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Intravitreal antivascular endothelial growth factor (anti-VEGF) treatment was not associated with cardiovascular risk in a meta-analysis, though safety signals for mortality and nonocular bleeding emerged instead.

People with retinal diseases had similar major cardiovascular event rates -- counting MI, stroke, or death due to vascular or unknown causes -- whether they had been randomized to anti-VEGF treatment or not (2.70% vs 2.32%; OR 1.16, 95% CI 0.85-1.58).

This was consistent across the diseases and drugs studied across 74 randomized trials averaging 16 months of follow-up, according to Theodora Bejan-Angoulvant, MD, PhD, of CHRU de Tours, France, and colleagues in .

Incidence of mortality was generally similar between anti-VEGF and control groups (1.23% vs 0.90%; OR 1.27, 95% CI 0.82-1.96), though there was a significant interaction by underlying disease such that there was a short-term mortality risk among people with diabetic retinopathy but not those with age-related macular degeneration (AMD) or retinal vein occlusion.

What's more, Bejan-Angoulvant's group found a significant link between anti-VEGF injections and nonocular hemorrhage (OR 1.46, 95% CI 1.01-2.10), especially in people with AMD.

These safety signals were not backed by strong evidence, however, as the studies in the meta-analysis were not powered to assess small increases in systemic adverse events with anti-VEGF therapy, and trialists often provided limited information on how they monitored for these events.

"The overall quality of evidence for the main outcomes and for nonocular hemorrhage risk was considered low, mainly owing to the risk of bias and indirectness," Bejan-Angoulvant and colleagues added, reporting that only one trial was considered to be at low overall risk of bias.

Study authors also noted that they had not adjusted for multiple analyses and that they couldn't adjust for "treatments that may increase hemorrhagic risk, such as antithrombotic drugs, that are commonly prescribed in patients with diabetes and people older than 60 years at high cardiovascular risk."

"Cardiologists and ophthalmologists should be aware of these safety signals, especially in patients at high risk," they maintained. "Continued surveillance for SAEs [systemic adverse events] in patients treated with intravitreal anti-VEGF drugs by means of population-based studies remains warranted."

Mark Breazzano, MD, of Johns Hopkins' Wilmer Eye Institute in Baltimore, said the finding of no increase in mortality overall was "reassuring," though he agreed that select groups at higher risks should be followed in future studies.

"Certainly this might be a concern because we know transient changes in VEGF levels, though small, can be found in the bloodstream after injection," he told 番茄社区app.

Anti-VEGF drugs were originally developed as cancer treatments. The intravitreal injections are among the most common procedures done by ophthalmologists worldwide and are considered a first-line standard therapy for retinal conditions such as "wet" macular degeneration. They allow some patients to restore vision whereas previous treatments would, at their best, just slow the progression of disease, according to Breazzano.

Yet the use of anti-VEGF drugs in oncology -- particularly bevacizumab (Avastin) -- has been linked to serious cardiovascular, venous thromboembolic, hemorrhagic, and infectious events. These safety concerns have also carried over to ophthalmology, where these agents, now including ranibizumab (Lucentis) and aflibercept (Eylea) with ocular indications, are common. Bevacizumab, too, is often used in ophthalmology off-label, at lower doses than in oncology.

"The consents crafted prior to onset of injection therapy are often voluminous disclosures which occasionally scare patients into refusing to receive critical treatment to prevent blindness. These concerns never turned into the potential clinical nightmares predicted, over the last 15-plus years of treatment of eye patients," said Richard Rosen, MD, of New York Eye and Ear Infirmary of Mount Sinai in New York City, who was not involved with the meta-analysis.

The 74 studies in the meta-analysis included people with AMD (n=14,190), diabetic retinopathy (n=5,424), retinal vein occlusion (n=3,757), or myopic choroidal neovascularization (n=122).

Anti-VEGF drugs did not appear to increase the risk of the individual endpoints of cardiovascular mortality, MI, stroke, cardiac failure, venous thromboembolism, or arterial hypertension.

"Because of the low incidence, the lack of adequate power to show an increased risk, the absence of adjudication of SAEs, exclusion of patients with cardiovascular disease history, and potential attrition bias in included studies (loss to follow-up), our results should be interpreted with caution and considered as safety signals," Bejan-Angoulvant and colleagues concluded.

Nevertheless, this is an "important paper" as many do wonder about the possible systemic risks of these injections on top of other potential complications such as endophthalmitis, Breazzano said.

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