Posted inInteresting Papers

Anti-VEGF Therapy vs. Panretinal Photocoagulation: Long-Term Impact on Retinal Vessel Caliber in Proliferative Diabetic Retinopathy

  • Study Overview:
    • Post hoc analysis of the DRCR Retina Network Protocol S randomized clinical trial comparing ranibizumab (anti-VEGF) versus panretinal photocoagulation (PRP) for proliferative diabetic retinopathy (PDR).
    • Objective: Evaluate long-term effects on retinal vessel caliber (central retinal arteriole equivalent [CRAE] and central retinal venular equivalent [CRVE]) at 2 and 5 years.
    • Participants: 107 eyes (90 participants) with type 1 or 2 diabetes and PDR, analyzed using fundus photographs.

 

  • Methodology:
    • Integrative Vessel Analysis (IVAN) software measured CRAE and CRVE at 1 disc diameter from the optic nerve edge on fundus photographs at baseline, 2, and 5 years.
    • Inclusion Criteria: Eyes with good-quality fundus photos at all three time points; poor-quality images (e.g., due to vitreous hemorrhage) were excluded.
    • Statistical Analysis: Mixed linear regression models adjusted for baseline CRAE/CRVE, diabetic retinopathy severity score (DRSS), intraocular pressure (IOP), and other factors. No multiplicity adjustments; results are exploratory.
    • Treatment Details:
      • Ranibizumab group: Mean 11.3 injections by 2 years, 22.0 by 5 years; excluded after PRP (4 eyes at 2 years, 5 at 5 years).
      • PRP group: All received PRP; 54% received ranibizumab for diabetic macular edema (DME) by 2 years, 59% by 5 years.

 

  • Key Results:

 

    • CRAE Changes:
      • At 2 years: Ranibizumab group decreased by 2 μm vs. PRP group by 12 μm (mean difference 10 μm; 95% CI, 4-16; p=0.003).
      • At 5 years: Ranibizumab group decreased by 9 μm vs. PRP group by 13 μm (mean difference 4 μm; 95% CI, -2 to 10; p=0.22; not statistically significant).
      • PRP group showed greater CRAE reduction early (within 2 years), possibly due to laser-induced peripheral retinal tissue destruction reducing vascular demand.
      • Ranibizumab group had more CRAE reduction after 2 years, suggesting delayed vascular effects.

 

    • CRVE Changes:
      • At 2 years: Ranibizumab group decreased by 14 μm vs. PRP group by 19 μm (mean difference 4 μm; 95% CI, -3 to 11; p=0.26; not significant).
      • At 5 years: Ranibizumab group decreased by 18 μm vs. PRP group by 28 μm (mean difference 11 μm; 95% CI, 3-19; p=0.01).
      • PRP group showed greater CRVE reduction at 5 years, possibly due to long-term vascular remodeling or reduced vascular permeability.
    • Both treatments led to vessel caliber narrowing over 5 years, potentially reflecting worsening retinal ischemia or reduced metabolic demand in PDR.

 

  • Multivariable Analysis:
    • Baseline DRSS ≥61B associated with larger CRAE decrease at 5 years (p=0.04) and CRVE decreases at 2 (p=0.01) and 5 years (p=0.003).
    • Higher baseline IOP linked to smaller CRAE decreases at 2 years (p=0.04).
  • Supplemental Findings:
    • No significant variation in CRAE changes by baseline center-involved DME (CI-DME).
    • CRVE decreases were greater in PRP group with baseline CI-DME, but sample size was small (n=28).
    • Correlation with Visual Field (VF) Loss: Modest positive correlations between VF sensitivity loss and CRAE (r=0.30) and CRVE (r=0.56) reductions at 5 years in a subgroup (n=38), suggesting possible link to retinal ischemia.

 

  • Clinical Implications:

    • PRP causes more immediate arteriolar narrowing (by 2 years), likely due to peripheral retinal destruction, while ranibizumab effects are delayed.

    • PRP leads to greater venular narrowing by 5 years, possibly due to reduced vascular permeability or long-term remodeling.

    • Vessel caliber narrowing may correlate with VF loss, potentially due to retinal ischemia; further research is needed using advanced imaging (e.g., ultrawidefield fluorescein angiography, OCT angiography).

    • Anti-VEGF does not reverse retinal non-perfusion, a key limitation in stabilizing PDR at a cellular level.

 

  • Limitations:
    • No untreated control group, making it hard to distinguish treatment effects from natural PDR progression.
    • Small sample size (27% of original Protocol S eyes) due to strict image quality requirements.
    • Potential underpowering for detecting some differences between groups.
    • Lack of measurements like axial length, which could influence vessel caliber.
  • Future Directions:
    • Investigate causes of vessel narrowing and its correlation with VF loss.
    • Use advanced imaging to better assess retinal ischemia and non-perfusion.
    • Larger studies to confirm findings and explore treatment-specific vascular effects.

Citation

Shen S, Josic K, Pak JW, et al. Long-term Effects of Anti-VEGF Therapy versus Panretinal Photocoagulation on Retinal Vessel Caliber in Eyes with Proliferative Diabetic Retinopathy. Ophthalmology Retina. 2025. doi: https://doi.org/10.1016/j.oret.2025.03.027