Central retinal vein occlusion (CRVO) is a frequently seen retinal vascular disease,1,2 with a prevalence of 0.80 per 1000 (95% confidence interval [CI], 0.61-0.99).3 In CRVO, there is an impediment of blood flow through the retinal venous system, with the occlusion typically occurring at or adjacent to the lamina cribrosa of the optic nerve, where the central retinal vein leaves the eye.
The landmark Central Vein Occlusion Study classified CRVO into perfused (non-ischemic) and non-perfused (ischemic) subtypes centered on the extent of capillary non-perfusion as delineated by fluorescein angiography,4 which affects visual prognosis and has guided treatment.5 Non-perfusion leads to retinal neovascularization but more importantly neovascularization of the iris and angle potentially leading to neovascular glaucoma and permanent severe visual loss.6,7
In eyes with CRVO, cystoid macular edema (CME) occurs due to leakage of fluid within the retina activated somewhat by release of vascular endothelial growth factor (VEGF) and interleukin-6 leading to elevated vascular permeability and vasodilation.2,8-12 Current treatment of CRVO is targeted at the management of macular edema, which is the predominant source of vision loss, as well as macular ischemia and neovascularization.13
Although macular grid laser reduced vision loss in eyes with CME due to branch retinal vein occlusion (BRVO), it was ineffective against CME due to CRVO.14 The last decade has seen a revolution in the management of macular edema, with safe and effective pharmacotherapy with anti-VEGF agents and corticosteroids dramatically improving visual outcomes. Numerous clinical trials have demonstrated that anti-VEGF treatment has greater effect than the natural history of the disease.15-19
The purpose of this meta-analysis was to examine the efficacy of current anti-VEGF treatments in the management of CME due to CRVO in both randomized controlled trials (RCTs) and real-world clinical settings based on literature published between January 2013 and June 2018.
Data Sources and Search Methods
A systematic review of the literature and meta-analysis was conducted. This review was performed in accordance with the protocols outlined in the Cochrane Handbook for Systematic Review of Interventions (v5.1.0). The outcomes are described as outlined in the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). In brief, EMBASE, PubMed, and Cochrane databases were searched for articles from their inception to June 2018 independently by 2 authors (K.S. and T.H.). The search strategy was centered on the amalgamation of medical subject headings and the keywords: “retinal vein occlusion”, “macular oedema”, “macular edema”, “anti-VEGF”, “CRVO”, “aflibercept”, “bevacizumab”, and “ranibizumab”.
The search was limited to clinical studies available in peer-reviewed, English language publications, and those published between January 2013 and June 2018. The reference lists of selected articles were examined for additional publications. In cases of published abstracts or where data were omitted or unclear, authors were contacted twice for interpretation and additional information.
Full-text articles were reviewed and were included on the foundation of predefined criteria, specifically: (1) a described outcome of CRVO; (2) inclusion of best-corrected visual acuity (BCVA) and central foveal thickness (CFT) as a study variable; and (3) at least 12 months of follow-up data. Randomized controlled trials, and real-world prospective and retrospective clinical studies were included.
In cases with multiple treatment arms, only those with an anti-VEGF were included. Likewise, for studies of eyes with both BRVO and CRVO, only the outcomes of eyes with CRVO were included.
Studies were excluded if results between BRVO and CRVO could not be differentiated, and specific type of anti-VEGF could not be ascertained from the results. Studies published as a series of publications from the same organization or author that included overlapping data were also excluded.
Data Collection and Risk of Bias Assessment
Data from eligible articles meeting inclusion criteria were extracted independently by 2 authors (K.S. and T.H.). The risk of bias was evaluated both qualitatively and quantitatively using the Downs and Black checklist.20 The same 2 authors evaluated data and categorized articles attained from the literature search to assess quality.
The Cochrane handbook was applied to obtain SD from range, median, or P value when presented.21 Best-corrected visual acuity was transposed to an Early Treatment Diabetic Retinopathy Score (ETDRS) letter score. Data were summarized both qualitatively and quantitatively. This was facilitated by extricating data of the following variables: study design (retrospective or prospective), target population (sample size), patient demographics (age), and baseline clinical features (BCVA, CFT, and treatment frequency). Any disagreement was resolved by discussion and consensus.
Data Synthesis and Analysis
Studies were evaluated for heterogeneity in addition to the risk of bias to ascertain irrelevance for inclusion in the analysis. The variance in mean change from baseline between the different therapies was utilized for each resultant variable. When vision was reported as Snellen acuity, it was converted to ETDRS letter score. Pooled estimates of the mean were calculated using random effects models, which were used to examine any heterogeneity amongst studies. Statistical heterogeneity between studies was quantified using the I2 statistic.22 Publication bias was evaluated by Egger's linear regression and visualized with funnel plots. All statistical analyses were performed using Comprehensive Meta-Analysis Version 2.0 (Wiley, Englewood, NJ, US).
Description of Studies
Overall, 717 studies were identified across all databases after duplicates were removed. After exclusion of studies on the basis of publication before 2013 or failure to meet inclusion criteria, 17 studies were included in our meta-analysis (Fig. 1).
Of the 17 studies included in this meta-analysis, there were 3 RCTs,23-25 5 prospective nonrandomized studies,26-30 and 9 retrospective observational clinical studies.31-39 Baseline characteristics of all included studies are summarized in Table 1.23-40 The included studies spanned from January 2013 to June 2018, with a total of 1070 eyes. The mean age of participants ranged from 53.5 to 72.0 years. Table 2 summarizes the prevalence of common cardiovascular risk factors. Numerous studies described the results of several heterogeneous study groups. For this reason, the study characteristics and statistical analyses were based on separable study populations in contrast to the entire studies. Injection protocols and treatment regimens are summarized in Table 3.
Visual Acuity Outcomes
At 12 months, BCVA improved by a mean of 14.4 ETDRS letters (95% CI, 10.3-18.5, P < 0.001; Fig. 2A). The mean improvement in BCVA was 20.4 letters (95% CI, 13.3-27.5, P < 0.001) for the prospective studies and 9.1 letters (95% CI, 5.0-13.2, P < 0.001) for the observational studies.
We assessed the mean change in BCVA for different anti-VEGF agents. The pooled mean improvement in BCVA was 16.5 letters (95% CI, 12.6-22.9, P < 0.001) for eyes treated with bevacizumab, 18.2 letters (95% CI, 10.1-22.9, P < 0.001) for aflibercept, and 8.5 letters gained (95% CI, 3.0-14.0, P < 0.001) for ranibizumab (Fig. 2B).
Subgroup analysis of pooled data by perfusion status demonstrated similar BCVA gains at 12 months, with 12.2 ETDRS letters (95% CI, -0.1 to 24.5) and 16.1 ETDRS letters (95% CI, -3.2 to 35.4) in the ischemic and non-ischemic groups, respectively (P = 0.012).
Four studies reported outcomes for a further 12 months of follow-up. The BCVA gains were sustained through to 24 months in these studies with a mean change from baseline of 14.2 ETDRS letters (95% CI, 10.7-17.7, P < 0.001) (Fig. 2C), with no significant difference between therapies; pooled for aflibercept, bevacizumab, and ranibizumab was 13.0, 15.7, and 13.2 ETDRS letters, respectively (P < 0.001).
Central Foveal Thickness
There was a significant decrease in the mean CFT from baseline among the 3 therapies to 12 months (Fig. 3A). Pooled CFT reductions for aflibercept, bevacizumab, and ranibizumab were 306.6 μm, 325.7 μm, and 246.1 μm, respectively (P < 0.001). The overall pooled mean estimate was 289.2 μm (95% CI, -321.0 to -257.3, P < 0.001) reduction in thickness on spectral-domain optical coherence tomography at 12 months (Fig. 3B).
This reduction in CFT was maintained at 24 months, with a mean CFT reduction of 327.4 μm (95% CI, -425.9 to -228.9, P < 0.001) (Fig. 3C).
The improvement in CFT followed the course of the BCVA gains, with continuous reduction in CFT occurring in the first 12 months and then stabilizing up to 24 months.
Subgroup analysis by study design demonstrated a significant difference in CFT reduction at 12 months, with prospective studies illustrating a mean reduction of 307.0 μm (95% CI, -346.5 to -267.6) compared with retrospective studies with a mean decrease of 270.6 μm (95% CI, -337.4 to -203.8, P < 0.001). Non-ischemic eyes also demonstrated a greater reduction of CFT compared with ischemic eyes (386.6 vs 318.5 μm; P = 0.001).
Number of Injections
The overall pooled number of injections administered was 5.5 (95% CI, 4.1-6.9, P < 0.001) (Fig. 4A). Figure 4B summarizes the mean number of injections by therapy administered.
Prospective studies administered a greater number of injections compared with retrospective studies, being 6.6 and 4.4 injections, respectively over 12 months (P < 0.001).
Rates of serious ocular adverse events were few and comparable among all treatments. There were inadequate data in regard to adverse effects in many studies, limiting the facility of meta-analyses to appraise the importance of adverse effects arising at differing time points throughout the studies. No significant heterogeneity was detected in this meta-analysis. Adverse events were more scrupulously reported in the RCTs,23-25 and were not reported at all in 1 study.31 At baseline, a significant proportion of patients had pre-existing cardiovascular risk factors.
A methodological assessment was performed using the Downs and Black checklist. The risk of bias was minimal among most areas. However, due to the quality of the difference in study design, there was no blinding of 367 of the study eyes and study professional to the anti-VEGF therapy received.26,27,31-39 Attrition rates were relatively low across the studies. Moreover, the outcomes of subgroup analyses were substantially guided by results from a small sample of patients.
There was indication of potential publication bias as represented by the funnel plots and by Egger's test (BCVA at 12 months, P < 0.001; BCVA at 24 months, P < 0.001; and CFT at 12 months, P < 0.01). Possible publication bias was demonstrated in the analyses of CFT at 24 months (I2 = 97.42%, P < 0.001), suggesting that the therapeutic result was overvalued owing to the small cohort sample sizes. Nonetheless, the inferences of homogeneity in this meta-analysis ought to be regarded with restraint due to the small sample sizes of the included studies41,42 and the varied breadth of baseline BCVA and CFT values.
Macular edema is the most common sight-threatening complication of CRVO. This meta-analysis consisted of 17 studies representing 1070 eyes, providing evidence for the efficacy and safety of anti-VEGF treatment of macular edema secondary to CRVO.
The promising CFT and BCVA outcome due to impediment of VEGF was prompt and effective. The improvement in CFT was significant during the 12 months of therapy and the absence of macular edema was maintained by pro re nata (PRN) treatment up to 24 months. Moreover, BCVA improved significantly concurrently with the resolution of macular edema and was maintained with as-needed injections up to 24 months. The demonstrated effects indicate that anti-VEGF therapy has the potential to assure for improved outcomes in the initial CRVO disease process.
The evidence for intravitreal anti-VEGF therapy has been established in this meta-analysis to be highly favorable in the treatment of macular edema secondary to CRVO equally in clinical trials and real-world clinical settings. These therapies improve both visual acuity and decrease macular thickening,43-45 although in general involve frequent intravitreal injections to maintain visual gains. However, this may be challenging as it is hypothesized that multiple injections increase the possibility of retinal ischemia,46-48 and impose immense economic affliction on the wider health care systems49 and patients.
The visual prognosis of eyes with CRVO is dependent upon the delay or speed in which treatment is initiated, extent of ischemia and restoration of the venous system patency by recanalization, termination of the occlusive thrombus, or the development of optociliary shunt vessels.50,51 These compensatory processes can improve vascular flow, reduce ischemia, and consecutively, reduce VEGF-mediated complications.50,52,53
The incidence rates of ocular complications, including neovascular glaucoma (3.6%), vitreous hemorrhage (<1%), glaucoma (1.2%), and neovascular glaucoma (<1%), were low. No reports of endophthalmitis or vitreous hemorrhage were noted in any study. Rates of systemic serious adverse events were also low with myocardial infarction, stroke, and arrhythmia reported in less than 1%. There was poor evidence relating anti-VEGF therapy to systemic disease, which is of significance noting the high incidence of preexisting cardiovascular diseases at baseline for most patients. The inconsistent reporting of adverse events amongst the studies may be a consequence of the variable paradigms among studies, which would be a weakness of the present analysis.
The disparity between perfusion status and morphological and functional effects might be rationalized by neuroretinal damage due to macular ischemia. Continual proximity to hypoxia and macular edema can cause considerable photoreceptor damage via the neuroretinal layers and retinal pigment epithelium.
Frequent injections are required to preserve the outcomes of anti-VEGF therapy. Of note, PRN therapy can resolve recurrent macular edema and vision loss rapidly. It is unclear, however, as to how sustainable frequent injections can be and how long should intravitreal therapy persist. There is the probability for the potential of enduring adverse events and the limitations of multiple and frequent injections. Consequently, the management and the decisive factors for PRN treatment need to be cautiously defined with the intention of reducing injection burden. Methodological improvements must be dedicated to the improvement of retinal ischemia and reduction of macular edema. Prompt treatment of macular edema advances the management of retinal vascular disease.
Both ranibizumab and aflibercept have been approved by the US Food and Drug Administration in the management of macular edema secondary to CRVO, although bevacizumab is an off-label treatment.54,55 Notwithstanding overall most eyes gained significant visual acuity, those treated with aflibercept and bevacizumab had significantly better outcomes than ranibizumab. It can be, however, noted that aflibercept was administered almost 2 times as much as ranibizumab and bevacizumab groups, although this is most likely due to the fact that most eyes within the aflibercept group were from RCTs, and most of the other studies incorporated a PRN treatment regimen. Prospective studies also administered more injections over the first 12 months than retrospective studies, probably related to the more robust study design.
There is currently no standard treatment protocol for ischemic CRVO in a clinical setting. This review demonstrated that the management and outcomes of patients with ischemic CRVO are highly variable, however, treatment with anti-VEGF therapy can lead to significant improvement in anatomical and functional outcomes.
This study had several limitations. Three anti-VEGF therapies were analyzed together. This meta-analysis presented substantial and compelling confirmation than solitary study as the amalgamated data from numerous randomized trials and real-world clinical studies facilitated the collective appraisal of effectiveness from qualitative and quantitative outlooks. However, comparing RCTs with observational studies predisposes bias due to uncontrolled confounding. There were also varying sample sizes, study designs, and treatment frequencies associated as confounding variables.
In summary, this meta-analysis demonstrated that anti-VEGF therapy is effective for improving the prognosis of CRVO with a good safety and tolerability, and hence is of significant clinical importance. Further larger prospective studies are warranted to ascertain specified treatment regimens, and further investigate the impact of anti-VEGF therapy on ischemia in the long term.
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