VEGF Inhibitors Safe for AMD, Despite Expectations

Neil Osterweil

April 09, 2014

TOKYO — Despite concerns, adverse cardiovascular effects might not be an issue for patients with neovascular age-related macular degeneration (AMD) who receive intraocular injections of vascular endothelial growth-factor (VEGF) inhibitors, according to a new study.

"We know that VEGF has an effect on endothelial cells, mostly through nitric oxide. Nitric oxide has an effect on inhibiting platelet activation, on the inhibition of inflammatory cells, and on vasodilatation. All of these factors are considered to be a key aspect in the question of thromboembolic events," explained Stephan Michels, MD, professor of medicine and chief physician at the Triemli Eye Hospital in Zurich.

He presented results from the prospective, randomized, double-blind Safety of Vascular Endothelial Growth Factor Antagonists in Age-related Macular Degeneration (SAVE-AMD) trial here at the World Ophthalmology Congress 2014.

Because endothelial cells release nitric oxide in response to shear stress from increased flow, flow-mediated dilatation (FMD) has been shown to be a good indicator of endothelial cell function, Dr. Michels explained.

The researchers used high-resolution ultrasonography to measure FMD as a proxy for nitric-oxide-dependent endothelial cell function.

There were no significant reductions in the primary end point of FMD 12 months after 2 intravitreal injections of an anti-VEGF agent, he reported.

In contrast, there was a significant reduction in FMD at 12 months in untreated control subjects with atrophic AMD. This suggests that other factors, such as patient age, have a greater effect on endothelial function than VEGF inhibition.

Targeting VEGF

Agents such as ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech), which are used to treat neovascular AMD and macular edema, target VEGF.

In this study, patients with neovascular AMD received 2 intravitreal injections, 1 month apart, of either ranibizumab 0.5 mg or bevacizumab 1.25 mg. Untreated patients with atrophic AMD served as the control group.

The 2-injection regimen was completed by 13 patients in the ranibizumab group and 13 in the bevacizumab group, and all met the study criteria.

The data safety monitoring committee stopped the study early after 3 thromboembolic events occurred in the treatment group: 1 fatal stroke, 1 pulmonary embolism, and 1 suspected transient ischemic attack. There were no similar events in the control group.

Because the sample size was not large enough to allow a drug–drug comparison, the investigators combined the 2 treatment groups.

There was a borderline significant reduction in the primary outcome — change in FMD — from baseline to month 2 in the treatment group (P = .056), but not in the control group. However, at month 12, there was no significant reduction in FMD from baseline in the treatment group.

"The most astonishing result was that we found a significant difference comparing baseline to month 12 in the control group," Dr. Michels said.

For the secondary outcome of mean change in ETDRS score for visual acuity, there were small but nonsignificant gains at both 2 and 12 months in the treatment group.

However, for the secondary outcome of decrease in central foveal thickness, measured with optical coherence tomography, bevacizumab was associated with improvement at 2 and 6 months (P < .001), and ranibizumab was associated with improvement at 2 months (P <. 001) and at 12 months (P < .01).

"The take-home message for me — and it was really also a big change, having had a totally different expectation — was that we did not find evidence of a significant impact of PRN use of ranibizumab or bevacizumab on systemic endothelial cell function," Dr. Michels said.

From a systemic perspective, we might have to rethink whether "anti-VEGF therapy as used in ophthalmology is actually protective," he added.

Evidence for or against cardiovascular adverse effects related to VEGF inhibitors is still unclear, said Anat Loewenstein, MD, chair of ophthalmology in the Sackler Faculty of Medicine at Tel Aviv University in Israel, who was not involved with the study.

"There have been concerns about systemic side effects that have never really been proven, because the trials that looked at it — the Comparison of AMD Treatments Trials (CATT) and Inhibit VEGF in Age-related choroidal Neovascularization (IVAN) trial — did not find concerns typical of what you might expect from vasosuppression," she told Medscape Medical News.

After the presentation, Dr. Loewenstein noted that the incidence of thromboembolic events seemed high for such a small study.

Dr. Michels concurred, and explained that the investigators expected that these events would be related to reductions in FMD, because the study excluded patients with risk factors known to affect FMD, such as diabetes, uncontrolled hypertension, and cancer. However, they found no evidence to support that hypothesis.

This study was supported by research grants to the Triemli Eye Hospital and the Werner H. Spross Foundation. Dr. Michels reports that the hospital is reimbursed for consultations he performs for various companies. Dr. Loewenstein has disclosed no relevant financial relationships.

World Ophthalmology Congress (WOC) 2014: Abstract FP-FR-18-5. Presented April 4, 2014.


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