We would like to address several challenges that have arisen from the interesting and well-documented study by Muftuoglu and associates, which can be specifically summarized below.

There were no details regarding the neovascular maculopathy in the 2 groups of patients (ie, treatment-resistant and with multiple recurrences) with neovascular age-related macular degeneration (AMD) before and after switching to aflibercept (Eylea; Regeneron, Tarrytown, NY) treatment, including choroidal neovascularization (CNV), 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 (ie, subretinal fibrosis).

Initially, a comparison had to be carried out between the 2 groups of patients to establish whether they are comparable. Accordingly, this comparison should have been conducted only if there were no significant differences between the demographics and baseline ocular characteristics of these 2 groups of patients.

The presumed pharmacological advantages of aflibercept over bevacizumab (Avastin; Genentech Inc, South Francisco, CA) or ranibizumab (Lucentis, Genentech, Inc.)—for example, a higher binding affinity for vascular endothelial growth factor-A (VEGF-A) and activity against VEGF-B and placental-derived growth factor and a longer duration of effect —were not confirmed by the results of this series. Therefore, half of the eyes did not achieve retinal dryness at the end of the study requiring more frequent injections; 45.6% of the eyes needed to have escalated aflibercept injections given monthly at a median time to switching to escalated regimen of 37 weeks to sustain initial anatomic improvements; and 39.5% of the eyes lost ≥1 line at last follow-up. These unsatisfactory outcomes can be explained by the nature of the study population made up of patients with chronic persistent wet AMD, who were previously treated with a median of approximately 14 anti-VEGF injections other than aflibercept (having a possible role in causing retinal thinning and geographic atrophy), and who had advanced choroidal neovascular membrane upon enrollment with limited potential to improve vision. Most likely, there was a chronic retinal capillaropathy attributable to permanent breakdown of the inner and outer blood-retinal barriers. This permanent retinal capillaropathy caused by persistent subretinal or intraretinal fluid was temporarily relieved by reduction of edematous component with treatment. However, the pathology was incurable because of irreversible ischemic changes to the macular ganglion cell complex, close to the foveola, with macular edema being a minor factor.

There was no insight into the mechanisms of resistance to anti-VEGF therapy. Tachyphylaxis may explain the decrease in the response to bevacizumab/ranibizumab, which was overcome by switching to a similar drug with different properties. It could be caused by the 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. A pharmacodynamic tolerance developed during aflibercept treatment, which may be caused by the increased expression of VEGF attributable to the elevated number 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 drug’s efficacy was restored by escalating to monthly aflibercept injections.

Altogether, regardless of the anti-VEGF agents used (eg, bevacizumab/ranibizumab/aflibercept), and regardless of the treatment approaches chosen (eg, treat-and-extend/pro re nata/escalated algorithm), the efficacy of therapy depends primarily on the promptness of the therapy after AMD diagnosis.