A Systematic Review and Meta-Analysis on the Safety of Vascular Endothelial Growth Factor (VEGF) Inhibitors for the Treatment of Retinopathy of Prematurity

<div><p>Introduction</p><p>Laser photocoagulation is the current gold standard treatment for proliferative retinopathy of prematurity (ROP). However, it permanently reduces the visual field and might induce myopia. Vascular endothelial growth factor (VEGF) inhibitors for the treatment of ROP may enable continuing vascularization of the retina, potentially allowing the preservation of the visual field. However, for their use in infants concern remains. This meta-analysis explores the safety of VEGF inhibitors.</p><p>Methods</p><p>The Ovid Interface was used to perform a systematic review of the literature in the databases PubMed, EMBASE and the Cochrane Library.</p><p>Results</p><p>This meta-analysis included 24 original reports (including 1.457 eyes) on VEGF inhibitor treatment for ROP. The trials were solely observational except for one randomized and two case-control studies. We estimated a 6-month risk of retreatment per eye of 2.8%, and a 6-month risk of ocular complication without the need of retreatment of 1.6% per eye. Systemic complications were only reported as isolated incidents.</p><p>Discussion</p><p>VEGF inhibitors seem to be associated with low recurrence rates and ocular complication rates. They may have the benefit of potentially allowing the preservation of visual field and lower rates of myopia. Due to the lack of data, the risk of systemic side effects cannot be assessed.</p></div

Cholesterol efflux capacity.

<p>Apolipoprotein B (apoB)-depleted sera of healthy subjects (control, n = 27) and patients with age-related macular degeneration (AMD, n = 29) were examined for (A) their ability to promote [³H]-cholesterol efflux from macrophages. [³H]-cholesterol-labeled RAW264.7 macrophages were incubated with 2.8% apoB-depleted sera for 4 hours. Cholesterol efflux is expressed as radioactivity in the supernatant relative to total radioactivity (in supernatant and cells). Values shown represent means of two independent experiments.</p

Characteristics of included studies.

<p>Studies are sorted by date of publication.</p><p>*Not all patients included for quantitative analysis, as only selected patient groups fitted our criteria (no combined treatment, no recurrences).</p><p>**The follow-up period is only reported if follow-up was a defined period of time.</p><p>Characteristics of included studies.</p

Characteristics of included studies for refractive error.

<p>Studies are sorted by date of publication.</p><p>*The follow-up period is only reported if follow-up was a defined period of time.</p><p>Characteristics of included studies for refractive error.</p

Systemic VEGF suppression after VEGF inhibitors.

<p>Research papers investigating systemic levels of VEGF after intravitreal injection of VEGF inhibitors over a defined period of time. *1 = infants with retinopathy of prematurity, unilateral injection of bevacizumab (14); 2 = infants with retinopathy of prematurity, unilateral injection of ranibizumab (105); 3 = patients with age-related macular degeneration (AMD), unilateral injection of bevacizumab (106); 4 = patients with AMD, bilateral injection of bevacizumab (106); 5 = patients with AMD, unilateral injection of ranibizumab (107); 6 = patients with AMD, unilateral injection of bevacizumab (108); 7 = patients with AMD, unilateral injection of ranibizumab (108); 8 = patients with AMD, unilateral injection of aflibercept (109); 9 = patients with AMD, unilateral injection of ranibizumab (109); 10 = patients with AMD, unilateral injection of ranibizumab (110); 11 = patients with AMD, unilateral injection of aflibercept (110); 12 = patients with AMD, unilateral injection of ranibizumab (111). ** y-axis in pg/ml.</p

Adverse events after anti-VEGF treatment in adults in relative risk.

<p>Studies are sorted by date of publication.</p><p>*Only vascular deaths were reported.</p><p>**Only cardiovascular events were reported.</p><p>***Events reported after 1 year (after 2 years).</p><p>Adverse events after anti-VEGF treatment in adults in relative risk.</p

Paraoxonase activity.

<p>Activity of HDL-associated paraoxonase was measured using phenylacetate as substrate. Paraoxonase activity of apoB-depleted sera was calculated from the slopes of the kinetic chart. Values shown represent means of four independent experiments.</p

Anti-oxidative capability.

<p>The anti-oxidative activity of HDL was determined by inhibition of AAPH-initiated oxidation of the fluorescent dye dihydrorhodamine (DHR). Incubation of DHR in presence of apoB-depleted sera from healthy subjects or AMD patients led to a reduction in the oxidation of DHR. Values shown represent means of two independent experiments.</p

HDL-apolipoproteins and HDL associated lipids.

<p>Levels of total cholesterol (A), non-esterified cholesterol (FC) (B), phospholipids (PL) (C), free fatty acids (FFA) (D), triglycerides (TG) (E) were measured enzymatically in apoB depleted serum. HDL associated apolipoproteins ApoA-I (F), apoA-II (G), apoC-II (H), apoC-III (I) and apoE (J) were determined in apoB-depleted serum by immunoturbidimetry.</p

Anti-inflammatory capacity.

<p>(A) U937 monocytes containing a reporter cassette for factor-κB (NF-κB) were pretreated in the absence and presence of 10% lipoprotein deficient sera (LPDS) in the presence of indicated concentrations of reconstituted HDL (rHDL). After 1 ½ hours, cells were stimulated with LPS (50 ng/ml) for 24 hours, followed by assessment of GFP expression by flow cytometry. (B) ApoB-depleted sera of healthy subjects and AMD patients were analyzed for their ability to inhibit lipopolysaccharide LPS-induced NF-κB activation in monocytes. U937 monocytes were pretreated with 7% apoB- depleted sera. After 1 ½ hours, cells were stimulated with LPS (50 ng/ml) for 24 hours, followed by assessment of GFP expression by means of flow cytometry. Values shown represent means of two independent experiments.</p