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Risk of Death Associated With Intravitreal Anti-Vascular Endothelial Growth Factor Therapy: A Systematic Review and Meta-analysis.

Importance
Although intravitreal anti-vascular endothelial growth factor (VEGF) treatment represents the first-line therapy for many retinal diseases, the issue of their systemic safety is debatable.


Objectives
To assess whether intravitreal anti-VEGF therapy might be associated with increased risk of mortality and which variables are associated with the increase.


Data Sources
PubMed, MEDLINE, and Embase databases, the Cochrane Library, and ClinicalTrials.gov were systematically searched from inception to May 6, 2019.


Study Selection
Randomized clinical trials comparing intravitreal anti-VEGF treatment with control groups and with follow-up of at least 6 months were selected.


Data Extraction and Synthesis
Data were independently collected by 2 investigators. Meta-analyses were conducted using the frequentist and Bayesian methods. For the frequentist approach, random- and fixed-effects models were used, with random-effects models considered the primary technique. Odds ratios (ORs) with 95% CIs were computed. For the bayesian approach, uninformative and informative priors were used. Odds ratios with 95% credible intervals (CrIs) were computed. Meta-regression analyses were based on random-effects models.


Main Outcomes and Measures
The primary outcome measure was the all-cause death rate. Secondary outcomes included meta-regression analyses on the following variables: type of drug, number of injections, follow-up time, diagnosis, and cardiovascular risk.


Results
Of 2336 studies identified, 34 unique studies with 8887 unique participants were included in the present meta-analysis. For the frequentist analysis, fixed- and random-effects models yielded similar estimates (ORs, 1.34 [95% CI, 0.95-2.07; P = .09] and 1.34 [95% CI, 0.89-2.01; P = .17], respectively). For the Bayesian approach, noninformative and informative priors yielded similar results (ORs, 1.34 [95% CrI, 0.79-2.34; 0.13 probability of OR≤1.00] and 1.40 [95% CrI, 0.82-2.32; 0.11 probability of OR≤1.00], respectively). Meta-regression analyses showed the following risk for 1 injection more: frequentist OR of 1.12 (95% CI, 1.04-1.22; P = .005) and Bayesian OR of 1.06 (95% CrI, 0.98-1.15; 0.06 probability of OR≤1.00).


Conclusions and Relevance
In this study, no difference was found in the mortality rate between intravitreal anti-VEGF treatment and control groups. Additional data seem warranted to determine whether the mortality rate is increased in patients receiving a greater number of injections.