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Updated: Aug 9, 2025
Optimization of the Retinal Vein Occlusion Mouse Model to Limit Variability
Published on: August 6, 2021
VEGF Inhibition in Retinal Vein Occlusion Does Not Associate with Cardiovascular Morbidity or Mortality
Katrine Hartmund Frederiksen1, Lonny Stokholm2, Sören Möller2
1Department of Ophthalmology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Purpose:
Intravitreal treatment with VEGF inhibitors has proven safe in clinical trials, but often on selected patient groups and without statistical power to investigate rare safety events. Data on anti-VEGF treatment in patients with retinal vein occlusion (RVO) are sparsely represented, and studies providing population-based, long-term follow-up are needed to assess the risks in routine clinical practice. We aimed to evaluate the association between treatment with anti-VEGF and the risk of incident cardiovascular disease (CVD) and all-cause mortality in patients with RVO, and whether this association was affected by selected risk factors.
Design:
A cohort study from January 2012 to December 2018 using Danish nationwide registries linked on an individual level.
Subjects:
Patients with RVO (n = 7235), exposed (n = 3508), and unexposed (n = 3727) to anti-VEGF, aged ≥ 40 years, alive, and living in Denmark.
Methods:
Cox proportional hazards analysis evaluating the effect of intravitreal VEGF inhibitory treatment on incident CVD and all-cause mortality.
Main Outcome Measures:
A predefined analysis plan specified primary outcomes as hazard ratios (HRs) of a composite CVD endpoint and all-cause mortality in patients treated with anti-VEGF compared with untreated. Secondary outcomes included cumulative dose analysis, HRs on subgroups of CVD, and stratified analyses evaluating the effect of sex, age, diabetes, intensive treatment, and preexisting CVD on the HRs.
Results:
We found no increased risk of composite CVD (HR, 1.07; 95% confidence interval [CI], 0.89-1.29) or all-cause mortality (HR, 0.88; 95% CI, 0.77-1.00) in patients with RVO treated with anti-VEGF. In the secondary analyses, we found no dose-response relationship. We found an increased risk of intracranial hemorrhage (HR, 1.66; 95% CI, 1.02-2.71), but no increased risks in remaining subgroups of CVD. We found no increased risk associated with selected predisposing risk factors, and no increased risk in patients with preexisting CVD.
Conclusion:
Treatment with anti-VEGF in patients with RVO is safe, when evaluated in a nationwide, population-based setting. An increased risk of intracranial hemorrhage might be present, but cannot be reliably quantified and should be further elucidated by larger population-based studies including all indications for anti-VEGF treatment.
Financial Disclosure(S):
Proprietary or commercial disclosure may be found after the references.
Insights
Intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for retinal vein occlusion (RVO) showed no increased risk of cardiovascular disease or mortality in a large Danish study. However, a potential increased risk of intracranial hemorrhage warrants further investigation.
Area of Science:
- Ophthalmology
- Cardiology
- Public Health
Background:
- Intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatments are used for retinal conditions, but safety data in retinal vein occlusion (RVO) patients, especially regarding cardiovascular events and mortality, are limited.
- Population-based, long-term studies are necessary to assess the real-world safety profile of anti-VEGF therapy in RVO management.
Purpose of the Study:
- To evaluate the association between anti-VEGF treatment and the risk of incident cardiovascular disease (CVD) and all-cause mortality in patients with RVO.
- To determine if selected risk factors modify this association.
Main Methods:
- A nationwide cohort study was conducted using Danish registries from January 2012 to December 2018.
- Cox proportional hazards analysis was used to compare outcomes between 3508 anti-VEGF-treated RVO patients (aged ≥40) and 3727 untreated RVO patients.
Main Results:
- No increased risk of composite CVD (HR, 1.07) or all-cause mortality (HR, 0.88) was observed in anti-VEGF treated RVO patients compared to untreated.
- An increased risk of intracranial hemorrhage (HR, 1.66) was noted, but without a clear dose-response relationship or increased risk in other CVD subgroups.
- Selected risk factors and pre-existing CVD did not significantly alter the observed risks.
Conclusions:
- Anti-VEGF treatment in RVO patients appears safe in a nationwide, population-based setting regarding major cardiovascular events and mortality.
- A potential increased risk of intracranial hemorrhage requires further investigation in larger studies encompassing all anti-VEGF indications.
