Effects of intravitreal aflibercept and ranibizumab on retinal vessel diameter measured using fluorescein angiography.

Abstract

Vascular endothelial growth factor (VEGF) plays an important role in intra-ocular neovascularization in a number of pathological conditions, making anti-VEGF agents a useful therapy in patients with neovascular age-related macular degeneration (N-AMD). Ranibizumab is a 48-kDa monovalent monoclonal antibody fragment consisting of an antigen-binding Fab region without the Fc domain. This structure was designed to prevent binding to Fc receptor, thus dramatically shortening the half-life of the fragment to approximately 2 hr after it enters the systemic circulation from the eye (Xu et al. 2013; Avery et al. 2014). In contrast, aflibercept forms a stable, inert 1:1 complex with the ligands VEGF-A, VEGF-B and placental growth factor (PlGF), preventing their binding and activation of their receptors, VEGFR-1 and -2. Because of its intact Fc region, aflibercept is recycled via binding to endothelial cell Fc receptors; its effects are thus long-lasting and result in a marked and prolonged reduction in plasma concentrations of free VEGF (Stewart 2011; Semeraro et al. 2013; Avery et al. 2014). However, this has the potential to cause adverse effects owing to blockage of the physiologic functions of VEGF. We therefore evaluated retinal vessel diameter changes after three consecutive monthly intravitreal (IVT) injections of aflibercept and ranibizumab in patients with N-AMD. Retinal vessel diameter significantly decreased in aflibercept-treated patients; Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) reduced from 106.7 ± 22.9 μm to 96.1 ± 24.1 μm (p = 0.028) and from 148.8 ± 19.6 μm to 140.8 ± 19.6 μm (p = 0.003), respectively. However, retinal vessel diameter was not significantly reduced in ranibizumab-treated patients; CRAE changed from 107.1 ± 23.3 μm to 104.4 ± 22.0 μm (p = 0.073) and CRVE changed from 139.0 ± 13.8 μm to 139.2 ± 14.2 μm (p = 0.794) (Table 1). As there should be no systemic accumulation because of reported quick clearance after IVT ranibizumab treatment, we thought that ranibizumab would have minimal effect on retinal vessel diameter change even though it would also be able to affect retinal vessel vasoconstriction by blocking NO production. However, aflibercept was expected to demonstrate greater systemic exposure and to produce a marked reduction in plasma-free VEGF (Avery et al. 2014). Therefore, aflibercept would lead to significant retinal vessel vasoconstriction by inhibiting NO production. Furthermore, ranibizumab is known to permeate the retina via intercellular clefts, whereas aflibercept is taken up by ganglion cells, cells of the inner and outer retinal layers and retinal pigment epithelium cells (Julien et al. 2014). Therefore, aflibercept was expected to be accumulated and remain much longer in the retina, leading to retinal venous constriction in addition to retinal arterial constriction, resulting from a greater reduction in VEGF than with ranibizumab. A major limitation of the current study is the absence of controls. Baseline retinal vessel diameter measurements in controls and their comparison with those obtained in eyes with active N-AMD may have elucidated whether our findings represent a return to normal diameter from a previous state of vasodilatation, true vasoconstriction or a combination of both. Second, even though we excluded some patients diagnosed with conditions that could affect retinal vessel diameter and showed there was no significant difference in mean intraocular pressure (IOP) between pre- and postinjection, we did not take the systemic blood pressure of the patients into consideration, which would influence retinal vessel diameter measurements. Third, our study was the relatively low number of eyes. Thus, further studies with a larger number of subjects together with co-measurement of ocular perfusion pressure are needed to confirm or not these results.