IMPORTANCE Few data exist regarding the systemic safety of intravitreal antivascular endothelial growth factor (anti-VEGF) monoclonal antibody (mAb).OBJECTIVE To conduct a systematic review and meta-analysis to evaluate the risk of major cardiovascular and nonocular hemorrhagic events in patients with neovascular age-related macular degeneration (AMD), diabetes mellitus-associated macular edema (DME), or retinal vein occlusions (RVOs) who receive intravitreal anti-VEGF mAbs.DATA SOURCES The MEDLINE and Cochrane Central databases were searched for potentially eligible studies.STUDY SELECTION Randomized clinical trials comparing ranibizumab or bevacizumab with no anti-VEGF treatment, as well as those comparing ranibizumab with bevacizumab in patients with AMD, DME, or RVOs. DATA EXTRACTION AND SYNTHESISWe used a fixed-effects model and report the results as odds ratios (ORs) and 95% CIs. MAIN OUTCOMES AND MEASURESPrimary end points were major cardiovascular and nonocular hemorrhagic events. Secondary end points were all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, venous thromboembolic events (VTEs), and hypertension.RESULTS Twenty-one trials that evaluated 9557 patients were retrieved. Anti-VEGF mAbs did not significantly increase the risk of major cardiovascular events (OR, 1.18; 95% CI, 0.81-1.71) or nonocular hemorrhagic events (OR, 1.42; 95% CI, 0.95-2.13) in treatment groups compared with control populations. Bevacizumab did not increase the risk of major cardiovascular events (OR, 0.94; 95% CI, 0.59-1.52) or nonocular hemorrhagic events (OR, 2.56; 95% CI, 0.78-8.38) compared with ranibizumab, but significantly increased VTEs (OR, 3.45; 95% CI, 1.25-9.54). Subgroup analysis showed a significant increase of nonocular hemorrhagic events in patients with AMD in ranibizumab vs control trials (OR, 1.57; 95% CI, 1.01-2.44). Anti-VEGF mAbs did not significantly increase overall mortality, cardiovascular mortality, stroke, myocardial infarction, VTEs, or hypertension. CONCLUSIONS AND RELEVANCEWe showed that intravitreal anti-VEGF-mAbs were not associated with significant increases in major cardiovascular or nonocular hemorrhagic events, but studies and meta-analyses were not powered enough to correctly assess these risks. Increased risks of VTEs with bevacizumab and nonocular hemorrhagic events in older patients with AMD with ranibizumab should be cautiously interpreted because more safety data are needed.

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The systemic safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) medications is still a matter of debate.OBJECTIVE This overview of systematic reviews evaluates systemic adverse events associated with intravitreal anti-VEGF treatments in patients with neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion. DESIGN, EVIDENCE, AND REPORTINGThis systematic search of PubMed and the Cochrane Central Register of Controlled Trials database includes meta-analyses and systematic reviews. We describe the summary measures of association between anti-VEGF treatments and outcomes reported in each systematic review. MAIN OUTCOMES AND MEASURESThe quality of the systematic reviews was assessed with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and A Measurement Tool to Assess Systematic Reviews (AMSTAR) checklist, version 1.FINDINGS We retrieved 21 systematic reviews published between January 1, 2011, and June 30, 2016. Of these, 11 analyzed systemic adverse events as the primary outcome. The median (interquartile range) PRISMA and AMSTAR scores were 23 of 27 (15-27) and 8 of 11 (5-11), respectively, but 5 reviews (25%) scored below 20 and 7, respectively. All reviews used an objective scale to assess methodological risk of bias in their included studies, the Cochrane Risk of Bias Tool being the most commonly used (16 reviews [76%]). Anti-VEGF treatments did not increase the risk of systemic adverse events when compared with control regimens; similarly, there was no increase in systematic adverse events when treatment was given on a monthly schedule vs an as-needed regimen. Compared with ranibizumab, bevacizumab did not appear to be associated with an increase in the risk of systemic adverse events in the most recent and exhaustive reviews. Compared with control treatments, ranibizumab may be associated with an increase in the risk of nonocular hemorrhage in patients with age-related macular degeneration.CONCLUSIONS AND RELEVANCE This overview of reviews and meta-analyses suggest that anti-VEGF treatments do not increase the risk of systemic adverse events, but that caution might be advisable in older patients with age-related macular degeneration who may be at higher risk of hemorrhagic events when receiving ranibizumab.