Elsevier

Ophthalmology Retina

Volume 2, Issue 2, February 2018, Pages 118-127
Ophthalmology Retina

Original article
Serum Vascular Endothelial Growth Factor Levels in the IVAN Trial; Relationships with Drug, Dosing, and Systemic Serious Adverse Events

https://doi.org/10.1016/j.oret.2017.05.015Get rights and content
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open access

Purpose

To describe serum vascular endothelial growth factor (sVEGF) in patients with neovascular age-related macular degeneration (nAMD) receiving anti-VEGF agents and associations between sVEGF and systemic serious adverse events (SSAEs).

Design

Exploratory analyses of a randomized controlled trial that enrolled 610 participants with nAMD and compared 2 anti-VEGF antibodies, ranibizumab and bevacizumab, and 2 treatment regimens, monthly vs. discontinuous, with 2 years' follow-up.

Participants

Adults aged 50+ years with treatment-naïve nAMD and a visual acuity of ≥25 letters (Snellen equivalent 20/320) in the affected eye.

Methods

Intravitreal injection of anti-VEGF antibodies.

Main Outcome Measures

sVEGF and occurrence of SSAE, with particular interest in arteriothromboembolic events (ATE) and immunologically mediated events (IME).

Results

On average, sVEGF (measured at months 0, 1, 11, 12, 23, and 24) decreased from a geometric mean of 168 pg/mL at baseline to 64 pg/mL at month 24. The decrease was greater with bevacizumab than with ranibizumab and was dependent on time since last treatment; at month 24 sVEGF was 11% lower with bevacizumab if treated ≥3 months previously, 51% lower if treated 2 months previously, and 76% lower if treated the previous month, compared with ranibizumab. The hazard of experiencing an ATE increased with age (hazard ratio [HR] = 2.01; 95% confidence interval [CI] = 1.32–3.05; P = 0.001) and higher sVEGF (HR = 1.16; 95% CI = 1.03–1.30, per 100 unit rise in sVEGF; P = 0.013). There was no association between sVEGF and the hazard of an IME (HR = 1.01; 95% CI = 0.76–1.33; P = 0.942); however, the hazard of an IME was significantly increased by treatment with bevacizumab compared with ranibizumab (HR = 3.53; 95% CI = 1.35–9.22; P = 0.010). The hazard of an “other SSAE” (not categorized as ATE or IME) increased with age (HR 1.51, 95% CI 1.14–2.01, P = 0.005) and decreased if an injection had been administered within the previous month (HR = 0.68; 95% CI = 0.45–1.03; P = 0.069).

Conclusions

The decrease in sVEGF is greater with bevacizumab than with ranibizumab, but this difference is eliminated when treatment is withheld for 3 months. Higher sVEGF increased the hazard of an ATE and bevacizumab increases the hazard of an IME compared with ranibizumab.

Abbreviations and Acronyms

ATE
arteriothromboembolic event
CI
confidence interval
DVT
deep vein thrombosis
GMR
geometric mean ratio
HR
hazard ratio
IME
immunologically mediated event
nAMD
neovascular age-related macular degeneration
pVEGF
plasma vascular endothelial growth factor
RPE
retinal pigment epithelium
SSAE
systemic serious adverse event
sVEGF
serum vascular endothelial growth factor
VEGF
vascular endothelial growth factor

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Supplemental material available at www.ophthalmologyretina.org.

Financial Disclosure(s):

Funding: The IVAN trial is funded by the UK National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 07/36/01). The views and opinions expressed are those of the authors and do not necessarily reflect those of the HTA programme, the NIHR, the UK National Health Service, or the Department of Health.

Conflicts of Interest: C.A.R.: Lecture honorarium — Novartis. B.C.R.: Teaching fee — Janssen-Cilag. S.D.: Lecture honoraria — Novartis; her employing institution has received payments from Novartis. A.J.L.: Chief investigator — trial investigating treatment of chorioretinopathy; Is principal investigator — trials sponsored by Novartis, the manufacturers of ranibizumab; Advisory boards — Novartis and Bayer. U.C.: Principal investigator — trials sponsored by Novartis; advisory boards — Novartis, Bayer, and Roche outside the submitted work; employing institution has received payments — Novartis, Bayer, Neovista, Oraya, and Alcon.

Author Contributions:

Research design: Rogers, Scott, Reeves, Chakravarthy

Data acquisition and/or research execution: Downes, Lotery, Dick, Chakravarthy

Data analysis and/or interpretation: Rogers, Scott, Reeves

Manuscript preparation: Rogers, Scott, Reeves, Downes, Lotery, Dick, Chakravarthy

Human Subjects: This study includes human subject/tissues. Participants gave written informed consent for collection and analysis of serum samples in the IVAN trial, which was approved by a UK NHS Research Ethics Committee (reference: 07/NIR03/37).