Frequency of Intravitreal Anti-VEGF Injections and Risk of Death: A Systematic Review with Meta-analysis

Topic: To investigate whether an increasing number of intravitreal anti-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 the overall population, whereas some warning signals of higher mortality were found in patients with diabetes exposed to intense and prolonged treatment. Concerns have been raised about whether an increasing number of anti-VEGF injections could be associated with a higher mortality. Methods: Randomized clinical trials enrolling arms with different intensities of anti-VEGF therapy were searched. The primary outcome measure was the incidence rate ratio (IRR) of death with 95% confidence interval (CI) for receiving 5 injections. 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. Overall mortality rates of 1.02% and 3.36% were 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, in diabetic macular edema (DME) studies, a higher risk was marginally associated with an increasing number of injections 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 patients with DME.