Cardiovascular Events and Bleeding Risk Associated With Intravitreal Antivascular Endothelial Growth Factor Monoclonal Antibodies

Abstract

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.

Efficacy of Antibody Delivery to the Retina and Optic Nerve by Topical Administration

“…11,13 Thulliez et al concluded that intravitreal anti-VEGF antibodies did not result in statistically significant increases in major cardiovascular or systemic hemorrhages, but agreed that ''studies and meta-analyses were not powered enough to correctly assess these risks''. 45 Thus, caution is still urged for patients receiving intravitreal injections of anti-VEGF antibodies who are especially at risk for systemic adverse events.…”

Unilateral metamorphopsia in a 73 year old woman

“…Its use is now extremely limited. 51 Although anti-VEGF treatments have been suspected to increase the risk of systemic arterial thromboembolic events [52][53][54][55] and intraocular pressure, 56-59 the results of clinical trials are still inconclusive. The risks of intravitreal anti-VEGF drugs in pregnant or lactating women have not been studied.…”

Update on the Management of Diabetic Macular Edema

“…Despite ample research and large meta-analyses demonstrating little systemic risk with anti-VEGF treatments in most patients, [23][24][25][26][27] clinicians should be mindful of these agents in this higher-risk population. A recent meta-analysis looking specifically at diabetic patients with intensive (monthly for 2 years) intravitreal anti-VEGF injections found an increased risk of death and potentially cerebrovascular accidents, although not myocardial infarction or arteriothrombotic events, in this high-risk group.…”