The mainstay of neovascular age-related macular degeneration (AMD) treatment consists of antiangiogenic therapies. The two most commonly used intravitreal injections (IVIs) are ranibizumab (Lucentis; Genentech, South San Francisco, CA) and bevacizumab (Avastin; Genentech, South San Francisco, CA).1,2 Both can be administered monthly, and studies demonstrate similar efficacy.3,4 While IVIs are a very safe procedure, there exists the potential for endophthalmitis and uveitis.2
The promise of fewer IVIs to achieve a similar or superior result has led to U.S. Food and Drug Administration approval of aflibercept (Eylea; Regeneron,Tarrytown, NY) in November of 2011 for the treatment of neovascular AMD.5 Aflibercept is a fusion protein that combines two important domains — the binding domain of human VEGF receptor 1 (VEGFR1) and 2 (VEGFR2) — with the human immunoglobulin G antibody's constant chain portion.6 It acts as a decoy receptor6,7 that reduces choroidal neovascularization by binding to VEGF form A (using both its VEGFR1 and VEGFR2 domains) as well as to placental growth factor (PlGF). This sequesters both these angiogenic factors from binding to their actual receptors (VEGFR1, 2), thus blocking the signal for new blood vessel formation.
Aflibercept is favorable because it requires IVIs every 2 months (after three monthly IVIs) and has been found to be as effective as monthly ranibizumab for treating AMD.8–11 This may be due to the fact that aflibercept has a greater binding affinity for VEGF than ranibizumab or bevacizumab.6,12–14 Furthermore aflibercept also binds VEGF-B and PlGF, and it has a longer half-life than ranibizumab.9,11 Fewer IVIs with equivalent visual acuity outcomes can reduce the number of office visits and could also impact the incidence of infections or other complications associated with monthly IVIs.
With three anti-VEGF treatments for AMD available today, the ophthalmic community has been extensively exploring the optimal treatment regimens for these agents.15–20 With the advent of aflibercept, it is common practice to switch patients who previously had a suboptimal response to ranibizumab or bevacizumab.21–23 However, some patients fail to improve despite exhausting all three options. The purpose of this investigation was to determine the characteristics of the patients who do not respond to aflibercept after switching from ranibizumab or bevacizumab.
Patients and Methods
A retrospective chart review was performed for 248 patients who were treated with aflibercept at the Byers Eye Institute at Stanford from November 2011 to August 2014. Ethics board approval was obtained from the Stanford University Human Subjects Institutional Review Board. All research was performed in accordance with the Declaration of Helsinki; the Health Insurance Portability and Accountability Act (HIPAA); and all local, state, and national laws.
Patients with AMD who were previously treated with ranibizumab or bevacizumab who later switched to aflibercept were identified. These patients switched due incomplete response to ranibizumab or bevacizumab, defined as the presence of intraretinal or subretinal fluid despite monthly treatment. This study included all consecutive nonresponders in the study population. Each patient's visual acuity was noted at baseline prior to aflibercept treatment; 1, 3, and 12 months after aflibercept; and at the most recent visit when aflibercept was given. Improvement in vision was defined as improvement by one line on the Snellen chart compared to baseline visual acuity. Decrease in vision was defined as loss of vision by one line on the Snellen chart when compared to baseline. This criterion was adopted because many of these patients started with poor baseline visual acuity at the time of the switch. Patients were categorized into those who improved, those who lost vision after aflibercept, or those who experienced a mixture of both. We compared patients who gained vision on aflibercept to patients who lost vision. Patients who gained vision had improvement in visual acuity at one or more subsequent visits and never fell to below baseline vision. Patients who lost vision had decreased visual acuity compared to baseline and never returned to baseline visual acuity. For analysis, visual acuity was converted to logMar as previously described.24
Based on the criterion described above, there were 29 eyes (25 patients) that were classified as having improved vision and 23 eyes (21 patients) that were classified as having decreased vision. Review of medical records was performed to record age, gender, race, BMI, obesity (BMI > 30), smoking, more than 10 pack years of smoking, comorbid conditions (hypertension, diabetes, malignancies), use of anti-inflammatory medication (bromfenac, triamcinolone acetonide), steroids use, number of previous injections of ranibizumab and bevacizumab, and use of Age-Related Eye Disease Study (AREDS) supplements. For demographic factors, each person was only analyzed one time even if they had two eyes in the study.
In addition, spectral-domain optical coherence tomography (SD-OCT) scans were carefully reviewed to identify the presence of baseline vitreomacular adhesions (VMA), subretinal fluid, intraretinal fluid, pigment epithelium detachment (PED), integrity of the ellipsoid zone (EZ), hyperreflective material above drusen, subretinal CNV or scar, epiretinal membrane, drusen, geographic atrophy (GA), and automatically generated metrics from SD-OCT analysis software (central cube thickness, central volume, central subfield thickness, GA area, drusen volume). We chose OCT to assess ocular findings instead of fundus fluorescein angiography (FFA) and indocyanine green (ICG) imaging because FFA and ICG are more invasive, and FFA/ICG was not performed on all our patients.
Statistical analysis was performed using the JMP statistical analysis software (Version 11; SAS Institute, Cary, NC). Each variable was tested independently in a univariate analysis to determine statistical significance using response to aflibercept as a binary categorical variable. A Wilcoxon rank-sum test was performed for continuous data variables if not normally distributed, and t test was performed for normally distributed variables. Statistical significance was taken for a P value of less than .05 and trending significance were taken for a P value that was less than .10 but greater than .05. Following this univariate analysis, the factors with a P value of less than .05 were entered into a multivariate nominal logistic regression using response to aflibercept as a dependent variable and the factors as predictors. The model selection was based on minimum Akaike's Information Criteria (AIC). AIC estimates the difference between a given model and a “true” model, and thus a minimum AIC is considered the best model.
The mean visual change over time is demonstrated in Figure 1, stratified by the two groups. Responders experienced improvement in visual acuity over time, and nonresponders experienced decrease in visual acuity over time. The baseline visual acuity in the responders in logMar was 0.462 ± 0.17 and the baseline visual acuity in non-responders was 0.487 ± 0.34 (P = .6246). Analysis of previous injection history revealed that positive responders to aflibercept had on average 12.103 ± 9.03 previous intravitreal injections of ranibizumab or bevacizumab prior to the switch, and negative responders had on average 14.304 ± 8.31 previous injections (P = .2335).
LogMar of visual acuity (VA) versus follow-up time points, stratified by group. Responders had VA improvement over time, corresponding to the LogMar numbers on the Y-axis. In contrast, nonresponders had VA decrease over time.
Out of a total 46 patients, 25 improved vision after aflibercept treatment (group 1) and 21 lost vision (group 2). The mean age of those with improved vision was 80.34 years, and the mean age of those with decreased vision was 84.21 years. Baseline demographics of patients are shown in Table 1.
The average BMI of patients who responded poorly to aflibercept was 28.18, whereas the patients who responded well averaged a BMI of 25.49 (P = .0252, univariate) (Figure 2). Using the Center for Disease Control and Prevention (CDC) definition of obesity at BMI of greater than 30, 33% of poor responders were obese and 0% of patients with improved vision were obese (P = .0014). Patients who responded well to aflibercept and those who did not had similar distribution in age, gender, race, smoking history, comorbid conditions (hypertension, diabetes, malignancies), and rate of anti-inflammatory use (bromfenac, triamcinolone-acetonide, steroids) (Table 1).
Average BMI stratified by group average BMI of responders to aflibercept after switching from ranibizumab or bevacizumab was 25.49, whereas nonresponders averaged a BMI of 28.18 (P = .0252).
SD-OCT imaging analysis of patient eyes revealed that 43.48% of patients with decreased vision after aflibercept had geographic atrophy at baseline, whereas only 17.24% of favorable responders had GA (P = .0381). All other examined features on SD-OCT scans were not significantly different (Table 2).
OCT Findings at Baseline
In the multivariate regression model, the factor significantly associated with favorable response to aflibercept was BMI (P = .013). Geographic atrophy had trending significance (P = .1) in the multivariate model.
The VEGF inhibitor drugs ranibizumab and bevacizumab have been established in multiple clinical trials as effective treatment for neovascular AMD.3,4,25–29 Aflibercept was shown to be noninferior to monthly ranibizumab in two pivotal trials when given every 2 months after three initial monthly loading doses.8,9 There have also been reports that aflibercept may be more effective for patients not responsive to ranibizumab or bevacizumab.21–23 Many patients previously on ranibizumab or bevacizumab were switched to aflibercept to determine whether their visual acuity could be increased. Some of these patients improved, but a subset of patients experienced a decline in vision.
This study examined the predisposing lifestyle and ocular factors associated with poor response after switching to aflibercept. Following univariate logistic regression, BMI and obesity were significantly higher in those with poor response to aflibercept when compared to those with a favorable response. Although the average BMI was 28.81 in poor responders, patients who responded well averaged 25.49 (P = .0252). By the CDC definition of obesity as BMI greater than 30, 33% of poor responders were obese, whereas 0% of patients with vision improvement after aflibercept were obese (P = .0014). Previous studies30–32 have found that elevated BMI and obesity are associated with an increased incidence of developing neovascular AMD. Our findings illustrate that in addition to being a risk a factor for developing neovascular AMD, elevated BMI and presence of obesity are also risk factors for a poor response to aflibercept treatment after switching from ranibizumab or bevacizumab.
In exploring the literature for reasons why higher body weight may be associated with poor response to aflibercept, oxidative damage and inflammation stand out as the two leading possibilities. High body weight has been associated with increased oxidative damage,30,33 which may lead to the recruitment of more blood vessels and exacerbate inflammation at the macula. In addition to the increased oxidative damage in obesity, there is also an increased level of inflammatory signals like C-reactive protein (CRP).34 Further studies have found that elevated levels of CRP are associated with AMD.35 Researchers have also hypothesized that white adipose tissue may act as a secretory agent, producing inflammatory factors, cytokines, and chemokines.36 In the excess of adipose tissue, as in high BMI, there are consequently more inflammatory cytokines, chemokines, and factors such as CRP all working together to promote inflammation. This excess or inflammation in high BMI patients may promote neovascularization, bringing immune mediators to sites of inflammation including the eye. Besides oxidative damage and inflammation, lack of proper nutrients may be a third mechanism by which high BMI correlates with poorer outcomes. Previous studies found obesity to be associated with lower intake of carotenoids, and it may also lower intake of other nutrients that protect against AMD.31,37,38 Taken together, the presence of greater oxidative damage, inflammation, and improper nutrient intake in obese individuals may all serve to explain why patients with higher BMI respond poorly to aflibercept after switching from ranibizumab or bevacizumab.
Another important finding was that patients who responded poorly to aflibercept after switching had significantly more GA at baseline compared to those who do not respond poorly (P = .0381, univariate analysis; P = .1, multivariate analysis). Both groups of patients received a similar average number of injections prior to aflibercept (P = .2335). It has been shown that more anti-VEGF therapy is associated with more GA,4 thus it is possible that aflibercept, with its higher binding affinity for VEGF, may exacerbate preexisting GA in switching patients. This hypothesis will require further exploration in larger, prospective studies.
This study is limited by its retrospective nature and small sample size. It also does not take into account the rationale for switching patients from ranibizumab or bevacizumab. Lastly, this study did not include genetic risk factors, as they are not commonly tested for in routine clinical practice.39 In future studies, we plan to explore if there are genetic predispositions to having favorable response to aflibercept. Certain polymorphisms have been associated with increased susceptibility to the development of neovascular AMD.40–44 Some polymorphisms have also affected how patients respond to ranibizumab,45–51 bevacizumab,52 or both.53,54 It would be of interest to determine if the same polymorphisms can predict the prognosis of those on aflibercept, especially after switching from previous treatment with ranibizumab and bevacizumab.
To our knowledge, this is the first study to examine factors influencing response to aflibercept after switching from ranibizumab and bevacizumab. We found that elevated BMI and presence of GA at baseline were associated with poor response to aflibercept after switching from ranibizumab or bevacizumab. This may have clinical impact when considering switching from one anti-VEGF agent to another.
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|Improved Vision (n = 25)||Decreased Vision (n = 21)||P Value|
|Age||80.49 ± 9.708||84.14 ± 7.1||.12|
| BMI||25.49± 1.76||28.18± 4.44||.0252*|
| Obesity (BMI > 30)||0%||33%||.0049*|
| Previous smoker||56%||38.1%||.2259|
| > 10 pack years||28.57%||6.25%||.0858|
OCT Findings at Baseline
|Improved Vision (n = 31 eyes)||Decreased Vision (n = 23 eyes)||P Value|
|Pigment Epithelium Detachment||62.07%||47.83%||.3044|
|Ellipsoid Zone Integrity||92.86%||100%||.1910|
|Drusen Volume (mm3) in a 3 mm Circle||0.1338 ± 0.151||0.083 ± 0.133||.0827|
|Drusen Volume (mm3) in a 5 mm Circle||0.1617 ± 0.169||0.1172 ± 0.172||.1644|
|Central Subfield Thickness (µm)||261.034 ± 58.8||239.696 ± 90.5||.2571|
|Cube Volume (mm3)||9.39 ± 0.83||9.0 ± 1.07||.1590|
|Cube Thickness (µm)||262 ± 22.5||249.304 ± 30.3||.1015|
|Geographic Atrophy Area (mm2) in a 5 mm Circle||2.179 ± 2.57||3.3 ± 3.41||.2364|