The unit of analysis will be the eye for which the data have been reported on. The unit of analysis for the demographic and quality of life measures will be the individual. If participants with bilateral disease are randomised to different treatments we will report these studies separately.
Dealing with missing data
We will attempt to contact relevant authors for missing data. If the authors do not respond within four weeks or are not able to provide additional data, we may impute data quoting confidence intervals where possible.
Assessment of heterogeneity
We will assess heterogeneity by examining the study characteristics. We will examine forest plots of available studies and will compute the I2 value with a confidence interval to assess inconsistency between studies. Typically we would view values of I2 of greater than 50% to indicate substantial inconsistency but this will depend on the magnitude and direction of effects.
Assessment of reporting biases
We will examine funnel plots from each meta‐analysis to assess reporting bias if there are a sufficient number of trials.
Data synthesis
We will analyze data using a random‐effects model unless there are fewer than three trials in which a case a fixed‐effect model will be used. If we view heterogeneity as substantial, we will collate results in tabular form.
Subgroup analysis and investigation of heterogeneity
If we have sufficient studies available we will look at treatment effects separately for ischaemic and non‐ischaemic BRVO.
Sensitivity analysis
Sensitivity analyses will be conducted to examine whether the results of our review would be affected by including studies at high risk of bias.
