Intense Anti-VEGF Therapy May Increase Mortality Risk in Patients With DME

Patients who receive more frequent anti-VEGF injections for diabetic macular edema have a marginally higher death risk, research shows.

Intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment intensity is not significantly associated with a higher risk of mortality, according to a systematic review published in Ophthalmology Retina. However, researchers found that increasing the number of anti-VEGF injections is slightly associated with a higher death risk in patients with diabetic macular edema (DME).  

The investigators searched for randomized clinical trials which enrolled arms with different intensity of anti-VEGF treatment. They defined the primary outcome measure as the incidence rate ratio (IRR) of death with 95% confidence interval (CI) for undergoing 5 injections. They used mixed regression models to explore the association between the mean number of injections and all-cause mortality. The team also performed separate regression analyses to investigate the association in subgroups of studies with different diseases and different drugs.

The review included 52 trials. Researchers determined there were 134 deaths out of 13,099 patients (1.02%) at 12 months. At 24 months, they found that there were 326 deaths out of 9,691 patients (3.36%).

Univariate regression demonstrated that a higher number of injections was not associated with a significant increase in mortality at both 12 months (IRR=1.16, 95% CI=0.87-1.53; P =.31) and at 24 months (IRR=1.05, 95% CI=0.95-1.15; P =.34).

When subgroups by disease and drug were taken into account, the overall mortality was approximately 1% at 12 months. At 24 months, the overall mortality was roughly 3% in most subgroups. 

Based on the subgroup analyses, a higher number of injections was marginally associated with elevated risk of death in DME studies (5 studies with 74 deaths) at 24 months (IRR=1.17, 95% CI=1.02-1.33; P =.03). 

DME patients that need for an intensive and prolonged intravitreal anti-VEGF therapy are likely to present a poor metabolic control, with high level of glycosylated hemoglobin and impaired renal function,” according to the researchers. “A higher mortality in this category of patients could be related to some extent to this complex systemic condition.”

Study limitations include the strict eligibility criteria and most of the studies were sponsored by pharmaceutical companies. Also, investigators advise that patients with high cardiovascular risk should interpret these results with caution.   


Reibaldi M, Fallico M, Avitabile T, et al. Frequency of intravitreal anti-vascular endothelial growth factor injections and risk of death. Ophthalmol Retina. Published online December 30, 2021. doi:10.1016/j.oret.2021.12.019