Purpose: To evaluate potential safety risks associated with nonspecific inhibition of vascular endothelial growth factor (VEGF). Design: A perspective, reviewing the current literature. Methods: Herein, we discuss the systemic safety of VEGF-targeted therapies, address safety issues for VEGF-targeted therapies in neovascular age-related macular degeneration, and propose the consideration of methods for identifying low rate systemic safety signals from patients treated with these agents. Results: Several prospective, randomized clinical trials have demonstrated that intravitreal anti-VEGF therapies generally are well tolerated. However, within these trials, there is some circumstantial evidence that links systemic VEGF inhibition to systemic adverse events, particularly systemic thromboembolic events. Because all of the intravitreal anti-VEGF agents have been associated with detectable levels in the systemic circulation, there is a scientific rationale for the occurrence of potential systemic adverse events. However, if safety issues are present, they occur at very low rates and may go undetected in controlled clinical trials of premarketed drugs. Conclusions: We propose that highly sensitive methodologies be put into place for identifying low rate safety signals, including postmarketing clinical trials, chart reviews, electronic medical records, and various national and international registries and databases, to evaluate the systemic safety of antiangiogenic agents in ocular diseases such as neovascular age-related macular degeneration.
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