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Intravitreal anti-VEGF treatments for neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion did not appear to increase the risk of systemic adverse events, particularly cardiovascular adverse events, French researchers found.

According to analysis of 21 systematic reviews and meta-analyses, intravitreal anti-VEGF was not associated with an increased risk of systemic adverse events (SAEs) when compared with control regimens, nor when treatment was given on a monthly schedule versus an as-needed regimen, according to Marie Thulliez, MD, of Bretonneau Hospital, in Tours, France, and colleagues.

However, caution might be advisable in older patients with AMD who may be at higher risk of hemorrhagic events when receiving ranibizumab, they wrote online in .

The overview included studies with ranibizumab, bevacizumab, aflibercept, and pegaptanib published from Jan. 1, 2011 to June 30, 2016, with systemic adverse events the primary outcome in 11 and secondary outcome in 10. Ten reviews studied patients with AMD; six reviews studied patients with DME; and three reviews included patients with all 3 diseases and analyzed SAEs as the main outcome.

Ten reviews compared ranibizumab and a control regimen, while eight compared ranibizumab and bevacizumab, and five compared two or more anti-VEGF regimens with control treatment; others considered various dosing regimens.

Comparisons of bevacizumab and ranibizumab included only patients with AMD; one review linked bevacizumab with an increased risk of venous thrombotic events (RR 3.45, 95% CI 1.25-9.54) and four other reviews reported a lower range of relative risk (2.32 to 2.78) but with wide and nonsignificant confidence intervals, authors noted.

"Bevacizumab also increased the relative risk of SAEs by 20% to 35% in 3 reviews, but not in the and most exhaustive Cochrane Review, which included unpublished data (RR 1.08, 95% CI 0.90-1.31)."

Compared with ranibizumab, aflibercept was not associated with increased nor reduced risks in two reviews. No increased or decreased risks were observed with monthly versus as-needed anti–VEGF treatments in two additional reviews.

Ranibizumab was associated with an increased risk of nonocular hemorrhages in [older] patients with AMD in four reviews, but not in patients with DME or RVO. "This finding could be explained by the confounding effect of age, a factor already described to increase bleeding risk in patients who are medically ill," they noted.

High-dose aflibercept and ranibizumab had increased 2-year rates of overall and vascular mortality compared with control regimens in one meta-analysis, however sensitivity analysis rendered the finding nonsignificant. Moreover, vascular deaths were not adjudicated in half of the included studies, which could also introduce bias in risk estimates, the group noted.

Based on their review process, the group offered several recommendations "that may improve the design and conduct of future systematic reviews," such a systematic use of the PRISMA and AMSTAR checklist, more frequent assessment for publication bias, use of the Cochrane risk of bias tool to facilitate the comparison of inter-reviewer agreement, and more frequent use of an a priori design.

Sunir Garg, MD, of Wills Eye Hospital in Philadelphia commented on concerns about cardiovascular adverse events with bevacizumab.

"This drug was originally developed as a cancer treatment, and was given intravenously at much higher doses than we use in the eye, so I think these findings give doctors and their patients greater confidence that by doing intravitreal shots, we're not only able to help their eyes and vision but we are also able to ensure that they remain safe systemically," said Garg, who is a clinical spokesperson for the American Academy of Ophthalmology,

While Garg, who was not involved in the study, lauded the authors' suggested checklists and protocols for future reviews "It's not a definitive study. To answer this question fully, we would need a trial of 50,000 patients followed in time, which is not feasible for financial and practical reasons, so these types of studies get us as close to an answer as we're likely to get, so that's very reassuring to ophthalmologists."

Limitations include using only reviews that reported 95% CIs for SAEs, failure to re-extract data from original research, and inability to analyze the risks related to treatment duration or treatment doses.

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