Serum vascular endothelial growth factor levels in the IVAN trial; relationships with drug, dosing and systemic serious adverse events: Serum VEGF associations with drug, dosing and systemic SAEs

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 seriousadverse events (SSAEs).

Design: Exploratory analyses of a randomized controlled trial which enrolled 610 participants with nAMD and compared two anti-VEGF antibodies, ranibizumab and bevacizumab and two treatment regimens,monthly versus discontinuous with two 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. Exposure: Intravitrealinjection of anti-VEGF antibodies.

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

Results: On average, sVEGF (measuredat months 0, 1, 11, 12, 23 and 24) decreased from a geometric mean of 168pg/ml at baseline to 64pg/ml at month 24. The decrease was greater with bevacizumab than ranibizumab and 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 to ranibizumab. The hazard of experiencing an ATE increased with age (hazard ratio (HR) 2.01, 95% confidence interval (CI) 1.32 to 3.05, p=0.001) and higher sVEGF (HR 1.16, 95% CI 1.03 to 1.30, per 100 unit rise in sVEGF, p=0.013). There was no association between sVEGF andthe hazard of an IME (HR 1.01, 95% CI 0.76 to 1.33, p=0.942); however, the hazard of an IME was significantly increased by treatment with bevacizumab compared to ranibizumab (HR 3.53, 95% CI 1.35 to 9.22, p=0.010). Thehazard of an ‘other SSAE’ increased with age (HR 1.51, 95% CI 1.14 to 2.01, p=0.005) and decreased if an injection had been administered within the previous month (HR 0.68, 95% CI 0.45 to 1.03, p=0.069).

Conclusion: The decrease in sVEGF is greater with bevacizumab than 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 to ranibizumab.