Next Article in Journal
Compared the Microbiota Profiles between Samples from Bronchoalveolar Lavage and Endotracheal Aspirates in Severe Pneumonia: A Real-World Experience
Next Article in Special Issue
Age-Related Macular Degeneration: New Insights in Diagnosis, Treatment, and Prevention
Previous Article in Journal
Predictive Validity of Motor Fitness and Flexibility Tests in Adults and Older Adults: A Systematic Review
Previous Article in Special Issue
Exploring Consensus on Preventive Measures and Identification of Patients at Risk of Age-Related Macular Degeneration Using the Delphi Process
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 11
Issue 2
10.3390/jcm11020325
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Managing Neovascular Age-Related Macular Degeneration in Clinical Practice: Systematic Review, Meta-Analysis, and Meta-Regression

by
Daniele Veritti
1,
Valentina Sarao
1,2,
Valentina Soppelsa
1,
Carla Danese
1,
Jay Chhablani
3 and
Paolo Lanzetta
1,2,*
1
Department of Medicine-Ophthalmology, University of Udine, 33100 Udine, Italy
2
Istituto Europeo di Microchirurgia Oculare (IEMO), 33100 Udine, Italy
3
Medical Retina and Vitreoretinal Surgery, University of Pittsburgh School of Medicine, Pittsburg, PA 15261, USA
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2022, 11(2), 325; https://doi.org/10.3390/jcm11020325
Submission received: 25 November 2021 / Revised: 3 January 2022 / Accepted: 7 January 2022 / Published: 10 January 2022
(This article belongs to the Special Issue Diagnosis, Treatment and Prevention of Age-Related Macular Degeneration)
Browse Figure
Versions Notes

Abstract

:
The use of anti-vascular endothelial growth factor (VEGF) agents has profoundly changed the prognosis of neovascular age-related macular degeneration (nAMD). As clinical experiences have accumulated, it has become mandatory to summarize data to give information that can be useful in everyday practice. We conducted a systematic review to identify randomized controlled trials (RCTs) and observational studies that reported 12-month changes in best-corrected visual acuity (BCVA) in patients with nAMD on anti-VEGF monotherapy. Data were analyzed in a random-effects meta-analysis with BCVA change as the primary outcome. Meta-regression was conducted to evaluate the impact of multiple covariates. Four hundred and twelve heterogeneous study populations (109,666 eyes) were included. Anti-VEGFs induced an overall improvement of +5.37 ETDRS letters at 12 months. Meta-regression showed that mean BCVA change was statistically greater for RCTs (p = 0.0032) in comparison with observational studies. Populations following a proactive regimen had better outcomes than those following a reactive treatment regimen. Mean BCVA change was greater in younger populations, with lower baseline BCVA and treated with a higher number of injections (p < 0.001). Our results confirm that anti-VEGFs may produce a significant functional improvement at 12 months in patients with nAMD.

1. Introduction

Neovascular age-related macular degeneration (nAMD) is the leading cause of irreversible vision loss among the over-50s living in developed countries, with a prevalence rate between 5.8% and 15.1% of the population, which constantly increases with age [1].
In recent times, intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy has become the treatment of choice for nAMD, supported by evidence from randomized clinical trials (RCTs) as well as routine clinical practice, demonstrating efficacy in preventing visual loss and improving vision [1,2]. Currently, three anti-VEGF drugs (ranibizumab, aflibercept, and brolucizumab) are authorized for the treatment of nAMD, whilst bevacizumab, developed and approved for different types of tumors, is widely employed in an off-label fashion in many countries. The magnitude of effect of anti-VEGF drugs on visual acuity was evident from the early monthly dosing trials. Later, studies based on a pro re nata (PRN) or a treat and extend (TAE) dosing strategy led to results that in some cases emulated those obtained with monthly dosing [2]. However, the published outcomes of real-world experiences show large variability, making it challenging to incorporate this evidence into clinical decision making. Treatment outcomes in routine practice may be different from what is obtained in RCTs. This can reflect the fact that study populations in RCTs are highly selective and may not entirely represent real-world patients. Moreover, patients in real-world clinical settings may be treated with dosing and/or regimens that differ from what recommended in the product’s label, mainly due to logistic problems and economic considerations [3,4,5,6]. Consequently, it is not clear to what extent the outcomes from RCTs can be replicated in everyday clinical practice. The objective of this study was to synthesize the evidence available about the efficacy of intravitreal anti-VEGFs for the treatment of nAMD based on a systematic review and a meta-analysis of published RCTs and observational/real-life studies. Moreover, we intended to identify clinical and study factors that may have an impact on the reporting of outcomes through a meta-regression model. Specifically, the aim of this work is to give an answer to the following ten questions:
Are results between RCTs and real-life/observational studies different?
  • Are results between RCTs and real-life/observational studies different, when analyzing each anti-VEGF agent?
  • Is the outcome influenced by the treatment regimen?
  • Is the outcome influenced by the treatment regimen, when considering only real-life/observational studies?
  • If proactive regimens produce better results, is this accurate when considering each anti-VEGF agent?
  • Is the outcome influenced by the frequency of treatments?
  • If the number of treatments has an effect on the results, is this accurate when considering each anti-VEGF agent?
  • Comprehensively, which agent shows more favorable results?
  • In real life/observational studies, which agent produces better results?
  • Are real-life visual results influenced by baseline characteristics?

2. Materials and Methods

A stepwise procedure, which includes a systematic literature review (SLR), a meta-analysis, and a meta-regression, was utilized to assess the efficacy/effectiveness of intravitreal therapy in patients affected by nAMD.

2.1. Systematic Literature Review

A SLR of available studies, which include patients affected by naïve nAMD and treated with intravitreal ranibizumab, aflibercept, bevacizumab, or brolucizumab with 52-week follow-up, was conducted. The present review was completed according to the protocols reported in the Cochrane Handbook for Systematic Review of Interventions (v5.1.0). The outcomes are expressed as reported in the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) [7]. In brief, EMBASE, PubMed, and Cochrane databases were searched for papers until March 2021 independently by 3 authors (VSa, VSo, and CD). The research strategy was focused on a mix of medical subject headings and the keywords: “age-related macular degeneration”, “choroidal neovascularization”, “anti-VEGF”, “AMD”, “CNV”, “aflibercept”, “bevacizumab”, “ranibizumab”, and “brolucizumab”.
The review was restricted to clinical studies available in peer-reviewed, English language publications, and those published until March 2021. Conference abstracts/papers, editorials, proposals, reviews, notes, letters to authors, news, and commentaries were not included in the review. The reference lists from selected articles were inspected for additional publications. The risk of bias was estimated both quantitatively and qualitatively with the Downs and Black checklist.

2.2. Meta-Analysis

A meta-analysis of the outcomes obtained from the SLR was performed. Inclusion criteria for the meta-analysis consisted of studies including naïve nAMD patients treated with ranibizumab, aflibercept, bevacizumab, or brolucizumab in monotherapy and reported 1-year (±4 weeks) effectiveness outcomes. The main aim of this meta-analysis was to extract a pooled estimate for effectiveness (best-corrected visual acuity (BCVA) change from baseline to week 52 in Early Treatment Diabetic Retinopathy Study (ETDRS) letters). Visual acuities expressed in LogMAR unit or decimal scale were converted to ETDRS letters before performing statistical analysis. Randomized controlled trials, real-life prospective, and retrospective clinical studies were considered. Papers that investigated specific populations affected by retinal angiomatous proliferation, polypoidal choroidal vasculopathy, or fibrovascular pigment epithelial detachment were excluded from the analysis. Studies in which a specific type of anti-VEGF could not be extracted from the results were also not considered. Publications from the same author/organization that included duplicated data were not included.
The treatment strategy was categorized into one of three groups. Populations treated on a fixed protocol such as monthly or bimonthly were codified as fixed. Those being injected under a PRN interval were categorized as PRN and in the same manner TAE approaches constituted the TAE group.
Fixed-effects and random-effects models were utilized to obtain estimates. Heterogeneity was determined with the I2 statistic. Egger’s linear regression was used to evaluate publication bias along with visualization of funnel plots.

2.3. Meta-Regression and Moderators Selection

We performed a meta-regression analysis. Pre-selected primary moderators were chosen on the basis of existing evidence. Moderators of interest were age at baseline, baseline BCVA, study type (RCT, real-life/observational study), drug, number of injections, and treatment schedule. The output variable considered was mean BCVA change in ETDRS letters at 52 weeks (±4 weeks).

2.4. Compliance with Ethics Guidelines

The present study is based on previously published articles and does not imply any new studies of human participants. This work did not necessitate ethical approval as it did not include human participants or animal subjects.

3. Results

3.1. Study Selection

The primary search produced 7709 reports. After screening of titles and abstracts and removal of duplicates, 683 potentially relevant papers were identified, and the full texts were extracted and individually screened for eligibility. Two hundred and seventy-six studies with 412 heterogeneous populations fulfilled inclusion criteria and were included in the analysis. [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283]. The flowchart of selection steps is illustrated in Figure 1.

3.2. Study Characteristics

Attributes of the 276 analyzed studies are detailed in Table 1. Some studies consist of different heterogeneous study groups, which were considered as individual study populations in the present analysis. Most studies were real-life/observational, which was defined as single-arm interventional designs and retrospective chart reviews. Of the 276 studies included, 81 were randomized clinical trials, 95 were prospective cohort studies, and 100 were retrospective cohort studies. A total of 73 trials were conducted in Asia and Australia; 161 were conducted in Europe; and 42 in the United States. Less than half of the included studies (36%) were comparative. Four hundred and twelve heterogeneous study populations were found. The numerosity of the study populations ranged from 9 to 8598 eyes, with a total of 109,666 eyes enrolled. Specifically, 24,517 eyes were treated with aflibercept, 65,591 eyes with ranibizumab, 1038 eyes with brolucizumab and 18,520 eyes with bevacizumab. The relatively low number of subjects treated with brolucizumab is a consequence of the limited number of eligible studies available in literature so far. Therefore, this imbalance in sample size impacts the meta-regression analysis, limiting the sense of a comparison between brolucizumab and other anti-VEGFs. Nevertheless, brolucizumab data were included in the meta-analysis and in the meta-regression processes that did involve a comparison among drugs. Overall, the mean age varied from 63 to 90 years. Mean baseline BCVA ranged from 31 to 77 ETDRS letters. Two hundred and seventy-six studies were separately scored for their methodological quality using the Downs and Black checklist. Methodological quality ranged from 13 to 20, with a mean overall score of 17.3. For the most part, reduced quality across studies can be ascribed to poor reporting of blinding, loss to follow-up and characteristics of subjects lost to follow-up, randomization process, adjustment for confounding variables, and estimates of random variability.

3.3. Meta-Analysis

We found a high heterogeneity among studies considered in the analysis (I2 = 94.478%; p < 0.0001), and thereafter we chose a random-effects model. None of studies showed a significant effect on overall effect size, as showed by a leave-one-out sensitivity analysis. The meta-analysis provided an overall gain in BCVA of +5.37 ETDRS letters (95% CI: 5.01–5.72) at 12 months.

3.4. Meta-Regression

Several moderators showed robust effect modification. We applied a meta-regression process to provide answers to the following clinically significant questions.
  • Are results between RCTs and real-life/observational studies different?
A statistically significant (p = 0.0032) regression of difference in means on study type showed a coefficient of +1.32 ETDRS letters favoring RCTs over real-life/observational studies (CI 95%: +0.45; +2.20).
2.
Are results between RCTs and real-life/observational studies different, when analyzing each anti-VEGF agent?
A statistically significant regression of difference in means on study type for aflibercept and ranibizumab (p = 0.042 and p = 0.0009, respectively) showed a coefficient of +1.80 (aflibercept) and +1.84 (ranibizumab) ETDRS letters advantaging RCTs over real-life/observational studies (CI 95%: +0.06; +3.53 for aflibercept and CI 95%: +0.75; +2.92 for ranibizumab). The same analysis performed for bevacizumab resulted in a not statistically significant difference (p = 0.95).
3.
Is the outcome influenced by the treatment regimen?
Regression of difference in means on regimen was statistically significant, higher benefit was seen for fixed and TAE regimen over PRN regimen. Fixed regimen showed a coefficient of +2.23 ETDRS letters over PRN. (CI 95%: +1.32; +3.14; p < 0.0001). Treat and extend regimen showed a coefficient of +2.40 ETDRS letters over PRN. (CI 95%: +1.41; +3.39; p < 0.0001). No statistically significant difference was found between fixed and TAE regimen (p = 0.78).
4.
Is the outcome influenced by the treatment regimen, when considering only real-life/observational studies?
Regression of difference in means on regimen was statistically significant, in favor of fixed and TAE regimen over PRN regimen, when including only real-life/observational studies. Fixed regimen showed a coefficient of +1.68 ETDRS letters over PRN. (CI 95%: +0.70; +2.67; p = 0.0008). Treat and extend regimen showed a coefficient of +2.02 ETDRS letters over PRN. (CI 95%: +0.98; +3.06; p = 0.0001). No statistically significant difference was found between fixed and TAE regimen (p = 0.61).
5.
If proactive regimens produce better results, is this accurate when considering each anti-VEGF agent?
In patients treated with aflibercept, a statistically significant difference indicating more favorable results for fixed regimen over PRN regimen (coefficient +2.01 ETDRS letters; CI 95%: +0.62; +3.41; p = 0.005), and TAE regimen over PRN regimen (coefficient +2.58 ETDRS letters; CI 95%: +1.01; +4.15; p = 0.001) was described. Similarly, ranibizumab-treated populations had better outcomes in studies utilizing fixed regimen over PRN regimen (coefficient +2.47 ETDRS letters; CI 95%: +1.06; +3.88; p = 0.0006), and TAE regimen over PRN regimen (coefficient +2.33 ETDRS letters; CI 95%: +0.98; +3.69; p = 0.008). In patients treated with bevacizumab, regression of difference in means on regimen was not significant (p > 0.5).
6.
Is the outcome influenced by the frequency of treatments?
A highly statistically significant effect resulted from regression of difference in means on mean number of treatments (coefficient +0.51 ETDRS letters; CI 95%: +0.34; +0.68; p < 0.0001).
7.
If the number of treatments has an effect on the results, is this accurate when considering each anti-VEGF agent?
When looking at ranibizumab-treated populations, outcomes were significantly influenced by mean number of treatments (coefficient +0.69 ETDRS letters; CI 95%: +0.47; +0.91; p < 0.0001). The same analysis was not statistically significant for aflibercept (coefficient +0.32 ETDRS letters; CI 95%: −0.12; +0.76; p = 0.16) and bevacizumab (coefficient +0.16 ETDRS letters; CI 95%: −0.23; +0.55; p = 0.42).
8.
Comprehensively, which agent shows more favorable results?
Regression of difference in means on drug showed that the studies employing aflibercept reported significantly superior results over ranibizumab (coefficient +1.78 ETDRS letters; CI 95%: +0.4; +4.15; p < 0.0001). A non-statistically significant trend for better results for aflibercept-treated populations over bevacizumab-treated populations was seen (coefficient +0.97 ETDRS letters; CI 95%: +0.09; +2.04; p = 0.07). The comparisons between the results published for brolucizumab-treated populations and the populations treated with other anti-VEGF agents were not statistically significant (p > 0.3). However, a non-significant trend towards better outcomes in the brolucizumab studies was detected (coefficient +0.03, +1.00, +1.78 ETDRS letters against aflibercept, bevacizumab, and ranibizumab, respectively).
When the same analyses were performed posing the treatment regimen as a precondition, no statistically significant differences among anti-VEGF drugs were found. In the populations treated with a fixed regimen, a trend to better outcomes (not statistically significant) was found for aflibercept (coefficient +0.87, +0.25 ETDRS letters over bevacizumab, and ranibizumab, respectively). When considering the populations treated with a PRN regimen, a trend to better outcomes (not statistically significant) was found for aflibercept (coefficient +0.04, +0.85 ETDRS letters over bevacizumab and ranibizumab, respectively). In the populations treated with a TAE regimen, a trend to better outcomes (not statistically significant) was found for aflibercept (coefficient +0.50, +0.89, and +1.01 ETDRS letters over bevacizumab, brolucizumab, and ranibizumab, respectively).
9.
In real life/observational studies, which agent produces better results?
Aflibercept reported significantly better results over ranibizumab (coefficient +1.94 ETDRS letters; CI 95%: +1.05; +2.82; p < 0.0001), as shown by regression of difference in means on drug in real life/observational studies.
10.
Are real-life visual results influenced by baseline characteristics?
Regression of difference in means was significant on age (coefficient −0.17 ETDRS letters; CI 95%: −0.26; −0.07; p < 0.001) and baseline BCVA (coefficient −0.11 ETDRS letters; CI 95%: −0.16; −0.07; p < 0.0001).

3.5. Publication Bias and Sensitivity Analysis

Funnel plot asymmetry was seen in the present meta-analysis. Egger’s linear regression (intercept = 3.11, p < 0.001) and by Begg’s rank correlation test (Kendall’s τ = 0.245, p < 0.001) also suggest the existence of publication bias. After imputing missing studies in the funnel plot, adjustment of effect size for possible publication bias using the trim-and-fill correction results in decreased, albeit still highly significant estimate of pooled mean difference (adjusted = +4.35 ETDRS letters; CI 95%: +4.02; +4.68; p < 0.0001). A ‘one-study-removed’ technique and a ‘cumulative meta-analysis’ technique were used to evaluate the potential influence of a small-study effect. Both techniques express negative results.

4. Discussion

Neovascular AMD is the main cause of vision loss in adult patients in developed countries [1,2]. The present study was conducted to synopsize the clinical evidence from RCTs and real-life/observational studies on functional results of intravitreal anti-VEGF treatment in the management of nAMD, obtaining a pooled estimate for BCVA change from baseline to week 52. This meta-analysis consists of 109,666 eyes and it is the largest and most comprehensive research to date that aim at synthetizing the clinical efficacy of intravitreal ranibizumab, aflibercept, bevacizumab, and brolucizumab in the treatment of nAMD at 12 months. The results obtained from this meta-analysis support the utilization of anti-VEGF agents as an effective therapeutic option for the treatment of nAMD, showing that significant BCVA gain is attainable. The present meta-analysis reports an overall increase in BCVA of approximately +5.3 ETDRS letters after one year of intravitreal anti-VEGF therapy. A high variability was found between studies, as demonstrated by the wide variance in pooled effect size (p heterogeneity, <0.0001). The interpretation of average effect size is increasingly complex as the presence of intertwined modifiers, independent predictors, and confounding variables multiplies. It remains an important goal to identify under what conditions anti-VEGF therapies may unlock their full potential. To elaborate on this matter, a meta-regression was carried out. RCTs showed an overall gain in visual acuity of +6.42 letters (95% CI: 5.50–7.33). Real-life/observational studies were calculated to have an increase of +5.01 letters (95% CI: 4.65–5.38). A statistically significant difference in BCVA was noticed between RCTs and real-life studies (p < 0.01) and, as expected, we found a higher variability in real-life results. This is in line with previous reports indicating that outcomes achieved with anti-VEGFs in real-life studies for the treatment of nAMD are not as good as those obtained in RCTs. However, it remains a matter of discussion whether a difference of +1.3 ETDRS letters is clinically meaningful. In the present meta-analysis and meta-regression, we choose a random-effects approach as the observed heterogeneity in the estimates may be attributed to between-study heterogeneity in true effects and within-study sampling error.
Growing evidence suggests that the regimen employed, and the frequency of anti-VEGF injections, have an impact on the visual outcome when treating a patient affected by nAMD [2]. Data from our analysis confirm this hypothesis. In detail, we found a statistically significant correlation between the number of anti-VEGF administrations and BCVA change (p < 0.0001). At month 12, each additional treatment induces a +0.51-letter gain. Yet, these results are not uniform among all anti-VEGF agents. The drug most dependent on the number of injections per year seems to be ranibizumab (coefficient +0.69 ETDRS letters per injection). We believe that this finding can be ascribed to both pharmacological properties and to the characteristics of the studies analyzed. In detail, the variability in the number of injections is much wider in ranibizumab studies than in those using aflibercept and bevacizumab. This is mainly because the larger part of ranibizumab studies apply a PRN regimen that involves a wider variability in the number of injections. Moreover, we investigated the role of the treatment regimen employed in obtaining the most favorable results. Results from the present meta-regression indicate that better outcomes are seen when employing a proactive treatment regimen (fixed or TAE) over a reactive treatment regimen (PRN). These results are also confirmed when analyzing real-life studies alone. Actually, many factors may interfere with the therapeutic efficacy of PRN treatment regimen in a real-life scenario, including administrative and logistic considerations. For example, improper appointment scheduling for treatment and monitoring visits is indeed a real-world factor that may result in unsatisfactory outcomes. Moreover, strict adherence to rigorous retreatment criteria is often difficult to obtain in a real-life scenario, due to inhomogeneity in imaging technologies and physicians’ knowledge and skills. This represents a limitation in maximizing visual gains, leading to suboptimal outcomes for the patients.
When analyzing baseline characteristics that may influence visual outcomes, our meta-regression showed that the 12-month BCVA change negatively correlated with baseline BCVA, which is consistent with prior experiences, revealing an inverse correlation between baseline BCVA and long-term BCVA change. Our analysis also revealed a negative correlation in BCVA change with increasing age. This negative correlation may be a consequence of worsened functional results at later age of presentation, when both the advanced stage of the disease and a decreased response to therapy may lead to inferior clinical outcomes. Key results from our work are reported in Table 2.
The main strength of the present work is that it provides an exhaustive and paradigmatic overview of the various therapeutic approaches used in real-life clinical practice and in RCTs for nAMD patients. We employed a predefined search strategy, three independent reviewers performed data extraction, and subgroup and sensitivity analysis were also conducted.
However, some limitations of the current study should not be ignored. First, the enrolled studies were limited to English language. This may have led to studies not being included, resulting in a not quite comprehensive data set. Second, the quality of included studies is variable. Real-life/observational studies exhibit a higher level of bias than RCT, including publication bias. Third, the heterogeneity among studies was notable, possibly due to confounding variables such as sample sizes, ethnic distribution of the study population, study designs, CNV types, and treatment modalities. Actually, uncontrolled confounding predisposes to bias when comparing observational studies and RCT. Fourth, the data used to establish these results might suffer from sample selection bias.
Finally, our results, from a methodological point of view, are also susceptible to ecological bias and study-level confounding, which means that the observed across-study relationships may not properly mirror the individual-level relationships within trials. In this sense, a network meta-analysis is probably less prone to misinterpretation. For all these motives, care must be exercised in conjecturing any form of quantitative relationship, which may alter over time and with a larger number of reports/studies included in the analysis.

5. Conclusions

In conclusion, the evidence for intravitreal therapy with anti-VEGF agents has been confirmed in this meta-analysis to be highly beneficial in the therapy of nAMD both in clinical trials and in real-life experiences. Frequency of injections and proactive treatment regimens are both factors related to best outcomes with currently available anti-VEGF agents.

Author Contributions

D.V. and V.S. (Valentina Sarao) contributed equally to this paper. Conceptualization, D.V.; V.S. (Valentina Sarao) and P.L.; literature search, V.S. (Valentina Sarao), V.S. (Valentina Soppelsa), and C.D.; formal analysis, D.V.; writing—original draft preparation, D.V. and V.S. (Valentina Sarao); writing—review and editing, D.V., V.S. (Valentina Sarao) and P.L.; supervision, J.C. and P.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Not applicable.

Conflicts of Interest

Daniele Veritti has been involved as a consultant for Bayer, Novartis, and Roche. Valentina Sarao has been involved as a consultant for Centervue and Roche. Valentina Soppelsa and Carla Danese declare no conflicts of interest. Jay Chhablani has been involved as a consultant for Allergan, Novartis, OD-OS. Paolo Lanzetta has been involved as a consultant for Aerie, Apellis, Bayer, Biogen, Centervue, Novartis, and Roche.

References

  1. Veritti, D.; Sarao, V.; Lanzetta, P. Neovascular Age-Related Macular Degeneration. Ophthalmologica 2012, 227, 11–20. [Google Scholar] [CrossRef] [PubMed]
  2. Lanzetta, P.; Mitchell, P.; Wolf, S.; Veritti, D. Different Antivascular Endothelial Growth Factor Treatments and Regimens and Their Outcomes in Neovascular Age-Related Macular Degeneration: A Literature Review. Br. J. Ophthalmol. 2013, 97, 1497–1507. [Google Scholar] [CrossRef]
  3. Veritti, D.; Sarao, V.; Lanzetta, P. Bevacizumab and Triamcinolone Acetonide for Choroidal Neovascularization Due to Age-Related Macular Degeneration Unresponsive to Antivascular Endothelial Growth Factors. J. Ocul. Pharmacol. Ther. 2013, 29, 437–441. [Google Scholar] [CrossRef]
  4. Veritti, D.; Macor, S.; Menchini, F.; Lanzetta, P. Effects of vegf inhibition on retinal morphology, neovascular network size, and visual acuity in patients with vascularized pigment epithelium detachment because of occult choroidal neovascularization. Retina 2013, 33, 982–989. [Google Scholar] [CrossRef] [PubMed]
  5. Sarao, V.; Parravano, M.; Veritti, D.; Arias, L.; Varano, M.; Lanzetta, P. Intravitreal aflibercept for choroidal neovascularization due to age-related macular degeneration unresponsive to ranibizumab therapy. Retina 2016, 36, 770–777. [Google Scholar] [CrossRef]
  6. Veritti, D.; Sarao, V.; Parravano, M.; Arias, L.; Varano, M.; Lanzetta, P. One-Year Results of Aflibercept in Vascularized Pigment Epithelium Detachment Due to Neovascular AMD: A Prospective Study. Eur. J. Ophthalmol. 2017, 27, 74–79. [Google Scholar] [CrossRef] [PubMed]
  7. PRISMA-P Group; Moher, D.; Shamseer, L.; Clarke, M.; Ghersi, D.; Liberati, A.; Petticrew, M.; Shekelle, P.; Stewart, L.A. Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 Statement. Syst. Rev. 2015, 4, 1. [Google Scholar] [CrossRef] [Green Version]
  8. Chiam, P.J.; Ho, V.W.; Hickley, N.M.; Kotamarthi, V. 6-Weekly Bevacizumab versus 4-Weekly Ranibizumab for Neovascular Age-Related Macular Degeneration: A 2-Year Outcome. Int. J. Ophthalmol. 2016, 9, 551. [Google Scholar] [CrossRef] [PubMed]
  9. Vardarinos, A.; Gupta, N.; Janjua, R.; Iron, A.; Empeslidis, T.; Tsaousis, K.T. 24-Month Clinical Outcomes of a Treat-and-Extend Regimen with Ranibizumab for Wet Age-Related Macular Degeneration in a Real Life Setting. BMC Ophthalmol. 2017, 17, 58. [Google Scholar] [CrossRef] [Green Version]
  10. Arias, L.; Ruiz-Moreno, J.M.; Gómez-Ulla, F.; Fernández, M.; Montero, J. A 1-year retrospective review of ranibizumab for naïve nonsubfoveal choroidal neovascularization secondary to age-related macular degeneration. Retina 2009, 29, 1444–1449. [Google Scholar] [CrossRef]
  11. Toalster, N.; Russell, M.; Ng, P. A 12-month prospective trial of inject and extend regimen for ranibizumab treatment of age-related macular degeneration. Retina 2013, 33, 1351–1358. [Google Scholar] [CrossRef]
  12. Wu, W.-C.; Chen, J.-T.; Tsai, C.-Y.; Wu, C.-L.; Cheng, C.-K.; Shen, Y.-D.; Tsai, A.; Wu, P.-C. A 12-Month, Prospective, Observational Study of Ranibizumab in Treatment-Naïve Taiwanese Patients with Neovascular Age-Related Macular Degeneration: The RACER Study. BMC Ophthalmol. 2020, 20, 462. [Google Scholar] [CrossRef]
  13. Park, D.H.; Sun, H.J.; Lee, S.J. A Comparison of Responses to Intravitreal Bevacizumab, Ranibizumab, or Aflibercept Injections for Neovascular Age-Related Macular Degeneration. Int. Ophthalmol. 2017, 37, 1205–1214. [Google Scholar] [CrossRef]
  14. Ohnaka, M.; Nagai, Y.; Sho, K.; Miki, K.; Kimura, M.; Chihara, T.; Takahashi, K. A Modified Treat-and-Extend Regimen of Aflibercept for Treatment-Naïve Patients with Neovascular Age-Related Macular Degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 2017, 255, 657–664. [Google Scholar] [CrossRef]
  15. Boyer, D.S.; Heier, J.S.; Brown, D.M.; Francom, S.F.; Ianchulev, T.; Rubio, R.G. A Phase IIIb Study to Evaluate the Safety of Ranibizumab in Subjects with Neovascular Age-Related Macular Degeneration. Ophthalmology 2009, 116, 1731–1739. [Google Scholar] [CrossRef]
  16. Sodhi, S.K.; Trimboli, C.; Kalaichandran, S.; Pereira, A.; Choudhry, N. A Proof of Concept Study to Evaluate the Treatment Response of Aflibercept in WARMD Using OCT-A (Canada Study). Int. Ophthalmol. 2021, 41, 1697–1708. [Google Scholar] [CrossRef]
  17. Aaberg, T., Jr.; Williams, P.D.; Callanan, D.; Solley, W.; Avery, R.L.; Pieramici, D. A Prospective Pilot Study Comparing Combined Intravitreal Ranibizumab and Half-Fluence Photodynamic Therapy with Ranibizumab Monotherapy in the Treatment of Neovascular Age-Related Macular Degeneration. OPTH 2012, 6, 1519. [Google Scholar] [CrossRef] [Green Version]
  18. Krebs, I.; Schmetterer, L.; Boltz, A.; Told, R.; Vécsei-Marlovits, V.; Egger, S.; Schönherr, U.; Haas, A.; Ansari-Shahrezaei, S.; Binder, S.; et al. A Randomised Double-Masked Trial Comparing the Visual Outcome after Treatment with Ranibizumab or Bevacizumab in Patients with Neovascular Age-Related Macular Degeneration. Br. J. Ophthalmol. 2013, 97, 266–271. [Google Scholar] [CrossRef]
  19. Eldem, B.M.; Muftuoglu, G.; Topbaş, S.; Çakir, M.; Kadayifcilar, S.; Özmert, E.; Bahçecioğlu, H.; Sahin, F.; Sevgi, S.; The SALUTE Study Group. A Randomized Trial to Compare the Safety and Efficacy of Two Ranibizumab Dosing Regimens in a Turkish Cohort of Patients with Choroidal Neovascularization Secondary to AMD. Acta Ophthalmol. 2015, 93, e458–e464. [Google Scholar] [CrossRef]
  20. Leung, K.; Downes, S.; Chong, V. A Retrospective Analysis of the Effect of Subretinal Hyper-Reflective Material and Other Morphological Features of Neovascular Age-Related Macular Degeneration on Visual Acuity Outcomes in Eyes Treated with Intravitreal Aflibercept over One Year. Vision 2018, 2, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Johnston, R.L.; Carius, H.-J.; Skelly, A.; Ferreira, A.; Milnes, F.; Mitchell, P. A Retrospective Study of Ranibizumab Treatment Regimens for Neovascular Age-Related Macular Degeneration (NAMD) in Australia and the United Kingdom. Adv. Ther. 2017, 34, 703–712. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Frennesson, C.I.; Nilsson, S.E.G. A Three-Year Follow-up of Ranibizumab Treatment of Exudative AMD: Impact on the Outcome of Carrying Forward the Last Acuity Observation in Drop-Outs. Acta Ophthalmol. 2014, 92, 216–220. [Google Scholar] [CrossRef] [PubMed]
  23. Wakuta, M.; Nomi, N.; Ogata, T.; Ota, M.; Yamashiro, C.; Hatano, M.; Yanai, R.; Tokuda, K.; Kimura, K. A Trinity Regimen with Aflibercept for Treatment-Naïve Neovascular Age-Related Macular Degeneration: 2-Year Outcomes. Graefes Arch. Clin. Exp. Ophthalmol. 2020, 258, 1663–1670. [Google Scholar] [CrossRef] [PubMed]
  24. Lazzeri, S.; Ripandelli, G.; Sartini, M.S.; Parravano, M.; Varano, M.; Nardi, M.; Di Desidero, T.; Orlandi, P.; Bocci, G. Aflibercept Administration in Neovascular Age-Related Macular Degeneration Refractory to Previous Anti-Vascular Endothelial Growth Factor Drugs: A Critical Review and New Possible Approaches to Move Forward. Angiogenesis 2015, 18, 397–432. [Google Scholar] [CrossRef]
  25. Udaondo, P.; Salom, D.; García-Delpech, S.; Cisneros-Lanuza, Á. Aflibercept as First-Line Therapy in Patients with Treatment-Naïve Neovascular Age-Related Macular Degeneration: Prospective Case Series Analysis in Real-Life Clinical Practice. Ophthalmologica 2016, 236, 29–35. [Google Scholar] [CrossRef] [PubMed]
  26. Jaggi, D.; Nagamany, T.; Ebneter, A.; Munk, M.; Wolf, S.; Zinkernagel, M. Aflibercept for Age-Related Macular Degeneration: 4-Year Outcomes of a ‘Treat-and-Extend’ Regimen with Exit-Strategy. Br. J. Ophthalmol. 2020. [Google Scholar] [CrossRef]
  27. Framme, C.; Eter, N.; Hamacher, T.; Hasanbasic, Z.; Jochmann, C.; Johnson, K.T.; Kahl, M.; Sachs, H.; Schilling, H.; Thelen, U.; et al. Aflibercept for Patients with Neovascular Age-Related Macular Degeneration in Routine Clinical Practice in Germany. Ophthalmol. Retin. 2018, 2, 539–549. [Google Scholar] [CrossRef]
  28. Gascon, P.; Ramtohul, P.; Delaporte, C.; Kerever, S.; Denis, D.; Comet, A. Aflibercept in Real-Life for the Treatment of Age-Related Macular Degeneration Using a Treat and Extend Protocol: The Armada Study. Eur. J. Ophthalmol. 2021, 112067212110057. [Google Scholar] [CrossRef]
  29. Oca Lázaro, A.I.; Velilla Osés, S.; Negredo Bravo, L.J. Aflibercept intravítreo en dosis fijas en pacientes naïve con degeneración macular asociada a la edad neovascular: Resultados a un año en práctica clínica real. Arch. Soc. Española Oftalmol. 2019, 94, 430–435. [Google Scholar] [CrossRef]
  30. Berg, K.; Roald, A.B.; Navaratnam, J.; Bragadóttir, R. An 8-Year Follow-up of Anti-Vascular Endothelial Growth Factor Treatment with a Treat-and-Extend Modality for Neovascular Age-Related Macular Degeneration. Acta Ophthalmol. 2017, 95, 796–802. [Google Scholar] [CrossRef] [Green Version]
  31. Fung, A.E.; Lalwani, G.A.; Rosenfeld, P.J.; Dubovy, S.R.; Michels, S.; Feuer, W.J.; Puliafito, C.A.; Davis, J.L.; Flynn, H.W.; Esquiabro, M. An Optical Coherence Tomography-Guided, Variable Dosing Regimen with Intravitreal Ranibizumab (Lucentis) for Neovascular Age-Related Macular Degeneration. Am. J. Ophthalmol. 2007, 143, 566–583.e2. [Google Scholar] [CrossRef]
  32. Hautamäki, A.; Luoma, A.; Immonen, I. Anterior chamber flare during bevacizumab treatment in eyes with exudative age-related macular degeneration. Retina 2016, 36, 2183–2190. [Google Scholar] [CrossRef]
  33. Arai, Y.; Takahashi, H.; Inoda, S.; Tan, X.; Sakamoto, S.; Inoue, Y.; Fujino, Y.; Kawashima, H.; Yanagi, Y. Aqueous Humour Proteins and Treatment Outcomes of Anti-VEGF Therapy in Neovascular Age-Related Macular Degeneration. PLoS ONE 2020, 15, e0229342. [Google Scholar] [CrossRef]
  34. Küçük, B.; Kadayıfçılar, S.; Eldem, B. Assessment of the Long-Term Visual and Anatomical Outcomes of Ranibizumab to Treat Neovascular Age-Related Macular Degeneration. Int. J. Ophthalmol. 2018, 11, 645–649. [Google Scholar] [CrossRef] [PubMed]
  35. Lövestam Adrian, M.; Vassilev, Z.P.; Westborg, I. Baseline Visual Acuity as a Prognostic Factor for Visual Outcomes in Patients Treated with Aflibercept for Wet Age-Related Macular Degeneration: Data from the INSIGHT Study Using the Swedish Macula Register. Acta Ophthalmol. 2019, 97, 91–98. [Google Scholar] [CrossRef] [PubMed]
  36. Aurell, S.; Sjövall, K.; Paul, A.; Morén, Å.; Granstam, E. Better Visual Outcome at 1 Year with Antivascular Endothelial Growth Factor Treatment According to Treat-and-extend Compared with pro Re Nata in Eyes with Neovascular Age-related Macular Degeneration. Acta Ophthalmol. 2019, 97, 519–524. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Bellerive, C.; Cinq-Mars, B.; Lalonde, G.; Malenfant, M.; Tourville, É.; Tardif, Y.; Giasson, M.; Hébert, M. Bevacizumab and Ranibizumab for Neovascular Age-Related Macular Degeneration: A Treatment Approach Based on Individual Patient Needs. Can. J. Ophthalmol. 2012, 47, 165–169. [Google Scholar] [CrossRef] [PubMed]
  38. Li, X.; Hu, Y.; Sun, X.; Zhang, J.; Zhang, M. Bevacizumab for Neovascular Age-Related Macular Degeneration in China. Ophthalmology 2012, 119, 2087–2093. [Google Scholar] [CrossRef] [PubMed]
  39. Shienbaum, G.; Gupta, O.P.; Fecarotta, C.; Patel, A.H.; Kaiser, R.S.; Regillo, C.D. Bevacizumab for Neovascular Age-Related Macular Degeneration Using a Treat-and-Extend Regimen: Clinical and Economic Impact. Am. J. Ophthalmol. 2012, 153, 468–473.e1. [Google Scholar] [CrossRef]
  40. Lushchyk, T.; Amarakoon, S.; Martinez-Ciriano, J.P.; van den Born, L.I.; Baarsma, G.S.; Missotten, T. Bevacizumab in Age-Related Macular Degeneration: A Randomized Controlled Trial on the Effect of Injections Every 4 Weeks, 6 Weeks and 8 Weeks. Acta Ophthalmol. 2013, 91, e456–e461. [Google Scholar] [CrossRef]
  41. Amarakoon, S.; Martinez-Ciriano, J.P.; van den Born, L.I.; Baarsma, S.; Missotten, T. Bevacizumab in Age-Related Macular Degeneration: A Randomized Controlled Trial on the Effect of on-Demand Therapy Every 4 or 8 Weeks. Acta Ophthalmol. 2019, 97, 107–112. [Google Scholar] [CrossRef] [Green Version]
  42. Suzuki, M.; Gomi, F.; Sawa, M.; Tsujikawa, M.; Sakaguchi, H. Bevacizumab Treatment for Choroidal Neovascularization Due to Age-Related Macular Degeneration in Japanese Patients. Jpn. J. Ophthalmol. 2010, 54, 124–128. [Google Scholar] [CrossRef]
  43. De Bats, F.; Grange, J.-D.; Cornut, P.-L.; Feldman, A.; Burillon, C.; Denis, P.; Kodjikian, L. Bevacizumab versus Ranibizumab in the Treatment of Exudative Age-Related Macular Degeneration: A Retrospective Study of 58 Patients. J. Français D’ophtalmologie 2012, 35, 661–666. [Google Scholar] [CrossRef] [PubMed]
  44. Subramanian, M.L.; Abedi, G.; Ness, S.; Ahmed, E.; Fenberg, M.; Daly, M.K.; Houranieh, A.; Feinberg, E.B. Bevacizumab vs Ranibizumab for Age-Related Macular Degeneration: 1-Year Outcomes of a Prospective, Double-Masked Randomised Clinical Trial. Eye 2010, 24, 1708–1715. [Google Scholar] [CrossRef] [Green Version]
  45. Subramanian, M.L.; Ness, S.; Abedi, G.; Ahmed, E.; Daly, M.; Feinberg, E.; Bhatia, S.; Patel, P.; Nguyen, M.; Houranieh, A. Bevacizumab vs Ranibizumab for Age-Related Macular Degeneration: Early Results of a Prospective Double-Masked, Randomized Clinical Trial. Am. J. Ophthalmol. 2009, 148, 875–882.e1. [Google Scholar] [CrossRef] [PubMed]
  46. Chew, J.K.; Zhu, M.; Broadhead, G.K.; Luo, K.; Hong, T.; Chang, A.A. Bilateral Neovascular Age-Related Macular Degeneration: Comparisons between First and Second Eyes. Ophthalmologica 2017, 238, 23–30. [Google Scholar] [CrossRef] [PubMed]
  47. Chavan, R.; Panneerselvam, S.; Adhana, P.; Narendran, N.; Yang, Y. Bilateral Visual Outcomes and Service Utilization of Patients Treated For 3 Years with Ranibizumab for Neovascular Age-Related Macular Degeneration. OPTH 2014, 717. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Sawada, T.; Kakinoki, M.; Wang, X.; Kawamura, H.; Saishin, Y.; Ohji, M. Bimonthly Injections of Ranibizumab for Age-Related Macular Degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 2014, 252, 1545–1551. [Google Scholar] [CrossRef] [PubMed]
  49. Cohen, S.Y.; Maloberti, B.; Fajnkuchen, F.; Nghiem-Buffet, S.; Delahaye-Mazza, C.; Grenet, T.; Quentel, G. Bimonthly Ranibizumab for Neovascular Age-Related Macular Degeneration. Ophthalmologica 2014, 231, 80–85. [Google Scholar] [CrossRef] [PubMed]
  50. López Gálvez, M.I.; Arias Barquet, L.; Figueroa, M.; García-Layana, A.; Ruiz Moreno, J.M.; The In-Eye Study Group; Fernandez Rodríguez, M.; García Arumí, J.; Amat Peral, P. Bimonthly, Treat-and-extend and As-needed Ranibizumab in Naïve Neovascular Age-related Macular Degeneration Patients: 12-month Outcomes of a Randomized Study. Acta Ophthalmol. 2020, 98. [Google Scholar] [CrossRef] [PubMed]
  51. Dugel, P.U.; Jaffe, G.J.; Sallstig, P.; Warburton, J.; Weichselberger, A.; Wieland, M.; Singerman, L. Brolucizumab Versus Aflibercept in Participants with Neovascular Age-Related Macular Degeneration: A Randomized Trial. Ophthalmology 2017, 124, 1296–1304. [Google Scholar] [CrossRef]
  52. Cohen, S.Y.; Oubraham, H.; Uzzan, J.; Dubois, L.; Tadayoni, R. Causes of unsuccessful ranibizumab treatment in exudative age-related macular degeneration in clinical settings. Retina 2012, 32, 1480–1485. [Google Scholar] [CrossRef] [PubMed]
  53. Veloso, C.E.; de Almeida, L.N.F.; Nehemy, M.B. CFH Y402H Polymorphism and Response to Intravitreal Ranibizumab in Brazilian Patients with Neovascular Age-Related Macular Degeneration. Rev. Col. Bras. Cir. 2014, 41, 386–392. [Google Scholar] [CrossRef] [Green Version]
  54. Kim, M.; Kim, E.; Seo, K.; Yu, S.-Y.; Kwak, H.-W. Change of Retinal Pigment Epithelial Atrophy after Anti-Vascular Endothelial Growth Factor Treatment in Exudative Age-Related Macular Degeneration. Indian J. Ophthalmol. 2016, 64, 427. [Google Scholar] [CrossRef]
  55. Nishimura, T.; Machida, S.; Hara, Y. Changes in Cone-Driven Functions after Intravitreal Aflibercept Injections in Patients with Age-Related Macular Degeneration. Doc. Ophthalmol. 2020, 141, 137–147. [Google Scholar] [CrossRef] [PubMed]
  56. Costagliola, C.; Semeraro, F.; Cipollone, U.; Rinaldi, M.; della Corte, M.; Romano, M.R. Changes in Neovascular Choroidal Morphology after Intravitreal Bevacizumab Injection: Prospective Trial on 156 Eyes throughout 12-Month Follow-Up. Graefes Arch. Clin. Exp. Ophthalmol. 2009, 247, 1031–1037. [Google Scholar] [CrossRef] [PubMed]
  57. Cohen, S.Y.; Mimoun, G.; Oubraham, H.; Zourdani, A.; Malbrel, C.; Queré, S.; Schneider, V. Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: The lumiere study. Retina 2013, 33, 474–481. [Google Scholar] [CrossRef] [PubMed]
  58. Souied, E.H.; Oubraham, H.; Mimoun, G.; Cohen, S.Y.; Quere, S.; Derveloy, A. Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: The twin study. Retina 2015, 35, 1743–1749. [Google Scholar] [CrossRef] [PubMed]
  59. Ting, D.S.W.; Ng, W.Y.; Ng, S.R.; Tan, S.P.; Yeo, I.Y.S.; Mathur, R.; Chan, C.M.; Tan, A.C.S.; Tan, G.S.W.; Wong, T.Y.; et al. Choroidal Thickness Changes in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy: A 12-Month Prospective Study. Am. J. Ophthalmol. 2016, 164, 128–136.e1. [Google Scholar] [CrossRef]
  60. Piermarocchi, S.; Miotto, S.; Colavito, D.; Leon, A.; Segato, T. Combined Effects of Genetic and Non-Genetic Risk Factors Affect Response to Ranibizumab in Exudative Age-Related Macular Degeneration. Acta Ophthalmol. 2015, 93, e451–e457. [Google Scholar] [CrossRef] [PubMed]
  61. Coscas, F.; Querques, G.; Forte, R.; Terrada, C.; Coscas, G.; Souied, E.H. Combined fluorescein angiography and spectral-domain optical coherence tomography imaging of classic choroidal neovascularization secondary to age-related macular degeneration before and after intravitreal ranibizumab injections. Retina 2012, 32, 1069–1076. [Google Scholar] [CrossRef]
  62. Biswas, P.; Sengupta, S.; Choudhary, R.; Home, S.; Paul, A.; Sinha, S. Comparative Role of Intravitreal Ranibizumab versus Bevacizumab in Choroidal Neovascular Membrane in Age-Related Macular Degeneration. Indian J. Ophthalmol. 2011, 59, 191. [Google Scholar] [CrossRef]
  63. Falcão, M.S.; Carneiro, A.M.; Mendonça, L.S.; Fonseca, S.L.; Brandão, E.M.; Falcão-Reis, F. Comparative Study of 1+PRN Ranibizumab versus Bevacizumab in the Clinical Setting. OPTH 2012, 6, 1149. [Google Scholar] [CrossRef] [Green Version]
  64. Schauwvlieghe, A.M.E.; Dijkman, G.; Hooymans, J.M.; Verbraak, F.D.; Hoyng, C.B.; Dijkgraaf, M.G.W.; Peto, T.; Vingerling, J.R.; Schlingemann, R.O. Comparing the Effectiveness of Bevacizumab to Ranibizumab in Patients with Exudative Age-Related Macular Degeneration. The BRAMD Study. PLoS ONE 2016, 11, e0153052. [Google Scholar] [CrossRef] [Green Version]
  65. Au, A.; Parikh, V.S.; Singh, R.P.; Ehlers, J.P.; Yuan, A.; Rachitskaya, A.V.; Sears, J.E.; Srivastava, S.K.; Kaiser, P.K.; Schachat, A.P.; et al. Comparison of Anti-VEGF Therapies on Fibrovascular Pigment Epithelial Detachments in Age-Related Macular Degeneration. Br. J. Ophthalmol. 2017, 101, 970–975. [Google Scholar] [CrossRef]
  66. Cui, J.; Sun, D.; Lu, H.; Dai, R.; Xing, L.; Dong, H.; Wang, L.; Wei, D.; Jiang, B.; Jiao, Y.; et al. Comparison of Effectiveness and Safety between Conbercept and Ranibizumab for Treatment of Neovascular Age-Related Macular Degeneration. A Retrospective Case-Controlled Non-Inferiority Multiple Center Study. Eye 2018, 32, 391–399. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Böhni, S.C.; Bittner, M.; Howell, J.P.; Bachmann, L.M.; Faes, L.; Schmid, M.K. Comparison of Eylea with Lucentis as First-Line Therapy in Patients with Treatment-Naïve Neovascular Age-Related Macular Degeneration in Real-Life Clinical Practice: Retrospective Case-Series Analysis. BMC Ophthalmol. 2015, 15, 109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Ozkaya, A.; Alkin, Z.; Perente, I.; Yuksel, K.; Baz, O.; Alagoz, C.; Yazici, A.T.; Demirok, A. Comparison of Intravitreal Bevacizumab Treatment between Phakic and Pseudophakic Neovascular Age-Related Macular Degeneration. Nep. J. Oph. 2014, 6, 145–152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Ozkaya, A.; Alkin, Z.; Yilmaz, I.; Yazici, A.T. Comparison of Intravitreal Ranibizumab between Phakic and Pseudophakic Neovascular Age-Related Macular Degeneration Patients: Two-Year Results. Saudi. J. Ophthalmol. 2015, 29, 182–186. [Google Scholar] [CrossRef] [Green Version]
  70. Gillies, M.C.; Walton, R.J.; Arnold, J.J.; McAllister, I.L.; Simpson, J.M.; Hunyor, A.P.; Guymer, R.; Essex, R.W.; Morlet, N.; Barthelmes, D. Comparison of Outcomes from a Phase 3 Study of Age-Related Macular Degeneration with a Matched, Observational Cohort. Ophthalmology 2014, 121, 676–681. [Google Scholar] [CrossRef]
  71. Mori, R.; Tanaka, K.; Haruyama, M.; Kawamura, A.; Furuya, K.; Yuzawa, M. Comparison of pro Re Nata versus Bimonthly Injection of Intravitreal Aflibercept for Typical Neovascular Age-Related Macular Degeneration. Ophthalmologica 2017, 238, 17–22. [Google Scholar] [CrossRef] [PubMed]
  72. Berg, K.; Pedersen, T.R.; Sandvik, L.; Bragadóttir, R. Comparison of Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration According to LUCAS Treat-and-Extend Protocol. Ophthalmology 2015, 122, 146–152. [Google Scholar] [CrossRef]
  73. Krebs, I.; Vécsei Marlovits, V.; Bodenstorfer, J.; Glittenberg, C.; Ansari Shahrezaei, S.; Ristl, R.; Binder, S. Comparison of Ranibizumab Monotherapy versus Combination of Ranibizumab with Photodynamic Therapy with Neovascular Age-Related Macular Degeneration. Acta Ophthalmol. 2013, 91, e178–e183. [Google Scholar] [CrossRef] [Green Version]
  74. Garweg, J.G.; Niderprim, S.A.; Russ, H.M.; Pfister, I.B. Comparison of Strategies of Treatment with Ranibizumab in Newly-Diagnosed Cases of Neovascular Age-Related Macular Degeneration. J. Ocul. Pharmacol. Ther. 2017, 33, 773–778. [Google Scholar] [CrossRef] [PubMed]
  75. Inoue, M.; Yamane, S.; Sato, S.; Sakamaki, K.; Arakawa, A.; Kadonosono, K. Comparison of Time to Retreatment and Visual Function Between Ranibizumab and Aflibercept in Age-Related Macular Degeneration. Am. J. Ophthalmol. 2016, 169, 95–103. [Google Scholar] [CrossRef]
  76. Taipale, C.; Lindholm, J.-M.; Kaarniranta, K.; Tuuminen, R. Comparison of Two Different Treat-and-Extend Protocols with Aflibercept in Wet Age-Related Macular Degeneration: Two-Year Results. Adv. Ther. 2020, 37, 2256–2266. [Google Scholar] [CrossRef] [PubMed]
  77. Erden, B. Comparison of Two Different Treatment Regimens’ Efficacy in Neovascular Age-Related Macular Degeneration in Turkish Population—Based on Real Life Data-Bosphorus RWE Study Group. Int. J. Ophthalmol. 2020, 13, 104–111. [Google Scholar] [CrossRef]
  78. Gupta, B.; Adewoyin, T.; Patel, S.-K.; Sivaprasad, S. Comparison of Two Intravitreal Ranibizumab Treatment Schedules for Neovascular Age-Related Macular Degeneration. Br. J. Ophthalmol. 2011, 95, 386–390. [Google Scholar] [CrossRef]
  79. Feng, X.-F.; Constable, I.J.; McAllister, I.L.; Isaacs, T. Comparison of Visual Acuity Outcomes between Ranibizumab and Bevacizumab Treatment in Neovascular Age-Related Macular Degeneration. Int. J. Ophthalmol. 2011, 4, 85–88. [Google Scholar] [CrossRef]
  80. Nischler, C.; Oberkofler, H.; Ortner, C.; Paikl, D.; Riha, W.; Lang, N.; Patsch, W.; Egger, S.F. Complement Factor H Y402H Gene Polymorphism and Response to Intravitreal Bevacizumab in Exudative Age-Related Macular Degeneration. Acta Ophthalmol. 2011, 89, e344–e349. [Google Scholar] [CrossRef]
  81. Studnička, J.; Říhová, B.; Rencová, E.; Rozsíval, P.; Dubská, Z.; Chrapek, O.; Kolář, P.; Kandrnal, V.; Demlová, R.; Pitrová, Š.; et al. Cost and Effectiveness of Therapy for Wet Age-Related Macular Degeneration in Routine Clinical Practice. Ophthalmologica 2013, 230, 34–42. [Google Scholar] [CrossRef] [PubMed]
  82. Scholler, A.; Richter-Mueksch, S.; Weingessel, B.; Vécsei-Marlovits, P.-V. Differences of Frequency in Administration of Ranibizumab and Bevacizumab in Patients with Neovascular AMD. Wien. Klin. Wochenschr. 2014, 126, 355–359. [Google Scholar] [CrossRef] [PubMed]
  83. Yıldırım, Ş.; Akkın, C.; Öztaş, Z.; Nalçacı, S.; Afrashi, F.; Menteş, J. Direct Treatment Costs of Neovascular Age-Related Macular Degeneration and Comparison of Gained and/or Preserved Vision with Expenditure. TJO 2018, 27–32. [Google Scholar] [CrossRef] [PubMed]
  84. Cho, H.J.; Kim, J.M.; Kim, H.S.; Lee, D.W.; Kim, C.G.; Kim, J.W. Effect of Epiretinal Membranes on Antivascular Endothelial Growth Factor Treatment for Neovascular Age-Related Macular Degeneration. J. Ocul. Pharmacol. Ther. 2017, 33, 452–458. [Google Scholar] [CrossRef]
  85. Gillies, M.C.; Hunyor, A.P.; Arnold, J.J.; Guymer, R.H.; Wolf, S.; Ng, P.; Pecheur, F.L.; McAllister, I.L. Effect of Ranibizumab and Aflibercept on Best-Corrected Visual Acuity in Treat-and-Extend for Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial. JAMA Ophthalmol. 2019, 137, 372. [Google Scholar] [CrossRef]
  86. Panos, G.; Gatzioufas, P.; Dardabounis, T. Hafezi Effect of Ranibizumab on Serous and Vascular Pigment Epithelial Detachments Associated with Exudative Age-Related Macular Degeneration. DDDT 2013, 7, 565. [Google Scholar] [CrossRef] [Green Version]
  87. Habibi, I.; Kort, F.; Sfar, I.; Chebil, A.; Bouraoui, R.; Ben Abdallah, T.; Gorgi, Y.; El Matri, L. Effect of Risk Alleles in CFH, C3, and VEGFA on the Response to Intravitreal Bevacizumab in Tunisian Patients with Neovascular Age-related Macular Degeneration. Klin. Monatsbl. Augenheilkd. 2016, 233, 465–470. [Google Scholar] [CrossRef]
  88. Katz, G.; Giavedoni, L.; Muni, R.; Evans, T.; Pezda, M.; Wong, D.; Moffat, A.; Altomare, F.; Boyd, S.; Berger, A. Effectiveness at 1 Year of Monthly versus Variable-Dosing Intravitreal Ranibizumab in the Treatment of Choroidal Neovascularization Secondary to Age-Related Macular Degeneration. Retina 2012, 32, 293–298. [Google Scholar] [CrossRef]
  89. Zhao, C.; Zhang, Z.; Chen, L.; Wang, F.; Xu, D. Effectiveness of Intravitreal Injection of Ranibizumab for Neovascular Age-Related Macular Degeneration with Serous Pigment Epithelial Detachment. Med. Sci. Monit. 2016, 22, 833–839. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Bandukwala, T.; Muni, R.H.; Schwartz, C.; Eng, K.T.; Kertes, P.J. Effectiveness of Intravitreal Ranibizumab for the Treatment of Neovascular Age-Related Macular Degeneration in a Canadian Retina Practice: A Retrospective Review. Can. J. Ophthalmol. 2010, 45, 590–595. [Google Scholar] [CrossRef]
  91. Nunes, R.P.; Hirai, F.E.; Barroso, L.F.; Badaró, E.; Novais, E.; Rodrigues, E.B.; Maia, M.; Magalhães Júnior, O.; Farah, M.E. Effectiveness of Monthly and Fortnightly Anti-VEGF Treatments for Age-Related Macular Degeneration. Arq. Bras. Oftalmol. 2019, 82, 225–232. [Google Scholar] [CrossRef]
  92. Kumar, A.; Sahni, J.N.; Stangos, A.N.; Campa, C.; Harding, S.P. Effectiveness of Ranibizumab for Neovascular Age-Related Macular Degeneration Using Clinician-Determined Retreatment Strategy. Br. J. Ophthalmol. 2011, 95, 530–533. [Google Scholar] [CrossRef] [Green Version]
  93. Rothenbuehler, S.P.; Waeber, D.; Brinkmann, C.K.; Wolf, S.; Wolf-Schnurrbusch, U.E.K. Effects of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Attributable to Age-Related Macular Degeneration. Am. J. Ophthalmol. 2009, 147, 831–837. [Google Scholar] [CrossRef]
  94. Nomura, Y.; Takahashi, H.; Tan, X.; Fujimura, S.; Obata, R.; Yanagi, Y. Effects of Vitreomacular Adhesion on Ranibizumab Treatment in Japanese Patients with Age-Related Macular Degeneration. Jpn. J. Ophthalmol. 2014, 58, 443–447. [Google Scholar] [CrossRef]
  95. for the ALTAIR Investigators; Ohji, M.; Takahashi, K.; Okada, A.A.; Kobayashi, M.; Matsuda, Y.; Terano, Y. Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-Week Findings from ALTAIR: A Randomized Controlled Trial. Adv. Ther. 2020, 37, 1173–1187. [Google Scholar] [CrossRef] [Green Version]
  96. Mitchell, P.; Holz, F.G.; Hykin, P.; Midena, E.; Souied, E.; Allmeier, H.; Lambrou, G.; Schmelter, T.; Wolf, S. Efficacy and safety of intravitreal aflibercept using a treat-and-extend regimen for neovascular age-related macular degeneration: The aries study. Retina 2021, 41, 1911. [Google Scholar] [CrossRef]
  97. Schmidt-Erfurth, U.; Eldem, B.; Guymer, R.; Korobelnik, J.-F.; Schlingemann, R.O.; Axer-Siegel, R.; Wiedemann, P.; Simader, C.; Gekkieva, M.; Weichselberger, A. Efficacy and Safety of Monthly versus Quarterly Ranibizumab Treatment in Neovascular Age-Related Macular Degeneration: The EXCITE Study. Ophthalmology 2011, 118, 831–839. [Google Scholar] [CrossRef]
  98. Mekjavic, P.J.; Kraut, A.; Urbancic, M.; Lenassi, E.; Hawlina, M. Efficacy of 12-Month Treatment of Neovascular Age-Related Macular Degeneration with Intravitreal Bevacizumab Based on Individually Determined Injection Strategies after Three Consecutive Monthly Injections. Acta Ophthalmol. 2011, 89, 647–653. [Google Scholar] [CrossRef]
  99. Kertes, P.J.; Galic, I.J.; Greve, M.; Williams, G.; Baker, J.; Lahaie, M.; Sheidow, T. Efficacy of a Treat-and-Extend Regimen With Ranibizumab in Patients With Neovascular Age-Related Macular Disease: A Randomized Clinical Trial. JAMA Ophthalmol. 2020, 138, 244. [Google Scholar] [CrossRef] [Green Version]
  100. Saito, M.; Kano, M.; Itagaki, K.; Sekiryu, T. Efficacy of Intravitreal Aflibercept in Japanese Patients with Exudative Age-Related Macular Degeneration. Jpn. J. Ophthalmol. 2017, 61, 74–83. [Google Scholar] [CrossRef]
  101. Wolf, A.; Kampik, A. Efficacy of Treatment with Ranibizumab in Patients with Wet Age-Related Macular Degeneration in Routine Clinical Care: Data from the COMPASS Health Services Research. Graefes Arch. Clin. Exp. Ophthalmol. 2014, 252, 647–655. [Google Scholar] [CrossRef] [Green Version]
  102. Castro-Navarro, V.; Cervera-Taulet, E.; Montero-Hernández, J.; Navarro-Palop, C. Estrategia «Tratar y Extender» con aflibercept: Efecto en diferentes tipos de neovascularización coroidea asociada a la edad. Arch. Soc. Española Oftalmol. 2017, 92, 112–119. [Google Scholar] [CrossRef]
  103. Rush, R.B.; Rush, S.W.; Aragon, A.V.; Ysasaga, J.E. Evaluation of Choroidal Neovascularization With Indocyanine Green Angiography in Neovascular Age-Related Macular Degeneration Subjects Undergoing Intravitreal Bevacizumab Therapy. Am. J. Ophthalmol. 2014, 158, 337–344. [Google Scholar] [CrossRef]
  104. Zhao, J.; Li, X.; Tang, S.; Xu, G.; Xu, X.; Zhang, F.; Zhang, M.; Shamsazar, J.; Pilz, S.; Nieweg, A. EXTEND II: An Open-Label Phase III Multicentre Study to Evaluate Efficacy and Safety of Ranibizumab in Chinese Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration. BioDrugs 2014, 28, 527–536. [Google Scholar] [CrossRef]
  105. On Behalf of the EXTEND III Study Group; Kwon, O.-W.; Lee, F.L.; Chung, H.; Lai, C.-C.; Sheu, S.-J.; Yoon, Y.-H. EXTEND III: Efficacy and Safety of Ranibizumab in South Korean and Taiwanese Patients with Subfoveal CNV Secondary to AMD. Graefes Arch. Clin. Exp. Ophthalmol. 2012, 250, 1467–1476. [Google Scholar] [CrossRef]
  106. Williams, G.S.; Seow, E.; Evans, H.; Owoniyi, M.; Evans, S.; Blyth, C. Factors Affecting Visual Acuity after One Year of Follow up after Repeated Intravitreal Ranibizumab for Macular Degeneration. Saudi J. Ophthalmol. 2015, 29, 187–191. [Google Scholar] [CrossRef] [Green Version]
  107. Yamashiro, K.; Tomita, K.; Tsujikawa, A.; Nakata, I.; Akagi-Kurashige, Y.; Miyake, M.; Ooto, S.; Tamura, H.; Yoshimura, N. Factors Associated With the Response of Age-Related Macular Degeneration to Intravitreal Ranibizumab Treatment. Am. J. Ophthalmol. 2012, 154, 125–136. [Google Scholar] [CrossRef]
  108. Kikushima, W.; Sakurada, Y.; Sugiyama, A.; Tanabe, N.; Kume, A.; Iijima, H. Factors Predictive of Visual Outcome 1 Year After Intravitreal Aflibercept Injection for Typical Neovascular Age-Related Macular Degeneration. J. Ocul. Pharmacol. Ther. 2016, 32, 376–382. [Google Scholar] [CrossRef]
  109. Sül, S.; Karalezli, A.; Karabulut, M. First-Year Outcomes of Cataract Surgery Combined with Intravitreal Ranibizumab Injection in Wet Age-Related Macular Degeneration. Turk. J. Ophthalmol. 2019, 49, 15–19. [Google Scholar] [CrossRef]
  110. Talks, J.S.; Lotery, A.J.; Ghanchi, F.; Sivaprasad, S.; Johnston, R.L.; Patel, N.; McKibbin, M.; Bailey, C.; Mahmood, S.; Lobo, A.; et al. First-Year Visual Acuity Outcomes of Providing Aflibercept According to the VIEW Study Protocol for Age-Related Macular Degeneration. Ophthalmology 2016, 123, 337–343. [Google Scholar] [CrossRef]
  111. Ozkaya, A.; Alkin, Z.; Togac, M.; Ahmet, S.; Perente, I.; Taskapili, M. Five-Year Outcomes of Ranibizumab in Neovascular Age-Related Macular Degeneration: Real Life Clinical Experience. Korean J. Ophthalmol. 2017, 31, 424. [Google Scholar] [CrossRef] [Green Version]
  112. Luigi Grenga, P.; Fragiotta, S.; Meduri, A.; Lupo, S.; Marenco, M.; Vingolo, E.M. Fixation Stability Measurements in Patients with Neovascular Age-Related Macular Degeneration Treated with Ranibizumab. Can. J. Ophthalmol. 2013, 48, 394–399. [Google Scholar] [CrossRef]
  113. Warwick, A.N.; Leaver, H.H.; Lotery, A.J.; Goverdhan, S.V. Fixed Bimonthly Aflibercept in Naïve and Switched Neovascular Age-Related Macular Degeneration Patients: One Year Outcomes. Int. J. Ophthalmol. 2016, 9, 1156. [Google Scholar] [CrossRef]
  114. El-Mollayess, G.M.; Mahfoud, Z.; Schakal, A.R.; Salti, H.I.; Jaafar, D.; Bashshur, Z.F. Fixed-Interval Versus OCT-Guided Variable Dosing of Intravitreal Bevacizumab in the Management of Neovascular Age-Related Macular Degeneration: A 12-Month Randomized Prospective Study. Am. J. Ophthalmol. 2012, 153, 481–489.e1. [Google Scholar] [CrossRef]
  115. Tsunekawa, Y.; Kataoka, K.; Asai, K.; Ito, Y.; Terasaki, H. Four-Year Outcome of Aflibercept Administration Using a Treat-and-Extend Regimen in Eyes with Recurrent Neovascular Age-Related Macular Degeneration. Jpn. J. Ophthalmol. 2021, 65, 69–76. [Google Scholar] [CrossRef] [PubMed]
  116. Nishikawa, K.; Oishi, A.; Hata, M.; Miyake, M.; Ooto, S.; Yamashiro, K.; Miyata, M.; Tamura, H.; Ueda-Arakawa, N.; Takahashi, A.; et al. Four-Year Outcome of Aflibercept for Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy. Sci. Rep. 2019, 9, 3620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Subhi, Y.; Henningsen, G.Ø.; Larsen, C.T.; Sørensen, M.S.; Sørensen, T.L. Foveal Morphology Affects Self-Perceived Visual Function and Treatment Response in Neovascular Age-Related Macular Degeneration: A Cohort Study. PLoS ONE 2014, 9, e91227. [Google Scholar] [CrossRef] [Green Version]
  118. Sakai, T.; Okude, S.; Tsuneoka, H. Foveal Threshold and Photoreceptor Integrity for Prediction of Visual Acuity after Intravitreal Aflibercept on Age-Related Macular Degeneration. OPTH 2018, 12, 719–725. [Google Scholar] [CrossRef] [Green Version]
  119. Chhablani, J.; Kozak, R.I.; Mojana, F.; Cheng, L.; Morrison, V.L.; Wang, H.; Kim, J.S.; Dustin, L.; Azen, S.; Freeman, W.R. Fundus autofluorescence not predictive of treatment response to intravitreal bevacizumab in exudative age-related macular degeneration. Retina 2012, 32, 1465–1470. [Google Scholar] [CrossRef] [PubMed]
  120. Coco, R.M.; Sanabria, M.R.; Castrejon, M.; Lopez-Galvez, M.I.; Monje-Fernandez, L.; Fernandez-Munoz, M.; Anton, A.; de Juan-Marcos, L.; Villaron-Alvarez, S.; Fernandez, I. Funduscopic Results after 4-Year Follow-up Treatment with Ranibizumab for Age-Related Macular Degeneration in a Region of Spain. BMC Ophthalmol. 2014, 14, 138. [Google Scholar] [CrossRef] [Green Version]
  121. Monés, J.; Biarnés, M.; Trindade, F.; Casaroli-Marano, R. FUSION Regimen: Ranibizumab in Treatment-Naïve Patients with Exudative Age-Related Macular Degeneration and Relatively Good Baseline Visual Acuity. Graefes Arch. Clin. Exp. Ophthalmol. 2012, 250, 1737–1744. [Google Scholar] [CrossRef] [Green Version]
  122. Rodríguez, F.; Rios, H.; Aguilar, M.; Rosenstiehl, S.; Gelvez, N.; Lopez, G.; Tamayo, M. Genetic Association with Intravitreal Ranibizumab Response for Neovascular Age-Related Macular Degeneration in Hispanic Population. Taiwan J. Ophthalmol. 2019, 9, 243. [Google Scholar] [CrossRef]
  123. Kloeckener-Gruissem, B.; Barthelmes, D.; Labs, S.; Schindler, C.; Kurz-Levin, M.; Michels, S.; Fleischhauer, J.; Berger, W.; Sutter, F.; Menghini, M. Genetic Association with Response to Intravitreal Ranibizumab in Patients with Neovascular AMD. Invest. Ophthalmol. Vis. Sci. 2011, 52, 4694. [Google Scholar] [CrossRef]
  124. de Massougnes, S.; Dirani, A.; Mantel, I. Good visual outcome at 1 year in neovascular age-related macular degeneration with pigment epithelium detachment: Factors Influencing the Treatment Response. Retina 2018, 38, 717–724. [Google Scholar] [CrossRef] [PubMed]
  125. Dugel, P.U.; Koh, A.; Ogura, Y.; Jaffe, G.J.; Schmidt-Erfurth, U.; Brown, D.M.; Gomes, A.V.; Warburton, J.; Weichselberger, A.; Holz, F.G. HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology 2020, 127, 72–84. [Google Scholar] [CrossRef]
  126. Tuerksever, C.; Pruente, C.; Hatz, K. High Frequency SD-OCT Follow-up Leading to up to Biweekly Intravitreal Ranibizumab Treatment in Neovascular Age-Related Macular Degeneration. Sci. Rep. 2021, 11, 6816. [Google Scholar] [CrossRef] [PubMed]
  127. Menghini, M.; Kloeckener-Gruissem, B.; Fleischhauer, J.; Kurz-Levin, M.M.; Sutter, F.K.P.; Berger, W.; Barthelmes, D. Impact of Loading Phase, Initial Response and CFH Genotype on the Long-Term Outcome of Treatment for Neovascular Age-Related Macular Degeneration. PLoS ONE 2012, 7, e42014. [Google Scholar] [CrossRef] [Green Version]
  128. Wickremasinghe, S.S.; Janakan, V.; Sandhu, S.S.; Amirul-Islam, F.M.; Abedi, F.; Guymer, R.H. Implication of recurrent or retained fluid on optical coherence tomography for visual acuity during active treatment of neovascular age-related macular degeneration with a treat and extend protocol. Retina 2016, 36, 1331–1339. [Google Scholar] [CrossRef] [PubMed]
  129. Hata, M.; Oishi, A.; Yamashiro, K.; Ooto, S.; Tamura, H.; Nakanishi, H.; Ueda-Arakawa, N.; Akagi-Kurashige, Y.; Kuroda, Y.; Takahashi, A.; et al. Incidence and causes of vision loss during aflibercept treatment for neovascular age-related macular degeneration: One-Year Follow-Up. Retina 2017, 37, 1320–1328. [Google Scholar] [CrossRef] [PubMed]
  130. Barikian, A.; Mahfoud, Z.; Abdulaal, M.; Safar, A.; Bashshur, Z.F. Induction With Intravitreal Bevacizumab Every Two Weeks in the Management of Neovascular Age-Related Macular Degeneration. Am. J. Ophthalmol. 2015, 159, 131–137. [Google Scholar] [CrossRef]
  131. Oubraham, H.; Cohen, S.Y.; Samimi, S.; Marotte, D.; Bouzaher, I.; Bonicel, P.; Fajnkuchen, F.; Tadayoni, R. Inject and extend dosing versus dosing as needed: A Comparative Retrospective Study of Ranibizumab in Exudative Age-Related Macular Degeneration. Retina 2011, 31, 26–30. [Google Scholar] [CrossRef] [PubMed]
  132. Papavasileiou, E.; Zygoura, V.; Richardson, T.; Cortis, D.; Eleftheriadis, H.; Jackson, T.L. Intravitreal Aflibercept (A-IVI) for the Treatment of Neovascular Age-Related Macular Degeneration (Nv-AMD): One Year Experience. Hell. J. Nucl. Med. 2015, 18 (Suppl. 1), 29–32. [Google Scholar] [PubMed]
  133. Heier, J.S.; Brown, D.M.; Chong, V.; Korobelnik, J.-F.; Kaiser, P.K.; Nguyen, Q.D.; Kirchhof, B.; Ho, A.; Ogura, Y.; Yancopoulos, G.D.; et al. Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-Related Macular Degeneration. Ophthalmology 2012, 119, 2537–2548. [Google Scholar] [CrossRef]
  134. UK Aflibercept Users Group; Chatziralli, I.; Regan, S.O.; Mohamed, R.; Talks, J.; Sivaprasad, S. Intravitreal Aflibercept for Neovascular Age-Related Macular Degeneration in Patients Aged 90 Years or Older: 2-Year Visual Acuity Outcomes. Eye 2018, 32, 1523–1529. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Hatz, K.; Prünte, C. Intravitreal aflibercept in neovascular age-related macular degeneration with limited response to ranibizumab: A Treat-and-Extend Trial. Retina 2017, 37, 1185–1192. [Google Scholar] [CrossRef]
  136. Ruys, J.; Mangelschots, E.; Jacob, J.; Mergaerts, F.; Kozyreff, A.; Dirven, W. Intravitreal Aflibercept Treatment Strategies in Routine Clinical Practice of Neovascular Age-Related Macular Degeneration in Belgium: A Retrospective Observational Study. Ophthalmol. Ther. 2020, 9, 993–1002. [Google Scholar] [CrossRef]
  137. Smit, C.; Wiertz-Arts, K.; van de Garde, E.M. Intravitreal Aflibercept versus Intravitreal Ranibizumab in Patients with Age-Related Macular Degeneration: A Comparative Effectiveness Study. J. Comp. Eff. Res. 2018, 7, 561–567. [Google Scholar] [CrossRef] [Green Version]
  138. Rudnisky, C.J.; Liu, C.; Ng, M.; Weis, E.; Tennant, M.T.S. Intravitreal bevacizumab alone versus combined verteporfin photodynamic therapy and intravitreal bevacizumab for choroidal neovascularization in age-related macular degeneration: Visual Acuity After 1 Year of Follow-Up. Retina 2010, 30, 548–554. [Google Scholar] [CrossRef]
  139. Selid, P.D.; Jundt, M.C.; Fortney, A.C.; Beal, J.R. Intravitreal Bevacizumab and Aflibercept for the Treatment of Exudative Age-Related Macular Degeneration. Ophthalmic. Surg. Lasers Imaging Retina 2014, 45, 275–281. [Google Scholar] [CrossRef]
  140. Fong, D.S.; Custis, P.; Howes, J.; Hsu, J.-W. Intravitreal Bevacizumab and Ranibizumab for Age-Related Macular Degeneration. Ophthalmology 2010, 117, 298–302. [Google Scholar] [CrossRef]
  141. Takahashi, M.; Sato, T.; Kishi, S. Intravitreal Bevacizumab for Age-Related Macular Degeneration with Good Visual Acuity. Jpn. J. Ophthalmol. 2010, 54, 565–570. [Google Scholar] [CrossRef]
  142. Carneiro, Â.M.; Falcão, M.S.; Brandão, E.M.; Falcão-Reis, F.M. Intravitreal bevacizumab for neovascular age-related macular degeneration with or without prior treatment with photodynamic therapy: One-Year Results. Retina 2010, 30, 85–92. [Google Scholar] [CrossRef]
  143. Arevalo, J.F.; Sánchez, J.G.; Wu, L.; Berrocal, M.H.; Alezzandrini, A.A.; Restrepo, N.; Maia, M.; Farah, M.E.; Brito, M.; Díaz-Llopis, M.; et al. Intravitreal Bevacizumab for Subfoveal Choroidal Neovascularization in Age-Related Macular Degeneration at Twenty-Four Months: The Pan-American Collaborative Retina Study. Ophthalmology 2010, 117, 1974–1981.e1. [Google Scholar] [CrossRef]
  144. Bashshur, Z.F.; Bazarbachi, A.; Schakal, A.; Haddad, Z.A.; El Haibi, C.P.; Noureddin, B.N. Intravitreal Bevacizumab for the Management of Choroidal Neovascularization in Age-Related Macular Degeneration. Am. J. Ophthalmol. 2006, 142, 1–9. [Google Scholar] [CrossRef]
  145. El-Mollayess, G.M.; Mahfoud, Z.; Schakal, A.R.; Salti, H.I.; Jaafar, D.; Bashshur, Z.F. Intravitreal bevacizumab in the management of neovascular age-related macular degeneration: Effect of Baseline Visual Acuity. Retina 2013, 33, 1828–1835. [Google Scholar] [CrossRef]
  146. Axer-Siegel, R.; Bor, E.; Bourla, D.H.; Weinberger, D.; Mimouni, K. Intravitreal bevacizumab treatment for exudative age-related macular degeneration with good visual acuity. Retina 2012, 32, 1811–1820. [Google Scholar] [CrossRef]
  147. Inoue, M.; Arakawa, A.; Yamane, S.; Kadonosono, K. Intravitreal Injection of Ranibizumab Using A pro Re Nata Regimen for Age-Related Macular Degeneration and Vision-Related Quality of Life. OPTH 2014, 8, 1711. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  148. Iacono, P.; Parodi, M.B.; Introini, U.; La Spina, C.; Varano, M.; Bandello, F. Intravitreal ranibizumab for choroidal neovascularization with large submacular hemorrhage in age-related macular degeneration. Retina 2014, 34, 281–287. [Google Scholar] [CrossRef] [PubMed]
  149. Kato, A.; Yasukawa, T.; Suga, K.; Hirano, Y.; Nozaki, M.; Yoshida, M.; Ogura, Y. Intravitreal Ranibizumab for Patients with Neovascular Age-Related Macular Degeneration with Good Baseline Visual Acuity. Ophthalmologica 2015, 233, 27–34. [Google Scholar] [CrossRef] [PubMed]
  150. Iordanous, Y.; Powell, A.-M.; Mao, A.; Hooper, P.L.; Eng, K.T.; Schwartz, C.; Kertes, P.J.; Sheidow, T.G. Intravitreal Ranibizumab for the Treatment of Fibrovascular Pigment Epithelial Detachment in Age-Related Macular Degeneration. Can. J. Ophthalmol. 2014, 49, 367–376. [Google Scholar] [CrossRef] [PubMed]
  151. Sun Baek, J.; Cho, H.J.; Cho, S.W.; Kim, C.G.; Kim, J.W. Intravitreal ranibizumab injection for neovascular age-related macular degeneration in phakic versus pseudophakic eyes. Retina 2013, 33, 467–473. [Google Scholar] [CrossRef]
  152. Abdin, A.D.; Suffo, S.; Asi, F.; Langenbucher, A.; Seitz, B. Intravitreal Ranibizumab versus Aflibercept Following Treat and Extend Protocol for Neovascular Age-Related Macular Degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 2019, 257, 1671–1677. [Google Scholar] [CrossRef] [PubMed]
  153. Menon, G.; Chandran, M.; Sivaprasad, S.; Chavan, R.; Narendran, N.; Yang, Y. Is It Necessary to Use Three Mandatory Loading Doses When Commencing Therapy for Neovascular Age-Related Macular Degeneration Using Bevacizumab? (BeMOc Trial). Eye 2013, 27, 959–963. [Google Scholar] [CrossRef] [Green Version]
  154. Karagiannis, D.; Chatziralli, I.; Kaprinis, K.; Georgalas, I.; Parikakis, E.; Mitropoulos, P. Location of Submacular Hemorrhage as a Predictor of Visual Outcome after Intravitreal Ranibizumab for Age-Related Macular Degeneration. CIA 2017, 12, 1829–1833. [Google Scholar] [CrossRef] [Green Version]
  155. Inan, Ü.Ü.; Baysal, Z.; Inan, S. Long-Term Changes in Retinal Layers in Patients Undergoing Intravitreal Ranibizumab for Neovascular Age-Related Macular Degeneration: Retinal Layers after Anti-VEGF Therapy. Int. Ophthalmol. 2019, 39, 2721–2730. [Google Scholar] [CrossRef] [PubMed]
  156. Inan, S.; Baysal, Z.; Inan, U.U. Long-Term Changes in Submacular Choroidal Thickness after Intravitreal Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration: 14-Mo Follow-Up. Curr. Eye Res. 2019, 44, 908–915. [Google Scholar] [CrossRef] [PubMed]
  157. Traine, P.G.; Pfister, I.B.; Zandi, S.; Spindler, J.; Garweg, J.G. Long-Term Outcome of Intravitreal Aflibercept Treatment for Neovascular Age-Related Macular Degeneration Using a “Treat-and-Extend” Regimen. Ophthalmol. Retin. 2019, 3, 393–399. [Google Scholar] [CrossRef] [PubMed]
  158. Eleftheriadou, M.; Vazquez-Alfageme, C.; Citu, C.M.; Crosby-Nwaobi, R.; Sivaprasad, S.; Hykin, P.; Hamilton, R.D.; Patel, P.J. Long-Term Outcomes of Aflibercept Treatment for Neovascular Age-Related Macular Degeneration in a Clinical Setting. Am. J. Ophthalmol. 2017, 174, 160–168. [Google Scholar] [CrossRef] [PubMed]
  159. Calvo, P.; Abadia, B.; Ferreras, A.; Ruiz-Moreno, O.; Leciñena, J.; Torrón, C. Long-Term Visual Outcome in Wet Age-Related Macular Degeneration Patients Depending on the Number of Ranibizumab Injections. J. Ophthalmol. 2015, 2015, 1–5. [Google Scholar] [CrossRef] [Green Version]
  160. Costagliola, C.; Romano, M.R.; Rinaldi, M.; dell’Omo, R.; Chiosi, F.; Menzione, M.; Semeraro, F. Low Fluence Rate Photodynamic Therapy Combined with Intravitreal Bevacizumab for Neovascular Age-Related Macular Degeneration. Br. J. Ophthalmol. 2010, 94, 180–184. [Google Scholar] [CrossRef] [Green Version]
  161. Ranchod, T.M.; Ray, S.K.; Daniels, S.A.; Leong, C.J.; Ting, T.D.; Verne, A.Z. LUCEDEX: A Prospective Study Comparing Ranibizumab plus Dexamethasone Combination Therapy Versus Ranibizumab Monotherapy for Neovascular Age-Related Macular Degeneration. Retina 2013, 33, 1600–1604. [Google Scholar] [CrossRef]
  162. Koizumi, H.; Yamamoto, A.; Ogasawara, M.; Maruko, I.; Hasegawa, T.; Itagaki, K.; Sekiryu, T.; Okada, A.A.; Iida, T. Macular Atrophy after Aflibercept Therapy for Neovascular Age-Related Macular Degeneration: Outcomes of Japanese Multicenter Study. Jpn. J. Ophthalmol. 2020, 64, 338–345. [Google Scholar] [CrossRef] [PubMed]
  163. Kuroda, Y.; Yamashiro, K.; Ooto, S.; Tamura, H.; Oishi, A.; Nakanishi, H.; Miyata, M.; Hata, M.; Takahashi, A.; Wakazono, T.; et al. Macular atrophy and macular morphology in aflibercept-treated neovascular age-related macular degeneration. Retina 2018, 38, 1743–1750. [Google Scholar] [CrossRef]
  164. Gillies, M.C.; Hunyor, A.P.; Arnold, J.J.; Guymer, R.H.; Wolf, S.; Pecheur, F.L.; Munk, M.R.; McAllister, I.L. Macular Atrophy in Neovascular Age-Related Macular Degeneration. Ophthalmology 2020, 127, 198–210. [Google Scholar] [CrossRef] [Green Version]
  165. Pushpoth, S.; Sykakis, E.; Merchant, K.; Browning, A.C.; Gupta, R.; Talks, S.J. Measuring the Benefit of 4 Years of Intravitreal Ranibizumab Treatment for Neovascular Age-Related Macular Degeneration. Br. J. Ophthalmol. 2012, 96, 1469–1473. [Google Scholar] [CrossRef]
  166. Michalewska, Z.; Michalewski, J.; Nawrocki, J.; Izdebski, B. Morphological Changes in Spectral Domain Optical Coherence Tomography Guided Bevacizumab Injections in Wet Age-Related Macular Degeneration, 12-Months Results. Indian J. Ophthalmol. 2014, 62, 554. [Google Scholar] [CrossRef]
  167. Holz, F.G.; Tadayoni, R.; Beatty, S.; Berger, A.; Cereda, M.G.; Cortez, R.; Hoyng, C.B.; Hykin, P.; Staurenghi, G.; Heldner, S.; et al. Multi-Country Real-Life Experience of Anti-Vascular Endothelial Growth Factor Therapy for Wet Age-Related Macular Degeneration. Br. J. Ophthalmol. 2015, 99, 220–226. [Google Scholar] [CrossRef]
  168. Tarakcioglu, H.N.; Ozkaya, A.; Kemer, B.; Taskapili, M. Multimodal Imaging Based Biomarkers Predictive of Early and Late Response to Anti-VEGFs during the First Year of Treatment for Neovascular Age-Related Macular Degeneration. J. Français D’ophtalmologie 2019, 42, 22–31. [Google Scholar] [CrossRef] [PubMed]
  169. Epstein, D.; Amrén, U. Near vision outcome in patients with age-related macular degeneration treated with aflibercept. Retina 2016, 36, 1773–1777. [Google Scholar] [CrossRef]
  170. Subhi, Y.; Sørensen, T.L. Neovascular Age-Related Macular Degeneration in the Very Old (≥90 Years): Epidemiology, Adherence to Treatment, and Comparison of Efficacy. J. Ophthalmol. 2017, 2017, 1–9. [Google Scholar] [CrossRef] [PubMed]
  171. Rasmussen, A.; Sander, B.; Larsen, M.; Brandi, S.; Fuchs, J.; Hansen, L.H.; Lund-Andersen, H. Neovascular Age-Related Macular Degeneration Treated with Ranibizumab or Aflibercept in the Same Large Clinical Setting: Visual Outcome and Number of Injections. Acta Ophthalmol. 2017, 95, 128–132. [Google Scholar] [CrossRef]
  172. Maberley, D.A.L.; Zhang, R.; Ding, L.; Flatt, A.H.; Etminan, M.; Hewitt, M. One-Year Effectiveness Study of Intravitreous Bevacizumab in Neovascular Age-Related Macular Degeneration: A Population-Based Retrospective Cohort Study. Can. J. Ophthalmol. 2018, 53, 627–631. [Google Scholar] [CrossRef] [PubMed]
  173. Arora, S.; McKibbin, M. One-Year Outcome after Intravitreal Ranibizumab for Large, Serous Pigment Epithelial Detachment Secondary to Age-Related Macular Degeneration. Eye 2011, 25, 1034–1038. [Google Scholar] [CrossRef]
  174. Gabai, A.; Veritti, D.; Lanzetta, P. One-Year Outcome of Ranibizumab for Neovascular Age-Related Macular Degeneration: A Thorough Analysis in a Real-World Clinical Setting. Eur. J. Ophthalmol. 2014, 24, 396–401. [Google Scholar] [CrossRef] [PubMed]
  175. Takayama, K.; Kaneko, H.; Sugita, T.; Maruko, R.; Hattori, K.; Ra, E.; Kawano, K.; Kataoka, K.; Ito, Y.; Terasaki, H. One-Year Outcomes of 1 + pro Re Nata versus 3 + pro Re Nata Intravitreal Aflibercept Injection for Neovascular Age-Related Macular Degeneration. Ophthalmologica 2017, 237, 105–110. [Google Scholar] [CrossRef]
  176. Wang, F.; Yuan, Y.; Wang, L.; Ye, X.; Zhao, J.; Shen, M.; Zhang, Q.; Xu, D.; Qin, G.; Zhang, W.; et al. One-Year Outcomes of 1 Dose versus 3 Loading Doses Followed by Pro Re Nata Regimen Using Ranibizumab for Neovascular Age-Related Macular Degeneration: The ARTIS Trial. J. Ophthalmol. 2019, 2019, 7530458. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  177. Yamamoto, A.; Okada, A.A.; Nakayama, M.; Yoshida, Y.; Kobayashi, H. One-Year Outcomes of a Treat-and-Extend Regimen of Aflibercept for Exudative Age-Related Macular Degeneration. Ophthalmologica 2017, 237, 139–144. [Google Scholar] [CrossRef]
  178. Singh, S.R.; Fung, A.T.; Fraser-Bell, S.; Lupidi, M.; Mohan, S.; Gabrielle, P.-H.; Zur, D.; Iglicki, M.; López-Corell, P.; Gallego-Pinazo, R.; et al. One-Year Outcomes of Anti-Vascular Endothelial Growth Factor Therapy in Peripapillary Choroidal Neovascularisation. Br. J. Ophthalmol. 2020, 104, 678–683. [Google Scholar] [CrossRef]
  179. Ono, A.; Shiragami, C.; Manabe, S.; Takasago, Y.; Osaka, R.; Kobayashi, M.; Yamashita, A.; Tsujikawa, A.; Hirooka, K. One-Year Outcomes of Fixed Treatment of Intravitreal Aflibercept for Exudative Age-Related Macular Degeneration and the Factor of Visual Prognosis. Medicine 2018, 97, e11737. [Google Scholar] [CrossRef]
  180. Sonmez, K.; Sonmez, P.A.; Ozkan, S.S.; Atmaca, L.S. One-year outcomes of less frequent bevacizumab in age-related macular degeneration. Retina 2011, 31, 645–653. [Google Scholar] [CrossRef] [PubMed]
  181. Figurska, M.; Matysik-Wożniak, A.; Adamiec-Mroczek, J.; Dolar-Szczasny, J.; Misiuk-Hojło, M.; Teper, S.; Święch-Zubilewicz, A.; Ulińska, M.; Rejdak, R.; Rękas, M. One-Year Outcomes of the Polish Treatment Program for the Wet Form of Age-Related Macular Degeneration Using Intravitreal Therapy. Eur. J. Ophthalmol. 2020, 30, 586–594. [Google Scholar] [CrossRef]
  182. Hjelmqvist, L.; Lindberg, C.; Kanulf, P.; Dahlgren, H.; Johansson, I.; Siewert, A. One-Year Outcomes Using Ranibizumab for Neovascular Age-Related Macular Degeneration: Results of a Prospective and Retrospective Observational Multicentre Study. J. Ophthalmol. 2011, 2011, 1–8. [Google Scholar] [CrossRef]
  183. Almuhtaseb, H.; Kanavati, S.; Rufai, S.R.; Lotery, A.J. One-Year Real-World Outcomes in Patients Receiving Fixed-Dosing Aflibercept for Neovascular Age-Related Macular Degeneration. Eye 2017, 31, 878–883. [Google Scholar] [CrossRef] [Green Version]
  184. Oishi, A.; Tsujikawa, A.; Yamashiro, K.; Ooto, S.; Tamura, H.; Nakanishi, H.; Ueda-Arakawa, N.; Miyake, M.; Akagi-Kurashige, Y.; Hata, M.; et al. One-Year Result of Aflibercept Treatment on Age-Related Macular Degeneration and Predictive Factors for Visual Outcome. Am. J. Ophthalmol. 2015, 159, 853–860.e1. [Google Scholar] [CrossRef]
  185. Arias, L.; Roman, I.; Masuet-Aumatell, C.; Rubio, M.J.; Caminal, J.M.; Catala, J.; Pujol, O. One-year results of a flexible regimen with ranibizumab therapy in macular degeneration: Relationship with the Number of Injections. Retina 2011, 31, 1261–1267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Ozkaya, A.; Alkin, Z.; Agca, A.; Satici, T.; Karakucuk, Y.; Yazici, A.T.; Demirok, A. One-Year Results of Treatment with Bevacizumab Alone or Ranibizumab Alone for Low Visual Acuity Due to Neovascular Age-Related Macular Degeneration. J. Ocul. Pharmacol. Ther. 2013, 29, 865–869. [Google Scholar] [CrossRef]
  187. Jaki Mekjavic, P.; Zaletel Benda, P. Outcome of 5-Year Treatment of Neovascular Age-Related Macular Degeneration With Intravitreal Anti-VEGF Using “Treat and Extend” Regimen. Front. Med. 2018, 5, 125. [Google Scholar] [CrossRef] [Green Version]
  188. Bandello, F.; Corvi, F.; La Spina, C.; Benatti, L.; Querques, L.; Capuano, V.; Naysan, J.; Chen, X.; Sarraf, D.; Parodi, M.B.; et al. Outcomes of Intravitreal Anti-VEGF Therapy in Eyes with Both Neovascular Age-Related Macular Degeneration and Diabetic Retinopathy. Br. J. Ophthalmol. 2016, 100, 1611–1616. [Google Scholar] [CrossRef] [PubMed]
  189. Hermann, M.M.; van Asten, F.; Muether, P.S.; Smailhodzic, D.; Lichtner, P.; Hoyng, C.B.; Kirchhof, B.; Grefkes, C.; den Hollander, A.I.; Fauser, S. Polymorphisms in Vascular Endothelial Growth Factor Receptor 2 Are Associated with Better Response Rates to Ranibizumab Treatment in Age-Related Macular Degeneration. Ophthalmology 2014, 121, 905–910. [Google Scholar] [CrossRef]
  190. Fulcher, C.; Hazel, C.A.; Pacey, I.; Ali, H.; Ghanchi, F.D. Predicting Visual Outcomes in Patients Treated with Aflibercept for Neovascular Age-Related Macular Degeneration: Data from a Real-World Clinical Setting. Eur. J. Ophthalmol. 2020, 30, 543–549. [Google Scholar] [CrossRef] [PubMed]
  191. Mathew, R.; Richardson, M.; Sivaprasad, S. Predictive Value of Spectral-Domain Optical Coherence Tomography Features in Assessment of Visual Prognosis in Eyes With Neovascular Age-Related Macular Degeneration Treated With Ranibizumab. Am. J. Ophthalmol. 2013, 155, 720–726.e1. [Google Scholar] [CrossRef]
  192. Bloch, S.B.; la Cour, M.; Sander, B.; Hansen, L.K.H.; Fuchs, J.; Lund-Andersen, H.; Larsen, M. Predictors of 1-Year Visual Outcome in Neovascular Age-Related Macular Degeneration Following Intravitreal Ranibizumab Treatment. Acta Ophthalmol. 2013, 91, 42–47. [Google Scholar] [CrossRef]
  193. Finger, R.P.; Wickremasinghe, S.S.; Baird, P.N.; Guymer, R.H. Predictors of Anti-VEGF Treatment Response in Neovascular Age-Related Macular Degeneration. Surv. Ophthalmol. 2014, 59, 1–18. [Google Scholar] [CrossRef] [PubMed]
  194. Kodjikian, L.; Decullier, E.; Souied, E.H.; Roux, A.; Aulagner, G.; Huot, L.; for the GEFAL Study Group. Predictors of one-year visual outcomes after anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration. Retina 2018, 38, 1492–1499. [Google Scholar] [CrossRef] [PubMed]
  195. Byun, Y.J.; Lee, S.J.; Koh, H.J. Predictors of Response after Intravitreal Bevacizumab Injection for Neovascular Age-Related Macular Degeneration. Jpn. J. Ophthalmol. 2010, 54, 571–577. [Google Scholar] [CrossRef] [PubMed]
  196. Ogasawara, M.; Koizumi, H.; Yamamoto, A.; Itagaki, K.; Saito, M.; Maruko, I.; Okada, A.A.; Iida, T.; Sekiryu, T. Prognostic Factors after Aflibercept Therapy for Typical Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy. Jpn. J. Ophthalmol. 2018, 62, 584–591. [Google Scholar] [CrossRef] [PubMed]
  197. Pokroy, R.; Mimouni, M.; Barayev, E.; Segev, F.; Geffen, N.; Nemet, A.Y.; Segal, O. Prognostic value of subretinal hyperreflective material in neovascular age-related macular degeneration treated with bevacizumab. Retina 2018, 38, 1485–1491. [Google Scholar] [CrossRef] [PubMed]
  198. Datseris, I.; Kontadakis, G.A.; Diamanti, R.; Datseris, I.; Pallikaris, I.G.; Theodossiadis, P.; Tsilimbaris, M.K. Prospective Comparison of Low-Fluence Photodynamic Therapy Combined with Intravitreal Bevacizumab versus Bevacizumab Monotherapy for Choroidal Neovascularization in Age-Related Macular Degeneration. Semin. Ophthalmol. 2015, 30, 112–117. [Google Scholar] [CrossRef]
  199. Flaxel, C.; Schain, M.B.; Hamon, S.C.; Francis, P.J. Prospective randomized controlled trial of combination ranibizumab (lucentis) and bromfenac (xibrom) for neovascular age-related macular degeneration: A Pilot Study. Retina 2012, 32, 417–423. [Google Scholar] [CrossRef]
  200. Wykoff, C.C.; Croft, D.E.; Brown, D.M.; Wang, R.; Payne, J.F.; Clark, L.; Abdelfattah, N.S.; Sadda, S.R. Prospective Trial of Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration. Ophthalmology 2015, 122, 2514–2522. [Google Scholar] [CrossRef] [Green Version]
  201. Sacu, S.; Michels, S.; Prager, F.; Weigert, G.; Dunavoelgyi, R.; Geitzenauer, W.; Pruente, C.; Schmidt-Erfurth, U. Randomised Clinical Trial of Intravitreal Avastin vs Photodynamic Therapy and Intravitreal Triamcinolone: Long-Term Results. Eye 2009, 23, 2223–2227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  202. Regillo, C.D.; Brown, D.M.; Abraham, P.; Yue, H.; Ianchulev, T.; Schneider, S.; Shams, N. Randomized, Double-Masked, Sham-Controlled Trial of Ranibizumab for Neovascular Age-Related Macular Degeneration: PIER Study Year 1. Am. J. Ophthalmol. 2008, 145, 239–248.e5. [Google Scholar] [CrossRef] [PubMed]
  203. Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration. N. Engl. J. Med. 2011, 364, 1897–1908. [CrossRef] [PubMed] [Green Version]
  204. Rosenfeld, P.J.; Brown, D.M.; Heier, J.S.; Boyer, D.S.; Kaiser, P.K.; Chung, C.Y.; Kim, R.Y. Ranibizumab for Neovascular Age-Related Macular Degeneration. N. Engl. J. Med. 2006, 355, 1419–1431. [Google Scholar] [CrossRef] [Green Version]
  205. McKibbin, M.; Papastefanou, V.; Matthews, B.; Cook, H.; Downey, L. Ranibizumab Monotherapy for Sub-Foveal Haemorrhage Secondary to Choroidal Neovascularisation in Age-Related Macular Degeneration. Eye 2010, 24, 994–998. [Google Scholar] [CrossRef] [Green Version]
  206. Kang, S.; Roh, Y.-J. Ranibizumab Treatment Administered as Needed for Occult and Minimally Classic Neovascular Membranes in Age-Related Macular Degeneration. Jpn. J. Ophthalmol. 2011, 55, 123–127. [Google Scholar] [CrossRef]
  207. Raja, M.S.A.; Saldana, M.; Goldsmith, C.; Burton, B.J.L. Ranibizumab Treatment for Neovascular Age-Related Macular Degeneration in Patients with Good Baseline Visual Acuity (Better than 6/12): 12-Month Outcomes. Br. J. Ophthalmol. 2010, 94, 1543–1545. [Google Scholar] [CrossRef]
  208. Holz, F.G.; Figueroa, M.S.; Bandello, F.; Yang, Y.; Ohji, M.; Dai, H.; Wykrota, H.; Sharma, S.; Dunger-Baldauf, C.; Lacey, S.; et al. Ranibizumab treatment in treatment-naive neovascular age-related macular degeneration: Results From LUMINOUS, a Global Real-World Study. Retina 2020, 40, 1673–1685. [Google Scholar] [CrossRef]
  209. Rush, R.B.; Rush, S.W. Ranibizumab Versus Bevacizumab for Neovascular Age-Related Macular Degeneration With an Incomplete Posterior Vitreous Detachment. Asia-Pac. J. Ophthalmol. 2016, 5, 171–175. [Google Scholar] [CrossRef] [PubMed]
  210. Kodjikian, L.; Souied, E.H.; Mimoun, G.; Mauget-Faÿsse, M.; Behar-Cohen, F.; Decullier, E.; Huot, L.; Aulagner, G. Ranibizumab versus Bevacizumab for Neovascular Age-Related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial. Ophthalmology 2013, 120, 2300–2309. [Google Scholar] [CrossRef]
  211. Chakravarthy, U.; Harding, S.P.; Rogers, C.A.; Downes, S.M.; Lotery, A.J.; Wordsworth, S.; Reeves, B.C. Ranibizumab versus Bevacizumab to Treat Neovascular Age-Related Macular Degeneration. Ophthalmology 2012, 119, 1399–1411. [Google Scholar] [CrossRef]
  212. Brown, D.M.; Kaiser, P.K.; Michels, M.; Soubrane, G.; Heier, J.S.; Kim, R.Y.; Sy, J.P.; Schneider, S. Ranibizumab versus Verteporfin for Neovascular Age-Related Macular Degeneration. N. Engl. J. Med. 2006, 355, 1432–1444. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  213. Cebeci, Z.; Yilmaz, Y.C.; Kir, N. Real-Life Experience of Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration from Turkey. Int. J. Ophthalmol. 2018, 11, 267–273. [Google Scholar] [CrossRef] [PubMed]
  214. Garweg, J.G.; Gerhardt, C.; Kodjikian, L.; Pfister, I.B. Real-Life Experience with Aflibercept and Ranibizumab in the Treatment of Newly Diagnosed Neovascular Age-Related Macular Degeneration over 24 Months. J. Ocul. Pharmacol. Ther. 2017, 33, 567–572. [Google Scholar] [CrossRef]
  215. Providência, J.; Rodrigues, T.M.; Oliveira, M.; Bernardes, J.; Marques, J.P.; Murta, J.; Silva, R. Real-World Results of Aflibercept versus Ranibizumab for the Treatment of Exudative AMD Using a Fixed Regimen. Biomed. Res. Int. 2018, 2018, 9276580. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  216. Rao, P.; Lum, F.; Wood, K.; Salman, C.; Burugapalli, B.; Hall, R.; Singh, S.; Parke, D.W.; Williams, G.A. Real-World Vision in Age-Related Macular Degeneration Patients Treated with Single Anti–VEGF Drug Type for 1 Year in the IRIS Registry. Ophthalmology 2018, 125, 522–528. [Google Scholar] [CrossRef]
  217. Lotery, A.; Griner, R.; Ferreira, A.; Milnes, F.; Dugel, P. Real-World Visual Acuity Outcomes between Ranibizumab and Aflibercept in Treatment of Neovascular AMD in a Large US Data Set. Eye 2017, 31, 1697–1706. [Google Scholar] [CrossRef] [Green Version]
  218. Horner, F.; Lip, P.L.; Clark, H.; Chavan, R.; Sarmad, A.; Mushtaq, B. Real-World Visual And Clinical Outcomes For Patients With Neovascular Age-Related Macular Degeneration Treated With Intravitreal Ranibizumab: An 8-Year Observational Cohort (AMD8). OPTH 2019, 13, 2461–2467. [Google Scholar] [CrossRef] [Green Version]
  219. Verbraak, F.D.; Ponsioen, D.L.; Tigchelaar-Besling, O.A.M.; Nguyen, V.; Gillies, M.C.; Barthelmes, D.; Klaver, C.C.W. Real-world Treatment Outcomes of Neovascular Age-related Macular Degeneration in the Netherlands. Acta Ophthalmol. 2020, 99, e884–e892. [Google Scholar] [CrossRef]
  220. Mantel, I.; Niderprim, S.-A.; Gianniou, C.; Deli, A.; Ambresin, A. Reducing the Clinical Burden of Ranibizumab Treatment for Neovascular Age-Related Macular Degeneration Using an Individually Planned Regimen. Br. J. Ophthalmol. 2014, 98, 1192–1196. [Google Scholar] [CrossRef]
  221. Jang, L.; Gianniou, C.; Ambresin, A.; Mantel, I. Refractory Subretinal Fluid in Patients with Neovascular Age-Related Macular Degeneration Treated with Intravitreal Ranibizumab: Visual Acuity Outcome. Graefes Arch. Clin. Exp. Ophthalmol. 2015, 253, 1211–1216. [Google Scholar] [CrossRef] [PubMed]
  222. Burés Jelstrup, A.; Pomares, E.; Navarro, R.; on behalf of the BIOIMAGE Study Group. Relationship between Aflibercept Efficacy and Genetic Variants of Genes Associated with Neovascular Age-Related Macular Degeneration: The BIOIMAGE Trial. Ophthalmologica 2020, 243, 461–470. [Google Scholar] [CrossRef]
  223. Sulzbacher, F.; Roberts, P.; Munk, M.R.; Kaider, A.; Kroh, M.E.; Sacu, S.; Schmidt-Erfurth, U.; for the Vienna Eye Study Center. Relationship of Retinal Morphology and Retinal Sensitivity in the Treatment of Neovascular Age-Related Macular Degeneration Using Aflibercept. Investig. Ophthalmol. Vis. Sci. 2015, 56, 1158–1167. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  224. Duval, M.-V.; Rougier, M.-B.; Delyfer, M.-N.; Combillet, F.; Korobelnik, J.-F. Réponse visuelle et anatomique en condition de « vraie vie » du traitement par aflibercept chez les patients naïfs atteints de dégénérescence maculaire liée à l’âge exsudative. J. Français D’ophtalmologie 2017, 40, 270–278. [Google Scholar] [CrossRef]
  225. Yang, Y.; Downey, L.; Mehta, H.; Mushtaq, B.; Narendran, N.; Patel, N.; Patel, P.J.; Ayan, F.; Gibson, K.; Igwe, F.; et al. Resource Use and Real-World Outcomes for Ranibizumab Treat and Extend for Neovascular Age-Related Macular Degeneration in the UK: Interim Results from TERRA. Ophthalmol. Ther. 2017, 6, 175–186. [Google Scholar] [CrossRef]
  226. Clemens, C.R.; Wolf, A.; Alten, F.; Milojcic, C.; Heiduschka, P.; Eter, N. Response of Vascular Pigment Epithelium Detachment Due to Age-Related Macular Degeneration to Monthly Treatment with Ranibizumab: The Prospective, Multicentre RECOVER Study. Acta Ophthalmol. 2017, 95, 683–689. [Google Scholar] [CrossRef] [Green Version]
  227. Nemcansky, J.; Stepanov, A.; Koubek, M.; Veith, M.; Klimesova, Y.M.; Studnicka, J. Response to Aflibercept Therapy in Three Types of Choroidal Neovascular Membrane in Neovascular Age-Related Macular Degeneration: Real-Life Evidence in the Czech Republic. J. Ophthalmol. 2019, 2019, 1–6. [Google Scholar] [CrossRef]
  228. Giacomelli, G.; Giansanti, F.; Finocchio, L.; Biagini, I.; Bacherini, D.; Virgili, G.; Menchini, U. Results of intravitreal ranibizumab with a prn regimen in the treatment of extrafoveal and juxtafoveal neovascular membranes in age-related macular degeneration. Retina 2014, 34, 860–867. [Google Scholar] [CrossRef]
  229. Nghiem-Buffet, S.; Giocanti-Auregan, A.; Jung, C.; Dubois, L.; Dourmad, P.; Galbadon, L.; Fajnkuchen, F.; Quentel, G.; Cohen, S.Y. Reticular pseudodrusen are not a predictive factor for the 1-year response to intravitreal ranibizumab in neovascular age-related macular degeneration. Retina 2017, 37, 53–59. [Google Scholar] [CrossRef] [PubMed]
  230. Parravano, M.; Oddone, F.; Tedeschi, M.; Lomoriello, D.S.; Chiaravalloti, A.; Ripandelli, G.; Varano, M. Retinal functional changes measured by microperimetry in neovascular age-related macular degeneration patients treated with ranibizumab. Retina 2009, 29, 329–334. [Google Scholar] [CrossRef]
  231. Cho, H.J.; Kim, C.G.; Yoo, S.J.; Cho, S.W.; Lee, D.W.; Kim, J.W.; Lee, J.H. Retinal Functional Changes Measured by Microperimetry in Neovascular Age-Related Macular Degeneration Treated with Ranibizumab. Am. J. Ophthalmol. 2013, 155, 118–126.e1. [Google Scholar] [CrossRef] [PubMed]
  232. Cho, H.J.; Kim, H.S.; Yoo, S.G.; Han, J.I.; Lew, Y.J.; Cho, S.W.; Lee, T.G.; Kim, J.W. Retinal pigment epithelial tear after intravitreal ranibizumab treatment for neovascular age-related macular degeneration. Retina 2016, 36, 1851–1859. [Google Scholar] [CrossRef]
  233. Heimes, B.; Farecki, M.-L.; Bartels, S.; Barrelmann, A.; Gutfleisch, M.; Spital, G.; Lommatzsch, A.; Pauleikhoff, D. Retinal pigment epithelial tear and anti-vascular endothelial growth factor therapy in exudative age-related macular degeneration: Clinical Course and Long-Term Prognosis. Retina 2016, 36, 868–874. [Google Scholar] [CrossRef]
  234. Figurska, M. Retinal Pigment Epithelial Tears Following Ranibizumab Therapy for Fibrovascular Retinal Pigment Epithelial Detachment Due to Occult Age-Related Macular Degeneration. Med. Sci. Monit. 2012, 18, CR32–CR38. [Google Scholar] [CrossRef] [Green Version]
  235. Wickremasinghe, S.S.; Xie, J.; Guymer, R.H.; Wong, T.Y.; Kawasaki, R.; Qureshi, S. Retinal Vascular Changes Following Intravitreal Ranibizumab Injections for Neovascular AMD over a 1-Year Period. Eye 2012, 26, 958–966. [Google Scholar] [CrossRef] [Green Version]
  236. Westborg, I.; Albrecht, S.; Rosso, A. Risk for low visual acuity after 1 and 2 years of treatment with ranibizumab or bevacizumab for patients with neovascular age-related macular degeneration. Retina 2017, 37, 2035–2046. [Google Scholar] [CrossRef] [PubMed]
  237. Almuhtaseb, H.; Johnston, R.L.; Talks, J.S.; Lotery, A.J. Second-Year Visual Acuity Outcomes of NAMD Patients Treated with Aflibercept: Data Analysis from the UK Aflibercept Users Group. Eye 2017, 31, 1582–1588. [Google Scholar] [CrossRef] [Green Version]
  238. Bloch, S.B.; Lund-Andersen, H.; Sander, B.; Larsen, M. Subfoveal Fibrosis in Eyes with Neovascular Age-Related Macular Degeneration Treated with Intravitreal Ranibizumab. Am. J. Ophthalmol. 2013, 156, 116–124.e1. [Google Scholar] [CrossRef]
  239. Husum, Y.S.; Moe, M.C.; Bragadóttir, R.; Jørstad, Ø.K. Switching to Aflibercept versus Continuing Bevacizumab for Treatment-resistant Neovascular Age-related Macular Degeneration: A One-year Comparative Observational Study. Acta Ophthalmol. 2021, 156, 116–124. [Google Scholar] [CrossRef] [PubMed]
  240. Chandra, S.; Arpa, C.; Menon, D.; Khalid, H.; Hamilton, R.; Nicholson, L.; Pal, B.; Fasolo, S.; Hykin, P.; Keane, P.A.; et al. Ten-Year Outcomes of Antivascular Endothelial Growth Factor Therapy in Neovascular Age-Related Macular Degeneration. Eye 2020, 34, 1888–1896. [Google Scholar] [CrossRef]
  241. Reinsberg, M.; Hilgers, R.-D.; Lüdeke, I.; Nassar, K.; Grisanti, S.; Grisanti, S.; Lüke, J.; Lüke, M. Testing the Clinical Value of Multifocal Electroretinography and Microperimetry and the Effects of Intravitreal Therapy with Ranibizumab on Macular Function in the Course of Wet Age-Related Macular Degeneration: A 1-Year Prospective Study. OPTH 2017, 11, 621–629. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  242. Jain, N.; Yadav, N.K.; Jayadev, C.; Srinivasan, P.; Mohan, A.; Shetty, B.K. The ARMOUR Study: Anti-VEGF in Neovascular AMD—Our Understanding in a Real-World Indian Setting. Asia-Pac. J. Ophthalmol. 2017, 6, 488–492. [Google Scholar] [CrossRef]
  243. Kalouda, P.; Anastasakis, A.; Tsika, C.; Tsilimbaris, K.M. The Effect of Intravitreal Anti-VEGF on the Pigment Epithelial Detachment in Eyes with the Exudative Type of Age-Related Macular Degeneration. Semin. Ophthalmol. 2015, 30, 6–10. [Google Scholar] [CrossRef] [PubMed]
  244. Makri, O.E.; Vavvas, D.; Plotas, P.; Pallikari, A.; Georgakopoulos, C.D. The Effect of Ranibizumab on Normal Neurosensory Retina in the Eyes of Patients with Exudative Age Related Macular Degeneration. TOOPHTJ 2017, 11, 368–376. [Google Scholar] [CrossRef]
  245. Chrapek, O.; Jarkovsky, J.; Studnicka, J.; Sin, M.; Kolar, P.; Jirkova, B.; Dusek, L.; Pitrova, S.; Rehak, J. The Efficacy of Ranibizumab Treatment in Clinical Practice in Patients with the Wet Form of Age-Related Macular Degeneration. The Results of the Czech National Registry. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc. Czech Repub. 2015, 159, 407–412. [Google Scholar] [CrossRef] [Green Version]
  246. Francis, P.J. The Influence of Genetics on Response to Treatment with Ranibizumab (Lucentis) for Age-Related Macular Degeneration: The Lucentis Genotype Study (an American Ophthalmological Society Thesis). Trans. Am. Ophthalmol. Soc. 2011, 109, 115–156. [Google Scholar]
  247. Zarranz-Ventura, J.; Liew, G.; Johnston, R.L.; Xing, W.; Akerele, T.; McKibbin, M.; Downey, L.; Natha, S.; Chakravarthy, U.; Bailey, C.; et al. The Neovascular Age-Related Macular Degeneration Database: Multicenter Study of 92 976 Ranibizumab Injections. Ophthalmology 2014, 121, 1092–1101. [Google Scholar] [CrossRef] [PubMed]
  248. Unsal, E.; Cubuk, M.O. The Results of Aflibercept Therapy as a First Line Treatment of Age-Related Macular Degeneration. J. Curr. Ophthalmol. 2019, 31, 66–71. [Google Scholar] [CrossRef]
  249. Alkin, Z.; Ozkaya, A.; Osmanbasoglu, O.A.; Agca, A.; Karakucuk, Y.; Yazici, A.T.; Demirok, A. The Role of Epiretinal Membrane on Treatment of Neovascular Age-Related Macular Degeneration with Intravitreal Bevacizumab. Sci. World J. 2013, 2013, 1–7. [Google Scholar] [CrossRef] [PubMed]
  250. Weingessel, B.; Hintermayer, G.; Maca, S.M.; Rauch, R.; Vecsei-Marlovits, P.V. The Significance of Early Treatment of Exudative Age-Related Macular Degeneration: 12 Months’ Results. Wien. Klin. Wochenschr. 2012, 124, 750–755. [Google Scholar] [CrossRef]
  251. Razi, F.; Haq, A.; Tonne, P.; Logendran, M. Three-Year Follow-up of Ranibizumab Treatment of Wet Age-Related Macular Degeneration: Influence of Baseline Visual Acuity and Injection Frequency on Visual Outcomes. OPTH 2016, 10, 313. [Google Scholar] [CrossRef] [Green Version]
  252. Itagaki, K.; Sekiryu, T.; Kasai, A.; Sugano, Y.; Ogasawara, M.; Saito, M. Three-Year Outcome of Aflibercept Treatment for Japanese Patients with Neovascular Age-Related Macular Degeneration. BMC Ophthalmol. 2020, 20, 276. [Google Scholar] [CrossRef]
  253. Eleftheriadou, M.; Gemenetzi, M.; Lukic, M.; Sivaprasad, S.; Hykin, P.G.; Hamilton, R.D.; Rajendram, R.; Tufail, A.; Patel, P.J. Three-Year Outcomes of Aflibercept Treatment for Neovascular Age-Related Macular Degeneration: Evidence from a Clinical Setting. Ophthalmol. Ther. 2018, 7, 361–368. [Google Scholar] [CrossRef] [Green Version]
  254. Lala, C.; Framme, C.; Wolf-Schnurrbusch, U.E.K.; Wolf, S. Three-Year Results of Visual Outcome with Disease Activity-Guided Ranibizumab Algorithm for the Treatment of Exudative Age-Related Macular Degeneration. Acta Ophthalmol. 2013, 91, 526–530. [Google Scholar] [CrossRef] [PubMed]
  255. Muniraju, R.; Ramu, J.; Sivaprasad, S. Three-Year Visual Outcome and Injection Frequency of Intravitreal Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration. Ophthalmologica 2013, 230, 27–33. [Google Scholar] [CrossRef]
  256. Guymer, R.H.; Markey, C.M.; McAllister, I.L.; Gillies, M.C.; Hunyor, A.P.; Arnold, J.J.; FLUID Investigators. Tolerating Subretinal Fluid in Neovascular Age-Related Macular Degeneration Treated with Ranibizumab Using a Treat-and-Extend Regimen: FLUID Study 24-Month Results. Ophthalmology 2019, 126, 723–734. [Google Scholar] [CrossRef] [PubMed]
  257. Matsumoto, H.; Morimoto, M.; Mimura, K.; Ito, A.; Akiyama, H. Treat-and-Extend Regimen with Aflibercept for Neovascular Age-Related Macular Degeneration. Ophthalmol. Retin. 2018, 2, 462–468. [Google Scholar] [CrossRef]
  258. DeCroos, F.C.; Reed, D.; Adam, M.K.; Salz, D.; Gupta, O.P.; Ho, A.C.; Regillo, C.D. Treat-and-Extend Therapy Using Aflibercept for Neovascular Age-Related Macular Degeneration: A Prospective Clinical Trial. Am. J. Ophthalmol. 2017, 180, 142–150. [Google Scholar] [CrossRef]
  259. Figueras-Roca, M.; Parrado-Carrillo, A.; Nguyen, V.; Casaroli-Marano, R.P.; Moll-Udina, A.; Gillies, M.C.; Barthelmes, D.; Zarranz-Ventura, J. Treat-and-Extend versus Fixed Bimonthly Treatment Regimens for Treatment-Naive Neovascular Age–Related Macular Degeneration: Real World Data from the Fight Retinal Blindness Registry. Graefes Arch. Clin. Exp. Ophthalmol. 2020, 259, 1463–1470. [Google Scholar] [CrossRef]
  260. Silva, R.; Berta, A.; Larsen, M.; Macfadden, W.; Feller, C.; Monés, J. Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration. Ophthalmology 2018, 125, 57–65. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  261. Modjtahedi, B.S.; Luong, T.Q.; Chiu, S.; van Zyl, T.; Lin, J.C.; Fong, D.S. Treatment Course of Patients with Exudative Age-Related Macular Degeneration Using Ocular Hypotensives. OPTH 2020, 14, 187–195. [Google Scholar] [CrossRef] [Green Version]
  262. Busbee, B.G.; Ho, A.C.; Brown, D.M.; Heier, J.S.; Suñer, I.J.; Li, Z.; Rubio, R.G.; Lai, P. Twelve-Month Efficacy and Safety of 0.5 Mg or 2.0 Mg Ranibizumab in Patients with Subfoveal Neovascular Age-Related Macular Degeneration. Ophthalmology 2013, 120, 1046–1056. [Google Scholar] [CrossRef] [Green Version]
  263. Veritti, D.; Sarao, V.; Missiroli, F.; Ricci, F.; Lanzetta, P. Twelve-month outcomes of intravitreal aflibercept for neovascular age-related macular degeneration: Fixed Versus As-Needed Dosing. Retina 2019, 39, 2077–2083. [Google Scholar] [CrossRef]
  264. Gillies, M.C.; Nguyen, V.; Daien, V.; Arnold, J.J.; Morlet, N.; Barthelmes, D. Twelve-Month Outcomes of Ranibizumab vs. Aflibercept for Neovascular Age-Related Macular Degeneration: Data from an Observational Study. Ophthalmology 2016, 123, 2545–2553. [Google Scholar] [CrossRef] [Green Version]
  265. Kim, J.H.; Lee, D.W.; Chang, Y.S.; Kim, J.W.; Kim, C.G. Twelve-Month Outcomes of Treatment Using Ranibizumab or Aflibercept for Neovascular Age-Related Macular Degeneration: A Comparative Study. Graefes Arch. Clin. Exp. Ophthalmol. 2016, 254, 2101–2109. [Google Scholar] [CrossRef]
  266. Barakat, A.; Rufin, V.; Tran, T.H.C. Two Year Outcome in Treatment-Naive Patients with Neovascular Age-Related Macular Degeneration (NAMD) Using an Individualized Regimen of Aflibercept. J. Français D’ophtalmologie 2018, 41, 603–610. [Google Scholar] [CrossRef] [PubMed]
  267. Parvin, P.; Zola, M.; Dirani, A.; Ambresin, A.; Mantel, I. Two-Year Outcome of an Observe-and-Plan Regimen for Neovascular Age-Related Macular Degeneration Treated with Aflibercept. Graefes Arch. Clin. Exp. Ophthalmol. 2017, 255, 2127–2134. [Google Scholar] [CrossRef] [Green Version]
  268. Ito, A.; Matsumoto, H.; Morimoto, M.; Mimura, K.; Akiyama, H. Two-Year Outcomes of a Treat-and-Extend Regimen Using Intravitreal Aflibercept Injections for Typical Age-Related Macular Degeneration. Ophthalmologica 2017, 238, 236–242. [Google Scholar] [CrossRef] [PubMed]
  269. Ebneter, A.; Michels, S.; Pruente, C.; Imesch, P.; Eilenberger, F.; Oesch, S.; Thomet-Hunziker, I.P.; Hatz, K. Two-Year Outcomes of Intravitreal Aflibercept in a Swiss Routine Treat and Extend Regimen for Patients with Neovascular Age-Related Macular Degeneration. Sci. Rep. 2020, 10, 20256. [Google Scholar] [CrossRef]
  270. Yamamoto, A.; Okada, A.A.; Sugitani, A.; Kunita, D.; Rii, T.; Yokota, R. Two-Year Outcomes of pro Re Nata Ranibizumab Monotherapy for Exudative Age-Related Macular Degeneration in Japanese Patients. OPTH 2013, 7, 757. [Google Scholar] [CrossRef] [Green Version]
  271. Maruko, I.; Ogasawara, M.; Yamamoto, A.; Itagaki, K.; Hasegawa, T.; Arakawa, H.; Nakayama, M.; Koizumi, H.; Okada, A.A.; Sekiryu, T.; et al. Two-Year Outcomes of Treat-and-Extend Intravitreal Aflibercept for Exudative Age-Related Macular Degeneration. Ophthalmol. Retin. 2020, 4, 767–776. [Google Scholar] [CrossRef]
  272. Stepanov, A.; Nemcansky, J.; Veith, M.; Manethova, K.; Stredova, M.; Pencak, M.; Tarkova, A.; Studnicka, J. Two-Year Results of a Combined Regimen of Aflibercept Treatment in Three Types of Choroidal Neovascular Membrane in the Wet Form of Age-Related Macular Degeneration: Real-Life Evidence in the Czech Republic. Eur. J. Ophthalmol. 2020, 31, 2488–2495. [Google Scholar] [CrossRef] [PubMed]
  273. Chen, X.; Al-Sheikh, M.; Chan, C.K.; Hariri, A.H.; Abraham, P.; Lalezary, M.; Lin, S.G.; Sadda, S.; Sarraf, D. Type 1 versus type 3 neovascularization in pigment epithelial detachments associated with age-related macular degeneration after anti-vascular endothelial growth factor therapy: A Prospective Study. Retina 2016, 36, S50–S64. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  274. Lee, A.Y.; Lee, C.S.; Egan, C.A.; Bailey, C.; Johnston, R.L.; Natha, S.; Hamilton, R.; Khan, R.; Al-Husainy, S.; Brand, C.; et al. UK AMD/DR EMR REPORT IX: Comparative Effectiveness of Predominantly as Needed (PRN) Ranibizumab versus Continuous Aflibercept in UK Clinical Practice. Br. J. Ophthalmol. 2017, 101, 1683–1688. [Google Scholar] [CrossRef]
  275. Inoue, M.; Arakawa, A.; Yamane, S.; Kadonosono, K. Variable response of vascularized pigment epithelial detachments to ranibizumab based on lesion subtypes, including polypoidal choroidal vasculopathy. Retina 2013, 33, 990–997. [Google Scholar] [CrossRef] [PubMed]
  276. Muether, P.S.; Hermann, M.M.; Viebahn, U.; Kirchhof, B.; Fauser, S. Vascular Endothelial Growth Factor in Patients with Exudative Age-Related Macular Degeneration Treated with Ranibizumab. Ophthalmology 2012, 119, 2082–2086. [Google Scholar] [CrossRef]
  277. Nakata, I.; Yamashiro, K.; Nakanishi, H.; Tsujikawa, A.; Otani, A.; Yoshimura, N. VEGF Gene Polymorphism and Response to Intravitreal Bevacizumab and Triple Therapy in Age-Related Macular Degeneration. Jpn. J. Ophthalmol. 2011, 55, 435–443. [Google Scholar] [CrossRef]
  278. dos Reis Veloso, C.E.; de Almeida, L.N.F.; Recchia, F.M.; Pelayes, D.; Nehemy, M.B. VEGF Gene Polymorphism and Response to Intravitreal Ranibizumab in Neovascular Age-Related Macular Degeneration. Ophthalmic. Res. 2014, 51, 1–8. [Google Scholar] [CrossRef]
  279. Larsen, M.; Schmidt-Erfurth, U.; Lanzetta, P.; Wolf, S.; Simader, C.; Tokaji, E.; Pilz, S.; Weisberger, A. Verteporfin plus Ranibizumab for Choroidal Neovascularization in Age-Related Macular Degeneration. Ophthalmology 2012, 119, 992–1000. [Google Scholar] [CrossRef]
  280. Shona, O.; Gupta, B.; Vemala, R.; Sivaprasad, S. Visual Acuity Outcomes in Ranibizumab-Treated Neovascular Age-Related Macular Degeneration; Stratified by Baseline Vision. Clin. Exp. Ophthalmol. 2011, 39, 5–8. [Google Scholar] [CrossRef]
  281. Makri, O.E.; Tsapardoni, F.N.; Tsekouras, I.K.; Lagogiannis, A.P.; Chairas, N.; Pallikari, A.; Pagoulatos, D.D.; Georgakopoulos, C.D. Visual and Anatomic Outcomes of Aflibercept Treatment in Treatment-Naive Patients with Neovascular Age-Related Macular Degeneration; Real-Life Data over 24 Months. Hell. J. Nucl. Med. 2019, 22 (Suppl. 2), 55–62. [Google Scholar] [PubMed]
  282. Canan, H.; Sızmaz, S.; Altan-Yaycıoğlu, R.; Sarıtürk, Ç.; Yilmaz, G. Visual Outcome of Intravitreal Ranibizumab for Exudative Age-Related Macular Degeneration: Timing and Prognosis. CIA 2014, 9, 141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  283. Basheer, K.; Mensah, E.; Khanam, T.; Minakaran, N. Visual Outcomes of Age-Related Macular Degeneration Patients Undergoing Intravitreal Ranibizumab Monotherapy in an Urban Population. OPTH 2015, 9, 959. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Jcm 11 00325 g001 550
Figure 1. Flowchart of selection of studies and reason for exclusion.
Figure 1. Flowchart of selection of studies and reason for exclusion.
Jcm 11 00325 g001
Table
Table 1. Study Characteristics.
Table 1. Study Characteristics.
Study TypeRandomized
Controlled Studies		Observational/
Real-Life Studies		Prospective
Studies		Retrospective Studies
Eyes (populations)27,785 (81)81,881 (331)39,008 (202)70,288 (210)
DrugAfliberceptRanibizumabBrolucizumabBevacizumab
Eyes (populations)24,517 (102)65,591 (230)1038 (3)18,520 (77)
RegimenFixedPro-re-nataTreat
and Extend
Eyes (populations)13,318 (74)81,651 (270)7285 (57)
Table
Table 2. Efficacy of intravitreal anti-VEGFs for the treatment of neovascular AMD at 12 months: key results.
Table 2. Efficacy of intravitreal anti-VEGFs for the treatment of neovascular AMD at 12 months: key results.
  • The use of anti-VEGF agents leads to a significant visual improvement in neovascular AMD patients.
  • Randomized clinical trials typically produce higher visual gains over real-life studies.
  • Proactive treatment regimen (fixed or treat-and-extend) usually leads to better outcomes over a reactive treatment regimen (pro-re-nata)
  • Frequency of anti-VEGF injections is a relevant factor and influences the visual outcome.
  • High baseline visual acuity and increased age reduce the functional response to intravitreal anti-VEGF therapy.
Legend: AMD: Age-related macular degeneration; VEGF: Vascular endothelial growth factor.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Veritti, D.; Sarao, V.; Soppelsa, V.; Danese, C.; Chhablani, J.; Lanzetta, P. Managing Neovascular Age-Related Macular Degeneration in Clinical Practice: Systematic Review, Meta-Analysis, and Meta-Regression. J. Clin. Med. 2022, 11, 325. https://doi.org/10.3390/jcm11020325

AMA Style

Veritti D, Sarao V, Soppelsa V, Danese C, Chhablani J, Lanzetta P. Managing Neovascular Age-Related Macular Degeneration in Clinical Practice: Systematic Review, Meta-Analysis, and Meta-Regression. Journal of Clinical Medicine. 2022; 11(2):325. https://doi.org/10.3390/jcm11020325

Chicago/Turabian Style

Veritti, Daniele, Valentina Sarao, Valentina Soppelsa, Carla Danese, Jay Chhablani, and Paolo Lanzetta. 2022. "Managing Neovascular Age-Related Macular Degeneration in Clinical Practice: Systematic Review, Meta-Analysis, and Meta-Regression" Journal of Clinical Medicine 11, no. 2: 325. https://doi.org/10.3390/jcm11020325

APA Style

Veritti, D., Sarao, V., Soppelsa, V., Danese, C., Chhablani, J., & Lanzetta, P. (2022). Managing Neovascular Age-Related Macular Degeneration in Clinical Practice: Systematic Review, Meta-Analysis, and Meta-Regression. Journal of Clinical Medicine, 11(2), 325. https://doi.org/10.3390/jcm11020325

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop