Whether using aflibercept, bevacizumab, or ranibizumab to treat patients with retinal disease, ophthalmologists can rest assured that available treatments share a similar adverse event profile, according to the results of a long-term study published in Ophthalmology.1 

The authors accessed the records of 87,844 patients who received anti-vascular endothelial growth factor (VEGF) injections for age-related macular degeneration, diabetic retinal disease, or retinal venous occlusive disease between January 2007 and June 2018. Of the patient records reviewed, 7942 received aflibercept, 69,007 received bevacizumab, and 10,895 received ranibizumab. A fourth anti-VEGF agent, brolucizumab, which was approved by the US Food and Drug Administration in October 2019, was not included in the study.

The goal of the study was to compare the risk of acute myocardial infarction, cerebrovascular disease, major bleeding, stroke, hypertension, hyperlipidemia, moderate or severe renal disease, congestive heart failure, peripheral vascular disease, chronic pulmonary disease, metastatic solid tumor, any cancers, or hospitalization for any other reason among the different treatments.1 

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Previous research by the same group showed that anti-VEGF therapy was not associated with increased risk for cerebrovascular disease, major bleeding, or myocardial infarction when compared with macular laser treatment for diabetic macular edema; however, the authors noted an increased risk of all-cause hospital admission following treatment. In that research, the rates of all primary systemic serious adverse events associated with anti-VEGF treatment were similar to those seen with corticosteroid use.2

The 3 agents reviewed in the most recent study have notable pharmacodynamic and pharmacokinetic profile differences, leading to variations in both the magnitude and duration of free VEGF in the serum. It is therefore reasonable to suspect they may have different effects on systemic health, which is why clinicians may alternate treatment regimens, rotating both the medication used and injection timing.

The researchers “observed no differences in the risk of acute myocardial infarction, cerebrovascular disease, major bleeding, or all-cause hospitalization, following treatment initiation with intravitreal bevacizumab, ranibizumab, or aflibercept during routine clinical practice.”

Within each of the individual agents’ clinical trials, anti-VEGF treatments have led to very few serious adverse events. However, those trials have not provided comparative systemic safety profiles between the different agents.


  1. Maloney MH, Payne SR, Herrin J,et al. Risk of systemic adverse events following intravitreal vevacizumab, ranibizumab, and aflibercept in routine clinical practice.  Ophthalmology.  Published online August 8, 2020. doi: https://doi.org/10.1016/j.ophtha.2020.07.062 
  2. Maloney MH, Schilz SR, Herrin J, Sangaralingham LR, Shah ND, Barkmeier AJ. Risk of systemic adverse events associated with intravitreal anti-VEGF therapy for diabetic macular edema in routine clinical practice. Ophthalmology. 2019;126(7):1007-1015. doi: https://doi.org/10.1016/j.ophtha.2018.09.040