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

Diabetic Retinopathy Clinical Research Network

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1054-1063
Number of pages10
JournalOphthalmology
Volume125
Issue number7
DOIs
StatePublished - Jul 1 2018

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Endothelial Growth Factors
Macular Edema
Vascular Endothelial Growth Factor A
Therapeutics
Injections
Ranibizumab
Bevacizumab
aflibercept

All Science Journal Classification (ASJC) codes

  • Ophthalmology

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Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti–Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema. / Diabetic Retinopathy Clinical Research Network.

In: Ophthalmology, Vol. 125, No. 7, 01.07.2018, p. 1054-1063.

Research output: Contribution to journalArticle

@article{68c4db15560644bda3f0055d92249a76,
title = "Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti–Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema",
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.",
author = "{Diabetic Retinopathy Clinical Research Network} and Jampol, {Lee M.} and Glassman, {Adam R.} and Danni Liu and Aiello, {Lloyd Paul} and Bressler, {Neil M.} and Duh, {Elia J.} and Susan Quaggin and Wells, {John A.} and Wykoff, {Charles C.} and David Browning and Antoszyk, {Andrew N.} and Price, {Angela K.} and Fredenberg, {Sherry L.} and Herby, {Jenna T.} and Fleming, {Christina J.} and McClain, {Ashley A.} and Ennis, {Sarah A.} and Gallagher, {Kelly R.} and Karow, {Angella S.} and Grupp, {Autumn C.} and Danielle Puskas and Lynn Watson and Bojaj, {Swann J.} and Balasubramaniam, {Uma M.} and Donna McClain and Styles, {Donna R.} and Kuopus, {Jeff A.} and Kathryn Kimrey and Clark, {Loraine M.} and Jackson, {Lisa A.} and McOwen, {Michael D.} and Matt Dunlap and Held, {Susannah J.} and Pieramici, {Dante J.} and Nasir, {Ma'an A.} and Castellarin, {Alessandro A.} and Dilsher Dhoot and Sarah Fishbein and Jack Giust and Lisha Wan and Hanna, {Michelle S.} and Rabena, {Melvin D.} and Jerry Smith and Bone, {Layne J.} and Kelly Avery and Matthew Giust and Aimee Walker and Shook, {Aimee H.} and Sara Esau and Ruvalcaba, {Nitce L.}",
year = "2018",
month = "7",
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doi = "10.1016/j.ophtha.2018.01.019",
language = "English (US)",
volume = "125",
pages = "1054--1063",
journal = "Ophthalmology",
issn = "0161-6420",
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TY - JOUR

T1 - Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti–Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema

AU - Diabetic Retinopathy Clinical Research Network

AU - Jampol, Lee M.

AU - Glassman, Adam R.

AU - Liu, Danni

AU - Aiello, Lloyd Paul

AU - Bressler, Neil M.

AU - Duh, Elia J.

AU - Quaggin, Susan

AU - Wells, John A.

AU - Wykoff, Charles C.

AU - Browning, David

AU - Antoszyk, Andrew N.

AU - Price, Angela K.

AU - Fredenberg, Sherry L.

AU - Herby, Jenna T.

AU - Fleming, Christina J.

AU - McClain, Ashley A.

AU - Ennis, Sarah A.

AU - Gallagher, Kelly R.

AU - Karow, Angella S.

AU - Grupp, Autumn C.

AU - Puskas, Danielle

AU - Watson, Lynn

AU - Bojaj, Swann J.

AU - Balasubramaniam, Uma M.

AU - McClain, Donna

AU - Styles, Donna R.

AU - Kuopus, Jeff A.

AU - Kimrey, Kathryn

AU - Clark, Loraine M.

AU - Jackson, Lisa A.

AU - McOwen, Michael D.

AU - Dunlap, Matt

AU - Held, Susannah J.

AU - Pieramici, Dante J.

AU - Nasir, Ma'an A.

AU - Castellarin, Alessandro A.

AU - Dhoot, Dilsher

AU - Fishbein, Sarah

AU - Giust, Jack

AU - Wan, Lisha

AU - Hanna, Michelle S.

AU - Rabena, Melvin D.

AU - Smith, Jerry

AU - Bone, Layne J.

AU - Avery, Kelly

AU - Giust, Matthew

AU - Walker, Aimee

AU - Shook, Aimee H.

AU - Esau, Sara

AU - Ruvalcaba, Nitce L.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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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U2 - 10.1016/j.ophtha.2018.01.019

DO - 10.1016/j.ophtha.2018.01.019

M3 - Article

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AN - SCOPUS:85042941882

VL - 125

SP - 1054

EP - 1063

JO - Ophthalmology

JF - Ophthalmology

SN - 0161-6420

IS - 7

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