More Safety Data Needed for Intravitreal Anti-VEGF Agents

By Will Boggs MD

August 05, 2014

NEW YORK (Reuters Health) - Intravitreal use of bevacizumab and ranibizumab does not appear to cause major cardiovascular events or non-ocular bleeding in patients with eye disease, according to a meta-analysis from France.

However, bevacizumab increased venous thromboembolic events (VTEs) compared with ranibizumab; and patients on the latter drug had a higher rate of non-ocular bleeding than did control groups, Dr. Theodora Bejan-Angoulvant from Hopital Bretonneau in Tours and colleagues report.

"Increased risks of VTEs with bevacizumab and nonocular hemorrhagic events in older patients with AMD (age-related macular degeneration) with ranibizumab should be cautiously interpreted because more safety data are needed," the researchers warn in JAMA Ophthalmology, online July 24.

Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies have been shown to preserve visual acuity in AMD, diabetic macular edema (DME) and retinal vein occlusion (RVO), but the systemic safety of their intravitreal injection is largely unknown.

In their systematic review and meta-analysis of 21 trials, including 9,557 patients, the French team found no evidence of an increased risk of major cardiovascular events after intravitreal anti-VEGF treatment, and there was no significant heterogeneity among the trials analyzed.

The type of disease, type of anti-VEGF agent, and the quality of the studies did not significantly influence the treatment effects, and there were no significant differences in the risks of major cardiovascular events in the three trials that directly compared bevacizumab with ranibizumab or in trials that used low-dose versus high-dose ranibizumab.

Intravitreal anti-VEGF treatment also did not significantly raise the risk of non-ocular hemorrhagic events. Still, the subset of patients with AMD, but not DME or RVO, had a significantly increased bleeding risk in ranibizumab vs. control trials (odds ratio, 1.57).

Among secondary endpoints, anti-VEGF treatments did not significantly increase the risks of overall mortality, cardiovascular mortality, stroke, myocardial infarction, hypertension, or venous thromboembolism (VTE).

The rate of VTEs was significantly increased with bevacizumab versus ranibizumab in trials comparing the two agents (OR, 3.45).

Dr. Khalil Ghasemi Falavarjani, who has studied the use of anti-VEGF agents for retinal diseases but was not part of the new work, said the drugs improve visual function and quality of life and reduce the economic burden from blindness.

As a result, he told Reuters Health by email, the findings should not affect "the routine practice of intravitreal injections," although "the surgeon may want to pay special attention to injecting certain agents in certain patients with systemic diseases."

"For example, in a patient with history of multiple thrombotic events, ranibizumab may be preferred over bevacizumab," said Dr. Falavarjani from Iran University of Medical Sciences in Tehran.

Dr. Francesco Semeraro from University of Brescia in Italy, who has also studied intravitreal use of anti-VEGF agents, told Reuters Health, "We have to consider that by performing an injective therapy with one of the anti-VEGF drugs, we expose patients to a suppression, albeit moderate, of serum VEGF, with moderate effects on the vascular system."

He said this means patients on anti-VEGF agents should be stratified according to cardio- and cerebrovascular risks and undergo long-term general monitoring.

"It is desirable that the scientific community improves the pharmacovigilance program on all anti-VEGF drugs, expanding knowledge with studies that compare head-to-head all compounds belonging to anti-VEGF armamentarium," Dr. Semeraro said in an email.

The authors did not receive external funding for the analysis, though two of them report multiple ties to drugmakers.

Dr. Bejan-Angoulvant did not respond to a request for comments.


JAMA Ophthalmol 2014.


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