Comments to: Clinical Experience of Switching Anti-VEGF Therapy from Ranibizumab to Aflibercept in Age-Related Choroidal Neovascularization

The study was retrospectively conducted with the existence of a selection bias, which was caused by inclusion of patients with active nAMD irrespective of the response of their eyes to ranibizumab in the period before switching, aiming to reduce the total number of appointments and treatments.

There were no data on the lesion types of neovascular maculopathy before and after switching, including choroidal neovascularization (CNV) (occult/minimally classic, predominantly classic/missing), cystic changes within neurosensory retina, serous or hemorrhagic detachment of the neurosensory retina or retinal pigment epithelium (RPE), retinal hard exudates, subretinal and sub-RPE fibrovascular proliferation, and disciform scar (subretinal fibrosis).

A washout period of 4 to 5 weeks between the last injection with ranibizumab and the first aflibercept injection seems to be too short for patients who have been treated with a mean of 9.95 ranibizumab injections for 14 up to 38 months. A real washout period is essential between the 2 periods of treatment in terms of aliased effects. Thus, the impact of the significant carryover effects of the ranibizumab may be confounded in this study with direct effects of the aflibercept treatment, in the sense that these effects could not be estimated separately, being able to bias the interpretation of data analysis.

The baseline value of the mean central retinal thickness (CRT) (322.3 µm) can be considered as approximately normal because it exceeded by only 7.1 µm the upper level of the normal CRT (270 ± 22.5 µm) (2) plus 2 standard deviations. The effectiveness of the significant reduction of the CRT with 75.6 µm after switching cannot be evaluated because there were no data referring to the retinal fluid status at the end of the follow-up; namely, the presence (termed wet) or absence (denoted dry) of the retinal fluid. Moreover, nothing was stated regarding the time to absence of the retinal fluid (retinal dryness) as well as the type of retinal dryness, i.e., simple (1 episode of absent retinal fluid) or sustained (2 or more consecutive episodes) retinal dryness.

The gradual decrease of the therapeutic benefit from prolonged use of ranibizumab might have been caused in this series by development of tachyphylaxis or tolerance. Tachyphylaxis could be caused by the depletion or marked reduction of the amount of neurotransmitter responsible for creating the drug's effect or by the depletion of receptors available to which the drug or neurotransmitter can bind. This state was overcome by switching to aflibercept, a similar drug with different properties. Pharmacodynamic tolerance may be caused by the increased expression of vascular endothelial growth factor (VEGF) due to elevated numbers of macrophages in CNV, increased expression of VEGF receptors, changes in signal transduction, or a shift of the stimulus for CNV growth towards other growth factors. The tolerance requires an increased dosage or shorter dosing time intervals to achieve the desired effect.

The strategy of switching to aflibercept in eyes with persistent retinal fluid after repeated ranibizumab injections should take into account the currently available recommendations (3, 4). Thus, eyes treated with monthly aflibercept had better visual acuity at week 52 than those treated with aflibercept less frequently or those treated with ranibizumab. Moreover, in eyes treated with monthly aflibercept, a dry retina was more likely to be sustained than in those treated with aflibercept every 2 months or ranibizumab every month.