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

Question Does intravitreal anti-vascular endothelial growth factor therapy increase the risk of mortality among patients with retinal disease? Findings A frequentist meta-analysis on all-cause mortality that included 8887 unique patients in 34 unique studies provided an increased odds of 1.34 between anti-vascular endothelial growth factor therapy and control groups. No definitive linear increase in risk for 1 injection more or higher mortality in studies with longer follow-up were shown by meta-regression analyses. Meaning This study revealed little evidence of increased mortality and cannot determine whether the increased death risk suggested from studies in which monthly injections were delivered for as long as 2 years was associated with the larger number of injections or with longer follow-up. This meta-analysis assesses whether intravitreal anti-vascular endothelial growth factor therapy and which variables might be associated with increased risk of mortality among patients with retinal disease. 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.