Retinal vein occlusion (RVO) is the second most prevalent retinal vascular disease, after diabetic retinopathy,1,2 3 2,4 5
Numerous studies have demonstrated the role of vascular endothelial growth factor (VEGF) in the development and persistence of macular edema.6,7 8,9 10,11
When an insufficient response is observed after treatment with one anti-VEGF therapy, switching to another therapy may be considered. This strategy is based on several reports,12–14
Aflibercept is a recombinant fusion protein consisting of the key human VEGF receptor extracellular domains from receptors 1 and 2 (VEGFR1 and VEGFR2) fused to the Fc domain of human IgG1. Aflibercept is hypothesized to be superior to both bevacizumab and ranibizumab owing to its higher binding affinity for VEGF-A and additionally to placental growth factors 1 and 2 (PlGF1 and PlGF2) and VEGF-B, and by having a longer half-life in the vitreous compared with ranibizumab.15
To further assess the efficacy of aflibercept as a further therapy option in RVO, we report clinical outcomes in RVO patients with lack or incomplete response to initial bevacizumab and/or ranibizumab treatment.
METHODS
Protocol/Inclusion and Exclusion Criteria
This is a retrospective clinical study conducted at a tertiary referral center, Sydney Retina. Ethics was approved by the University of Sydney local ethics committee and adhered to the tenets of the declaration of Helsinki. All patients provided informed consent. A treatment database of all patients attending the clinic between January 2015 and January 2017 requiring ongoing anti-VEGF therapy was reviewed. Patients who were switched to aflibercept from bevacizumab and/or ranibizumab were identified.
Inclusion criteria included eyes with a diagnosis of RVO, with recurrent or persistent edema on spectral domain optical coherence tomography (SD-OCT). Eyes must have received a minimum of 4 ranibizumab and/or bevacizumab injections in the preceding 6 months before switching to aflibercept. Eyes were excluded due to significant concomitant ocular pathology such as age-related macular degeneration, diabetic retinopathy, history of vitrectomy or intravitreal corticosteroids, and if <12 months of follow-up post switch was available.
On switching to aflibercept, all included eyes were treated with 3 monthly injections followed by a pro re nata regimen. Data collected on follow-up visits included corrected visual acuity (VA), intraocular pressure (IOP), and central foveal thickness (CFT) as measured with SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany). Progression scans utilizing eye and landmark tracking were undertaken to ensure accurate measurement of the same anatomical location.
Endpoints of the Study
The primary outcomes were the mean change in VA, CFT, and change in injection interval at 12 months’ post switch to aflibercept.
VA was performed using a Snellen chart with the patient's regular correction, where available, and complemented with pin-hole correction. Values were converted to ETDRS letter score for statistical analysis.
CFT was measured using the macular volume scans obtained on Spectralis OCT. A thickness map centered on the foveal centre using the ETDRS grid. CFT was defined as the distance between the inner limiting membrane and Bruch's membrane in the central 1-mm diameter area. Foveal thickness calculations were implemented using the manufacturer's built-in software (Spectralis Acquisition and Viewing Modules, version 6.0; Heidelberg Engineering). Segmentation lines were manually adjusted in the case of software error. Follow-up scans were obtained by use of the progression scanning tool.
Statistical Analyses
Statistical analysis was performed using SPSS software (version 24.0, IBM, Armonk, NY). Descriptive data were presented as means and standard deviation. Paired t test was used to compare outcome variables between baseline and follow up visits. Interobserver agreement was assessed using the interclass correlation coefficient.
Linear regression was used to assess the effects of age, number of injections, baseline BCVA on both BCVA, and CFT. A 95% confidence interval with 5% level of significance was adopted; thus, P values of <0.05 were considered to be statistically significant. Missing data were imputed using the last observation carried forward method. Treatment exposure and follow-up frequency were only analyzed in patients concluding the entire 12 months of the study.
RESULTS
Study Patients
A total of 27 eyes of 27 patients with macular edema secondary to RVO were identified. 13 eyes (n = 13) were classified as BRVO and 14 eyes as CRVO. Baseline characteristics of the 27 patients are summarized in Table 1 . 11 (n = 11) eyes were previously treated with bevacizumab alone, 1 patient was treated with ranibizumab alone, and 15 eyes had previous treatment with both bevacizumab and ranibizumab. Mean patient age was 73.2 ± 11.4 years. Before switching, patients had received a mean of 29.5 ± 19.2 injections over a mean period of 43.3 ± 33.3 months. 6 (43%) CRVO eyes were classified as ischemic CRVO.
TABLE 1: Baseline and Clinical Characteristics of Included Patients
A history of systemic hypertension was present in 21 (77.8%) of the patients, diabetes mellitus in 5 (18.5%), and hyperlipidaemia in 17 (62.3%). Baseline was defined as the first visit aflibercept was administered.
Visual and Anatomical Outcomes
Vision improved during the study from a mean of 54.2 ± 23.7 letters at baseline to 62.8 ± 19.4 letters at month 12 (P < 0.01). At 12 months, VA of 18 (67%) eyes improved by ≥5 letters and in 6 (22%) eyes VA improved by ≥15 letters. 3 (11%) eyes lost ≥1 letter. 3 (11%) eyes lost between 5 and 10 ETDRS letters, and 6 (22%) were stable compared with baseline.
Analysis by RVO subtype demonstrated a significant difference in VA at all time points. At baseline switch to aflibercept, those with CRVO had lost 6.1 letters from initiation of anti-VEGF treatment (Fig. 1 ). Those in the BRVO group had gained 10.4 letters since starting anti-VEGF therapy; however, in the 12 months immediately before switching (baseline), BRVO patients had lost 3.1 letters, and had persisting macular edema despite monthly intravitreal injections. Baseline VA in the BRVO group was 72.1 ± 7.6 letters, and 37.6 ± 21.3 letters in the CRVO group (P = 0.018). Eyes with BRVO gained 5.2 ± 5.7 letters at month 12 on average, compared with eyes with CRVO, which gained 11.7 ± 17.3 letters (P = 0.006).
FIGURE 1: Mean change in VA in ETDRS letters from baseline to 12 months’ post-switch to aflibercept. VA indicates visual acuity; ETDRS, early treatment of diabetic retinopathy score; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion.
Pre-treatment VA and at time of switch was not significantly different among CRVO perfusion status groups (ischemic vs non-ischemic, P = 0.567 and 0.968, respectively). Vision in eyes with ischemic CRVO improved by 14.8 ± 18.9 letters at month 12, compared with 9.4 ± 16.8 letters in eyes with nonischemic CRVO (P = 0.852) (Fig. 2 ).
FIGURE 2: Example of treatment resistant patient at baseline (A), month 1 (B), and month 12 (C).
There was a reduction in CFT from an average of 460.4 ± 178.2 μm at baseline to 279.5 ± 58.2 μm at month 12 (P < 0.01). This significant reduction in CFT was already apparent at 1 month [with mean reduction of 146.1 ± 171.5 μm (P < 0.01)] (Fig. 3 ).
FIGURE 3: Mean change in CFT in microns from baseline to 12 months’ post-switch to aflibercept. CFT indicates central foveal thickness; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion.
Eyes with CRVO had a greater anatomical reduction in CFT (Table 1 ). There was no difference in CFT reduction among perfusion status in CRVO subgroup (Fig. 4 ). 16 (59%) eyes had complete resolution of macular edema at month 12. 2 (2%) eyes showed chronic thinning of the neuroretina, and 11 eyes (46%) had attenuation of the ellipsoid zone. (Fig. 5 )
FIGURE 4: CRVO subgroup analysis -Mean change in VA in ETDRS letters from baseline to 12-months post-switch to aflibercept. CRVO indicates central retinal vein occlusion; VA, visual acuity; ETDRS, early treatment of diabetic retinopathy score.
FIGURE 5: CRVO subtype analysis. Mean change in CFT in microns from baseline to 12-months post-switch to aflibercept. CFT indicates central foveal thickness; CRVO, central retinal vein occlusion.
A multiple regression analysis was performed in which VA at 12 months was regarded as a dependent variable and the impact of the subsequent risk factors as resultant independent variables: extent of the RVO, hypertension, hyperlipidemia, and diabetes mellitus. A longer duration of RVO was associated with worse vision at 12 months after the switch (P < 0.001). This was repeated for analysis of CFT at 12 months, which indicated that those with RVO and hypertension have substantially thicker CFT (P < 0.001) than those without hypertension.
Treatment Intensity or Injection Frequency
Before baseline, patients had received a mean of 30 injections over a mean period of >3 years. The mean injection interval was 5 weeks preceding baseline. After switching to aflibercept, eyes had undergone a mean of 8.1 intravitreal injections over the 12-month study period, with a mean injection interval of 7 weeks, increasing the injection intervals by 1.6 ± 2.1 weeks (P = 0.18) (Table 1 ).
A significant correlation was found between CFT at time of switching and the total number of aflibercept injections required for resolution of macular edema (R 2 R 2
Safety Outcomes
No eyes in the study developed significant ocular or systemic complications such as endophthalmitis, uveitis, prolonged elevation of IOP, or vascular events.
DISCUSSION
This study has demonstrated that switching to intravitreal aflibercept after suboptimal response to bevacizumab and/or ranibizumab may lead to both anatomical and functional improvement in eyes with macular edema due to RVO. On average, there was an 8.7-letter improvement in vision with 70% of patients gaining at least 5 letters (one line). There was a corresponding reduction in CFT on average of 180.9 microns.
Although bevacizumab, ranibizumab, and aflibercept have shown similar efficacy in RVO,16–18 10,19
Numerous studies have investigated outcomes of aflibercept in cases of persistent macular edema despite previous bevacizumab or ranibizumab treatment in RVO,12–14,20–24 25
However, unlike the previously reported studies, this study included eyes switched late after on average >25 previous injections. Controlling edema earlier by switching earlier may be associated with a better visual outcome with lower prevalence of thinning of the neuroretina and ischemia, which is often noted in eyes with persistent macular edema.26,27
The outcomes presented here suggest that by switching anti-VEGF therapy to aflibercept in eyes with chronic disease, and persistent macular edema due to RVO, a prolongation of the treatment interval can be attained, and improvements in both functional and anatomical outcomes, despite extensive previous treatment. A spontaneous deterioration in the natural disease process of CME as expressed by Rogers et al28
Possible explanations for these findings may be aflibercepts’ higher binding affinity and the added binding to PlGF, compared with ranibizumab and bevacizumab.15 29 30
Functional and anatomic outcomes showed small but significant gains over the course of the 12-month study period after switching to aflibercept associated with the ability to extend injection intervals.
The main limitations of this study are its retrospective nature, absence of control group, small sample size, and limited follow-up period. Larger, longer, prospective clinical studies are required.
REFERENCES
1. Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study.
Transact Am Ophthalmol Soc 2000; 98:133–141. discussion 141-143.
2. Jaulim A, Ahmed B, Khanam T, Chatziralli IP. Branch retinal vein occlusion: epidemiology, pathogenesis, risk factors, clinical features, diagnosis, and complications. An update of the literature.
Retina 2013; 33:901–910.
3. Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia.
Ophthalmology 2010; 117:313–319. e311.
4. Parodi MB, Bandello F. Branch retinal vein occlusion: classification and treatment.
Ophthalmologica 2009; 223:298–305.
5. Wykoff CC, Brown DM, Croft DE, Major JC Jr, Wong TP. Progressive retinal nonperfusion in ischemic central retinal vein occlusion.
Retina 2015; 35:43–47.
6. Pai SA, Shetty R, Vijayan PB, et al. Clinical, anatomic, and electrophysiologic evaluation following intravitreal bevacizumab for macular edema in retinal vein occlusion.
Am J Ophthalmol 2007; 143:601–606.
7. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator.
Mol Ther 2008; 16:791–799.
8. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study.
Ophthalmology 2011; 118:1594–1602.
9. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study.
Ophthalmology 2011; 118:2041–2049.
10. Rhoades W, Dickson D, Nguyen QD, Do DV. Management of macular edema due to central retinal vein occlusion—the role of aflibercept.
Taiwan J Ophthalmol 2017; 7:70–76.
11. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study.
Ophthalmology 2010; 117:1102–1112. e1101.
12. Konidaris V, Al-Hubeshy Z, Tsaousis KT, Gorgoli K, Banerjee S, Empeslidis T. Outcomes of switching treatment to aflibercept in patients with macular oedema secondary to central retinal vein occlusion refractory to ranibizumab.
Int Ophthalmol 2018; 38:207–213.
13. Papakostas TD, Lim L, van Zyl T, et al. Intravitreal aflibercept for macular oedema secondary to central retinal vein occlusion in patients with prior treatment with bevacizumab or ranibizumab.
Eye (Lond) 2016; 30:79–84.
14. Pfau M, Fassnacht-Riederle H, Becker MD, Graf N, Michels S. Clinical outcome after switching therapy from ranibizumab and/or bevacizumab to aflibercept in central retinal vein occlusion.
Ophthalm Res 2015; 54:150–156.
15. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab.
Angiogenesis 2012; 15:171–185.
16. Scott IU, Figueroa MJ, Oden NL, Ip MS, Blodi BA, VanVeldhuisen PC. SCORE2 Report 5: vision-related function in patients with macular edema secondary to central retinal or hemiretinal vein occlusion.
Am J Ophthalmol 2017; 184:147–156.
17. Wang JK, Su PY, Hsu YR, Chen YJ, Chen FT, Tseng YY. Comparison of the efficacy of intravitreal aflibercept and bevacizumab for macular edema secondary to branch retinal vein occlusion.
J Ophthalmol 2016; 2016:8421940.
18. Lotery AJ, Regnier S. Patterns of ranibizumab and aflibercept treatment of central retinal vein occlusion in routine clinical practice in the USA.
Eye (Lond) 2015; 29:380–387.
19. Scott IU, VanVeldhuisen PC, Ip MS, et al. Effect of bevacizumab vs aflibercept on visual acuity among patients with macular edema due to central retinal vein occlusion: the SCORE2 randomized clinical trial.
JAMA 2017; 317:2072–2087.
20. Wirth MA, Becker MD, Graf N, Michels S. Aflibercept in branch retinal vein occlusion as second line therapy: clinical outcome 12 months after changing treatment from bevacizumab/ranibizumab-a pilot study.
Int J Retina Vitreous 2016; 2:20.
21. Eadie JA, Ip MS, Kulkarni AD. Response to aflibercept as secondary therapy in patients with persistent retinal edema due to central retinal vein occlusion initially treated with bevacizumab or ranibizumab.
Retina 2014; 34:2439–2443.
22. Lehmann-Clarke L, Dirani A, Mantel I, Ambresin A. The effect of switching ranibizumab to aflibercept in refractory cases of macular edema secondary to ischemic central vein occlusion.
Klin Monbi Augenheilkd 2015; 232:552–555.
23. Tagami M, Sai R, Fukuda M, Azumi A. Prolongation of injection interval after switching therapy from ranibizumab to aflibercept in Japanese patients with macular edema secondary to branch retinal vein occlusion.
Ophthalmol 2017; 11:403–408.
24. Cohen MN, Houston SK, Juhn A, et al. Effect of aflibercept on refractory macular edema associated with central retinal vein occlusion.
Can J Ophthalmol 2016; 51:342–347.
25. Spooner K, Hong T, Bahrami B, Chang A. A meta-analysis of patients with treatment-resistant macular oedema secondary to retinal vein occlusions following switching to aflibercept.
Acta Ophthalmol 2019; 97:15–23.
26. Podkowinski D, Philip AM, Vogl WD, et al. Neuroretinal atrophy following resolution of macular oedema in retinal vein occlusion.
Br J Ophthalmol 2019; 103:36–42.
27. Kim CS, Shin KS, Lee HJ, Jo YJ, Kim JY. Sectoral retinal nerve fiber layer thinning in branch retinal vein occlusion.
Retina 2014; 34:525–530.
28. Rogers SL, McIntosh RL, Lim L, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review.
Ophthalmology 2010; 117:1094–1101. e1095.
29. Christoforidis JB, Williams MM, Kothandaraman S, Kumar K, Epitropoulos FJ, Knopp MV. Pharmacokinetic properties of intravitreal I-124-aflibercept in a rabbit model using PET/CT.
Curr Eye Res 2012; 37:1171–1174.
30. Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab.
Retina 2017; 37:1847–1858.
