Anti-VEGF agents have revolutionized the treatment of retinal diseases, but evidence shows that these drugs warrant concern for systemic side effects such as cardiovascular events. Therefore, regular safety updates on anti-VEGFs’ systemic effects are necessary. A recent study evaluated systemic adverse events (SAEs) associated with intravitreal anti-VEGF drugs compared with non-anti-VEGF treatments for patients with ocular diseases and found no association with an increase in major cardiovascular events in the trial.

Researchers analyzed a total of 74 randomized clinical trials (32 trials (43%): 14,190 AMD patients; 24 trials (32%): 5,424 DR patients); 17 trials (23%): 3,757 RVO patients; one trial (1%): 122 myopic CNV patients).

From their literature review, they found that anti-VEGF drug administration didn’t increase major cardiovascular events compared with control agents, or total mortality. “There was an interaction in mortality risk depending on the underlying disease with an increase in the risk of death in patients with DR; however, no increase was observed in patients with AMD or RVO,” the study authors wrote in their paper. 

Anti-VEGF agents did, however, increase the risk of non-ocular hemorrhage, “mainly in patients with AMD.” While the researchers noted that increased mortality in patients with diabetes or AMD with non-ocular hemorrhages could “represent a safety signal,” the evidence wasn’t strong, and “studies were not sufficiently powered to correctly assess a small increase in the incidence of SAEs.”

“Direct comparisons between bevacizumab and ranibizumab showed an increased risk of SAEs and a decreased risk of hypertension with bevacizumab,” they wrote. “No significant differences were observed between aflibercept and bevacizumab or ranibizumab, but the number of studies was low.”

The researchers concluded that continued surveillance for systemic adverse events in patients receiving anti-VEGF therapy is important. “Cardiologists and ophthalmologists should be aware of these safety signals, especially in patients at high risk,” they noted.

Ntjam NN, Thulliez M, Paintaud G, et al. Cardiovascular adverse events with intravitreal anti-vascular endothelial growth factor drugs: A systemic review and meta-analysis of randomized clinical trials. JAMA Ophthalmol. April 15, 2021. [Epub ahead of print].