Frequency of intravitreal anti-vascular endothelial growth factor injections and risk of death: a systematic review with meta-analysis

Topic: To investigate whether an increasing number of intravitreal anti-vascular endothelial growth factor (VEGF) injections is associated with a higher mortality risk. Clinical relevance: The issue of systemic safety of intravitreal anti-VEGF therapy has been long discussed. Evidence from meta-analyses of randomized studies has shown no increased risk of mortality in overall population, while some warning signal of higher mortality were found in diabetic patients exposed to intense and prolonged treatment. Concerns have been raised as to whether an increasing number of anti-VEGF injections could be associated with a higher mortality. Methods: Randomized clinical trials enrolling arms with different intensity of anti-VEGF therapy were searched. The incidence rate ratio (IRR) of death with 95% confidence interval (CI) for receiving 5 injections was the primary outcome measure. The relationship between the number of injections and all-cause mortality was investigated. Separate regression analyses were conducted to investigate this relationship in subgroups of studies with different diseases and drugs. Results: Fifty-two trials were included. An overall mortality rate of 1.02% and 3.36% was recorded at 12 and 24 months, respectively. Univariate regression showed that a larger number of injections was not associated with a significant increase in mortality both at 12 months (IRR=1.16,95%CI=0.87-1.53;p=0.31) and at 24 months (IRR=1.05,95%CI=0.95-1.15;p=0.34). According to subgroup analyses, a higher risk was marginally associated with an increasing number of injections in diabetic macular edema (DME) studies at 24 months (IRR=1.17,95%CI=1.02-1.33;p=0.03). Conclusion: No significant influence of anti-VEGF treatment intensity on mortality was shown, supporting a message of reassurance over safety concerns of this therapy. Marginal evidence of a higher risk associated with a more intense treatment was found in DME patients.