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

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-naive 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.