Author reply – Corrected Proof

Beaumont et al and Ueta raise concerns about the systemic safety of aflibercept for intravitreal injection, particularly regarding cerebrovascular risk and stroke, based on their analysis of safety data from the VIEW studies comparing aflibercept to ranibizumab. They acknowledge similar rates of serious adverse events (SAEs) overall between aflibercept and ranibizumab, as well as similar rates of myocardial infarction, stroke, and vascular death as confirmed by masked adjudication using the strict and well-accepted Antiplatelet Trialists' Collaboration (APTC) criteria. However, they focus on numerical imbalances in certain other adverse events (AE) classifications to raise the question of whether aflibercept might be associated with a higher risk of stroke, while overlooking data that point to a higher incidence of cardiovascular events with ranibizumab. While Beaumont et al point out that the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) drew attention to the issue of cerebrovascular events, they should have also pointed out that like the previous Food and Drug Administration (FDA) assessment, the CHMP concluded that “overall the safety profile of aflibercept appears to be similar to the already marketed comparator drug, ranibizumab.” Beaumont et al concede that their approach suffers from being a post-hoc subgroup analysis; it is well known that selectively singling out relatively small numbers of individual classes of AEs for post-hoc assessment, as these letters do, can lead to erroneous conclusions. Importantly, their assessments of statistical significance were neither prespecified nor corrected for multiplicity so that any claims made concerning statistical significance of any imbalances are invalid. In addition, since the overall SAEs between all treatments were well balanced, any numerical imbalances in the first year favoring ranibizumab had to be (and were) contrasted by other numerical imbalances favoring aflibercept (i.e., there were imbalances against ranibizumab regarding serious infections) (; available at http://aaojournal.org).