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ORIGINAL ARTICLE
Year : 2021  |  Volume : 24  |  Issue : 12  |  Page : 1824-1827

Results of the switch from intravitreal ranibizumab to intravitreal aflibercept therapy in patients with neovascular age-related macular degeneration: A 42-month retrospective real-world study


1 Department of Ophthalmology, Gaziosmanpaşa Training Hospital, İstanbul, Turkey
2 Department of Ophthalmology, Afyon University of Health Sciences, Afyonkarahisar, Turkey
3 Department of Ophthalmology, Bafra State Hospital, Samsun, Turkey

Date of Submission28-Dec-2020
Date of Acceptance22-Jun-2021
Date of Web Publication09-Dec-2021

Correspondence Address:
Dr. E Ertan
Department of Ophthalmology, Gaziosmanpaşa Training Hospital, İstanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_696_20

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   Abstract 


Aim: The study aimed to evaluate the functional and anatomical results of patients treated with intravitreal ranibizumab (IVR) for neovascular age-related macular degeneration (n-AMD) but switched to intravitreal aflibercept (IVA) treatment due to insufficient response treatment. Material and Methods: At least six doses of n-AMD were administered IVR to 33 patients who were switched to IVA treatment due to insufficient response and were included in the study. The patients were evaluated at the beginning of the IVR treatment during the transition to IVA treatment and at 6, 12, 18, 24, 30, 36, and 42 months of IVA treatment. Results: After an average of 10.1 ± 5.04 IVR injections, the patients who were accepted as insufficient response were treated with IVA. The central macular thickness of the patients was evaluated at the beginning of the treatment, immediately before, and after the initiation of IVA treatment at 6, 12, 18, 24, 30, 36, 42 months. It was as follows: 325.21 ± 123.04, 351.42 ± 126.09, 284.81 ± 112.65, 296.68 ± 89.17, 282.61 ± 81.58, 292.27 ± 109, 92,269.75 ± 97.14, 267.50 ± 87.56, and 266.82 ± 88.35 μm. According to the best-corrected visual acuity (BCVA), it was initially 0.89 ± 0.65; 1.08 ± 0.53 during the transition to IVA; 0.91 ± 0.46 6 months after IVA; 12th 1.14 ± 0.59; 0.94 ± 0.55 at 18th; 1.07 ± 0.49 at 24th; 1.15 ± 0.57 at 30th; 1.06 ± 0.45 at 36th, and 1.13 ± 0.46 LogMAR ( Logarithm of the Minimum Angle of Resolution) at the 42nd month. Conclusion: In conclusion, in n-AMD patients with inadequate response to intravitreal ranibizumab or with relapse, and therefore, switched to aflibercept treatment, the anatomical improvement and sustainment were observed, however, functional recovery could not be achieved.

Keywords: Aflibercept, age-related macular degeneration, ranibizumab, switch


How to cite this article:
Ertan E, Efe N, Sabaner M C, Dogan M. Results of the switch from intravitreal ranibizumab to intravitreal aflibercept therapy in patients with neovascular age-related macular degeneration: A 42-month retrospective real-world study. Niger J Clin Pract 2021;24:1824-7

How to cite this URL:
Ertan E, Efe N, Sabaner M C, Dogan M. Results of the switch from intravitreal ranibizumab to intravitreal aflibercept therapy in patients with neovascular age-related macular degeneration: A 42-month retrospective real-world study. Niger J Clin Pract [serial online] 2021 [cited 2022 Jan 25];24:1824-7. Available from: https://www.njcponline.com/text.asp?2021/24/12/1824/332087




   Introduction Top


Age-related macular degeneration (AMD) is one of the top causes of irreversible blindness among people aged 50 years or older worldwide.[1] In AMD, the growth of new choroidal vessels in the macula caused by vascular endothelial growth factor (VEGF) and vascular leakage may result in vision loss.[2] Severe visual loss may occur in the neovascular form of the disease consisting of abnormal development of new blood vessels under or within the central region of the retina. While the underlying pathological mechanisms of neovascularization are not fully clear, VEGF-A, which plays a role in angiogenesis and vascular permeability, has been associated with neovascularization.[3] Therefore, intravitreal administration of anti-VEGF agents has become the standard treatment for neovascular AMD (n-AMD).[4] Ranibizumab was the first to demonstrate the effectiveness of intravitreal anti-VEGF agents in n-AMD treatment. Monthly injections or pro re nata (PRN) ranibizumab treatment hindered visual loss and even increased visual acuity (VA) in some patients.[5] Compared to other anti-VEGF agents, aflibercept is a novel fusion protein that binds both the VEGF and placental growth factor.[6] Studies have shown that an aflibercept injection every 8 weeks and monthly ranibizumab treatment maintain similar VA.[7] One meta-analysis showed that aflibercept yielded positive anatomical results in patients resistant to previous treatments with other anti-VEGF agents.[8] Although the treatment protocols varied among different studies, monthly injection fixed-interval treatment protocol or PRN injections upon active symptoms were implemented in most of the prior studies.[5],[9],[10] In this study, visual and anatomical outcomes of switching from ranibizumab to aflibercept therapy were measured in patients with n-AMD at 42 months.


   Material and Methods Top


Medical records of all patients diagnosed with n-AMD who were treated at our hospital, a tertiary care clinic, retina center, between January 2014 and June 2019 were retrospectively reviewed. Patients with a known diagnosis of n-AMD who were resistant to intravitreal ranibizumab injection with PRN regimen and switched to aflibercept treatment were included in the study.

Inclusion criteria for our study were as follows: Presence of n-AMD previously treated with intravitreal ranibizumab which was switched to intravitreal aflibercept, persistent intraretinal or subretinal fluid, minimum of six ranibizumab injections with PRN regimen before the transition, a final injection of ranibizumab 28–35 days within switching to aflibercept, and at least 42 months of follow-up after switching to aflibercept.

Exclusion criteria were as follows: History of vitrectomy, choroidal neovascularization (CNV) lesions secondary to causes other than AMD; the presence of −6.00 D or greater myopia; and uncontrolled glaucoma, uveitis, or any other ocular disease that could potentially confound the assessment of safety and/or efficacy of treatment.

The study included a total of 33 eyes of 33 patients. The presence of resistant and/or recurrent subretinal and/or intraretinal fluid was accepted as the indication for transition to aflibercept despite at least six doses of ranibizumab. During the monthly follow-up period, the patients underwent complete ophthalmologic examinations including best-corrected visual acuity (BCVA) with using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, intraocular pressure (IOP) measurement, fundus examination, and spectral-domain optical coherence tomography (SD-OCT, Heidelberg Spectralis, Heidelberg Engineering, Heidelberg, Germany) scanning.

After switching from ranibizumab (IVR), all the patients received a loading dose of three monthly aflibercept injections (IVA) (2 mg/0.05 mL), and received a monthly follow-up. Retreatment with a single aflibercept injection was performed according to any of the following: VA loss of at least five letters with SD-OCT evidence of fluid in the macula, persistent or recurrent intraretinal or subretinal fluid in SD-OCT, or new subretinal hemorrhage from CNV.

The demographic characteristics of the patients were recorded. The main outcomes of the study were variations of BCVA and central macular thickness (CMT) after switching to aflibercept at months 0, 6, 12, 18, 30, 36, and 42 and the frequency of aflibercept injections.

SPSS version 18.0 (Chicago, USA) statistical package program was used for data analysis. Shapiro–Wilk's test was used to assess the distribution of the variables. Paired t-test was used to compare the parametric data measured before and during the injections. Wilcoxon 2-Related samples test was used to compare the nonparametric measurements obtained before and during the injections. Spearman's test was used to determine the correlations between the changes in the CMT, BCVA, and the number of injections at the end of 42 months. Evaluations were made at a 95% confidence interval, and P < 0.05 was considered statistically significant.

Our study obtained ethics approval from the Afyon Kocatepe University, Clinical Research Ethical Committee (2011-253) and was conducted in accordance with the Declaration of Helsinki. All the study participants provided informed written consent.


   Results Top


The inclusion criteria were met by 33 eyes. The mean patient age was 71.57 ± 7.98 years (61–89 years) [Table 1]. In total, 21 (63%) patients were males and 12 (37%) were females. After mean 10.1 ± 5.04 IVR injections, patients considered to have insufficient response were switched to IVA. CMT was measured at the start of the treatment and immediately before and after the initiation of IVA treatment at 6, 12, 18, 24, 30, 36, and 42 months as follows: 325.21 ± 123.04, 351.42 ± 126.09, 284.81 ± 112.65, 296.68 ± 89.17, 282.61 ± 81.58, 292.27 ± 109.92, 269.75 ± 97.14, 267.50 ± 87.56, and 266.82 ± 88.35 μm, respectively [Table 2]. BCVA LogMAR was initially 0.89 ± 0.65, 1.08 ± 0.53 during the transition to IVA, 0.91 ± 0.46 6 months after IVA; 1.14 ± 0.59 at 12 months, 0.94 ± 0.55 at 18 months, 1.07 ± 0.49 at 24 months, 1.15 ± 0.57 at 30 months, 1.06 ± 0.45 at 36 months, and 1.13 ± 0.46 at 42 months.
Table 1: Demographics of the study groups

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Table 2: Central macular thickness and best-corrected visual acuity parameters analysis between measurements

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There was no correlation between the changes in CMT and the number of injections (P = 0.878, r = -0.029), changes in BCVA and number of injections (P = 0.875, r = 0,029), or changes in CMT and BCVA (P = 0.321, r = 0.184) at the end of 42 months compared to the start of the treatment.

Systemic complications such as cardiovascular or cerebrovascular events or ocular complications such as endophthalmitis, vitreous hemorrhage, retinal detachment, or sustained IOP increase were not observed throughout the study period.


   Discussion Top


Within the scope of the study, n-AMD patients with insufficient response to ranibizumab were switched to intravitreal aflibercept treatment in which macular anatomical improvement was preserved or sustained throughout the 42-month follow-up period. At the end of 42 months, VA decreased while the anatomical structure was preserved. However, there was no correlation between improvement in VA and anatomical improvement. Similar to our results, Spooner et al.[11] and Cardoso et al.[12] observed a significant anatomical effect, resulting in CRT thinning, but found no association with VA improvement. Other studies have demonstrated positive anatomical results in the eyes that were resistant to other anti-VEGF treatments and switched to aflibercept.[13],[14],[15] Aflibercept also binds Placental growth factor (PlGF) and shows a greater binding affinity to VEGF compared to other anti-VEGF agents, which may be one of the reasons behind this positive effect.[6] In addition, repeated bevacizumab or ranibizumab injections have been shown to cause immunoreactivity against mouse-derived humanized monoclonal antibodies and/or loss of therapeutic effect and tachyphylaxis. The treatment can be interrupted for a short time in order to regain drug efficacy.[16],[17] Switching to aflibercept may also improve contrast sensitivity as well as vision-related quality of life despite the lack of changes in BCVA.[18] Long-term ranibizumab therapy may also lead to tolerance, which may also reduce drug efficacy over time, however, unlike tachyphylaxis, efficacy is not recoverable by discontinuation of treatment.[19] In our study, as in other studies, that achieved similar results, one of the advantages of aflibercept was that the average number of injections used in the aflibercept treatment was lower than in the ranibizumab treatment in the same period.[20],[21] According to the results of the studies, there is no consensus on the impact of switching from ranibizumab to aflibercept treatment on VA.[15],[22],[23] Long-term ranibizumab treatment risks of geographic atrophy, chronic structural changes in the macula, and loss of foveal photoreceptors may be the reasons causing inconsistency between anatomical and visual outcomes.[24] Controlling the formation of CNV-induced intraretinal or subretinal fluid with IVA injections, and persistence of injections may have affected CMT values at the 42-month follow-up. We believe that functional improvement is unassociated with anatomical improvement due to CNV-induced scar formation, and therefore, there is no correlation between the number of injections and BCVA. The safety of aflibercept has been well-established and has not shown inferiority to ranibizumab.[7] Significant incidences of adverse events that may be associated with aflibercept were not observed. The limitations of our study may be considered to be the lack of a control group and the lower number of patients. A long-term follow-up of the patients is vital for contributing in a study. Incomplete response to anti-VEGF therapy demonstrates the multifactorial pathophysiology of AMD. The refractory quality of these eyes may be reflected by the lack of sustained visual improvement, and the chronic disease course may be manifested as a ceiling effect of anti-VEGF therapy.


   Conclusion Top


In conclusion, in n-AMD patients with inadequate response to intravitreal ranibizumab or with relapse, and therefore switched to aflibercept treatment, anatomical improvement, and sustainment were observed, however, functional recovery could not be achieved.

Ethical approval

The study adhered to the tenets of the Declaration of Helsinki. Local ethics committee of clinical research approved the study protocol.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Frank RN, Amin RH, Eliott D, Puklin JE, Abrams GW. Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am J Ophthalmol 1996;122:393-403.  Back to cited text no. 3
    
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Seguin-Greenstein S, Lightman S, Tomkins-Netzer O. A meta-analysis of studies evaluating visual and anatomical outcomes in patients with treatment resistant neovascular age-related macular degeneration following switching to treatment with aflibercept. J Ophthalmol 2016;2016:4095852.  Back to cited text no. 8
    
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Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group; Martin DF, Maguire MG, Fine SL, Ying G-S, Jaffe GJ, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: Two-year results. Ophthalmology 2012;119:1388-98.  Back to cited text no. 9
    
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Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet 2013;382:1258-67.  Back to cited text no. 10
    
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Spooner K, Hong T, Wijeyakumar W, Chang AA. Switching to aflibercept among patients with treatment-resistant neovascular age-related macular degeneration: A systematic review with meta-analysis. Clin Ophthalmol 2017;11:161-77.  Back to cited text no. 11
    
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Cardoso PN, Pinheiro AF, Meira J, Pedrosa AC, Falcão MS, Pinheiro-Costa J, et al. Switch to aflibercept in the treatment of neovascular AMD: Long-term results. J Ophthalmol 2017;2017:6835782.  Back to cited text no. 12
    
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Chang AA, Li H, Broadhead GK, Hong T, Schlub TE, Wijeyakumar W, et al. Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration. Ophthalmology 2014;121:188-92.  Back to cited text no. 13
    
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Singh RP, Srivastava S, Ehlers JP, Bedi R, Schachat AP, Kaiser PK. A single-arm, investigator-initiated study of the efficacy, safety and tolerability of intravitreal aflibercept injection in subjects with exudative age-related macular degeneration, previously treated with ranibizumab or bevacizumab: 6-month interim analysis. Br J Ophthalmol 2014;98(Suppl 1):i22-7.  Back to cited text no. 14
    
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Jørstad ØK, Faber RT, Moe MC. Two-year functional and anatomical results after converting treatment resistant eyes with exudative age-related macular degeneration to aflibercept in accordance with a treat and extend protocol. Acta Ophthalmol 2017;95:460-3.  Back to cited text no. 15
    
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Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009;29:723-31.  Back to cited text no. 16
    
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Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 2008;115:2199-205.  Back to cited text no. 17
    
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Nixon DR, Flinn NA. Evaluation of contrast sensitivity and other visual function outcomes in neovascular age-related macular degeneration patients after treatment switch to aflibercept from ranibizumab. Clin Ophthalmol 2017;11:715-21.  Back to cited text no. 18
    
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Binder S. Loss of reactivity in intravitreal anti-VEGF therapy: Tachyphylaxis or tolerance? Br J Ophthalmol 2012;96:1-2.  Back to cited text no. 19
    
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Fassnacht-Riederle H, Becker M, Graf N, Michels S. Effect of aflibercept in insufficient responders to prior anti-VEGF therapy in neovascular AMD. Graefes Arch Clin Exp Ophthalmol 2014;252:1705-9.  Back to cited text no. 20
    
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Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol 2014;98:1636-41.  Back to cited text no. 21
    
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Arcinue CA, Ma F, Barteselli D, Sharpsten L, Gomez ML, Freeman WR. One-year outcomes of aflibercept in recurrent or persistent neovascular age-related macular degeneration. Am J Ophthalmol 2015;159:426-36.  Back to cited text no. 22
    
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Pinheiro-Costa J, Costa JM, Beato JN. Switch to aflibercept in the treatment of neovascular AMD: One-year results in clinical practice. Ophthalmologica 2015;233:155-61.  Back to cited text no. 23
    
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Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: Two-year results. Ophthalmology 2012;119:1388-98.  Back to cited text no. 24
    



 
 
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