Factors with P values between 0.05 and 0.2 in the univariate analysis that were included in the multivariate model were increasing age (P = 0.06), the drug type (aflibercept, P = 0.14), the presence of retinal hyperpigmentation (P = 0.07), increasing RPE detachment at baseline (P = 0.13), and thicker subretinal tissue complex at baseline (P = 0.11). After multivariate stepwise logistic regression analysis including parameters with a P value < 0.2 (continuous parameters were used if available), the final multivariate model was significant (P < 0.0001) and the R2 value was 0.34. The model contained the following baseline factors as significantly associated with de novo MA incidence (Table 3): a lower number of injections within the 2 years of observation (P = 0.011), the presence of depigmentation (P = 0.0004), the presence of reticular pseudodrusen (P = 0.0005), lower baseline visual acuity (P = 0.0006), and neovascularization type of RAP (P = 0.0011). The drug was not associated with MA incidence (P = 0.21).
Localization of New Macular Atrophy Regarding Choroidal Neovascularization Complex
De novo MA was observed completely outside the baseline CNV complex in 7 eyes (10.8%), completely within the baseline boundaries of the CNV complex in 48 eyes (73.8%), and the localization was mixed in 10 eyes (15.4%). Performing the multivariate analysis after exclusion of MA purely within or purely outside the CNV complex, respectively, did change the final model in the following way (Table 4): The model including those eyes with some MA appearing within the baseline area of CNV (inside and mixed) did show significant impact of fewer injections (P = 0.030), intraretinal fluid (P = 0.034), and confirmed the factors of depigmentation (P = 0.016), reticular pseudodrusen (P = 0.001), and RAP (P = 0.011). However, the baseline visual acuity lost its significance (P = 0.07), although it was retained as a factor in the stepwise regression.
The model including those eyes with some MA appearing outside the baseline area of CNV (outside and mixed) did confirm the factor of fewer injections (P = 0.028), depigmentation (P = 0.009), and reticular pseudodrusen (P = 0.009). However, baseline visual acuity was not retained in the model after stepwise regression, and RAP lost significance in the final model (P = 0.054).
Comparison With the Nonneovascular Fellow Eye
Of the 149 study patients in this analysis, there were 93 patients with a fellow eye without neovascular complications during the study period. Of these, only 7 (8%) showed MA (GA) in the fellow eye at baseline of the study eye, and 86 (92%) had, at baseline, symmetrical lack of atrophy in either eye. At year 2, 13 additional fellow eyes had developed MA, which is an incidence rate of 15%, in the nonneovascular fellow eyes. The intereye concordance of MA in the study eye and in the fellow eye at year two was highly significant (P = 0.0003). Forty-eight patients (52%) showed no MA in either eye, and 16 patients (17%) showed MA in both eyes. The number of patients showing atrophy in the study eye or the fellow eye only was 25 (27%) and 4 (4%), respectively.
About the MA incidence within the patient group with de novo MA outside the previous CNV complex in the study eye, there was no significant difference between the study eyes (14.9%) and the untreated fellow eyes (16.4%).
In this study, we observed an MA incidence rate of 42% after 2 years of treatment under a variable dosing regimen with either ranibizumab or aflibercept for nAMD. The MA incidence associated risk factors were investigated using univariate and multivariate analysis, and intereye comparisons. The most intriguing (and new) finding was the association with fewer injections, whereas the other factors such as depigmentation, reticular pseudodrusen, RAP, lower baseline visual acuity, intraretinal cysts, and a high intereye correlation were expected findings based on the existing literature. Each point is separately discussed below.
In terms of incidence rates of MA in treated nAMD, the literature reports rates between 18% and 61%, depending on the imaging techniques and definitions applied.10,11,13,21 All reports agree on the fact that de novo development of MA in anti-VEGF treated nAMD is frequent and multifactorial.10,13 To date, most of the identified risk factors are ocular, with little evidence for influence of the treatment type and no evidence for systemic risk factors. However, our understanding of the risk factors is far from complete: multivariate models for MA incidence show only a weak-to-moderate goodness of fit (R2 of 0.34 in our study). Thus, further investigations on the associated factors are important to create a comprehensive model.
The most clinically relevant factors are those which can be potentially modified. Therefore, our study particularly focused on treatment-related factors. The prespecified criteria of including both factors with univariate results of P < 0.2 into the multivariate analysis and drug type and the number of administered injections reflect this particular interest in treatment parameters. In fact, in complex multifactorial disorders, the significance of some factors may only become apparent when controlling for all confounding factors, as can be performed with multivariate analysis.
The number of injections in this study was dependent on individual treatment requirements. The Observe-and-Plan regimen indicated retreatment according to disease activity signs (intra- or sub-retinal fluid, retinal hemorrhage), and applied serial planed injections (2–3) until adjustment of the next treatment plan was performed in periodical monitoring visits (every 3–6 months).19 The analysis of association with MA incidence was an analysis within this variable dosing regimen, contrasting with the previously reported comparisons between fixed monthly versus variable dosing pro re nata.10,11 Our results showed higher risk for MA in eyes with lower treatment needs. Although the catorical analysis did not reveal a clear dose-dependent effect, the more reliable analysis with injections as continuous variable did clearly show a significant association (Table 2), and it remained significant when including all other significant variables in the multivariate analysis (Tables 3 and 4). Initially, this may seem to contradict the previous studies that have reported higher risk in monthly versus variable dosing regimens. However, the “inversion” of the expected results is likely to be due to methodological differences; the comparison of fixed monthly retreatment with a variable dosing regimen as a category, as was performed in the previous reports,10,11 is like comparing overtreatment with individually adjusted treatment. Evidence from basic science suggests that the complete absence of VEGF isoforms 120 and 164 leads mice to an age-dependent degeneration of RPE and choriocapillaris similar to MA in AMD.22 Overtreatment associated with fixed monthly retreatment may result in complete and continuous VEGF suppression in at least a proportion of patients, thus, explaining the higher risk for MA in such a regimen. By contrast, comparing eyes within a variable dosing regimen according the eye's treatment needs differs completely. The retreatment decision is based on disease activity signs and, thus, verifiable periodic VEGF secretion, as was performed in the Observe-and-Plan regimen of this study. The treatment frequency was aimed at controlling disease activity without overtreatment. Therefore, we compared participants based on their level of need for treatment (n injections as continuous variable compared with MA incidence). Biological plausibility for lower treatment need eyes being at higher risk for MA may be found in the following hypothesis: 1) If the RPE requires minimal VEGF for survival,22 recurrences may provide the beneficial effect of transiently restoring adequate VEGF activity, helping to maintain the vitality of the RPE cells. This would be in favor of more frequent recurrences, as is the case for higher treatment need eyes. 2) The degenerative process of AMD may be ongoing while the patient is treated with anti-VEGF for neovascular complications. This may become more evident when the degree of exudative activity is low, as is in low treatment need eyes. 3) Despite the disastrous effect of the neovascular complex on retinal function, it may have some role in RPE survival. When the CNV complex is converted into scar tissue (low treatment need), its RPE supporting function may also disappear and MA may appear.
However, the drug type did not show any association with MA incidenc. To the best of our knowledge, this is the first comparison of MA incidence risk between treatment with ranibizumab and aflibercept. However, in terms of MA growth rate, Munk et al have performed a retrospective study and described less growth rate outside the CNV boundaries during the ranibizumab period compared with the subsequent use of aflibercept.(Munk et al14 #1193) Basic research results are contradictory regarding their respective toxicities. For example, Julien et al23 reported that aflibercept induced a higher rate of protein complex formation, hemolysis in the choriocapillaris, and RPE cell death than did ranibizumab in monkeys, whereas Malik et al24 reported no relevant toxicity on RPE cell cultures with either aflibercept or ranibizumab. Our clinical results support that no important difference exists in terms of MA incidence between these anti-VEGF drugs. However, our results should be reevaluated in comparative trials with larger numbers of treated eyes; as with our sample size of 149 eyes, the power afforded is insufficient to claim parity between treatment types.
In the literature, numerous investigations on the comparison between ranibizumab and bevacizumab can be found, with conflicting results. The analysis of the Comparison of AMD Treatments Trials indicated a higher MA risk for the ranibizumab group compared with the bevacizumab group,10 but this was not confirmed by the Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial11 nor by the meta-analysis that integrated both studies11 nor by the treat-and-extend management strategy in neovascular age-related macular degeneration (TREX-AMD) trial.13
In terms of ocular risk factors, this study identified as independent factors the presence of depigmentation, reticular pseudodrusen, lower baseline visual acuity, as well as the presence of RAP (or Type 3 neovascularization) and intraretinal cysts (in the subgroup with MA within the CNV area only). Depigmentation25 and reticular pseudodrusen26–29 have been previously reported as risk factors of MA in nonneovascular AMD, but so far not clearly identified in the context of treating nAMD. In our study, these parameters were also risk factors in the presence of neovascularization, a finding which is biologically plausible. These two factors probably correspond to the underlying degenerative process of AMD, rather than being related to neovascularization or its treatment. The relatively elevated odds ratio (OR 6.3 for depigmentation, OR 5.3 for reticular pseudodrusen) indicates their relevance for atrophy incidence. However, RAP and lower baseline visual acuity and intraretinal cysts, which have both been previously reported as risk factors for MA in nAMD,10 may be more closely associated with the neovascularization-related processes. This is in keeping with the observation that the risk factor of intraretinal cysts only retain statistical significance in the subgroup with MA appearing within the CNV complex area, and that the RAP group lost its significance in the subgroup with MA appearing outside the CNV complex area. However, RAP is also more frequently associated with MA in nonneovascular fellow eyes of RAP lesions,27 indicating an underlying risk profile for this phenotype. The absence of baseline subretinal fluid10 and subretinal tissue thickness,10,13 which are previously identified risk factors for MA, was statistically correlated with MA on the univariate analysis but was not independent. We also observed that a thinner choroid had a significant association with MA incidence in the univariate analysis, which has not been previously reported. However, as this factor is correlated with reticular pseudodrusen,30,31 it is not surprising that it did not retain statistical significance in the multivariate model. RPE detachment was not related with MA incidence. This corresponds well with previous reports.10,32
The association with MA in the fellow eye10 could not be included into the multivariate model because of the large reduction in sample size when restricted to eyes with nonneovascular fellow eyes. Thus, we approached this question in a separate subanalysis, which did indeed show an intereye correlation for MA presence and incidence. We, therefore, consider that it was justified to disallow both eyes of an individual into this analysis, opting for systematically including the right eye only. Although some precious information might get lost by this approach, we had to exclude only 13 eyes because of this reason and gained statistical reliability for the results.
A few limitations of this study need to be acknowledged. First, although the studies that served as the source of data for this analysis were both prospective with identical protocols and regimens, small differences because of nonconcurrent enrollment exist (i.e., the study team). Second, the number of included eyes was limited, and this would have reduced the statistical sensitivity for identifying less important factors. However, it did not influence the reliability of the significant results. Third, this was a post hoc analysis of prospective studies, and not initially designed to address the issue of MA incidence.
However, this study also had several strengths: the well-documented baseline, the identical regimen with 2 different drugs, the context of prospective research, the identical treatment duration of 2 years, and the absence of selection bias other than informed consent for participation in the original studies.
In conclusion, this study found that the number of injections was inversely related to MA incidence, suggesting 1) that high treatment numbers, if individually required, are not a risk factor and 2) that MA appearance may co-occur with low activity neovascular disorder. About reports in the literature, our results suggest that continuous and complete anti-VEGF suppression may be harmful but that the number of injections adjusted to the individuals' needs is not associated with increased MA risk. In addition, MA incidence was associated with a range of ocular factors, both related to the underlying degenerative process of AMD and to the neovascular complex with its exudative activity. Finally, there was no harmful effect found for the drug type (aflibercept vs. ranibizumab). Although significant, the multivariate model was incomplete, and there is room for improved understanding. Further studies are required to confirm our findings.
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Keywords:© 2019 by Ophthalmic Communications Society, Inc.
atrophy; retinal pigment epithelium; intravitreal injection; anti-VEGF; vascular endothelial growth factor; neovascular age-related macular degeneration; ranibizumab; aflibercept