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 Table of Contents  
Year : 2019  |  Volume : 9  |  Issue : 4  |  Page : 249-254

Real-world outcomes of intravitreal antivascular endothelial growth factors for neovascular age-related macular degeneration in Taiwan: A 4-year longitudinal study

1 College of Medicine, National Taiwan Universtiy, Taipei, Taiwan
2 College of Medicine, University of Queensland, Brisbane, Australia
3 Department of Ophthalmology, Changhua Christian Hospital, Changhua; College of Medicine, Chung-Shan Medical University, Taichung, Taiwan

Date of Submission02-Apr-2019
Date of Acceptance04-Aug-2019
Date of Web Publication13-Dec-2019

Correspondence Address:
Dr. San-Ni Chen
Department of Ophthalmology, Changhua Christian Hospital, No. 135, Nan-Hsiao Street, Changhua City
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1027-8117.271504

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PURPOSE: The purpose of the study is to report the long-term efficacy of patients with neovascular age-related macular degeneration (nAMD) treated with antivascular endothelial growth factor (VEGF) in Changhua Christian Hospital in Taiwan.
MATERIALS AND METHODS: Retrospective case series of patients with nAMD who were treated with intravitreal injection (IVI) of anti-VEGF and had a minimum follow-up of 48 months. Every patient was initially treated with three loading doses of either bevacizumab or ranibizumab, followed by a loose treat and extend regimen. Eyes were divided into two groups according to whether aflibercept was later used as a rescue therapy (Group 2) or not (Group 1). Patients underwent best-corrected visual acuity (BCVA) testing, optical coherence tomography, and ophthalmic examination at baseline and all the scheduled follow-up visits.
RESULTS: Seventy eyes in 63 patients were included (mean age 70.54 ± 9.18 years). The mean number of IVIs per year was 5.28 ± 1.36. The mean BCVA in logarithm of the minimal angle of resolution (logMar) improved from 0.89 ± 0.45 to 0.72 ± 0.49 for all patients (P = 0.004). Significant visual improvement was noted in Group 1 (P = 0.01) at 4 years of follow-up, but not in Group 2 (P = 0.16). Patients with initial poor BCVA (LogMar visual acuity >1.0), and older age (>70 years) had significant visual improvement, in contrast to no significant visual changes in patients with younger age and initial better BCVA.
CONCLUSION: Under a loose treat and extend protocol and rescue therapy of aflibercept, BCVA improvement was maintained for 4 years in patients with nAMD, especially in the older population (Registration Number: NCT03324542).

Keywords: Aflibercept, age-related macular degeneration, bevacizumab, long term efficacy, ranibizumab

How to cite this article:
Yang BC, Chou TY, Chen SN. Real-world outcomes of intravitreal antivascular endothelial growth factors for neovascular age-related macular degeneration in Taiwan: A 4-year longitudinal study. Taiwan J Ophthalmol 2019;9:249-54

How to cite this URL:
Yang BC, Chou TY, Chen SN. Real-world outcomes of intravitreal antivascular endothelial growth factors for neovascular age-related macular degeneration in Taiwan: A 4-year longitudinal study. Taiwan J Ophthalmol [serial online] 2019 [cited 2020 Sep 28];9:249-54. Available from: http://www.e-tjo.org/text.asp?2019/9/4/249/271504

  Introduction Top

Neovascular age-related macular degeneration (nAMD) is one of the most common disorders that cause irreversible blindness in the senior population in the developed world.[1] If left untreated, the patients may experience gradual central visual impairment and metamorphopsia which could severely affect their quality of life. However, with the development and application of intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF), the visual prognosis of nAMD has been greatly improved.[2] Currently, there are three commonly prescribed anti-VEGF agents.[3],[4],[5],[6],[7],[8] Aflibercept (Eylea; Regeneron Pharma, Tarrytown, NY, USA; Bayer, Basel, Switzerland), ranibizumab (Lucentis; Novartis Pharma, Basel, Switzerland; Genentech, South San Francisco, CA, USA), and bevacizumab (Avastin; Genentech). Generally speaking, the binding affinity of VEGF is stronger in aflibercept than in ranibizumab and bevacizumab.[8],[9] Previous studies have shown that aflibercept may be effective in eyes resistant to ranibizumab or bevacizumab.[10]

Although the studies of the 2 years results of anti-VEGF agents showed great efficacy in improving vision in nAMD,[7],[11] the visual outcome of the long-term treatment was inconsistent.[12],[13],[14],[15],[16],[17],[18] Besides, studies about the long-term efficacy in Asians were limited.[13],[14] In this retrospective study, we aim to investigate the 4 years result of nAMD treated with anti-VEGF agents in Taiwan.

  Materials and Methods Top

A retrospective, interventional, case series analysis o of patients with nAMD treated at the Ophthalmology Department at Changhua Christian Hospital, for at least 4 years was conducted. The study was approved by the Institutional Review Board of Changhua Christian Hospital (IRB aproval date is 2018/2/25; IRB approval number is cch-171009) and was adhered to the tenets of the Declaration of Helsinki. Only patients who were both treatment naive upon the initial visit and fulfilled the reimbursement criteria set by the Taiwan National Health Insurance Bureau (NHIB) for subsidized ranibizumab were included.

Ranibizumab has been reimbursed for the treatment of nAMD by the Taiwan NHIB since 2012, with a total reimbursement of three or seven injections for each eye depending on the clinical response of the patient in his or her lifetime, after which, the treatment is paid by the patients themselves. To be reimbursed by the NHIB, patients must be at least 50 years old at the time of diagnosis and had nAMD confirmed by fluorescein angiography (FA), with subretinal fluid or macular edema demonstrated by optical coherence tomography (OCT). In addition, there should be no macular scars on the fovea, and the best-corrected decimal visual acuity (BCVA) should be ranged from 0.05 to 0.5. The waiting period for the permission of reimbursement of ranibizumab was around 4 weeks, thus some patients would have a self-paid bevacizumab injection during the waiting period.

All eyes included in this study had both FA and indocyanine green angiography performed. After receiving an initial loading dose of 3 monthly IVIs of either ranibizumab or bevacizumab, the treatment was made on a loose treat and extend protocol based on the funduscopic examination, OCT findings, and BCVA. The loose treat and extend protocol is as follows: if under examination, there is resolution of macular edema and subretinal fluid by OCT, plus no retinal hemorrhage by biomicroscopy with 90D lens and a stabilized BCVA for two successive visits, the next treatment and follow-up were extended by 1 month. If the examination showed any signs of recurrence and the deterioration of visual acuity (VA) equal or more than one line, the treatment injection interval was then shortened by 1 month. Most, but not all, of our patients followed the above loose treat and extend strategy since some patients would insist on following up and treatment with less frequency in spite of disease activity. Generally speaking, the patients' follow-up interval and dosing schedule are made to be equal to or less frequent than a bimonthly basis after 1 year, even though there are signs of neovascular activity; either because of the economic burden or the fear of the surgical procedures of IVI by the patients. Aflibercept was considered when the patient had persistent subretinal fluid and macular edema despite of a bi-monthly injection of ranibizumab or bevacizumab for two times or more of visits. Patients had BCVA measured, along with funduscopic examination with 90D lens and OCT imaging with spectralis-OCT (Heidelberg Engineering, Heidelberg, Germany) at each visit.

Patients were divided into two groups based on whether aflibercept was later used as a rescue therapy. Group 1 received bevacizumab and ranibizumab only. Group 2 received bevacizumab, ranibizumab, and later aflibercept rescue therapy. Outcome measures include BCVA at 1, 2, 3, and 4 years of follow-up, and the average number of injections per year.

Statistical analysis

The BCVA obtained during each visit was converted from decimal to logarithm of the minimum angle of resolution (logMar) for calculation. Chi-square test was used to compare the baseline data, including age, sex, and eye. Mann–Whitney U-test was used to compare the difference of age, and average number of injections per year between the two groups. Mann–Whitney U-test, Wilcoxon test, and independent t-test were used for the comparison of BCVA at different time points in each group. Patients were also divided according to their initial BCVA (>1.0 or ≤1.0 in logMar) or age (>70 or ≤70 years of age) to see whether initial BCVA or age play a role in the visual changes. P < 0.05 was accepted as statistically significant. All the analyses were performed using SPSS software package (version 23.9; SPSS Inc., Chicago, IL, USA).

  Results Top

A total of 70 eyes of 63 patients (male: female = 39:24) with the mean age of 70.54 ± 9.18 years old were included in this study. The mean duration of follow-up is 5.53 ± 1.58 years. There were 28 patients in Group 1 and 35 patients in Group 2. Eighteen eyes in Group 2 had aflibercept injection as the rescue therapy within the 1st year, 12 eyes in the 2nd year, and five eyes beyond the 2 years. The proportion of male patients was similar between the two groups (46.2% vs. 53.8%). No difference in age, sex, and eye; lens status; mean number of IVI for each year; and duration of follow-up were noted between the two Groups. Statistically higher proportion of eyes having polypoidal choroidal vasculopathy (PCV) in Group 2 (P = 0.047). Regarding to VA, significant better initial VA was noted in Group 2 (P = 0.004). However, no difference of VA was noted between the two groups thereafter. Demographic data of patients and the comparison of baseline characteristics between different study groups were listed in [Table 1].
Table 1: Demographic data of patients and comparison of the baseline characteristics in different study groups

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There were eight eyes in eight patients, all of them in Group 2, who did not follow the treat and extend strategy, which means that when the treatment interval was extended to 3 months or beyond, though the subretinal fluid appeared, those patients insisted on not to shorten the duration for next treatment and rather stayed on a fixed dosing regimen (every 3 or 4 months). The average number of injection for those patients is fewer to that of the whole patient group (3.777 ± 1.023 injections/year). The initial and final VA in this particular population is 0.742 ± 0.512 and 0.881 ± 0.312 in logMar, respectively.

Significant better BCVA as compared to initial BCVA was noted throughout all the 4 years in the whole patient group and in Group 1. However, significant better BCVA was not maintained at 4 years of follow-up in eyes in Group 2 [Table 2]. [Figure 1] shows the distribution of logMar VA from baseline and each subsequent yearly time point. [Figure 2] shows the changes of logMar VA during the 4 years of follow-up.
Table 2: Comparison of visual acuity in logarithm of minimal angle of resolution between the initial point and at different time points in all groups

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Figure 1: Distribution of best-corrected visual acuity in logarithm of minimal angle of resolution from baseline to each subsequent yearly time point

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Figure 2: Changes of best-corrected visual acuity in logarithm of minimal angle of resolution visual acuity during the 4 years of follow-up

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Patients with better initial logMar BCVA (logMar VA ≤1.0) showed only significant visual improvement at 1-year follow-up, after which, the VA gradually declined and became worse than the initial VA at 4 years of follow-up. In contrast, eyes with worse initial logMar BCVA (logMar VA >1.0) had significant VA improvement, which was maintained till 4 years of follow-up [Table 3].
Table 3: Comparison of the initial best-corrected visual acuity and best-corrected visual acuity at different time points in eyes with initial visual acuity in logarithm of minimal angle of resolution >1.0 or ≤1.0

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As for age, there were 15 eyes in the younger age group (total 26 eyes) and 15 eyes in the older age group (total 44 eyes) had PCV subtype (P = 0.012). Patients with age equal or younger than 70 years of age showed no difference in VA at 4 years of follow-up as compared to the baseline VA. In contrast, patients with age >70 years of age showed significant better VA at 4 years. After further stratifying the patients by the initial VA in logMar (>1.0, or ≤1.0), only patients in the older age group with initial worse VA had significant VA improvement at 4 years of follow-up [Table 4].
Table 4: Comparison of overall best-corrected visual acuity progression between different age groups and stratified with initial visual acuity in logarithm of minimal angle of resolution >1.0 and ≤1.0

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In considering the effect of the rescue therapy of aflibercept in Group 2 eyes, significant visual improvement after shifting medication to aflibercept was noted. After stratifying patients by age, only patients older than 70 years of age had significant visual improvement after rescue therapy. In comparison, the BCVA progression for patients younger than 70 years old seemed were only stabilized after rescue therapy with aflibercept [Table 5]. The mean duration from the initiation of therapy with ranibizumab or bevacizumab to the shifting to aflibercept is 18.94 ± 11.18 months. Nine eyes had the shifting within the 1st year, 16 eyes in the 2nd year, and 10 eyes beyond the 2nd year. Using logistic regression, we found that age (β = 0.221, 95% confidence interval [CI]: 0.001–0.023) and initial BCVA (β = 0.464, 95% CI: 0.285–0.747) were showed significant association with VA improvement. Moreover, multicollinearity diagnostics showed that age and initial BCVA were independent risk factor for VA improvement.
Table 5: Comparison of overall best-corrected visual acuity progression before and after shifting to aflibercept in Group 2 eyes and stratified by age

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  Discussion Top

Up to now, reports about the long-term efficacy of anti-VEGF agents in nAMD varied a lot. The 5-year outcomes of CATT trial demonstrated that the visual gained during the first 2 years were not maintained at 5 years with any type of anti-VEGF agents, no matter in eyes with fixed dosing in the first 2 years and later Pro re nata (PRN) or in eyes with PRN dosing after the initial three loading doses, but overall, patients still had a better prognosis than the era before anti-VEGF therapy.[18] In contrast, another study with a fixed dosing regimen throughout a 7-year period and average annual injection number of 10.5 had visual gain of 12.1 letter at the end of follow-up.[12] However, in real life, very few patients can tolerate monthly injection either because of the economic burden of the medications or the intolerance to a frequent surgical procedure of IVI. Thus, treat and extend regimen has been advocated.[19] On the other hand, for patients who have insufficient response even with a frequent dosing, shifting to another anti-VEGF agent with stronger binding affinity may help improve the visual prognosis.[8]

In our retrospective study, the results showed that, concurrent to previous studies, maximal visual gain appeared to be within the 1st year of injection and gradually declined over time [Table 2]. Also in line with previous reports, our results showed that eyes with a worse initial VA had better visual improvement till 4 years of follow-up without decline. This phenomenon has been explained by the ceiling effect in eyes with better initial VA.[20] To our surprise, in our study, it seemed that patients with older age responded better to anti-VEGF, which is different from previous reports from Western countries.[21],[22] This may be explained by that the mean initial VA in the older age group is worse, which left more room for improvement. However, this could not be the whole story, as the final VA in the older age group is comparatively better than that in the younger age group as shown in [Table 4]. Another possible explanation is that the clinical characteristics of nAMD are inherently different between Asians and the population in Western countries, as soft drusen and geographic atrophy are less prevalent among Asians and the prevalence of PCV is far higher in Asian countries.[21] In this study, patients in the younger age group had higher prevalence of PCV. Previous study had shown that ranibizumab may improve and maintain the improvement of vision at 24 months of follow-up in typical age-related macular degeneration, but not in PCV patients,[22] which may explain the unsatisfactory visual outcome in the younger age group. In this study, whether the shifting to aflibercept in cases resistant to ranibizumab or bevacizumab significantly changed the VA outcomes were also evaluated. In this study, we noted significantly better BCVA in Group 2 at baseline. Eyes in this group also did not maintain significant visual improvement at 4 years of follow-up like eyes in Group 1 did [Table 2]. There may be several reasons for this. First, eyes in Group 2 had significantly more proportion of PCV, previous study had shown that eyes of PCV generally have better presenting BCVA, and worse response to bevacizumab and ranibizumab.[22] Second, since eyes in this group had significant better initial VA, which left less room for visual improvement. However, those patients did had visual improvement after shifting to aflibercept as compared to the preshifting [Table 5], especially in patients over 70 years of age. Thus, the rescue therapy of aflibercept did play an important role in maintaining visual outcome in cases resistant to ranibizumab or bevacizumab. As for the patients age 70 years or younger, we did not observe significant visual improvement after shifting to aflibercept. This may either be attributed to the small sample size of patients, which could not show the difference, or be attributed to the different proportion of PCV in the younger age group, which may respond worse to the anti-VEGF agents, even after shifting to aflibercept.

As compared to other studies of long-term efficacy of ranibizumab with treat and extend or pro en nata regimen, which mostly included Caucasian patients,[21],[23] our patients had an average younger age, a poorer initial VA, and were male predominant. These maybe attributed to that the disease characteristics are basically different between Asians and Caucasians. We also noted a similar number of annual injections, but better visual improvement, and a better maintenance. The poorer initial VA as well as the rescue therapy of aflibercept in resistant cases may explain the better visual improvement and the better maintenance of improvement in our patients.

There are several limitations of this study because of its retrospective nature and small number of patients. In addition, since we collect only cases with clinical follow-up 4 years of more, some of the patients with initial poor response, and some of the good responders who maintained initial visual gain without further treatment may be lost of follow-up and were not included in this study, thus patient selection bias is unavoidable.

  Conclusion Top

Patients with nAMD treated with anti-VEGF agents with a loose treat and extend regimen might have VA improvement maintained in a 4-year follow-up period, especially in patients with initial poor VA equal or <1.0 in logMar, and patients of older age. In addition, rescue therapy with aflibercept might be especially useful for older patients who are resistant to ranibizumab or bevacizumab. However, further study with larger sample size is necessary to further confirm our conclusion.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consents for their images and other clinical information to be reported in the journal. The patients understand that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

The authors declare that there are no conflicts of interests of this paper.

  References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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