Systemic Safety of Intravitreal Anti-vascular Endothelial Growth Factor Agents in Age-Related Macular Degeneration

Vaidehi S. Dedania; Sophie J. Bakri


Curr Opin Ophthalmol. 2016;27(3):224-243. 

In This Article

Abstract and Introduction


Purpose of review The purpose of review is to summarize the literature addressing nonocular adverse events in patients with neovascular age-related macular degeneration treated with intravitreal vascular endothelial growth factor (VEGF) inhibitors and to present possible mechanisms of effect.

Recent findings The incidence of overall nonocular serious adverse events varied from 0 to 39.3% and nonocular adverse events ranged from 0 to 86.9%. Few studies have reported a significant association between use of intravitreal anti-VEGF agents and overall incidence of adverse events, stroke, myocardial infarction, nonocular hemorrhage and death, with overall greater concern in patients treated with bevacizumab. Additionally, history of stroke or other arterial thromboembolic event may be a risk factor for future stroke in patients treated with intravitreal anti-VEGF agents. Theories explaining the mechanisms of increased risk of nonocular adverse events secondary to anti-VEGF agent use surround the necessity of VEGF for the normal functioning of the endothelium and the damage incurred with use of anti-VEGF agents.

Summary Current data are insufficient to definitively conclude that intravitreal anti-VEGF agents are safe, although there is a trend toward an overall favorable systemic safety profile. Caution should be exerted in patients with a history of cardiovascular disease, as these patients may be at greater risk for nonocular serious adverse events.


Neovascular age-related macular degeneration (AMD), accounting for the majority of severe vision loss because of AMD;[1] is characterized by pathologic choroidal neovascularization (CNV).[2,3] Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein and a key regulator of physiologic and pathologic angiogenesis. It has been isolated from CNV membranes and has emerged as a target for the treatment of CNV,[4] revolutionizing the management of neovascular AMD. The intravitreal anti-VEGF agents previously and currently employed include pegaptanib (Macugen, Pfizer, New York City, New York, USA) – a ribonucleic acid aptamer, ranibizumab (Lucentis; Genentech, Inc., South San Francisco, California, USA) – a humanized monoclonal antibody fragment, bevacizumab (Avastin; Genentech, Inc. South San Francisco, California, USA) – a recombinant full-length humanized monoclonal antibody (used off-label) and aflibercept (Eylea; Regeneron, Tarrytown, New York, USA) – a soluble decoy receptor fusion protein.[5–8]

Numerous trials [ANCHOR (Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD), MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD), PrONTO (Patients with Neovascular Age-Related Macular Degeneration treated with intraOcular Ranibizumab), HARBOR ( PHase III; double-masked, multicenter; randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration), VIEW 1/VIEW 2 (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD), CATT (Comparison of Age-Related Macular Degeneration Treatment Trials), IVAN (Inhibition of VEGF in Age-Related Choroidal Neovascularization)],[5,6,9–17] examining the efficacy and safety of intravitreal anti-VEGF therapies, have showed that frequent injections greatly reduce the risk of vision loss in patients with neovascular AMD,[9–16] although these medications can cause adverse events. Bevacizumab can be administered intravenously for the treatment of various tumors and has been associated with thromboembolic events, gastrointestinal perforations and hemorrhage, hypertension (HTN), and proteinuria.[18,19] Studies have reported detectable levels of anti-VEGF drug[20,21] and decreased VEGF in plasma after intravitreal injection of bevacizumab.[22] Although intravitreal injection limits the amount of drug reaching systemic circulation,[21,23] the blood–ocular barrier is believed to be damaged in neovascular diseases,[24] possibly facilitating systemic absorption of medication.

The purpose of this review is to describe the findings of studies evaluating safety of these medications and present possible mechanisms for nonocular adverse events.