Choroidal Thickness After Aflibercept for Neovascular AMD
Choroidal Thickness After Aflibercept for Neovascular AMD
Our findings indicate that three monthly intravitreal injections of aflibercept significantly reduce CT in eyes with previously treated neovascular AMD (ie, treated with ranibizumab or bevacizumab) as well as in treatment-naive eyes. This finding is in keeping with the findings of Branchini et al who reported a decrease in CT after treatment with ranibizumab or bevacizumab and Hikichi et al who reported a significant decrease in CT after ranibizumab treatment in eyes with polypoidal choroidal vasculopathy. Possible explanations for a decrease in CT could be that VEGF inhibitors, by decreasing levels of nitric oxide, induce choroidal vasoconstriction or that VEGF inhibitors reduce choroidal fenestrations.
Our results show that, after aflibercept therapy, the reduction in CT was greater in treatment-naive exudative AMD eyes than in eyes which had received previous bevacizumab or ranibiumab therapy. This finding may be a result of the significantly thinner baseline CT in the pretreated group compared with that in the treatment-naive group; the baseline subfoveal CT in the pretreated group was 182.8 μm (±57.3) compared with 226.4 μm (±68.5) in the treatment naïve group. A further plausible explanation is that the choroid has been previously exposed to other anti-VEGF agents. However, it is surprising that in extensively pretreated eyes (mean of 28.2 anti-VEGF injections over a mean of 37.7 months), aflibercept is still able to induce a further significant decrease in CT.
For all intravitreally applied pan-VEGF inhibitors, an effect on systemic VEGF levels has been shown. However, it is interesting that except for the subfoveal area, fellow eyes of treatment-naive eyes treated with aflibercept showed a statistically significant decrease in CT in all tested retinal areas, indicating a clinically relevant systemic effect. No significant difference was seen in fellow eyes of pretreated eyes after aflibercept therapy. The reason this effect was only seen in the treatment-naive group may be a decreased choroidal sensitivity in a choroid previously exposed to anti-VEGF agents as described above.
Klettner et al showed, in tissue culture, that aflibercept has a prolonged duration of VEGF inhibition compared with either bevacizumab or ranibizumab; this may partially explain the further choroidal thinning seen with aflibercept following pretreatment with other anti-VEGF agents. Our study indicates a significant reduction in CT with aflibercept in treatment-naive and pretreated eyes. These findings could account for superior efficacy of aflibercept in the treatment of IPCV and pigment epithelial detachments (PEDs) in AMD. While a reduction in CT in AMD may lead to a further reduction of exudative changes, especially PEDs, choroidal thinning has been associated with retinal pigment epithelium (RPE) atrophy. Therefore, the long-term implications of a pharmacologically induced thinned choroid are to be determined. In addition, Julien et al recently showed in monkeys that a 2 mg intravitreal injection of aflibercept induced more haemolysis in the choriocapillaris, resulting in more RPE cell death compared with 0.5 mg of ranibizumab.
It is not yet established that anti-VEGF agents indeed cause choroidal thinning or if this is part of the disease process of neovascular AMD. A direct comparison between untreated and treated eyes with neovascular AMD is impossible for ethical reasons. There is however some rationale that this effect can be attributed to anti-VEGF treatment. One would expect that upregulated VEGF in untreated neovascular AMD would rather lead to increased CT as a result of vasodilatation and increased blood vessel fenestration. This difference is also seen in our baseline findings, indicating a thicker choroid for eyes with neovascular AMD in comparison with fellow eyes with non-neovascular AMD. In addition, it is plausible that anti-VEGF agents could influence CT and vascular permeability. Our data suggest that aflibercept influences CT; if these findings are confirmed in prospective studies, CT may become a relevant parameter for drug selection and evaluation in follow-up.
Discussion
Our findings indicate that three monthly intravitreal injections of aflibercept significantly reduce CT in eyes with previously treated neovascular AMD (ie, treated with ranibizumab or bevacizumab) as well as in treatment-naive eyes. This finding is in keeping with the findings of Branchini et al who reported a decrease in CT after treatment with ranibizumab or bevacizumab and Hikichi et al who reported a significant decrease in CT after ranibizumab treatment in eyes with polypoidal choroidal vasculopathy. Possible explanations for a decrease in CT could be that VEGF inhibitors, by decreasing levels of nitric oxide, induce choroidal vasoconstriction or that VEGF inhibitors reduce choroidal fenestrations.
Our results show that, after aflibercept therapy, the reduction in CT was greater in treatment-naive exudative AMD eyes than in eyes which had received previous bevacizumab or ranibiumab therapy. This finding may be a result of the significantly thinner baseline CT in the pretreated group compared with that in the treatment-naive group; the baseline subfoveal CT in the pretreated group was 182.8 μm (±57.3) compared with 226.4 μm (±68.5) in the treatment naïve group. A further plausible explanation is that the choroid has been previously exposed to other anti-VEGF agents. However, it is surprising that in extensively pretreated eyes (mean of 28.2 anti-VEGF injections over a mean of 37.7 months), aflibercept is still able to induce a further significant decrease in CT.
For all intravitreally applied pan-VEGF inhibitors, an effect on systemic VEGF levels has been shown. However, it is interesting that except for the subfoveal area, fellow eyes of treatment-naive eyes treated with aflibercept showed a statistically significant decrease in CT in all tested retinal areas, indicating a clinically relevant systemic effect. No significant difference was seen in fellow eyes of pretreated eyes after aflibercept therapy. The reason this effect was only seen in the treatment-naive group may be a decreased choroidal sensitivity in a choroid previously exposed to anti-VEGF agents as described above.
Klettner et al showed, in tissue culture, that aflibercept has a prolonged duration of VEGF inhibition compared with either bevacizumab or ranibizumab; this may partially explain the further choroidal thinning seen with aflibercept following pretreatment with other anti-VEGF agents. Our study indicates a significant reduction in CT with aflibercept in treatment-naive and pretreated eyes. These findings could account for superior efficacy of aflibercept in the treatment of IPCV and pigment epithelial detachments (PEDs) in AMD. While a reduction in CT in AMD may lead to a further reduction of exudative changes, especially PEDs, choroidal thinning has been associated with retinal pigment epithelium (RPE) atrophy. Therefore, the long-term implications of a pharmacologically induced thinned choroid are to be determined. In addition, Julien et al recently showed in monkeys that a 2 mg intravitreal injection of aflibercept induced more haemolysis in the choriocapillaris, resulting in more RPE cell death compared with 0.5 mg of ranibizumab.
It is not yet established that anti-VEGF agents indeed cause choroidal thinning or if this is part of the disease process of neovascular AMD. A direct comparison between untreated and treated eyes with neovascular AMD is impossible for ethical reasons. There is however some rationale that this effect can be attributed to anti-VEGF treatment. One would expect that upregulated VEGF in untreated neovascular AMD would rather lead to increased CT as a result of vasodilatation and increased blood vessel fenestration. This difference is also seen in our baseline findings, indicating a thicker choroid for eyes with neovascular AMD in comparison with fellow eyes with non-neovascular AMD. In addition, it is plausible that anti-VEGF agents could influence CT and vascular permeability. Our data suggest that aflibercept influences CT; if these findings are confirmed in prospective studies, CT may become a relevant parameter for drug selection and evaluation in follow-up.
