Examining the Relationship Between Anti-VEGF Drugs and Major Cardiovascular Events

According to a recent review, intravitreal anti-vascular endothelial growth (anti-VEGF) drugs were not associated with an increase in major cardiovascular events.

A review of randomized clinical trials published in JAMA Ophthalmology found that intravitreal anti-vascular endothelial growth (anti-VEGF) drugs were not associated with an increase in major cardiovascular events.

Specifically, the systematic review of 74 trials of adults with retinal diseases who received intravitreal anti-VEGF drugs did not point to increased arterial or venous clotting events. Small increases in total mortality were noted in patients with diabetes and non-ocular hemorrhages—especially in patients with age-related macular degeneration (AMD)— but the evidence was not sufficient to draw definitive conclusions.

“Continued surveillances for systematic adverse events (SAEs) in patients with intravitreal anti-VEGF drugs by means of population-based studies remain warranted,” the authors wrote.

Since decreases in visual acuity are related to macular edema due to overexpression of VEGF stimulated by conditions of reduced oxygen, anti-VEGF drugs are used in practice. Intravitreal anti-VEGF monoclonal antibodies such as bevacizumab (Avastin) and ranibizumab (Lucentis), as well as fusion proteins such as aflibercept (Eylea) have improved visual acuity in patients. AMD, diabetic macular edema or proliferative diabetic retinopathy (DME/PDR), and retinal vein occlusion-related edema are the main causes of blindness in developed countries.

Despite previous findings pointing to a good safety profile, an increased risk of hemorrhages among patients with AMD treated with ranibizumab could not be ruled out, prompting the current review. Furthermore, use of anti-VEGF drugs in oncology is known to possibly increase the risk of serious adverse events. Exposure was highest with bevacizumab.

Study results showed that anti-VEGF drugs did not increase major adverse cardiovascular events (MACEs) compared with control agents (odds ratio [OR], 1.16; 95% CI, 0.85-1.58) or total mortality (OR, 1.27; 95% CI, 0.82-1.96). Administration of anti-VEGF drugs did increase the risk of non-ocular hemorrhage (OR, 1.46; 95% CI, 1.01-2.10), mainly in patients with AMD.

Results echoed a previous finding of increased risk of non-ocular hemorrhage, mainly among patients with AMD treated with ranibizumab. The prevalence of hemorrhagic events was 2.4%, with most such events considered serious. But the studies used in the authors’ review precluded evaluating if such events could be related to anti-clotting drugs typically taken by patients with diabetes over 60 at high cardiovascular risk.

Direct comparisons between bevacizumab and ranibizumab showed an increased risk of SAEs and a decreased risk of hypertension with bevacizumab, the researchers said. No significant differences were identified between aflibercept and bevacizumab or ranibizumab. Past data from humans and monkeys showed higher serum levels when they were administered bevacizumab than ranibizumab, but the new study’s meta-analysis did not support that finding.

Of the 74 trials used, 32 studies (43%) included 14,190 patients with AMD, 24 (32%) included 5424 patients with DME/PDR, 17 (23%) included 3757 patients with retinal vein occlusion, and 1 trial (1%) included 122 patients with myopic choroidal neovascularization. Mean patient age was 77.


Ngo Ntjam N, Thulliez M, Paintaud G, et al. Cardiovascular adverse events with intravitreal anti-vascular endothelial growth factor drugs: a systematic review and meta-analysis of randomized clinical trials. JAMA Ophthalmol. Published online April 15, 2021. doi:10.1001/jamaophthalmol.2021.0640

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