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Randomized Controlled Trial
. 2018 Jul;125(7):1054-1063.
doi: 10.1016/j.ophtha.2018.01.019. Epub 2018 Mar 7.

Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema

Lee M Jampol  1 , Adam R Glassman  2 , Danni Liu  3 , Lloyd Paul Aiello  4 , Neil M Bressler  5 , Elia J Duh  5 , Susan Quaggin  1 , John A Wells  6 , Charles C Wykoff  7 ; Diabetic Retinopathy Clinical Research Network
Collaborators, Affiliations
Randomized Controlled Trial

Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema

Lee M Jampol et al. Ophthalmology. 2018 Jul.

Abstract

Purpose: To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab.

Design: Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm.

Participants: Participants with available plasma samples (N = 436).

Methods: Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects.

Main outcome measures: Changes in the natural log (ln) of plasma VEGF levels.

Results: Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30±0.61 pg/ml, -0.31±0.54 pg/ml, and -0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and -0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was -0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar.

Conclusions: These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.

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Figures

Figure 1.
Figure 1.. Change in Plasma ln(VEGF) Concentrations (pg/ml) by Treatment Group Assignment and Visit.
A) All participants at 4 weeks. N=139/ 130/ 141 for aflibercept/ bevacizumab/ ranibizumab group. P=0.89/ <0.001/ <0.001 for aflibercept vs. bevacizumab/ aflibercept vs. ranibizumab/ bevacizumab vs. ranibizumab. B) All participants at 52 weeks. N=132/ 115/ 130 for aflibercept/ bevacizumab/ ranibizumab group. P=0.07/ 0.07/ <0.001 for aflibercept vs. bevacizumab/ aflibercept vs. ranibizumab/ bevacizumab vs. ranibizumab. C) All participants at 104 weeks. N=98/ 84/ 78 for aflibercept/ bevacizumab/ ranibizumab group. P=0.07/ 0.13/ 0.002 for aflibercept vs. bevacizumab/ aflibercept vs. ranibizumab/ bevacizumab vs. ranibizumab.
Figure 2.
Figure 2.. Mean Change in Plasma VEGF Concentrations (pg/ml) by Treatment Group Assignment in Participants with Complete Data through 52 and 104 Weeks.
A) Through 52 weeks on original scale. B) Through 52 weeks on log scale. N=122/ 111/ 121 for aflibercept/ bevacizumab/ ranibizumab group. Pairwise comparisons for aflibercept vs. bevacizumab/ aflibercept vs. ranibizumab/ bevacizumab vs. ranibizumab: P=0.88/ <0.0001/ <0.0001 at 4 weeks; and P=0.11/ 0.09 / 0.001 at 52 weeks. C) Through 104 weeks on original scale. D) Through 104 weeks on log scale. N=87/ 71/ 71 for aflibercept/ bevacizumab/ ranibizumab group. Pairwise comparisons for aflibercept vs. bevacizumab/ aflibercept vs. ranibizumab/ bevacizumab vs. ranibizumab: P=0.90/ <0.0001/ <0.0001 at 4 weeks; P=0.35/ 0.69 / 0.28 at 52 weeks; and P=0.23/ 0.23 / 0.03 at 104 weeks.
Figure 3.
Figure 3.. Change in Plasma ln(VEGF) Concentrations (pg/ml) at 52 weeks by Treatment Group Assignment and Injection Status.
A) No injections within 1 month. N=76/ 70/ 82 for aflibercept/ bevacizumab/ ranibizumab group. P=0.78/ 0.95/ 0.78 for aflibercept vs. bevacizumab/ aflibercept vs. ranibizumab/ bevacizumab vs. ranibizumab. B) Received injections within 1 month. N=56/ 45/ 48 for aflibercept/ bevacizumab/ ranibizumab group. P=0.03/ 0.003/ <0.001 for aflibercept vs. bevacizumab/ aflibercept vs. ranibizumab/ bevacizumab vs. ranibizumab. C) No injections within 2 months. N=43/ 42/ 50 for aflibercept/ bevacizumab/ ranibizumab group. P=0.43/ 0.79/ 0.44 for aflibercept vs. bevacizumab/ aflibercept vs. ranibizumab/ bevacizumab vs. ranibizumab. D) Received injections within 2 months. N=89/ 73/ 80 for aflibercept/ bevacizumab/ ranibizumab group. P=0.15/ 0.02/ <0.001 for aflibercept vs. bevacizumab/aflibercept vs. ranibizumab/ bevacizumab vs. ranibizumab.
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