Systemic safety issues
There is concern about adverse pulmonary effects of intravitreal anti-VEGF injections for ROP because babies with ROP often have lung disease, and there is evidence that inhibition of VEGF inhibits lung development and surfactant production.
“In addition, Kong et al reported reductions in levels of numerous cytokines after intravitreal injection of bevacizumab in babies,” Dr. Avery said. “Those mediators may also be involved in the development of bronchopulmonary dysplasia. Furthermore, in BEAT-ROP, there were 4 deaths from lung disease in the bevacizumab arm but only one in the control group of infants treated with laser.”
The finding that blood flow in the middle cerebral artery was reduced in babies given a single intravitreal injection of bevacizumab for ROP, combined with data from studies evaluating risk of neurodevelopmental delay, raise suspicion about potential neural adverse effect.
The latter research is comprised of retrospective studies, including one with 61 babies that reported a statistically significant, 5-fold increased risk of neurodevelopmental problems in children treated with bevacizumab and laser compared to laser alone.
No statistically significant adverse effects on neurodevelopment were found when comparing babies receiving bevacizumab only versus laser alone, but a strong trend was found. However, another larger retrospective study, including 125 babies treated for ROP, found a statistically significant, 3-fold increase in severe neurodevelopmental disability in babies receiving bevacizumab compared with those treated with laser.
“But there is inherent bias in these retrospective studies where sicker babies may have been more likely to get bevacizumab and despite regression analysis to correct for imbalances, it is hard to know how much weight to put on the evidence from these trials,” said Dr. Avery.
“For people who say they have never seen systemic effects in adults treated with anti-VEGF agents, however, I offer for consideration the findings of a meta-analysis I conducted.”
Dr. Avery was referring to a published paper assessing patients with diabetes receiving monthly injections for 2 years to treat diabetic macular edema. The results showed that in this high-risk group, anti-VEGF treated patients had a 3-fold risk of death compared to the sham or laser-treated controls.
Dr. Avery concluded that anti-VEGF therapy has been helpful in ROP, but there is biological plausibility that these agents reach the bloodstream and could potentially cause systemic side effects in the developing ROP baby. Given the large difference in systemic pharmacokinetics of these agents, he proposed prospective clinical trials to compare the safety and efficacy of these agents in the treatment of ROP.