Anti-VEGF Agents and the Risk of Arteriothrombotic Events

Blockade of vascular endothelial growth factor (VEGF) signaling, whether via sequestration of free VEGF or via inhibition of the tyrosine kinases activated by VEGF, is associated with decreased nitric oxide (NO) and prostaglandin-I 2 (PG-I 2) production along with vascular endothelial cell death. Systemic administration of drugs that block VEGF signaling (eg, for cancer treatment) is associated with systemic complications such as hypertension and thrombosis. Evidence regarding the risk of systemic serious adverse events after intravitreal injection of anti-VEGF agents in patients with diabetic macular edema or neovascular age-related macular degeneration is inconsistent, in part because of study design limitations (eg, bias of ascertainment through strict enrollment criteria and/or inadequate power to identify the risk of low frequency events). Studies involving patients at high risk of arteriothrombotic events (eg, patients with diabetic macular edema) who have high exposure to intravitreal anti-VEGF therapy (eg, monthly aflibercept or ranibizumab injection) demonstrate an increased risk of all-cause mortality compared with randomized controls. The pharmacokinetics of anti-VEGF drug clearance from the systemic circulation and the documented sustained reduction in free plasma VEGF levels after intravitreal aflibercept and bevacizumab injection are consistent with these findings. Although the frequency of systemic serious adverse events after intravitreal anti-VEGF therapy is low, some patients may be at higher risk (eg, those with recent stroke or multiple strokes), and physicians may wish to take special measures with these patients to minimize the risk of systemic complications.