Introduction

Central retinal vein occlusion (CRVO) is the second most common retinal vascular disorder after diabetic retinopathy, affecting mainly the adult population, and is considered an important cause of visual loss [1]. The exact pathogenesis is poorly understood, but several cardiovascular, thrombophilic, systemic and ocular conditions predispose to CRVO [2–6]. Local inflammation has been also implicated in the pathophysiology of CRVO [7]. In vivo assessment of vitreous fluid in patients with CRVO has shown elevated levels of pro-inflammatory mediators such as interleukin-6 (IL-6), interleukin-8 (IL-8), endothelin-1, pentraxin 3 and vascular endothelial growth factor (VEGF) [6–9]. Additionally, several studies have identified a direct correlation between VEGF levels and the severity of macular edema as well as the development of retinal ischemia in CRVO, which are considered the main causes of visual impairment in patients with CRVO [10, 11].

Various treatment modalities have been used to treat macular edema due to CRVO, including laser photocoagulation, intravitreal administration of steroids, surgical procedures and, most recently, intravitreal anti-VEGF agents [12]. Specifically, ranibizumab (Lucentis®; Novartis, Basel, Switzerland), a recombinant antigen-binding fragment that neutralizes all isoforms of VEGF-A, was approved by the US Food and Drug Administration (FDA) for the treatment of macular edema secondary to CRVO, showing resolution of macular edema and improvement in visual acuity (VA) in patients with CRVO over long-term follow-up [13–15]. Aflibercept (Eylea®; Bayer HealthCare, Leverkusen, Germany) is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. It binds to all VEGF-A isoforms with higher VEGF affinity than bevacizumab and ranibizumab, and was proven to be safe and effective in patients with CRVO in the large COPERNICUS and GALILEO trials [16–18]. Real-life data based on protocols that can differ from those used in clinical trials have also demonstrated significant anatomical and visual improvement in patients with CRVO treated with intravitreal ranibizumab or aflibercept, over various follow-up periods [19–21]. In addition, switching therapy from ranibizumab to aflibercept in cases of macular edema due to CRVO with insufficient response to ranibizumab was found to provide improved anatomical and functional outcome, prolonging the injection and relapse-free intervals [22]. However, there are no comparative studies evaluating the two approved anti-VEGF agents in terms of VA and central subfield thickness (CST), as well as optical coherence tomography (OCT) characteristics, in treatment-naïve patients with macular edema due to CRVO.

To this end, therefore, the present study was conducted to compare the efficacy and safety of two anti-VEGF agents, ranibizumab and aflibercept, for the treatment of macular edema due to CRVO over a follow-up period of 18 months.

Methods

In this retrospective observational study, medical records were examined for treatment-naïve patients with macular edema due to CRVO who commenced treatment with either ranibizumab or aflibercept in Ophthalmiatrion Athinon, First Department of Ophthalmology and Second Department of Ophthalmology, University of Athens, between 1 January 2014 and 1 May 2015. The study adhered to the Declaration of Helsinki and was approved by the institutional review board of the participating hospitals. Written informed consent was obtained from all participants.

Study participants included 62 patients (62 eyes) with macular edema due to CRVO (CST > 320 μm) who were treated with intravitreal injections of either 0.5 mg ranibizumab (n = 34) or 2.0 mg aflibercept (n = 28) and had at least 18 months of follow-up. Switching of treatment was not permitted during the follow-up period. Patients with age-related macular degeneration, diabetic retinopathy, a history of vitrectomy, previous laser photocoagulation, previous anti-VEGF injections, uncontrolled glaucoma, ocular inflammation or dense cataracts and those lost to follow-up were excluded from the study.

All patients initially received three intravitreal injections of either 0.5 mg ranibizumab or 2.0 mg aflibercept to the affected eye, and subsequently received additional injections pro re nata (PRN) if any of the following were observed: a decrease in best-corrected visual acuity (BCVA) ≥1 Snellen line, an increase in CST ≥ 50 μm or the presence of intraretinal/subretinal fluid (IRF/SRF) in OCT. If neovascularization was detected, scatter/panretinal photocoagulation was performed, as appropriate. The sterile protocol for intravitreal injection included the use of 5% povidone-iodine solution, topical anesthesia, eyelid-speculum application, and intravitreal injection of the medication via the pars plana in the inferotemporal quadrant 4 mm from the limbus in phakic eyes and 3.5 mm in pseudophakic eyes, followed by postoperative topical antibiotic eye drops.

All patients underwent clinic-based BCVA measurement at each visit. Spectral domain OCT (SD-OCT) and fluorescein angiography (FA) were performed at baseline using the Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany) to determine the type of CRVO (ischemic or non-ischemic), and SD-OCT was performed monthly thereafter. Retinal ischemia was assessed by FA every 3 months, or earlier at the physician’s discretion. Ischemic-type CRVO was defined as an area of retinal non-perfusion greater than 10 disk diameters, which could involve the periphery and/or the macula. Macular ischemia was defined as follows: 1) foveal avascular zone (FAZ) > 1000 μm, and 2) broken perifoveal capillary rings at the borders of the FAZ with distinct areas of capillary non-perfusion within one disk diameter of the foveal center in the transit phase of FA. In addition, the status of the ellipsoid zone and the type of macular edema (cystoid or diffuse) were recorded at each visit. The total number of injections was also recorded. The main outcomes included the mean change in BCVA and CST from baseline and the percentage of patients with resolution of edema (no SRF/IRF at the macula) at months 12 and 18.

Statistical analysis was performed using SPSS version 22.0 software (IBM Corp., Armonk, NY, USA). For the description of patient characteristics at baseline, mean ± standard deviation (SD) was used for continuous variables and counts with percentages for categorical variables. All variables were tested for normal distribution with the Kolmogorov–Smirnov test. Comparisons of the nominal variables between the two groups were carried out using the Student t test for independent samples or Mann–Whitney–Wilcoxon test, as appropriate. For categorical variables, chi-square or Fisher’s exact tests were performed. For longitudinal comparisons of BCVA and CST between baseline and each time point, the Wilcoxon matched-pairs signed-rank test was used; given that six comparisons were performed, the level of statistical significance was set at 0.05/6 = 0.008, according to the Bonferroni correction. A p value of <0.05 was considered significant, except for cases where the Bonferroni correction was adopted, as noted above.

Results

Table 1 shows the demographic and clinical characteristics of our study sample. The mean patients’ age was 64.8 ± 8.2 years in the ranibizumab group and 65.3 ± 6.3 years in the aflibercept group (p = 0.731), and 58.8% and 53.6% of patients were men, respectively (p = 0.215). In addition, 32.4% of patients in the ranibizumab group and 28.6% in the aflibercept group had previous open-angle glaucoma, controlled with eye drops (p = 0.108). Hypertension was present in 70.6% and 75% of patients in the ranibizumab and aflibercept groups, respectively (p = 0.089), and about 14.5% of patients in each group had diabetes mellitus without diabetic retinopathy (p = 0.912). Hyperlipidemia was present in 58.8% and 60.7% of those in the ranibizumab and aflibercept groups, respectively (p = 0.827). With regard to the type of CRVO, 23.5% of the patients in the ranibizumab group and 25% in the aflibercept group had the ischemic type at baseline (p = 0.787), while the duration of CRVO (according to patient reports) was less than 3 months in 73.5% of patients in the ranibizumab group and 75% in the aflibercept group (p = 0.615). None of the patients presented with neovascularization at baseline.

Table 1 Demographic and clinical characteristics of our study sample at baseline
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At baseline, the mean BCVA was 56.9 ± 8.4 ETDRS letters in the ranibizumab group and 55.3 ± 7.7 ETDRS letters in the aflibercept group (p = 0.268). Significant improvement in mean BCVA from baseline was shown by both groups at all time points (p < 0.0001 and p < 0.0001 for the ranibizumab and aflibercept groups, respectively), and no statistically significant difference was found between the groups at any time point except month 6, when BCVA was better in the ranibizumab group (66.2 ± 7.2 vs. 61.3 ± 7.3 letters, p = 0.007). Figure 1 shows the mean BCVA in each group at the various time points. There was no statistically significant difference between groups in the change in BCVA at either month 12 or month 18, with patients in the ranibizumab group gaining 9.0 letters and those in the aflibercept group 8.3 letters at month 12 (p = 0.765), and a gain of 7.9 letters and 7.5 letters in the ranibizumab and aflibercept groups at month 18, respectively (p = 0.881). At the 18-month follow-up, 35.3% (12/34) of patients in the ranibizumab group and 32.1% (9/28) of those in the aflibercept group had BCVA ≥6/12. It is also worth noting that at the end of follow-up (month 18), 50% of patients in the ranibizumab group and 42.9% in the aflibercept group had gained ≥10 letters, while a gain of ≥15 letters was demonstrated by 35.3% and 32.1% in the ranibizumab and aflibercept groups, respectively, as shown in Fig. 2.

Fig. 1
figure 1

Evolution of visual acuity in each group (ranibizumab and aflibercept) at baseline and months 1, 2, 3, 6, 12 and 18

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Fig. 2
figure 2

Percentage of patients in each group (ranibizumab and aflibercept) gaining ≥5, ≥10 and ≥15 letters at months 12 and 18

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The mean CST at baseline was 573.8 ± 132.3 μm in the ranibizumab group and 599.1 ± 123.7 μm in the aflibercept group (p = 0.325). Both groups demonstrated a significant reduction from baseline over the course of the study (p < 0.0001 for all comparisons). There was no statistically significant difference in CST between the two groups at any time point, although a slightly greater decrease in CST was shown at month 6 in the ranibizumab group (p = 0.078). Figure 3 illustrates the mean CST in each group over time. At month 12, the mean change in CST was −254.2 μm in the ranibizumab group and −241 μm in the aflibercept group, with no significant difference between groups (p = 0.753), while the mean change at month 18 was −233 μm and −234.6 μm in the ranibizumab and aflibercept groups, respectively (p = 0.917). At month 12, 19 of 34 patients (55.9%) in the ranibizumab group and 14 of 28 patients (50%) in the aflibercept group demonstrated complete resolution of macular edema. At month 18, complete resolution was seen in 50% and 42.9% of patients in the ranibizumab and aflibercept groups, respectively.

Fig. 3
figure 3

Evolution of central subfield thickness over time at baseline and months 1, 2, 3, 6, 12 and 18 in the two groups (ranibizumab and aflibercept)

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With regard to the type of macular edema, about 71% of the patients in each group had cystoid macular edema and 29% had diffuse macular edema at baseline (p = 0.742). Table 2 shows the evolution of macular edema over time. At the 12-month follow-up, cystoid macular edema was present in 23.5% and 28.6% of the ranibizumab and aflibercept groups, respectively, while about 21% of patients in each group had diffuse macular edema. At month 18, cystoid macular edema was evident in 26.5% of patients in the ranibizumab group and 28.6% of patients in the aflibercept group, while diffuse macular edema was present in 23.5% and 28.6%, respectively.

Table 2 Evolution of macular edema over time
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Ellipsoid zone disruption was observed in about 50% of patients in each group at baseline. At month 18, 26.4% of patients in the ranibizumab group and 25% in the aflibercept group showed disruption of the ellipsoid zone, reflecting a significant difference from baseline in both groups, but no significant difference between the two groups.

At baseline, 23.5% of patients in the ranibizumab group and 25% in the aflibercept group demonstrated retinal ischemia in an area greater than 10 disk diameters, which was located mainly at the peripheral retina, while macular ischemia was present in only one patient in the ranibizumab group. However, two additional patients, one in each group, progressed to ischemic-type RVO during the 18-month follow-up.

The mean number of injections over the 18-month period was 6.8 ± 1.3 and 6.1 ± 2.0 in the ranibizumab and aflibercept groups, respectively (p = 0.099). Of note, at the end of the follow-up (month 18), 41.2% of patients in the ranibizumab group and 46.4% in the aflibercept group needed further treatment with intravitreal injections due to persistent/recurrent macular edema, while three patients in each group discontinued treatment due to extensive ellipsoid zone disruption and macular ischemia.

No serious adverse ocular or systemic side effects, including intraocular pressure elevation, inflammatory reaction, endophthalmitis, retinal detachment, retinal tear, traumatic cataract or thromboembolic events, were reported from any of the patients in the study. Three patients (8.8%) in the ranibizumab group and two patients (7.2%) in the aflibercept group developed retinal neovascularization and received panretinal photocoagulation during the 18-month follow-up. All those patients had ischemic type of CRVO.

Discussion

This observational study included 62 treatment-naïve eyes with macular edema due to CRVO, treated with intravitreal injections of either ranibizumab or aflibercept in routine clinical practice. At the 18-month follow-up, both ranibizumab and aflibercept demonstrated a statistically significant improvement in BCVA compared to baseline, with no statistically significant difference between groups. Specifically, at 18 months, patients receiving ranibizumab and aflibercept showed a change of +7.9 and +7.4 ETDRS letters, respectively, with a similar number of injections. The two groups also exhibited a similar change in retinal thickness, and 50% of patients in the ranibizumab group and 42.9% in the aflibercept group showed complete resolution of macular edema at month 18.

Previous studies have examined the efficacy and safety of ranibizumab or aflibercept separately. The CRUISE study included 392 patients who had been diagnosed with macular edema due to CRVO within the prior 12 months. Patients were randomized 1:1:1 to receive six monthly intravitreal injections of 0.3 mg ranibizumab (n = 132), 0.5 mg ranibizumab (n = 130), or sham (n = 130), followed by a 6-month PRN period in which all patients could receive PRN ranibizumab retreatment if they met anatomical and functional retreatment criteria (CST ≥ 250 μm and BCVA ≤ 20/40). The 12-month results showed that patients in the ranibizumab group gained 13.9 letters, versus a gain of 7.3 letters in the sham group, suggesting that earlier treatment may lead to a greater functional improvement than delayed therapy. However, it should be noted that the CRUISE study did not include patients with ischemic CRVO [13].

Accordingly, the COPERNICUS study was a 2-year phase III multicenter, randomized, double-blind prospective study assessing the efficacy and safety of intravitreal aflibercept compared to sham injections in patients with macular edema due to CRVO. One hundred eighty-seven eyes were randomized in a 3:2 ratio to receive either 2 mg aflibercept (n = 114) or sham injections (n = 73) monthly for 6 months, with all patients receiving intravitreal injections of 2 mg aflibercept in a PRN regimen thereafter, according to specific retreatment criteria. The 1-year results showed a mean gain of 16.2 letters in the aflibercept group, while the sham treatment group gained only 3.8 letters. Of note, a subgroup analysis of ischemic and non-ischemic eyes showed a significant improvement in visual acuity in both groups in the aflibercept-treated eyes [16]. Similar results were observed in the GALILEO study, which had the same design as COPERNICUS but was conducted in Europe, and revealed a mean change in BCVA at 18 months of +13.7 and +6.2 letters in the aflibercept and sham groups, respectively, suggesting that patients with CRVO could benefit from early treatment with intravitreal aflibercept [18].

In our study, the change in BCVA from baseline to month 12 was +9.0 letters in the ranibizumab group and +8.3 letters in the aflibercept group, while at month 18 the change was +7.9 and +7.4 letters, respectively. These results were inferior to those reported for the pivotal CRUISE, COPERNICUS and GALILEO studies at both the 12- and 18-month follow-up. This difference may be explained in part by the fact that in our study, ischemic CRVO was present at baseline in 23.5% and 25% of patients in the ranibizumab and aflibercept groups, respectively, a higher percentage than that in the COPERNICUS and GALILEO studies, while the CRUISE study did not include ischemic cases at all. Farinha et al. also demonstrated worse functional outcome and larger final FAZ area in ischemic eyes with RVO [19]. This is in accordance with Sophie et al., who reported that retinal non-perfusion in patients with RVO may contribute to restricted visual gain over long-term follow-up [23]. However, in ischemic cases of CRVO, previous research suggests that intravitreal aflibercept is a promising alternative treatment for macular edema refractory to ranibizumab [24].

The superior outcomes in clinical trials compared to real-life data could also be attributable to the difference in treatment regimens: fixed-dose regimen of six monthly injections and PRN thereafter in clinical trials, compared to three monthly injections and PRN in our study. The mean numbers of injections in the CRUISE and COPERNICUS studies (fixed and PRN period) were 9.6 and 8.7, respectively, for the first year, whereas patients in our study received a mean 6.8 and 6.1 injections of ranibizumab and aflibercept, respectively, over 18 months. Our results are in line with those of Lotery and Regnier, who reported no difference between ranibizumab and aflibercept in the number of injections in the first year of treatment in routine clinical practice [25]. The CRYSTAL trial, however, showed that an “as-needed” medication regimen with frequent monitoring can also reduce the number of anti-VEGF injections needed to achieve and maintain good anatomic and functional outcomes, although the results presented were short-term [26]. Another possible reason for the discrepancy in outcomes between the clinical trials and the “real-life data” is that patients in the clinical trials were selected based on strict, specific criteria, while patients in daily practice were not subject to these stringent restrictions.

An interesting finding in our study was that the two treatment arms did not differ significantly with regard to the improvement in BCVA or reduction in CST across all time points of the follow-up. Our results are in line with those of the Protocol T study, which compared aflibercept and ranibizumab in patients with diabetic macular edema, and showed similar anatomical and functional results for the two medications [27]. It is worth noting that several studies have found that the VEGF load in RVO is much higher than in age-related macular degeneration or proliferative diabetic retinopathy. Therefore, it is possible that this higher VEGF load may cover the differences in anti-VEGF medications [28].

We also found a reduction in CST as well as in the percentage of cystoid macular edema in both groups. Notably, in cases where cystoid macular edema was present and was located in the outer retinal layers, there was an advanced disruption of the ellipsoid zone, leading to poor visual acuity. We postulated that the morphological changes at the microstructural level from chronic and recurrent edema may lead to irreversible photoreceptor damage [29, 30]. In addition, the cystoid type of edema has been associated with the disturbance of cell function and retinal architecture, resulting in retinal disorganization and affecting the ellipsoid zone and visual acuity to a greater extent than the diffuse type [29–31].

A potential limitation of the study is its retrospective nature and the relatively small sample size, which precluded meaningful sub-analysis of patients with ischemic CRVO. However, to our knowledge, this is the first study in the literature comparing ranibizumab and aflibercept for the treatment of macular edema due to CRVO in treatment-naïve patients, providing real-life data with 18-month follow-up. The strengths of the study also include the strict adherence to either ranibizumab or aflibercept monotherapy and the analysis of SD-OCT characteristics such as ellipsoid zone status. In addition, although the study was retrospective, the baseline characteristics of the two groups were balanced, showing that there was no selection bias.

In conclusion, our study showed similar efficacy for ranibizumab and aflibercept with regard to visual and anatomical outcomes in treatment-naïve patients with macular edema due to CRVO over an 18-month follow-up period, with a similar number of injections. There were no systemic adverse events, while 8.8% of patients in the ranibizumab group and 7.2% in the aflibercept group received panretinal photocoagulation due to the development of retinal neovascularization at the end of the follow-up. However, 41.2% of patients in the ranibizumab group and 46.4% of patients in the aflibercept group were found to need further treatment after the first year of follow-up due to persistent/recurrent macular edema, suggesting that patients with CRVO cannot be discharged and should be followed up periodically. Larger prospective studies are needed to validate our findings.